Next‐Generation Hydrogel Skin Adhesives: From Bioinspired Adhesion Chemistry to Regenerative Wound Interfaces

ABSTRACT

Hydrogel‐based skin adhesives have emerged as promising alternatives to conventional wound‐closure methods such as sutures and staples because they can establish conformal contact with soft, irregular, and wet tissue surfaces. Recent advances in polymer chemistry and biointerface engineering have enabled the development of hydrogel adhesives that combine strong wet adhesion with mechanical compliance, cytocompatibility, and therapeutic functionality. In this review, we summarize recent progress in the design of hydrogel‐based skin adhesives, with particular emphasis on the chemical and interfacial mechanisms governing tissue adhesion, including covalent bonding, supramolecular interactions, and bioinspired polyphenol‐mediated adhesion. We first outline key features of skin structure and wound healing that define the functional requirements of skin adhesives. We then discuss methods for evaluating adhesive performance, highlighting interfacial toughness and the need for standardized testing under clinically relevant conditions. Emerging strategies for on‐demand debonding that enable atraumatic removal after wound closure are also reviewed. In addition, we examine key biological design considerations, including cytocompatibility, immune regulation, angiogenesis, and antibacterial activity. Finally, we highlight current challenges and future opportunities for multifunctional hydrogel adhesive that not only close wounds but also actively support tissue repair and regeneration.

This review highlights the paradigm shift of hydrogel skin adhesives from passive structural sealants to dynamic regenerative biointerfaces. Diverse interfacial bonding chemistries, quantitative mechanical benchmarks, and triggerable on‐demand debonding strategies are systematically evaluated. Integrating these materials engineering principles with phase‐specific biological cues offers a clear translational roadmap for indication‐specific clinical wound management.

1. Introduction

Skin injuries caused by trauma, surgical procedures, burns, and chronic wounds remain a major clinical burden worldwide, creating a persistent need for effective wound closure and protection strategies [1, 2]. Conventional wound closure methods, such as sutures and staples, are widely used because they provide reliable mechanical fixation of tissue edges. However, these approaches are inherently invasive, often require additional procedures for removal, and may induce secondary tissue trauma, pain, inflammation, infection, and scar formation. Moreover, mechanical fixation is not always well suited to irregular wound geometries, fragile tissues, or highly mobile anatomical sites, and it generally provides limited sealing performance against external contaminants and body fluids [3]. These limitations have driven increasing interest in adhesive‐based wound closure systems as minimally invasive alternatives that can establish intimate contact with tissue surfaces while reducing procedural complexity and patient discomfort.

Several adhesive materials have been introduced into clinical practice, including cyanoacrylate glues and fibrin‐based sealants [3, 4]. Cyanoacrylate adhesives exhibit rapid polymerization and strong bonding strength (typically exhibiting shear adhesion strengths > 100–500 kPa), enabling fast wound closure without the need for suturing. However, their clinical use is often restricted by brittleness, poor flexibility, and potential cytotoxicity associated with degradation products such as formaldehyde. In contrast, fibrin glues exhibit excellent biocompatibility because they mimic the natural blood coagulation cascade, yet their adhesive strength is often insufficient (generally offering lap shear strengths of only ∼10–20 kPa) to maintain stable closure in mechanically dynamic or fluid‐rich environments. Furthermore, conventional adhesive dressings and patches frequently show limited adhesion to moist skin surfaces due to perspiration, body motion, and the presence of interfacial fluids such as blood or wound exudate. These limitations highlight the need for next‐generation skin adhesives capable of achieving strong and durable adhesion while maintaining biocompatibility and mechanical compatibility with skin tissues.

Among the various material platforms investigated for this purpose, hydrogel‐based adhesives have emerged as particularly promising candidates. Hydrogels are three‐dimensional (3D) crosslinked polymer networks with high water content that closely resemble the hydration and mechanical characteristics of biological tissues [5, 6]. Their soft and hydrated nature enables intimate conformal contact with irregular tissue surfaces, which enhances interfacial adhesion and reduces mechanical mismatch between the adhesive material and skin tissue. In addition, the chemical composition of hydrogels can be readily engineered to incorporate functional groups capable of forming covalent or noncovalent interactions with biological substrates. Through rational molecular design, hydrogel adhesives can therefore achieve strong wet adhesion while maintaining favorable mechanical flexibility, permeability, and cytocompatibility. These characteristics make hydrogel‐based systems highly attractive for wound closure and skin repair applications.

In recent years, extensive efforts have been devoted to developing skin adhesives with enhanced interfacial bonding mechanisms, tunable mechanical performance, and multifunctional biological properties relevant to wound management. Various chemical strategies have been explored to improve hydrogel–tissue adhesion, including covalent bonding, supramolecular interactions, and bioinspired polyphenol‐mediated chemistry derived from mussel adhesive proteins [7, 8]. In parallel, advances in polymer network engineering have enabled the development of mechanically robust hydrogels capable of sustaining large deformation while maintaining stable adhesion to dynamic tissue surfaces [7, 9]. Importantly, hydrogel adhesives are increasingly designed to incorporate therapeutic functionalities that support wound healing processes, including antibacterial activity to prevent infection, hemostatic capability to control bleeding, and the ability to maintain a moist microenvironment that promotes tissue regeneration [10, 11]. In addition, emerging systems are being engineered with on‐demand debonding mechanisms to allow atraumatic removal of the adhesive after wound closure, thereby minimizing secondary skin injury [12]. Furthermore, the paradigm of wound management is rapidly shifting from passive closure to active, smart interventions. Recent studies emphasize that functional adhesive hydrogels play a pivotal role in creating advanced biological interfaces and serve as versatile tissue adhesives for dynamic wound closure [13, 14].

Despite rapid advances in this field, research on skin adhesives remains conceptually fragmented. Many studies focus on specific adhesive chemistries or material formulations, while the actual performance of skin adhesives depends on a broader set of interconnected factors, including skin structure, wound healing biology, interfacial mechanics, testing methodologies, removability, and biological functionality after application. Consequently, a comprehensive and integrative framework is needed to assess how skin adhesives should be designed for actual wound environments (Figure 1A). In this review, we therefore extend beyond a simple overview of adhesive chemistries and present hydrogel skin adhesives as dynamic regenerative biointerfaces. We first discuss the structural and biological features of skin and the wound healing cascade that define material requirements for successful adhesion. We then examine the major chemical and interfacial mechanisms underlying hydrogel–tissue bonding, including covalent, supramolecular, and polyphenol‐mediated strategies (Figure 1B). Next, we review current approaches for assessing adhesive performance, with particular emphasis on interfacial toughness and the need for standardized testing under clinically relevant conditions, and we discuss emerging strategies for on‐demand debonding to enable atraumatic removal. Finally, we highlight key biological design considerations, including cytocompatibility, immune modulation, angiogenesis, and antibacterial functionality, and outline future directions for next‐generation hydrogel adhesives that not only close wounds but also actively support tissue repair and regeneration (Figure 1C).

FIGURE 1.

Design principles and multifunctional roles of hydrogel tissue adhesives. (A) Comparison between healthy skin (epidermis, dermis, and hypodermis) and wounded skin characterized by bleeding and inflammation. These physiological challenges define the requirements for effective wound closure and tissue repair. (B) Integration of diverse adhesion chemistries, including covalent bonding, supramolecular interactions, and polyphenol‐mediated networks, to achieve robust wet adhesion. Essential properties such as mechanical compliance and biocompatibility are highlighted for tissue integration. (C) Multifunctional therapeutic effects including hemostasis, antibacterial activity, and promoted angiogenesis. The mechanical integrity of these adhesives is quantitatively assessed via lap shear, burst, and peel tests. Images created with Biorender.com.

2. Skin Wound Healing

2.1. Human Skin: Structure, Function, and Relevance to Adhesive Design

Human skin is the largest organ of the body and serves as the first line of defense against the external environment. In addition to functioning as a physical barrier, it regulates water balance, temperature, sensory perception, and immune surveillance. Structurally, the skin consists of three interconnected layers–the epidermis, dermis, and hypodermis–each of which contributes differently to wound closure and adhesive performance (Figure 2A) [15]. For skin adhesives, this layered architecture is highly relevant because the chemical composition, hydration state, mechanical properties, and biological activity of each layer collectively determine interfacial bonding, mechanical compatibility, and the risk of tissue injury during removal.

FIGURE 2.

Comprehensive schematic of skin anatomy, wound healing stages, and molecular binding sites. (A) Detailed cross‐section illustrating the stratified layers (epidermis, dermis, and hypodermis) and appendages. The magnified inset highlights the epidermal sub‐layers, including the stratum corneum and granulosum, which maintain the primary physical barrier. (B) Sequential phases of tissue repair following injury. The process transitions from acute inflammation (leukocyte recruitment and cellular debris removal) to the formation of granulation tissue, followed by re‐epithelialization and ECM remodeling. (C) Identification of key functional groups (Amine, Thiol, Hydroxyl, and Carboxyl) ubiquitous within skin tissue. These chemical moieties serve as essential reactive sites for the integration and stabilization of therapeutic adhesives. Images created with Biorender.com.

The epidermis forms the outer barrier and is the first point of contact for skin adhesives. Because this superficial layer contains limited free water and is vulnerable to stripping injury during detachment, adhesives should establish sufficient interfacial contact without generating excessive peeling stresses, particularly in fragile skin [16, 17, 18]. Beneath this layer, the dermis provides the principal extracellular matrix (ECM) framework and contains abundant reactive biochemical groups, including amines, thiols, hydroxyls, and carboxyls, which can participate in covalent and noncovalent adhesive interactions [19, 20]. The dermis also largely determines tissue elasticity and compliance, indicating that mechanical matching between the adhesive and tissue is important for minimizing stress concentration and improving conformal integration. The hypodermis contributes to bulk deformability and mechanical support, especially in highly mobile anatomical regions.

From a materials perspective, this layered architecture implies that effective skin adhesives must adhere to chemically heterogeneous and hydrated tissue surfaces while maintaining mechanical compliance and enabling atraumatic removal. Given that wounded skin is further characterized by the presence of blood, exudate, inflammation, and continuous deformation, hydrogel‐based adhesives must operate reliably under wet, dynamic, and biologically active conditions [21, 22].

2.2. Wound Healing Phases and Their Implications for Skin Adhesive Design

Wound healing proceeds through the overlapping phases of hemostasis, inflammation, proliferation, and remodeling, each of which imposes distinct design requirements on skin adhesives (Figure 2B and Table 1) [21]. Accordingly, rather than functioning solely as passive sealants, hydrogel‐based skin adhesives should be engineered as dynamic biointerfaces whose interfacial chemistry, mechanical properties, transport characteristics, and degradation behavior are precisely aligned with the evolving demands of the healing wound.

TABLE 1.

Wound healing phases and corresponding biological events, major cellular and molecular mediators, and key design requirements for skin adhesives.

Wound healing phase	Biological events	Major cell types/mediators	Design requirements for skin adhesives
Hemostasis	Vasoconstriction, platelet adhesion and aggregation, thrombin generation, fibrin clot formation	Platelets, thrombin, fibrin, PDGF, TGF‐β, VEGF, FGF, IGF‐1	Rapid wet adhesion, resistance to dilution by blood or exudate, immediate sealing, conformal contact with irregular tissue surfaces, and preferably hemostatic capability
Inflammation	Pathogen clearance, removal of damaged tissue, cytokine signaling, initiation of immune regulation	Neutrophils, monocytes, macrophages, TNF‐α, IL‐1β, IL‐6, reactive oxygen species	Cytocompatibility in an inflamed microenvironment, minimal irritation and foreign‐body response, barrier function, and antibacterial activity
Proliferation	Granulation tissue formation, fibroblast migration, ECM deposition, angiogenesis, re‐epithelialization	Fibroblasts, endothelial cells, keratinocytes, type III collagen, fibronectin, VEGF, FGF	Maintenance of a moist environment, gas permeability, mechanical compliance, support for cell migration and matrix remodeling, and compatibility with angiogenesis
Remodeling	Collagen maturation, matrix reorganization, scar formation, vascular regression, wound contraction	Fibroblasts, myofibroblasts, MMPs, TIMPs, type I collagen	Controlled persistence, minimal chronic irritation, suitable degradation behavior, on‐demand debonding for atraumatic removal

During hemostasis, key material requirements include rapid adhesion under wet conditions, fast interfacial stabilization, resistance to dilution by blood or exudate, and effective sealing of irregular wound surfaces. Rapid gelation or curing, along with additional hemostatic functionality, is beneficial at this stage because it helps stabilize the wound before sufficient tissue integration occurs [23]. During inflammation, adhesives should remain cytocompatible under biologically active conditions, reduce nonspecific chemical reactivity and foreign‐body responses, and offer barrier or antibacterial functions to lower the risk of infection [24, 25].

During the proliferative phase of wound healing, the functional focus transitions to supporting tissue regeneration. Adhesives at this stage should maintain a moist environment, allow gas exchange, accommodate tissue deformation, and provide a mechanically suitable interface that promotes fibroblast activity, angiogenesis, and re‐epithelialization [19, 23]. Excessively stiff or highly reactive materials may disrupt these processes by restricting cell migration, amplifying fibrotic signaling, or inducing persistent interfacial irritation. During the subsequent remodeling phase, the adhesive should remain in place long enough to maintain wound closure, yet not adhere so strongly or persist so long that its removal results in epidermal injury, pain, or secondary tissue damage. Accordingly, controlled degradation or on‐demand debonding becomes increasingly critical as healing progresses [26, 27].

Taken together, these phase‐dependent requirements underscore that an ideal hydrogel‐based skin adhesive should integrate robust early‐stage fixation with later‐stage biological compatibility, adaptive mechanical behavior, and atraumatic removability. This framework provides a critical foundation for guiding material design beyond adhesion strength alone and toward clinically effective wound‐interface engineering.

3. Chemical and Interfacial Design of Skin Adhesives

Effective skin adhesives must maintain stable tissue interactions while preserving mechanical compliance, cytocompatibility, and functionality under wet and dynamic conditions. Hydrogels offer a suitable platform because their highly hydrated and soft polymer networks resemble native tissue mechanics. In addition, hydrogel chemistry can be engineered to introduce functional groups that interact with proteins and ECM components at the tissue interface, enhancing adhesive integration [28, 29]. Unlike conventional synthetic adhesives that rely primarily on hydrophobic interactions or solvent evaporation, hydrogel‐based adhesives operate in a hydrated environment where interfacial water, biological macromolecules, and tissue deformation strongly influence adhesion [28, 30]. Consequently, hydrogel–tissue bonding typically arises from a combination of chemical and physical interactions rather than a single bonding mechanism. These interactions can broadly be categorized into three major classes: covalent bonding, supramolecular (noncovalent) interactions, and polyphenol‐mediated adhesion. Each strategy offers distinct advantages and limitations in terms of adhesion strength, reversibility, wet adhesion capability, and biological compatibility (Table 2). Understanding these mechanisms provides important guidance for the rational design of next‐generation skin adhesives.

TABLE 2.

Comparative features of covalent, supramolecular, and polyphenol‐mediated adhesion strategies in skin adhesives.

Adhesion strategy	Chemical motifs	Interfacial interactions	Key advantages	Major limitations
Covalent bonding	NHS esters, aldehydes, Schiff base‐forming groups, photoactivated aldehyde precursors	Amide bond formation, imine formation, thioester formation, hemithioacetal formation	High interfacial strength, durable fixation, strong resistance to deformation, effective anchoring under demanding mechanical conditions	Potential cytotoxicity due to excessive chemical reactivity, nonspecific reactions with tissue proteins, limited removability, risk of tissue damage during detachment
Supramolecular interactions	Hydrogen‐bonding groups, ionic moieties, aromatic groups, hydrophobic domains	Hydrogen bonding, electrostatic interactions, van der Waals interactions, hydrophobic interactions, π–π stacking	Reversible and adaptive adhesion, self‐healing behavior, efficient energy dissipation, good tolerance to repeated tissue deformation	Lower peak adhesion strength than covalent systems, sensitivity to hydration and interfacial contamination, limited long‐term stability
Polyphenol‐mediated adhesion	Catechol, dopamine, L‐DOPA, tannic acid, GA, pyrogallol/gallol groups	Hydrogen bonding, π–π stacking, cation–π interactions, metal coordination, oxidation‐mediated covalent coupling	Strong wet adhesion, broad substrate affinity, compatibility with hemostatic and bioactive designs	Adhesion depends strongly on oxidation state, pH, and metal‐ion environment; excessive oxidation may reduce performance or increase cytotoxicity

3.1. Chemical Functionalities at the Skin Interface

The skin and wound interface present a chemically heterogeneous surface containing numerous functional groups derived from proteins, lipids, and ECM components. Among these, nucleophilic and polar groups such as primary amines (─NH₂), thiols (─SH), hydroxyl groups (─OH), and carboxyl groups (─COOH) are commonly accessible on exposed proteins and ECM molecules (Figure 2C) [7]. These functional groups can participate in a range of chemical interactions with appropriately engineered hydrogel networks.

Primary amine groups are abundant in lysine residues of proteins and represent one of the most reactive nucleophilic functionalities at the tissue interface. These groups readily undergo reactions with electrophilic moieties, such as N‐hydroxysuccinimide (NHS) esters or aldehydes, enabling covalent anchoring between hydrogel polymers and tissue proteins [8]. Thiol groups originating from cysteine residues can participate in thiol‐disulfide exchange reactions or Michael‐type additions with activated double bonds [31]. In addition to covalent reactions, hydroxyl and carboxyl groups contribute to hydrogen bonding, electrostatic interactions, and hydration‐mediated interactions that collectively influence adhesive performance.

Skin adhesion occurs under aqueous conditions, making interfacial water a key factor in adhesive performance. Water molecules can shield reactive groups, disrupt intermolecular bonding, and limit intimate contact between adhesives and tissue surfaces. Accordingly, effective hydrogel adhesives typically incorporate strategies that displace interfacial water, form strong chemical bonds resistant to hydration effects, or employ multivalent interactions capable of maintaining robust adhesion in wet environments.

3.2. Covalent Bonding Strategies

Covalent bonding represents one of the most effective approaches for achieving strong and durable adhesion to biological tissues. These interactions involve the formation of stable chemical bonds between functional groups in the hydrogel network and reactive groups present on tissue proteins. Because covalent bonds are significantly stronger than noncovalent interactions, they can provide robust fixation even under mechanical deformation and physiological loading conditions.

Among the available chemistries, NHS ester–amine coupling has been widely used in hydrogel‐based tissue adhesives. NHS ester‐functionalized polymers readily react with primary amines on tissue proteins under physiological conditions, forming stable amide bonds that anchor the hydrogel to the tissue surface (Figure 3A) [7]. These esters can also react with thiol groups to form thioesters, thereby broadening their reactivity and reinforcing adhesive performance. A representative example was reported by Wu et al., who developed a printable tissue adhesive based on a hydrophilic polyurethane grafted with NHS ester‐functionalized poly(acrylic acid) (PAA) (Figure 3B) [32]. In this system, the hydrophilic polymer chains promoted rapid interfacial hydration and conformal contact, while the NHS ester groups enabled efficient covalent coupling to tissue proteins. As a result, the adhesive exhibited an interfacial toughness exceeding 300 J m^{− 2} and a shear adhesion strength above 75 kPa on porcine skin. This example highlights a key advantage of NHS ester‐based systems: when interfacial contact is well established, rapid covalent bond formation can generate exceptionally strong adhesion.

FIGURE 3.

Covalent tissue adhesion via NHS ester‐mediated coupling. (A) Primary amine or thiol groups on the skin surface undergo nucleophilic substitution with NHS esters, resulting in the formation of stable amide bonds or thioesters that anchor the adhesive to the tissue. (B) A 3D‐printable tissue adhesive based on PU and PAA was developed. The hydrogel adhesive was printed as a dried mesh structure to facilitate rapid removal of interfacial water upon contact with tissue, while NHS ester functionalities grafted onto PAA enabled robust covalent bonding to the tissue surface. Adapted with permission [32]. Copyright 2024, Springer Nature.

Another widely used strategy involves Schiff base formation between aldehyde‐functionalized polymers and nucleophilic groups on tissue proteins. In these systems, aldehydes react with primary amines to form imine (C═N) bonds and can also interact with thiols to generate hemithioacetals, introducing a degree of reversibility at the interface (Figure 4A). Oxidized polysaccharides, including oxidized alginate and oxidized hydroxyethyl starch (HES), are frequently used to introduce aldehyde functionalities into hydrogel networks. For example, Lin et al. developed an injectable gelatin/oxidized alginate hydrogel in which dynamic imine bonds formed both within the polymer network and at the tissue interface, thereby combining tissue adhesion with self‐healing behavior (Figure 4B) [33]. In a related study, modified HES was incorporated into a hydrogel network to form C═N linkages with tissue surfaces upon contact, enabling stable skin adhesion together with self‐recovery, favorable biocompatibility, and high optical transparency (Figure 4C) [34]. Compared with NHS ester systems, aldehyde‐based chemistries often offer greater network adaptability because the interfacial bonds can remain dynamic, which may be advantageous for injectable, self‐healing, or mechanically compliant adhesives.

FIGURE 4.

Diverse skin adhesives leveraging Schiff base‐driven interfacial chemistry. (A) Surface amine and thiol groups on skin react with aldehyde groups in the adhesive to form imine bonds and hemithioacetals, enabling interfacial adhesion. (B) Oxidized alginate hydrogels achieved robust cutaneous adhesion through aldehyde‐mediated dynamic covalent interactions with tissue surfaces. Adapted with permission [33]. Copyright 2024, American Chemical Society. C) A HES‐based adhesive demonstrated therapeutic efficacy in skin wound models, accelerating regenerative outcomes upon implantation. Adapted with permission [34]. Copyright 2020, American Chemical Society. (D) A PGA adhesive bearing NB functionalities underwent UV‐triggered transformation into reactive nitrosobenzaldehyde species, enabling rapid and controllable bonding to tissue interfaces. Adapted with permission [35]. Copyright 2022, John Wiley and Sons.

Photoactivated covalent bonding provides an additional layer of control by enabling spatially and temporally regulated adhesion. Zhu et al. developed a light‐responsive adhesive patch based on o‐nitrobenzene (NB)‐modified polyglutamic acid (PGA), in which light exposure generated aldehyde groups that subsequently formed imine bonds with tissue amines (Figure 4D) [35]. Such strategies are particularly attractive when precise timing or localization of adhesion is desired, for example during minimally invasive placement or patterned fixation.

Despite their clear advantages, covalent bonding strategies also present important trade‐offs. The same high reactivity that enables strong interfacial fixation may lead to nonspecific reactions with cellular proteins, potentially causing cytotoxicity, tissue irritation, or undesired alterations in local biological function. In addition, strong or irreversible covalent anchoring can complicate adhesive removal and increase the risk of tissue damage during detachment. For this reason, covalent chemistries are rarely ideal as a stand‐alone solution when atraumatic removal, long‐term biocompatibility, or repeated deformation are major priorities. Instead, they are most effective when integrated with dynamic covalent motifs, energy‐dissipating supramolecular networks, or triggerable debonding mechanisms. Overall, covalent bonding offers the highest interfacial strength among current hydrogel adhesion strategies, but its successful implementation depends on balancing bond stability with biological tolerance and removability.

3.3. Noncovalent Interactions

In contrast to covalent bonding, supramolecular adhesion relies on reversible intermolecular forces, including hydrogen bonding, electrostatic interactions, van der Waals forces, hydrophobic interactions, and π–π stacking [36, 37]. Although these interactions are individually weaker than covalent bonds, their multivalent and cooperative nature can collectively generate substantial adhesion while also imparting dynamic mechanical adaptability. From a design perspective, this reversibility is the principal advantage of noncovalent strategies: rather than maximizing interfacial bond strength alone, they enable hydrogel adhesives to dissipate energy, accommodate tissue motion, and recover from deformation without catastrophic interfacial failure.

Hydrogen bonding is among the most commonly exploited supramolecular mechanisms in hydrogel adhesives. Polar groups such as hydroxyl, carboxyl, and amide moieties can form directional interactions with complementary groups on tissue proteins and ECM components. Wang et al., for example, developed poly(acrylic acid‐co‐1‐vinylimidazole) hydrogels capable of establishing extensive hydrogen‐bonding networks with biological tissues (Figure 5A) [38]. Because hydrogen bonds can reversibly break and reform under stress, such systems often exhibit improved toughness and mechanical compliance at the interface. In this respect, hydrogen‐bond‐dominated adhesives are especially useful when repeated deformation and energy dissipation are more important than maximizing instantaneous adhesion strength.

FIGURE 5.

Representative supramolecular strategies for hydrogel–tissue adhesion. (A) Hydrogen‐bond‐mediated wet tissue adhesion using a tough hydrogel with reversible interfacial interactions. Adapted with permission [38]. Copyright 2022, American Chemical Society. (B) Enhancement of hydrogel bioadhesion by interface‐induced surface hydrophobization, mediated by hydrophobic and van der Waals interactions. Adapted with permission [40]. Copyright 2024, Springer Nature.

Additional supramolecular contributions can arise from aromatic interactions. Chen et al. developed a wheat gluten/poly(acrylic acid) (G‐PAA) tough double‐network hydrogel in which hydrogen bonding and π–π interactions between gluten and PAA contributed simultaneously to cohesion and wet adhesion [39]. Notably, the optimized G‐PAA formulation achieved a lap shear adhesion strength of 82 kPa and an interfacial toughness of 97 J m^{− 2} in a 180° peel test on wet porcine skin. This example illustrates an important feature of supramolecular systems: although the interfacial chemistry is reversible, strong adhesion can still be achieved when multiple weak interactions are integrated into a mechanically dissipative network.

Hydrophobic and van der Waals interactions also play a significant role once close contact is established between the hydrogel and tissue surface. In wet environments, hydrophobic interactions are particularly valuable because they can promote displacement of interfacial water and facilitate molecular contact that would otherwise be hindered by hydration layers. Yi et al. introduced an interface‐driven network reconfiguration strategy in which hydrophobic silicone chains on a molding surface induced hydrogel surface reorganization through abundant noncovalent interactions, including hydrophobic and van der Waals interactions (Figure 5B) [40]. The resulting hydrogel surface became highly hydrophobic, with a water contact angle of up to ∼120°, markedly enhancing bioadhesion and transdermal delivery while leaving the bulk formulation unchanged. This study underscores that supramolecular adhesion is not limited to direct tissue binding motifs; it can also be enhanced by engineering the interfacial physicochemical state of the hydrogel surface.

The major strength of noncovalent strategies lies in their adaptability. Because the interfacial interactions are reversible, these adhesives often show self‐healing behavior, improved fatigue tolerance, and better accommodation of tissue movement than purely covalent systems. However, this same reversibility can also limit long‐term stability, particularly under highly hydrated conditions or in the presence of interfacial contaminants such as blood, proteins, or wound exudate. As a result, supramolecular interactions alone may be insufficient for applications requiring strong, persistent fixation in mechanically demanding environments. In practice, they are most effective when used to complement stronger anchoring chemistries by providing energy dissipation, interfacial adaptability, and mechanical resilience. Thus, compared with covalent bonding, noncovalent interactions generally offer lower peak adhesion strength but superior reversibility and tolerance to dynamic tissue motion.

3.4. Polyphenol‐Mediated Adhesion

Polyphenol‐based adhesive chemistries have attracted considerable attention because they combine strong wet‐surface affinity with remarkable chemical versatility. Inspired by the underwater adhesion mechanisms of mussels and other biological systems, polyphenolic motifs such as catechol and pyrogallol have been incorporated into hydrogel networks to establish robust interactions with a wide range of biological substrates [41]. Mechanistically, these groups occupy an intermediate position between purely covalent and purely supramolecular strategies: they can participate in multiple reversible interactions, including hydrogen bonding, π–π stacking, cation–π interactions, and metal coordination, while also undergoing oxidation to generate reactive quinone species capable of covalent coupling [31, 42, 43]. This multifunctionality is a major reason why polyphenol‐based systems are especially effective under wet conditions.

Catechol‐containing molecules such as dopamine and 3,4‐dihydroxyphenylalanine (L‐DOPA) have been the most extensively studied examples. Catechol groups contain an aromatic ring bearing two vicinal hydroxyl groups, which enable diverse interfacial interactions with proteins, ECM components, and lipid‐rich biological surfaces. One of the most important advantages of catechol chemistry is its strong affinity for wet interfaces: catechol groups can partially disrupt interfacial hydration layers and promote intimate surface contact, thereby overcoming one of the major limitations of conventional adhesives in biological environments [44, 45]. In addition, catechol oxidation can generate quinones that react with nucleophilic groups on tissue proteins, further reinforcing adhesion through covalent coupling.

Several representative hydrogel systems demonstrate how catechol chemistry translates into practical skin adhesion. Zhou et al. developed dopamine‐modified hyaluronic acid hydrogels that exhibited rapid gelation and strong adhesion to wet porcine skin (Figure 6A) [46]. In that system, increasing catechol density significantly enhanced adhesion energy, indicating that multivalent catechol‐mediated interactions and oxidative crosslinking were central contributors to interfacial performance. Similarly, Ryu et al. developed an injectable adhesive by combining catechol‐modified chitosan with the thermoresponsive triblock copolymer Pluronic F‐127, enabling in situ gelation and tissue adhesion at wound sites [47]. The resulting chitosan/Pluronic hydrogel, which retained residual catechol groups after gelation, exhibited strong adhesion to soft tissues and mucosal layers while also showing improved hemostatic performance (Figure 6B). These examples highlight why catechol‐based systems are often attractive for wound closure: they combine wet adhesion, injectability or in situ processability, and biologically relevant secondary functions such as hemostasis.

FIGURE 6.

Catechol‐mediated adhesion strategies in skin adhesives. (A) Dopamine‐conjugated hyaluronic acid adhesives demonstrate effective adhesion across multiple organ tissues, including the heart, liver, and kidney. Adapted with permission [46]. Copyright 2020, American Chemical Society. (B) A mussel‐inspired injectable adhesive exhibits robust bonding to a variety of wet biological surfaces. Adapted with permission [47]. Copyright 2011, American Chemical Society.

Beyond catechol, pyrogallol‐containing motifs such as tannic acid (TA) and gallic acid (GA) have emerged as promising alternatives. Pyrogallol groups contain three hydroxyl substituents on an aromatic ring, providing greater hydrogen‐bonding density and stronger metal‐coordination capacity than catechol [48]. These features can increase both interfacial adhesion and internal network reinforcement. For example, Chen et al. developed TA‐modified polyethylene glycol diacrylate (PEGDA) hydrogels in which gallol functionalities were introduced after network formation, thereby preserving the bulk mechanical properties of the hydrogel while significantly enhancing interfacial adhesion through multivalent hydrogen bonding and metal coordination (Figure 7A) [49]. Similarly, Fan et al. reported a pyrogallol‐functionalized hydrogel adhesive that achieved rapid and robust adhesion to diverse biological substrates, including skin and internal organs [50]. In that system, gallol groups supported strong hydrogen bonding and oxidation‐mediated covalent interactions, while also participating in Fe^{3 +}‐mediated coordination crosslinking that improved mechanical strength and energy dissipation (Figure 7B). Compared with catechol‐based systems, pyrogallol‐containing adhesives may provide even stronger multivalent interactions, although their higher oxidation susceptibility can complicate precise control over long‐term reactivity.

FIGURE 7.

Pyrogallol‐mediated adhesion strategies in skin adhesives. (A) A PEGDA‐based skin adhesive functionalized with gallol moieties achieves strong adhesion on wet porcine skin surfaces. Adapted with permission [49]. Copyright 2021, American Chemical Society. (B) A pyrogallol‐based hydrogel displays enhanced adhesive performance compared with conventional catechol‐based hydrogel systems. Adapted with permission [50]. Copyright 2017, American Chemical Society.

Despite their versatility, polyphenol‐mediated systems also present important design challenges. Their adhesive performance is strongly influenced by oxidation state, local pH, and the presence of metal ions, all of which can shift the balance between reversible surface interactions and irreversible covalent coupling. Excessive oxidation may reduce available catechol groups, alter network mechanics, or generate reactive quinone species that contribute to cytotoxicity. Several studies have indicated that oxidation‐driven quinone formation can lead to cellular stress and decreased viability, suggesting that biological responses may depend more on quinone exposure than on the overall polyphenol content [51]. In contrast, oxidation‐resistant catechol‐like designs have been reported to maintain adhesive performance while enhancing cytocompatibility [52]. Together, these findings suggest that the biological effects of polyphenol‐based adhesives are not uniform but depend strongly on formulation factors, including functional group density, oxidation kinetics, local pH, and approaches used to regulate quinone formation. Therefore, although polyphenol chemistry is highly attractive for wet adhesion and multifunctional interface design, its clinical application requires careful regulation of the redox environment and network structure to ensure both effective adhesion and biological safety.

3.5. Interfacial Chemistry in the Regulation of Regenerative Wound Interfaces

Rahmati et al. highlighted that biomaterial surface functional groups regulate protein adsorption and subsequent cell signaling, indicating that covalent adhesive chemistries should be evaluated not only by bonding strength but also by how they shape the biological microenvironment at the wound interface [53]. Consistent with this view, Chan et al. demonstrated that highly oxidized dextran–aldehyde/chitosan hydrogels exhibited moderate cytotoxicity toward human dermal fibroblasts and inhibited fibroblast migration, whereas reducing aldehyde content markedly improved fibroblast compatibility and eliminated pro‐inflammatory responses in vivo [54]. Zheng et al. further showed that an alginate‐based adhesive hydrogel could preserve fibroblast viability and proliferation while maintaining strong wet‐tissue adhesion, suggesting that amine‐reactive groups can remain compatible with tissue repair when their reactivity is appropriately balanced [55]. Ren et al. also reported that a catalyst‐free o‐phthalaldehyde/amine adhesive hydrogel exhibited good biocompatibility and accelerated cutaneous wound closure, supporting the notion that controlled covalent bonding can stabilize the wound interface without compromising healing [56]. Together, these studies suggest that the regenerative outcome of covalent adhesion depends less on the presence of covalent bonds and more on the controlled density and persistence of reactive groups, which must be optimized to achieve early fixation without inducing cytotoxicity, inhibiting fibroblast migration, or sustaining excessive inflammation.

Beyond covalent bonding, noncovalent interactions contribute to regeneration not only by providing reversible adhesion but also by regulating protein adsorption, hydration, and subsequent cell signaling at the material surface. Lv et al. showed that surface hydrophilicity influences macrophage polarization by modulating the adsorption and conformation of fibronectin and fibrinogen, which in turn affects integrin β1/β2 signaling pathways and macrophage phenotype [57]. Trel'ová et al. reported that soft zwitterionic hydrogel coatings, characterized by balanced electrostatic interactions and strong hydration, suppress nonspecific protein adsorption and significantly reduce fibroblast and macrophage adhesion [58]. In addition, Wei et al. showed that dynamic and reversible matrix interactions enhance endothelial integrin clustering, focal adhesion formation, and vascular morphogenesis [59]. Together, these studies indicate that noncovalent interactions act not only as reversible adhesion mechanisms but also as regulators of protein organization and cell signaling, thereby influencing immune responses, fibroblast activity, and angiogenesis during wound healing.

Particularly in bioinspired systems, polyphenol‐mediated interactions contribute to regeneration not only by providing strong wet adhesion but also by modulating redox balance, protein, and ECM interactions, and inflammatory signaling. Kim et al. showed that an epigallocatechin gallate‐crosslinked hyaluronic acid hydrogel achieved strong adhesion while eliciting minimal host response, indicating that polyphenol‐based interfaces can stabilize tissue contact without inducing significant inflammation [60]. Fu et al. reported that a protocatechuic aldehyde–collagen hydrogel promoted macrophage polarization toward the M2 phenotype, increased VEGF and TGF‐β expression, enhanced endothelial migration and tube formation, and improved collagen deposition in diabetic wounds [61]. Xu et al. similarly demonstrated that TA/ferric ion hydrogels enhanced M2 polarization and improved multiple regenerative outcomes, including granulation tissue formation, re‐epithelialization, collagen deposition, and angiogenesis [62]. However, Meng et al. showed that uncontrolled catechol oxidation can generate cytotoxic H₂O₂ and increase foreign‐body responses, highlighting the importance of controlling interfacial redox conditions [63]. Together, these findings suggest that polyphenol‐mediated adhesion should be considered not only as a wet adhesion mechanism but also as a regulator of macrophage activity, vascularization, and fibroblast‐driven ECM remodeling during wound healing. Therefore, the design of polyphenol‐based skin adhesives should go beyond optimizing adhesion strength and instead focus on controlling interfacial redox behavior, protein interactions, and surface reactivity to support tissue integration while reducing inflammation and cytotoxic effects.

3.6. Mechanical Evaluation of Adhesion Performance

Quantitative evaluation of adhesive performance is essential for determining whether hydrogel adhesives can maintain stable attachment to skin under physiological conditions. Because skin experiences continuous deformation during normal movement, adhesives must withstand complex mechanical stresses including tension, shear, and peeling forces. Among the various metrics used to characterize adhesion, interfacial toughness has emerged as one of the most informative parameters. Interfacial toughness represents the energy required to propagate a crack along the adhesive interface and is typically expressed in units of J m^{− 2}. Unlike simple adhesion strength measurements, which only quantify the maximum detachment force, interfacial toughness captures the combined effects of interfacial bonding strength and energy dissipation within the adhesive network [64, 65].

Several mechanical tests are commonly used to evaluate hydrogel adhesion. Lap shear tests measure the shear force required to detach bonded substrates, providing a simple metric for shear adhesion strength (Figure 8A). Tensile adhesion tests evaluate resistance to normal separation forces by pulling bonded substrates perpendicular to the adhesive interface (Figure 8B). Burst pressure tests assess the sealing capability of adhesives in defect‐repair applications by measuring the pressure required to rupture an adhesive seal over a tissue defect (Figure 8C). Peel tests, including 90° peel and T‐peel configurations, measure the energy required to progressively separate the adhesive interface and are often used to estimate interfacial fracture energy (Figure 8D).

FIGURE 8.

Mechanical evaluation methods for skin adhesives. (A) In lap shear adhesion test, adhesion strength is determined by quantifying the shear stress required to induce interfacial failure. (B) Tensile testing applies a normal force to the tissue‐adhesive interface to measure the peel force associated with adhesive detachment. (C) In burst pressure testing, a standardized perforation is created in the tissue, sealed with the adhesive, and subjected to increasing intraluminal pressure until rupture, thereby defining the burst pressure. (D) Peel testing assesses the force necessary to separate an adhesive applied either onto the tissue surface or between two tissue substrates.

To better understand the mechanical performance of emerging hydrogel adhesives, it is useful to compare them with clinically used sealants [66]. Fibrin glues are highly biocompatible but typically show weak adhesion, with shear strengths around 5–15 kPa and interfacial toughness below 20 J m^{− 2} [8, 67]. In contrast, cyanoacrylate‐based adhesives provide very strong fixation, often exceeding 100 kPa in shear strength, but their brittleness leads to low toughness and poor mechanical compliance on soft tissues. Recent developments in hydrogel‐based skin adhesives have bridged the gap between conventional materials by utilizing different interfacial bonding strategies. Covalent adhesives, such as those using NHS ester or aldehyde chemistry, form strong and often irreversible bonds with tissue amines. When combined with dissipative polymer networks, these systems can achieve high shear adhesion strengths (∼50 to >100 kPa) and interfacial toughness values exceeding 500–1,000 J m^{− 2} [8, 67]. Supramolecular interactions, including hydrogen bonding, electrostatic forces, and host–guest interactions, provide reversible and dynamic adhesion. Although their adhesion strength is typically lower (∼20–60 kPa), their ability to dissipate energy through sacrificial bonds results in high toughness (∼100 to >800 J m^{− 2}) and adaptability to dynamic tissue environments [12, 68]. Polyphenol‐based adhesives, mainly based on catechol chemistry, offer strong wet adhesion across various tissues, with shear strengths of ∼30–80 kPa and interfacial toughness of ∼100–300 J m^{− 2}, due to combined intermolecular interactions and oxidative crosslinking [69, 70]. Overall, these hydrogel systems achieve both strong adhesion and high toughness, outperforming fibrin glues in adhesion strength and cyanoacrylates in toughness.

Even with such representative benchmarks, direct comparison of adhesion values reported in the literature remains challenging. Adhesion measurements are strongly influenced by experimental conditions, including substrate type, material hydration state, contact time, adhesive thickness, testing geometry, and loading rate. For example, adhesion strengths measured on glass substrates or synthetic materials may differ substantially from those obtained on biological tissues such as porcine or human skin [71, 72]. Additionally, failure modes should be carefully distinguished, as cohesive failure within the hydrogel, interfacial failure, or substrate damage may lead to different interpretations of adhesion performance [73, 74]. Accordingly, reliable assessment of skin adhesives generally requires multiple complementary mechanical testing methods together with detailed reporting of experimental conditions. Standardized characterization practices are crucial for enabling meaningful comparisons among different adhesive systems and for informing the rational design of skin adhesives.

4. Strategies for On‐Demand Debonding of Skin Adhesives

While strong adhesion is essential for maintaining reliable fixation during wound closure, excessive adhesive strength can lead to tissue damage during removal. Medical adhesive‐related skin injury has increasingly been recognized as a significant clinical concern, particularly in vulnerable populations such as neonates, elderly patients, and individuals with compromised skin barrier function. Removal of strongly adhered dressings or adhesives may cause epidermal stripping, local inflammation, allergic dermatitis, or even partial‐thickness skin loss [75]. These complications highlight a fundamental design challenge in skin adhesive development: the same interfacial interactions that ensure robust adhesion during use can generate damaging stresses during detachment.

From a fracture mechanics perspective, adhesive removal corresponds to crack propagation within a multilayer system consisting of the hydrogel bulk, the hydrogel–tissue interface, and the underlying skin tissue. The locus of failure depends on the relative magnitudes of interfacial toughness, hydrogel cohesive fracture energy, and the intrinsic fracture resistance of the skin. Ideally, adhesive removal should occur either at the hydrogel–tissue interface or within the hydrogel network itself, rather than within the tissue substrate. However, when the interfacial adhesion energy exceeds the fracture resistance of the epidermis, detachment may instead occur within the skin, resulting in tissue damage.

To address this challenge, recent research has focused on on‐demand debonding strategies that enable controlled reduction of adhesion after wound closure. Rather than permanently lowering adhesive strength, these approaches aim to decouple strong initial fixation from atraumatic removal by incorporating external triggers capable of selectively weakening either interfacial bonding or the cohesive integrity of the hydrogel network. In general, such strategies can be classified into two main categories: (i) modulation of interfacial interactions and (ii) weakening of hydrogel network integrity. As summarized in Table 3, these approaches differ not only in debonding mechanism but also in their translational trade‐offs, including trigger safety, detachment speed, residue formation, and practicality in clinical settings.

TABLE 3.

Representative on‐demand debonding strategies for skin adhesives.

Debonding strategy	Representative trigger	Debonding mechanism	Key advantages	Major limitations
Competitive coordination / interfacial ligand redistribution	Fe3 + treatment or re‐equilibration in catechol‐containing systems	Redistribution of catechol binding sites, reducing interfacial adhesion	Preserves bulk network integrity; tunable and potentially reversible; suitable for catechol‐based systems	Applicable mainly to coordination‐mediated adhesives; may require precise control of ion exposure and distribution
Redox‐responsive interfacial bond cleavage	Biocompatible reducing solution (e.g., glutathione/sodium bicarbonate)	Cleavage of disulfide‐containing interfacial linkages and weakening of associated hydrogen‐bond interactions	Effective reduction in interfacial toughness; painless removal; chemically selective	Debonding may depend on trigger diffusion and exposure time; effectiveness can vary with adhesive thickness and wound fluid composition
Electroadhesion‐mediated detachment	External electric field	Reorientation of charge distribution and interfacial dipoles to counteract adhesive interactions	Nonchemical trigger; potentially rapid and reversible; avoids addition of exogenous reagents	Requires external hardware and controlled voltage delivery; applicability may depend on wound site and device geometry
Thermoresponsive network softening	Cooling or heating across LCST/UCST transition	Change in polymer hydration and chain conformation reduces cohesive strength and/or adhesion energy	Simple trigger; potentially fast; useful for reversible dressings and skin‐contact adhesives	Temperature window must remain safe and comfortable for tissue; mechanical performance may be sensitive to ambient conditions
Chelation‐induced weakening of ionic networks	EDTA or other chelating agents	Removal of ionic crosslinkers (e.g., Ca2 +), reducing network cohesion and fracture toughness	Straightforward topical trigger; effective in ionically crosslinked hydrogels; can allow residue‐free removal	Restricted mainly to ionically crosslinked systems; excessive network weakening may compromise structural integrity during removal
Enzymatic degradation of network polymers	Alginate lyase or other polymer‐specific enzymes	Cleavage of hydrogel backbone or crosslinked network components, causing loss of cohesive integrity	High chemical specificity; effective for degradable polymer systems	Enzyme activity can be slower, condition‐dependent; may increase the risk of incomplete degradation or residue
Photodegradable network cleavage	UV or light irradiation	Cleavage of photolabile linkers (e.g., nitrobenzyl‐based motifs), resulting in rapid network breakdown	Excellent spatial and temporal control; useful when localized detachment is required	Light penetration may be limited; UV exposure raises safety concerns; requires optical equipment

4.1. Modulation of Interfacial Adhesion

One debonding strategy involves disrupting the chemical interactions that mediate hydrogel–tissue adhesion. Because adhesion often arises from covalent bonds, metal coordination, hydrogen bonding, or electrostatic interactions at the interface, selective interference with these interactions can reduce interfacial toughness and promote detachment.

Competitive coordination in catechol‐based adhesive systems provides a representative approach for regulating adhesion. Catechol groups form strong coordination complexes with multivalent ions such as Fe^{3 +}, contributing to both surface adhesion and internal network crosslinking. Pu et al. designed a catechol‐containing hydrogel in which Fe^{3 +} ions were selectively confined to one surface by exposure to FeCl₃ [76]. Internal coordination between Fe^{3 +} and catechol groups redistributed binding sites and reduced tissue–adhesive interactions at the interface. This mechanism enabled tunable control of adhesion strength by shifting the coordination equilibrium.

Another strategy involves redox‐responsive cleavage of covalent bonds at the interface. Chen et al. developed a hydrogel adhesive incorporating disulfide linkages that could be cleaved through treatment with a biocompatible reducing solution containing sodium bicarbonate and glutathione [77]. Under reductive conditions, thiol–disulfide exchange reactions cleaved interfacial covalent bonds and weakened hydrogen‐bond interactions, producing an approximately tenfold reduction in interfacial toughness within 30 min. Notably, this process allowed painless removal of the adhesive without observable tissue damage.

In addition to chemical triggers, electroadhesion‐mediated detachment has been explored as a physical approach for controlling adhesion. Borden et al. developed electroadhesive patches capable of sealing defects in vascular tissues while allowing reversible attachment and detachment through application of an external electric field [78]. In this system, the applied voltage alters charge distribution and dipole orientation at the interface, generating electrostatic forces that counteract adhesive interactions and promote detachment. These strategies demonstrate that selective modulation of interfacial chemistry can provide a powerful means of reducing adhesion without compromising the structural integrity of the hydrogel network.

4.2. Debonding Through Hydrogel Network Integrity Modulation

A second debonding strategy focuses on reducing the cohesive integrity of the hydrogel network rather than disrupting interfacial interactions. By lowering the cohesive fracture energy of the hydrogel, crack propagation can be redirected into the adhesive layer even when interfacial bonding remains strong, enabling detachment without damaging the underlying tissue.

A widely studied strategy employs thermoresponsive polymers that undergo phase transitions in response to temperature changes. Materials exhibiting lower critical solution temperature (LCST) or upper critical solution temperature (UCST) behavior experience significant shifts in polymer hydration and chain conformation with temperature variation. Li et al. reported a temperature‐controlled hydrogel adhesive based on poly(N‐isopropylacrylamide‐co‐butyl acrylate), in which cooling below the critical solution temperature softened the network and reduced adhesion energy to ∼10 J m^{− 2}, enabling easy removal from skin [79].

Another effective approach involves modulating ionic crosslinks within the hydrogel network. In alginate‐based hydrogels, Ca^{2 +}‐mediated ionic junctions provide substantial mechanical strength and fracture toughness. Freedman et al. showed that chelating agents such as ethylenediaminetetraacetic acid (EDTA) can sequester Ca^{2 +} ions, destabilize the ionic network, and weaken hydrogel cohesion, thereby allowing residue‐free removal from skin [80].

More drastic reductions in adhesion can be achieved by direct cleavage of network components. For example, enzymatic treatment with alginate lyase can cleave alginate chains and disrupt hydrogel structure, resulting in rapid loss of adhesive integrity [80]. Similarly, photodegradable hydrogels incorporating nitrobenzyl‐based linkers undergo bond cleavage upon UV irradiation. Villiou et al. reported a catechol‐functionalized PEG hydrogel containing photodegradable nitrobenzyl triazole units that rapidly lost mechanical integrity following light exposure, facilitating adhesive detachment [81].

5. Challenges and Future Perspectives in Skin Adhesive Design

Over the past decade, skin adhesives have undergone substantial advances in interfacial chemistry, mechanical performance, and multifunctional bioactivity. Progress in covalent and supramolecular bonding strategies, bioinspired polyphenol chemistry, and stimuli‐responsive debonding systems has significantly expanded the functional capabilities of adhesive biomaterials for wound closure and tissue repair. However, successful clinical translation depends on more than achieving strong adhesion or mechanical stability. Skin adhesives must operate within the highly dynamic and biologically complex environment of wounded tissue, where interactions with immune cells, ECM components, vascular networks, and microbial populations collectively determine healing outcomes.

Consequently, next‐generation hydrogel adhesives must be engineered not merely as mechanical sealants but as bioactive interfaces capable of actively regulating the wound microenvironment. Achieving this objective requires careful balancing of multiple design parameters, including cytocompatibility, immunomodulatory capacity, angiogenic support, and antibacterial functionality. In the following sections, we discuss the key biological challenges that remain in the development of clinically effective skin adhesives. Furthermore, we discuss various application scenarios and translational considerations for next‐generation skin adhesives.

5.1. Cytocompatibility and Hemocompatibility

Cytocompatibility represents one of the most fundamental requirements for skin adhesives intended for biomedical applications. However, biological evaluation of adhesive materials often relies primarily on short‐term cell viability assays, which may not fully capture the long‐term interactions between adhesive materials and regenerating tissues. Because hydrogel adhesives frequently remain in contact with wounded tissue for several days or weeks, comprehensive evaluation should include assessments of long‐term cell proliferation, migration, and maintenance of cellular phenotype.

While reactive functional groups in adhesive enable efficient covalent anchoring to tissue proteins, excessive chemical reactivity may also lead to off‐target reactions with membrane proteins or intracellular biomolecules. For instance, high aldehyde concentrations can induce protein crosslinking and membrane damage, whereas overoxidized catechol species may generate reactive quinones capable of promoting oxidative stress [82, 83]. Therefore, careful control of reaction kinetics and functional group density is necessary to achieve rapid surface bonding while minimizing cytotoxic side effects.

Dynamic covalent systems, such as imine‐ and boronate‐based networks, can partly overcome this limitation by allowing reversible bond formation and reducing the buildup of permanently reactive chemical species. Nevertheless, their equilibrium behavior is strongly influenced by local pH and hydration levels [84, 85]. Because chronic wounds often present an alkaline pH (≈7.5–8.5) and increased protease activity, these conditions may destabilize the dynamic bonds and weaken adhesive stability. Therefore, standard in vitro cytocompatibility testing should be expanded to include wound‐mimicking microenvironmental models.

Hemocompatibility is another critical consideration for adhesives applied to bleeding wounds or highly vascularized tissues. Interactions between adhesive materials and blood components can influence platelet activation, coagulation pathways, and thrombus formation. Polyphenol‐containing hydrogels, for example, often promote platelet aggregation through protein adsorption and surface activation, which may accelerate hemostasis [86, 87]. However, excessive platelet activation could potentially increase the risk of thrombogenic complications. Consequently, optimizing hemocompatibility requires balancing pro‐hemostatic functionality with the need to avoid uncontrolled clot formation.

5.2. Immunomodulation and Inflammatory Regulation

Beyond basic cytocompatibility, the immune response plays a decisive role in determining the long‐term success of adhesive biomaterials. Following implantation or application to wounded tissue, adhesives inevitably interact with innate immune cells, including neutrophils, macrophages, and dendritic cells. While an appropriate inflammatory response is necessary for pathogen clearance and tissue repair, excessive or prolonged inflammation may delay healing and promote fibrosis.

Recent studies further indicate that immunomodulation in hydrogel wound systems can be dynamically programmed rather than treated as a static anti‐inflammatory function. For example, Qian et al. reported a photo‐enhanced glycyrrhizic acid–based hybrid hydrogel with intrinsic immunoregulatory activity capable of modulating macrophage responses without the need for exogenous cytokine delivery [88]. Zhou et al. developed a spatiotemporally controlled on–off immunomodulatory hydrogel targeting the NLRP3 inflammasome in biofilm‐infected diabetic wounds, demonstrating that inflammatory signaling can be regulated in a temporally staged manner rather than uniformly suppressed [89]. Xu et al. showed that a TA/ferric ion–decorated hydrogel promoted macrophage polarization toward the M2 phenotype via PI3K/Akt signaling while concurrently enhancing angiogenesis in diabetic wounds [62]. More recently, Wang et al. reported an injectable immunoregulatory hydrogel that sequentially guided macrophage phenotypic transitions from M0 to M1 and subsequently to M2, thereby reconciling early antibacterial defense with later regenerative repair [90]. Collectively, these findings suggest that next‐generation skin adhesives may benefit from temporally orchestrated immunoregulation rather than simple attenuation of inflammation.

5.3. Angiogenesis and Matrix Remodeling

Successful wound healing requires coordinated angiogenesis to restore oxygen and nutrient supply to regenerating tissue and to support the formation of granulation tissue [91]. Veith et al. further emphasized that impaired neovascularization is a central feature of chronic and nonhealing wounds, and that simple delivery of proangiogenic factors alone often shows limited durability or efficacy in clinically relevant wound environments [92]. Accordingly, hydrogel‐based skin adhesives should not be viewed only as passive carriers for VEGF, FGF, or other bioactive signals, but rather as provisional microenvironments that regulate how endothelial cells invade, assemble, and stabilize nascent vascular networks over time. In this context, the ability of an adhesive to sustain moist wound coverage, permit oxygen transport, and retain bioactive molecules in a controlled manner remains important, but these biochemical functions must be considered together with the mechanical properties that govern cell–matrix interaction.

Chaudhuri et al. demonstrated that matrix stress relaxation is a key regulator of cell spreading, proliferation, and matrix remodeling, showing that rapidly relaxing hydrogels with relaxation times on the order of approximately 1 min are markedly more permissive to cell‐mediated remodeling than more elastic or slowly relaxing matrices [93]. Shayan et al. further showed, in endothelial cell‐laden hydrogels with independently tunable stiffness and viscoelasticity, that fast‐relaxing and low‐stiffness matrices in the 500–3300 Pa range promoted greater endothelial spreading, wider vascular sprouts, and higher capillary density in vivo than slow‐relaxing counterparts [94]. Wei et al. similarly reported that matrix dynamics and plasticity regulate endothelial outgrowth by modulating integrin clustering, focal adhesion kinase signaling, and the balance between migration‐driven invasion and vessel stability [59]. Together, these findings suggest that angiogenesis is favored not simply by soft matrices, but by matrices that are both mechanically permissive and dynamically alterable.

Achterberg et al. reported that the elastic modulus of human dermis at the cell‐perception scale lies approximately within the 0.1–10 kPa range, indicating that skin adhesives intended to support regeneration should ideally maintain an interfacial modulus within a similarly soft, dermis‐relevant regime rather than drift toward pathologically stiff conditions [95]. He et al. showed that increasing substrate stiffness from 2 to 50 kPa, used to mimic normal versus fibrotic skin, promotes dermal fibroblast activation, enhanced proline metabolism, and collagen‐producing profibrotic behavior [96]. Thus, from a quantitative design perspective, a practical target for regenerative hydrogel adhesives would be a low‐kPa interfacial modulus, often on the order of a few kPa depending on wound site and healing stage, combined with relatively rapid stress relaxation on the scale of a few minutes. Such a design window may help preserve sufficient mechanical support for traction‐mediated matrix assembly while avoiding sustained myofibroblast activation and fibrosis. Overall, future skin adhesives should be engineered to balance biochemical proangiogenic signaling with dermis‐mimetic stiffness and fast viscoelastic relaxation, so that vascularization and matrix remodeling can proceed constructively rather than transition toward scar‐dominant healing.

5.4. Antibacterial Functionality

Preventing microbial infection is a major priority in wound management, as bacterial colonization can significantly impair healing and lead to chronic inflammation or systemic infection. Hydrogel‐based adhesives designed for wound closure must therefore incorporate strategies capable of suppressing bacterial growth while preserving compatibility with host tissues. One widely used approach involves incorporation of antimicrobial metal ions such as silver (Ag⁺), zinc (Zn^{2 +}), or copper (Cu^{2 +}). These ions exhibit broad‐spectrum antibacterial activity through mechanisms including disruption of bacterial membranes, protein denaturation, and interference with intracellular metabolic pathways [97]. Among these, silver‐based systems are particularly prevalent in hydrogel dressings because of their strong efficacy against both Gram‐positive and Gram‐negative bacteria [98]. However, achieving sustained antibacterial activity while maintaining cytocompatibility remains challenging. Excessive metal‐ion release may induce cytotoxic effects in keratinocytes or fibroblasts, whereas insufficient release may fail to effectively suppress bacterial proliferation. To address these challenges, recent studies have explored controlled‐release strategies such as nanoparticle encapsulation or coordination‐based binding within polymer networks [99].

In addition to metal ions, antimicrobial polymers such as chitosan have been incorporated into hydrogel adhesives. The cationic nature of chitosan allows electrostatic interactions with negatively charged bacterial membranes, resulting in membrane disruption and bacterial cell death [100, 101]. Nevertheless, antibacterial performance must be carefully evaluated under physiologically relevant conditions, as protein‐rich wound exudate can attenuate antimicrobial activity by binding or neutralizing active agents.

Ultimately, the design of antibacterial skin adhesives requires a careful balance between bactericidal potency and host‐cell compatibility. Excessive antimicrobial loading may impair tissue regeneration and induce local cytotoxicity, whereas insufficient antibacterial activity may permit persistent infection and chronic inflammation. Therefore, rational material design should aim to achieve sustained, localized antimicrobial activity that suppresses microbial colonization while preserving the biological processes essential for tissue repair.

5.5. Application Scenarios and Translational Considerations

From a translational perspective, next‐generation skin adhesives are not designed for a single universal wound type but rather for a broad spectrum of clinical scenarios with distinct mechanical and biological requirements. Representative indications include acute lacerations, surgical incisions, donor‐site wounds, burn injuries, highly mobile skin regions, and chronic wounds in which conventional sutures, staples, or passive dressings may be suboptimal. In these contexts, the function of the adhesive extends beyond simple wound‐edge fixation to encompass fluid sealing, hemostasis, barrier protection against contamination, maintenance of a moist healing environment, atraumatic removability, and active modulation of the wound microenvironment.

Different structural formats of skin adhesives correspond to different application methods and clinical uses. Preformed patches, tapes, and film‐type dressings are particularly suitable for superficial wounds and surgical incisions, as they provide immediate coverage, mechanical support, and barrier protection. Injectable or in situ gelling systems are more appropriate for irregular or deep wound sites, where conformal filling and close contact with the tissue are required before gelation. Sprayable, or printable systems can further broaden clinical applications by enabling rapid treatment of large wound areas or customized deposition on complex tissue geometries. Regardless of format, the mechanism of action generally involves conformal wet adhesion, interfacial bonding with tissue, and stabilization of the hydrogel network, often combined with additional functions such as antibacterial effects, immune modulation, angiogenesis support, or controlled debonding.

These differences suggest that the design of skin adhesives should be guided by the specific clinical application rather than adhesion strength alone. For example, adhesives for acute wounds may focus on rapid fixation and mechanical strength, while those for fragile or chronic wounds should prioritize atraumatic removal, immune compatibility, tolerance to exudate, and regenerative functionality. Therefore, future development is expected to move toward indication‐specific systems in which material chemistry, mechanical properties, degradation profiles, and biological functions are tailored to the requirements of each wound type.

6. Conclusions

Hydrogel‐based skin adhesives have emerged as a versatile class of biomaterials capable of simultaneously providing mechanical fixation, tissue sealing, and biofunctional interfaces for wound management. As discussed throughout this review, significant progress has been achieved in the rational design of hydrogel adhesives by leveraging diverse interfacial chemistries, including covalent bonding, supramolecular interactions, and polyphenol‐mediated adhesion mechanisms inspired by biological systems. Advances in polymer network engineering have further enabled the development of mechanically robust hydrogels that maintain conformal contact with soft and dynamically moving skin tissues. In parallel, the integration of stimuli‐responsive and debonding strategies has addressed one of the longstanding limitations of strong adhesives, which is the ability to achieve atraumatic removal, thereby enabling the design of biointerfaces that combine strong adhesion with controllable detachment. Collectively, these developments highlight how molecular‐level chemical design, network mechanics, and interfacial interactions can be synergistically engineered to improve the performance of next‐generation skin adhesive materials.

Despite these advances, several challenges remain before skin adhesives can achieve widespread clinical translation. In particular, the biological complexity of the wound microenvironment necessitates adhesive systems that go beyond mechanical sealing to actively support tissue regeneration. Future research should therefore focus on integrating cytocompatibility, immunomodulatory capability, angiogenic support, and antibacterial functionality within a single multifunctional material platform. Achieving such integration will require precise control over interfacial reaction kinetics, hydrogel mechanical properties, and the spatiotemporal presentation of bioactive signals. Emerging design strategies, including adaptive hydrogels with tunable viscoelasticity, bioactive interfaces that regulate immune responses, and dynamically responsive networks capable of evolving alongside tissue healing, hold considerable promise. Continued progress at the intersection of polymer chemistry, biointerface science, and wound biology will ultimately enable the development of clinically effective skin adhesives that not only close wounds but also guide the complex processes of tissue repair and regeneration.

Author Contributions

Eunyeong Moon: conceptualization, writing – original draft. Jin‐Ju Kim: conceptualization, writing – original draft, writing – review and editing. Won‐Woo Cho: conceptualization, funding acquisition, writing – original draft, writing – review and editing. Mehret Tesfaye Nake: conceptualization, writing – original draft.

Funding

Regional Innovation System & Education (RISE) program through the Gangwon RISE Center, funded by the Ministry of Education (MOE) and the Gangwon State (G.S.), Republic of Korea (2025‐RISE‐10‐006).

Conflicts of Interest

The authors declare no conflicts of interest

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.