Design principles of adhesive hydrogels for biomedical application

Abstract

Adhesive hydrogels have great potential for application in the biomedical field. Currently, for clinical applications, adhesive hydrogels need to have the following characteristics: good biocompatibility, strong tissue adhesion, highly adaptable tissue specificity and multifunctionality, which are also included in the design principles of current adhesive hydrogels. When targeting different types of diseases in different tissues, adhesive hydrogels need different degrees of attention to these four key properties according to the characteristics of the pathological microenvironment of the tissue. In this regard, this article reviews the clinical disease characteristics of different tissues, and correspondingly introduces the considerations in the design process of adhesive hydrogels for this type of disease and application, in order to deepen the understanding of the design principles of adhesive hydrogels in biomedical applications.

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Wider impact

Nowadays, owing to the great potential advantages of adhesive hydrogels in the application of tissue engineering, the development of adhesive hydrogels has gained significant interest. However, current reviews mainly discuss and introduce the composition basis, adhesion mechanisms and main challenges associated with adhesive hydrogels. They lack detailed design guidance for adhesive hydrogels in the application to different tissues and pathological conditions. Herein, we started with the design principle of adhesive hydrogels, where the core component factors of adhesive hydrogels were emphasized. Then, the clinical disease characteristics of different tissues was analyzed, and the correspondingly introduces the considerations in the design process of adhesive hydrogels for this type of disease and application was introduced to deepen the understanding of the design principles of adhesive hydrogels in biomedical applications. We believe that, under the instruction of our design principles, the future adhesive hydrogels will move more towards personalized and precise treatment to satisfy the repair requests of different tissue injuries under different pathological conditions.

1. Introduction

Annually, tens of millions of people suffer from a variety of tissue wounds. The current mainstream treatment method for tissue wounds caused by trauma events and surgical treatment is the closure of tissue wounds by surgical sutures and staples to promote tissue repair and regeneration.¹ However, this wound closure method has many disadvantages, such as causing additional mechanical damage to the tissues and being unable to effectively prevent the penetration of tissue fluid; in some application scenarios, postoperative suture removal and other operations might easily cause postoperative complications such as microbial infections.^2,3 Therefore, using surgical sutures and staples to force tissue wound closure through mechanical loading is not an ideal treatment method.

In contrast, currently developed adhesive hydrogels are excellent substitutes for sutures and staples in wound closure owing to their various advantages. For instance, compared with the wound closure mechanism of sutures and staples, which proceeds through mechanical loading and needs to create extra tissue defects, adhesive hydrogels can perform their functions through mild chemical and physical interactions with the injured tissues without causing new damage.⁴ Besides, dissimilar to the sutures and staples, which may result in fluid leakage, adhesive hydrogels can form a dense structure on the tissue surface that could effectively prevent fluid leakage.⁵ Further, compared with the complex surgical operations required for surgical sutures and staples in clinical applications, the wound closure method of adhesion hydrogels is simple and easy to implement. Furthermore, the additional functions of adhesive hydrogels, such as anti-bacterial activity and wound healing promotion, could greatly overcome the shortcomings of sutures and staples. Thus, adhesive hydrogels are becoming attractive candidates in the field of wound closure.^6,7

Many current adhesive hydrogels have been successfully commercialized and gradually applied in clinical treatment. Although these adhesive hydrogels are highly useful in surgery, they still have many intrinsic shortcomings that seriously limit their applications and treatment effects (Table 1). For example, the poor adhesion of fibrin glue, which has great biocompatibility, restricts its wound closure effect on surgical applications that require high adhesion.^8–10 Besides, the well-performing cyanoacrylate adhesive has a limited wound closure effect due to its poor biocompatibility and unsatisfactory adhesion force on wet tissue surfaces.^11–13 In addition to the inherent disadvantages of these commercial hydrogels, their poor physicochemical performance in actual clinical applications is attributed to the lack of a holistic understanding of tissue characteristics and the hydrated microenvironment, resulting in efficacy outcomes in clinical applications that fall short of those measured in vitro. Briefly, special components of tissue and diverse molecules in the hydrated microenvironment have a distinct effect on adhesive hydrogels, resulting in significantly diminished adhesion. For instance, the unique inorganic compositions in bone tissue may hinder robust adhesion between fibrin glue and bone owing to the lack of amino groups. In a hydrated microenvironment, the abundant water molecules inside would significantly disturb the adhesion formation of cyanoacrylate, which relies on the water-initiated anionic polymerization of the corresponding monomers. Due to the aforementioned tissue specificity, commercial adhesive hydrogels have a great performance gap in clinical treatment, which typically restricts their use to adjunctive or emergency roles. For these reasons, current commercial hydrogel adhesives are often unsatisfactory in actual clinical applications. To this end, it is necessary to develop adhesive hydrogels with better performance to meet the needs of clinical treatment.

Table 1 Advantages, disadvantages and clinical application scope of commercial adhesive hydrogels

Adhesive hydrogels	Advantages	Disadvantages	Clinical application scope
Hint: despite the seemingly broad clinical application prospects of these commercial adhesive hydrogels, their physicochemical performance in actual clinical applications is significantly inferior to the results measured in vitro owing to the organism characteristics of tissue specificity and pathological microenvironment. Consequently, in practical clinical settings, they are typically utilized as adjunctive methods for surgical suture assistance in wound closure or are restricted to emergency situations only.
Fibrin Glue^8–10	Excellent biocompatibility and biodegradable	Poor mechanics and adhesion	Plastic surgery, skin grafting
	Generally, no inflammatory occurrence	Potential risk of disease transmission	Control of bleeding during otolaryngology and head and neck surgery
	Excellent transmittance	Relative high cost	Closed pneumothorax
Cyanoacrylate adhesives^11–13	Strong adhesion	Poor biocompatibility	Thoracic surgery
	Fast polymerization	Potential cytotoxicity during degradation	Gastrointestinal surgery
	Utilization convenience	Low transmittance	Neurosurgery
		Poor adhesion in the presence of body fluids	Cardiovascular surgery
		Intense exothermic reaction during polymerization	Ophthalmology
			Epidermal wound healing
PEG-based adhesives^26–28	Excellent biocompatibility	Strong swelling	Surgical wound closure and hemostasis
	Low immunogenicity	Unstable mechanics and adhesion, especially in the moisture tissue surface	Dural repair and cerebrospinal fluid leak occlusion
	In situ gelation	Fast degradation may occur in a high-temperature environment	Postoperative adhesion prevention
	Controllable synthesis and degradation	Multistep synthesis	Drug delivery and controlled-release systems
Oxidized regenerated Cellulose^149–151	Intrinsic antimicrobial property	Poor coagulation performance in the hyperhemorrhagic environment	Orthopedics
	Excellent biocompatibility and absorbability		General surgery
	Utilization convenience		Control of mild to moderate hemorrhage
			Reduction of postoperative adhesion
GRF Glue (gelatin-Resorcinol-Formaldehyde)^29–31	Great gelation strength and adhesion	Poor biocompatibility and potential cytotoxicity owing to the presence of formaldehyde	Special applications of hemostasis in acute aortic dissection
Albumin-based adhesive^1,152,153	Contain biological components	High cost	The first domestically approved bioadhesive for the closure of pulmonary parenchymal air leaks
	Great biosafety

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Herein, we provide a comprehensive review of adhesive hydrogels. We started with the design principle of adhesive hydrogels, which emphasizes the core component factors of adhesive hydrogels. Then, by analyzing the clinical disease characteristics of different tissues and correspondingly introducing considerations in the design process of adhesive hydrogels for this type of disease and application, an in-depth understanding of the design principles of adhesive hydrogels in biomedical applications could be achieved, thus paving the way for the development of the design of future adhesive hydrogels.

2. Design principles for adhesive hydrogel

Adhesive hydrogels, which can interact with substrate interfaces, have great application potential in the biomedical field. The ideal adhesive hydrogel should have the following characteristics in clinical application: good biocompatibility, strong tissue adhesion, highly matched tissue specificity and multifunctionality that can meet biomedical application requirements (Fig. 1). These properties are important principles that must be followed for the application of tissue adhesives in the biomedical field. The concept of these principles is elaborated in detail later to illustrate their importance in adhesive hydrogels during biomedical applications.

Fig. 1 Design principles of adhesive hydrogels. Adhesive hydrogels need to have good biocompatibility, tissue adhesion, tissue-specific adaptability, and multifunctionality. The biocompatibility principle requires adhesive hydrogels to have good biological and material compatibility during their application. The tissue adhesion principle requires that the cross-linking and adhesion strategies used in adhesive hydrogels form stable tissue adhesion in the damaged pathological tissue microenvironment. The principle of tissue specificity requires adhesive hydrogels to be able to adapt to the characteristics of different tissues, such as the bone, gastrointestinal tract, muscles, nerves and cornea, while forming stable adhesion to assist the process of tissue repair. The multifunctional principle requires adhesive hydrogels to exhibit functions such as hemostasis, promotion of tissue repair, antibacterial activity, reactive oxygen species (ROS) scavenging and inflammatory regulation in the microenvironment to assist in the repair of tissue defects.

2.1 Biocompatibility

Biocompatibility refers to the ability of living tissues to react to inactive materials, generally referring to the compatibility between biomaterials and biological tissues.¹⁴ After biomaterials are applied to the human body, they have an impact on the specific biological tissue microenvironment, and the biological tissue also has similar effects on the biomaterial. The two continue to influence each other throughout the process until the biomaterials disappear. Generally, biocompatibility can be divided into two parts: biological and material reactions. Biological reaction includes blood reaction, immune reaction and tissue reaction; material reaction mainly manifests in changes in the physical and chemical properties of the material, such as the mechanical decrease caused by swelling and degradation.¹⁵ Of these two parts, the most important is the biological reaction, that is, biomaterials should not cause any adverse reactions, which may lead to further aggravation of the symptoms or the occurrence of other diseases in biological tissues during the entire process of biomedical application, such as acute tissue inflammation, secondary tissue damage and infection. For the material reaction, it is important to note that the influence of the tissue microenvironment on the material properties does not result in the execution of the normal functions of biomaterials. For instance, an acidic tissue microenvironment caused by microbial infection should not accelerate the collapse of adhesive hydrogels or cause adhesion failure.

2.2 Tissue adhesion

Adhesive performance, that is, the ability of the material to form linkages with the substrate through interfacial interactions, is a hallmark characteristic of adhesive hydrogels. Generally, application scenarios in the biomedical field require that adhesive hydrogels be able to establish stable connections with biological tissues in the tissue microenvironment to achieve clinical medical purposes. The internal factors that affect the adhesion ability of adhesive hydrogels can be divided into two parts: cohesion and adhesion (Table 2).^16,17 Cohesion, the magnitude of the interaction force inside the object, reflects the mechanical properties of the adhesive hydrogels. Adhesion, which is the interaction force between the interfaces of substances, reflects the adhesive strength and properties of adhesive hydrogels and biological tissue interfaces. The collapse of either side causes the adhesion failure of adhesive hydrogels. Among them, the mechanical properties of hydrogels can be classified by the type of their cross-linked network composition (i.e., covalent cross-linked network or non-covalent cross-linked network), while the interfacial connection strength can be distinguished from the level of interaction (i.e., molecular interaction or physical interlocking).¹⁸ In detail, for cohesion, the covalent cross-linking network significantly enhances the mechanical strength of hydrogels, while the non-covalent cross-linked network improves the energy dissipation ability.¹⁹ For adhesion, molecular interaction mainly involves the formation of interactions between molecules, while physical interlocking involves the penetration and entanglement of polymers between adhesive hydrogels and the biological tissue interface.⁴ In addition to the above-mentioned internal factors, many external factors also affect the adhesion ability of adhesive hydrogels. Among them, a particularly important factor is the tissue microenvironment during trauma. Furthermore, in different types of diseases, the pathological microenvironment is significantly different, which remarkably affects the adhesion of the adhesive hydrogels and limits their application.²⁰ For instance, the pathological microenvironment of bleeding wounds contains many blood-related components, while microbially infected wounds are mainly characterized by an acidic microenvironment. Thus, the tissue pathological microenvironment in specific diseases is a problem that requires special attention for biomedical applications.

Table 2 Tissue adhesion composition and its corresponding contribution towards tissue adhesion

Tissue adhesion composition	Constituent elements	Detail ingredients	Contribution toward tissue adhesion
Hint: in addition to the above factors, many factors in the tissue microenvironment also affect the tissue adhesion of adhesive hydrogels, such as water molecules, salt ions and enzymes, in the microenvironment.
Cohesion	Covalent interaction	Free radical chain polymerization^11,39,50,61,81	Core framework of adhesive hydrogels.
		Click chemistry^116	Provide strong mechanical support to meet the mechanical properties of tissue repair for adhesive hydrogels.
		Oxidation of phenolic groups^46,86,109
	Noncovalent interaction	Dynamic covalent cross-linking^33,38,41	The constituent that can be regenerated after stress damage.
		Guest–Host interactions^154,155	Impart strong energy dissipation capabilities to adhesive hydrogels to significantly improve their toughness and fatigue resistance.
		Hydrogen bonding interactions^37,44,103,111
		Metal−ligand coordination^71,97,156
		Electrostatic interactions^17,63
		Hydrophobic interactions^23,35,89,93
Adhesion	Molecular interaction	Anime-based covalent interaction^102,106	Adhesion performance varies depending on the type of interaction.
		Thiol-base covalent interaction^104	The molecular interaction could be divided into two types: the covalent interaction and the noncovalent interaction.
		Dynamic covalent cross-linking^43,49,52,64,65	Covalent interactions provide strong adhesion between the adhesion hydrogel and biological tissues.
		Hydrogen bonding interactions^3,48,69,84,92	Noncovalent interactions provide long-lasting adhesion of the adhesion hydrogel due to its repeated fracture and regeneration properties.
		Electrostatic interactions^2,80
		Hydrophobic interactions^157
	Physical interlocking	Polymer interlocking^8,16,96	Compared with molecular interactions, it can provide more powerful and significant adhesion properties.
		Mechanical interlocking^158	Its formation requires the participation and assistance of molecular interactions.
		Bioinspired strategy^159–161

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2.3 Tissue specificity

Tissues in different parts of the body are composed of different cell groups and different extracellular matrices, which means that the anatomical structures and physiological functions of different biological tissues are very different (Table 3).⁶ For example, in bone tissue, the extracellular matrix of bone cells contains not only organic substances, such as collagen, but also large amounts of inorganic components, which allows bone tissue to serve as a scaffold for the body, supporting body weight and assisting movement.²¹ The composition of the gastrointestinal system is more complex, from the acidic environment of the stomach to the alkaline environment of the intestines, plus the peristalsis of the intestines, which enables it to perform better digestive functions.²² Another example is the cornea, which contains a large amount of collagen. The unique arrangement of collagen in the cornea gives the cornea good optical properties, thereby better assisting the formation of the eye's visual function.²³ The tissue difference in anatomical construction and physiological function is the basis for adhesive hydrogel design and leads to different application requirements for adhesive hydrogels. On the one hand, adhesive hydrogels need to be individually designed according to the anatomical structure of the application site, thus maximizing the performance of the adhesive hydrogel; on the other hand, the design of adhesive hydrogels must also consider the physiological functions of the biological tissues at the application site, that is, the adhesive hydrogel should assist the functional execution of the tissue as much as possible during the application process or have no effect on the physiological function of the biological tissue.

Table 3 Tissue specificity of diverse tissues and their corresponding function requirements for adhesive hydrogels

Tissue	Tissue specificity	Special functions required
Bone	Composed of inorganic substances (hydroxyapatite) and organic components (Type I collagen).	Strong cohesion to withstand mechanical loads.
	Vital for the mechanical support of the human body and the normal progress of life activities.	Excellent adhesion towards the organic and inorganic components for eliminating potential risks related to biocompatibility.
Muscle (including heart and large intestine)	Their contraction and dilation are crucial to maintain life activities in humans.	For skeletal muscle, great toughness for fatigue resistance is necessary.
	Could be divided into three types: skeletal muscle, smooth muscle and cardiac muscle.	For cardiac muscle, in addition to good anti-fatigue performance, excellent biological activities for promoting myocardial repair are also required.
Gastrointestinal (stomach and intestinal)	Complicated microenvironment: the acidic pH environment of the stomach, the alkaline pH environment of the intestine, coupled with the peristalsis of the gastrointestinal tract and the rich and diverse microbial flora.	Great resistance to the acidic environment in the stomach and the alkaline environment in the intestine.
		Great adhesion to prevent fluid leakage
		Excellent mechanical toughness to withstand the peristalsis behavior.
		Maintaining microenvironment homeostasis of intestinal flora.
Nerve (brain and spinal cord)	Responsible for the organization and transmission of signals, contact, regulating and controlling the functional activities of each organ.	Excellent conductivity to support the signal transfer function of neural tissue during the repair process.
		Providing specific ECM to guide the oriented arrangement and promote the growth of regenerated neurons.
Cornea	Has a refractive effect and is an important component of the human visual function.	Good transparency to maintain the great optical properties of the cornea.
	Composed of avascular collagen-rich ECM.	Strong adhesion to overcome the multiple influences from the tear film.
	Covered by tear film, which contains a lipid layer, a water layer, and a mucin layer.	Providing a special regenerative environment to promote tissue repair and suppress the neovascular and scars.
Liver	Responsible for the metabolic functions. (Participates in vitamin metabolism, hormone metabolism, etc., and secretes bile and produces coagulation factors.)	Strong wet adhesion properties to overcome the interference of the moisture microenvironment on tissue adhesion.
	High moisture content with extremely wet tissue surface.	Powerful procoagulant properties to promote rapid coagulation of blood in the wound area of the liver to achieve the purpose of stopping bleeding.
Lung	The important composition of the respiratory system, as the main place to respond to gas exchange between the body and the outside world.	Good mechanical properties and fatigue resistance to resist the gas pressure that changes frequently with the respiration frequency.
	Frequent changes in air pressure occur as the breathing frequency changes (such as the difference between the resting state and the breathing frequency during exercise).	Anti-adhesion properties are necessary to avoid adhesion between the lung and the chest cavity.

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2.4 Multifunctionality

In addition to possessing the above-mentioned biocompatibility, adhesion and tissue specificity, adhesive hydrogels are also expected to have certain functionality to better achieve the purpose of biomedical applications, such as wound closure, hemostasis, and promotion of wound healing, which are foundational functions of tissue repair.¹ Besides, adhesive hydrogels are often expected to have specific antibacterial, anti-inflammatory and vascularization-related properties that could effectively assist the repair of damaged tissues and support the regeneration of native tissue. These properties are usually imparted by encapsulating adhesive hydrogels with special drugs or functionalizing hydrogels with specific chemical structures.^24,25 Additionally, owing to tissue specificity, different tissue regenerations have different requirements for the properties and functions of adhesive hydrogels, as shown in Table 3. For instance, considering the specific composition and function of bone tissue, adhesive hydrogels are required to have strong cohesion to withstand mechanical loads and form excellent adhesion with the organic components as well as the inorganic part to further eliminate potential risks related to biocompatibility. For the complicated microenvironment of gastric tissue, adhesive hydrogels should have the properties of great resistance to the acidic environment in the stomach and the alkaline environment in the intestine, good adhesion to prevent fluid leakage, excellent mechanical toughness to withstand the peristalsis behavior, and maintain microenvironment homeostasis of intestinal flora. It is obvious that different tissues under different pathological conditions have different needs for the function of adhesive hydrogels. Therefore, the multifunctional design of adhesive hydrogels is also an important principle for their application in the biomedical field.

For the concept mentioned above, all of the principles are crucial for the design of adhesive hydrogels. However, existing adhesive hydrogels, including commercial adhesive hydrogels, always focus excessively on the requirement of the tissue for a specific performance, neglecting the necessity of other principles and resulting in imbalanced characteristics of these hydrogels. Take the commercial adhesive hydrogels as an example (Table 1). Despite the excellent biocompatibility and low immunogenicity of PEG-based adhesives, their excessive swelling behaviors and the resultant unstable mechanics and adhesion hugely restrict their clinical adhesive applications, making them solely suitable for the prevention of fluid leakage in post-surgical suturing.^26–28 For GRF glue, although its excellent adhesive performance greatly ameliorates the shortcomings of PEG-based adhesives, the introduction of formaldehyde raises another concern about the potential cytotoxicity and poor biocompatibility, leading to the significant limitation of its application, which is permissible only in an emergency situation.^29–31 Besides, all commercial adhesive hydrogels share a common drawback, namely, due to the lack of understanding of characteristics such as tissue specificity and the tissue's hydrated microenvironment, their performance in clinical applications significantly falls short of the actual values measured in vitro. Such a lack of a holistic understanding of design principles would ultimately lead to extremely limited therapeutic efficacy in tissue repair. The following section discusses the above four principles of application of adhesive hydrogels in biomedical applications in detail based on the application scenarios to illustrate their importance and their instruction towards tissue regeneration. Then, in light of the drawbacks of the current research, a clearer, forward-looking roadmap will be provided to guide the future development of adhesive hydrogels.

3. Personalized design of adhesive hydrogel for wound healing under different pathological conditions

Wound healing refers to the healing process after the body is subjected to external forces, and the skin and other tissues are severed or damaged. It includes the regeneration of various tissues and the complex combination of granulation tissue proliferation and scar tissue formation, showing the synergistic effect of various processes. The various phases of wound healing are the hemostasis phase, tissue inflammation phase, cell proliferation phase, and tissue remodeling phase.³² However, during the hemostasis phase and inflammatory phase, the wound healing process is usually hindered due to bleeding, infection and other reasons, which ultimately affects the healing of the tissue wound.

The application of adhesive hydrogels to wounds can effectively stop wound bleeding and prevent microbial infection, thereby assisting in wound healing and regeneration. Simultaneously, the application also necessitates the adhesion principle which dictates that the adhesive hydrogel must sustainably and stably perform its core function, adhesion, within the tissue microenvironment caused by complex factors. Two internal factors, bulk cohesion and interfacial adhesion, affect the formation of stable adhesion of adhesive hydrogels.¹⁷ In addition to the above factors, external factors that affect the adhesion performance of adhesive hydrogels include the pathological microenvironment of tissue damage, as shown in Fig. 2 (such as large amounts of blood in the defect site during bleeding and the acidic microenvironment of the defect site during microbial infection). The following section discusses the factors to be considered during the design process of adhesive hydrogels intended for wound healing assistance; the necessity to consider the microenvironmental characteristics of various types of tissue injuries is also emphasized to enable adhesive hydrogels to exhibit stable adhesion functions.

Fig. 2 Microenvironmental pathology in different types of wound healing. Bleeding wounds: the presence of large amounts of water molecules, proteins and ions inside blood affects the stability and adhesion properties of adhesive hydrogels. Microbial-infected wounds: the presence of bacteria (or fungi) makes the microenvironment acidic and further aggravates tissue inflammation. Diabetic wounds: the presence of chronic inflammation results in difficulty in healing and the possibility of severe scarring.

3.1 Bleeding wounds

Traumatic bleeding is a kind of wound defect in which blood flows from the wound to the outside of the body, in which there are large amounts of water molecules and blood-related substances.³³ In such an application context, the performance of the adhesive function of the adhesive hydrogel is affected by many factors. For water molecules, on the one hand, they reduce the cross-linking density of the hydrogel through swelling, hydrolysis and other actions, thereby weakening its mechanical properties. On the other hand, they also decrease the adhesion of the hydrogel by interfering with the formation of the interaction between the adhesive hydrogel and the surface of the biological tissue (such as affecting the formation of chemical bonds and hydrogen bonds between the two interfaces, and preventing the physical interlocking caused by the penetration and entanglement of the hydrogel precursors), thereby leading to the occurrence of adhesion failure.³⁴ In order to overcome the huge challenges posed by water at tissue interfaces, various strategies have been developed and applied to ensure the sustained and stable adhesion of adhesive hydrogels. Regarding the effect of interfacial water on the cohesion of adhesive hydrogels, An's research work provided a very representative example, that is, by introducing hydrophobic regions into the interior of the adhesive hydrogel to limit the free diffusion of water molecules into the hydrogel network, which further limited the swelling and hydrolysis behavior of interfacial water, thus preventing the mechanical properties of the hydrogel from deteriorating and affecting its adhesion stability.³⁵ For the effect of tissue interface water on the adhesion between adhesive hydrogel and the surface of biological tissue, there are many case strategies available for reference. Zhang and his team proposed a simple and effective strategy by combining the precursor of adhesive hydrogel with a highly absorbent microsphere powder. When applied to the wound of the bleeding tissue, the microsphere powder quickly absorbed the interfacial blood and removed the interfacial water from the adhesive hydrogel. Subsequently, the hydrogel precursor was cross-linked and established a stable connection with the tissue interface to form a strong adhesive hydrogel.³⁶ In addition to the above-mentioned strategy of removing water from the tissue interface, Yang et al. also developed another unique strategy. They promoted the penetration of the adhesion-forming components of the adhesive hydrogel in the biological tissue, thereby increasing the interaction sites and strength between the adhesive hydrogel and the biological tissue, so as to improve the adhesion performance of the hydrogel and achieve the purpose of long-term adhesion.³⁷ Through the combined use of the above-mentioned strategies, the strong cohesion and adhesion of the adhesive hydrogel at the tissue wound site can be ensured in the presence of a hydration layer at the tissue interface, thereby meeting the adhesion principles requirements of the adhesive hydrogel in clinical application scenarios, such as tissue wounds.

3.2 Microbiologically infected wounds

In addition to the influence of tissue interface water on the adhesive properties of adhesive hydrogels, other factors in the tissue microenvironment also affect their adhesion. Taking bacterially infected tissue wounds as an example, after bacterial infection, the tissue microenvironment at the defect site becomes acidic, oxidative stress and inflammatory response intensify, leading to the complexity of the microenvironment at the wound site.^38,39 In such a tissue microenvironment, while the adhesive hydrogel exerts its adhesive function, it also needs to consider the impact of the acidic microenvironment on its adhesion. For example, the Schiff bases commonly used in adhesive hydrogels can usually catalyze the adhesion effect of hydrogels by inducing amino groups in biological tissues to react with the active carbonyl groups in adhesive components to form imine bonds.⁴⁰ However, the imine bond formed is unstable in an acidic environment and is easily re-hydrolyzed, resulting in a decrease in the adhesive properties of the tissue adhesive.⁴¹ Therefore, when this type of adhesive hydrogel is applied to tissue wounds infected by microorganisms, its adhesive properties are often affected by the acidic microenvironmental characteristics, resulting in a reduction in adhesion. As shown in the report of Jiang's research work, compared with the normal physiological microenvironment, the adhesive strength and adhesion durability of adhesive hydrogels involving Schiff base reaction in acidic microenvironments were significantly reduced.⁴² In addition to the above-mentioned acidic microenvironmental characteristics, there are many other factors in the wound site after bacterial infection that can cause the adhesion of the adhesive hydrogel to be impaired, such as reactive oxygen species in the pathological environment and degradation-related proteases, which may affect the adhesion of the hydrogel by destroying the internal structure of the adhesive hydrogel and reducing the mechanical properties of the adhesive hydrogel.^43,44 Therefore, when designing adhesive hydrogels, the design should be combined with the pathological microenvironment characteristics of tissue wounds to ensure the expected performance of the hydrogel adhesion function. Zhong et al. provided a very useful example. They cleverly utilized the pathological microenvironmental characteristics of tissue wounds after bacterial infection and designed a unique adhesive hydrogel based on chitosan and polyvinyl. The hydrogel was fabricated through a dynamic borate ester cross-link network and could form strong adhesion on the tissue surface through the multiple molecular interactions of phenolic chemistry. Besides, the instability of the borate ester cross-linking in the acid microenvironment allowed the explosive release of the antioxidant agent load in the hydrogel in the initial stage, showing a smart pH-responsive drug release behavior. In addition to the antibacterial functions of the chitosan components, the hydrogels presented a strong microenvironmental amelioration ability. Further, after the burst drug release, the self-healing property of the borate ester cross-linking enabled the reformation of the hydrogel network and the execution of the wound closure function, thus promoting the reconstruction of the natural structure of the damaged tissue and the regeneration of physiological functions.⁴⁵

3.3 Diabetic wounds

In addition to the importance of adhesion for wound repair, the multifunctional principle also plays an important role in wound healing. Taking diabetic tissue defects as an example, diabetic wounds lead to the formation of high concentrations of reactive oxygen species in the tissue during the inflammatory stage.⁴⁶ This oxidative stress environment aggravates the inflammation of the tissue, promotes the excessive production of proinflammatory cytokines and metal matrix proteinases, inhibits the transition of the tissue from the inflammatory stage to the proliferation stage, and hinders the repair and healing of the tissue.⁴⁷ In such a disease context, how to effectively curb the aggravation of tissue inflammation and promote the transition of the tissue repair process from the tissue inflammation stage to the cell proliferation stage is an issue that needs to be considered during the application of adhesive hydrogels. In this regard, You's research work provided a very representative strategy. They gave the adhesive hydrogel the ability to scavenge reactive oxygen species, so the adhesive hydrogel has a strong adhesion ability and, at the same time, can also reduce oxidative stress at the wound site, thereby weakening the inflammatory response in the wound microenvironment and promoting tissue wound healing. After being used in diabetic wounds, it can be observed that the concentration of reactive oxygen species, pro-inflammatory factors, metal matrix proteases and other substances related to pro-inflammatory reactions at the wound site were significantly reduced, while the regeneration and healing of tissue wounds were significantly improved.⁴⁸ Besides, the research work of Dai and his team provided another strategy, which was to give adhesive hydrogels the ability to inhibit signal pathways and directly regulate the inflammatory situation in the wound tissue microenvironment by limiting the expression of pro-inflammatory genes, thereby promoting the tissue wound repair process and promoting the repair and regeneration of the wound surface.⁴⁹ What is more, scars prone to form during the remodeling stage of tissue repair are another problem that must be paid attention to in tissue wounds. Scars are a general term for the appearance and histopathological changes in normal skin tissue caused by various injuries. They are an inevitable product of the human body's wound repair process. However, excessive scar formation can easily lead to complications, such as functional activity disorders of tissues during the tissue remodeling phase, which also require the specific regulation of adhesive hydrogels.^50,51 In this regard, Zhang et al. proposed an ingenious strategy. They loaded microspheres containing drugs related to inhibiting scar formation into adhesive hydrogels and specifically adjusted the release time of the drugs by controlling the degradation time of the microspheres. The drugs only worked in the tissue remodeling stage to inhibit the formation of post-healing scars without affecting the previous tissue repair process, thereby assisting in the reconstruction and regeneration of natural tissue structures.⁵²

4. Personalized design of adhesive hydrogel for the regeneration of different tissues

The process of repairing local tissues and cells by regenerating adjacent healthy cells to restore tissue integrity after they are damaged and die due to certain pathogenic factors is called tissue repair. Ideal tissue repair occurs when tissue defects are completely repaired by cells of the original nature, restoring the original structure and function. However, the inherent proliferation ability of various tissue cells in the human body is different. Some tissue injuries cannot be repaired by cells of the original nature and can rely only on the regeneration of other cells to repair tissue defects and restore the morphology and function of the tissue to a limited extent. This situation has a potential risk of causing post-healing complications of tissue trauma. In addition, in the process of tissue repair, many factors interfere with the normal process of tissue repair and lead to repair failure.⁶ In this regard, the intervention of adhesive hydrogels can effectively improve the microenvironment of the tissue defect site and assist in the functional reconstruction and structural regeneration of the tissue.^1,5 In addition, considering the differences in the anatomical structure and physiological function of different tissues, the subsequent subsections introduce the application examples of adhesive hydrogels in the repair process of different tissues, thereby presenting the tissue-specific design principle of adhesive hydrogels.

4.1 Bone tissue repair

Bone tissue primarily serves as a support and protective structure within the human body. Besides, it contains the functions of assisting in human locomotion, mineral storage and hematopoiesis.⁵³ The unique physiological functions of bone tissue, particularly its distinctive mechanical support and protective functions, are determined by its unique extracellular matrix structure. In detail, bone tissue is a multi-layered structure composed of inorganic and organic components. Among them, its inorganic components are mainly hydroxyapatite, and the main component of organic components is type I collagen.^54,55 At the nanoscale, the extracellular matrix of bone tissue is mainly composed of a precise assembly formed by collagen with a triple helix structure and hydroxyapatite nanocrystals, which are supplemented by water and other biomolecules.⁵⁶ Such an extracellular matrix structure is of vital importance for maintaining the mechanical strength and physiological function of bone tissue. However, the bond defect, especially the large bone defect resulting from infection, trauma and bone tumors, seriously disturbs the microenvironment homeostasis of bone tissue, leading to anatomical defects and abnormal physiological functions of bone tissue, and corresponding treatment is urgently needed.^57,58

Bone transplantation is the main treatment option for large bone defects in clinical practice, and it has become the second largest transplantation surgery after blood transfusion.⁵⁹ Transplantation is a technique that uses surgery or other methods to introduce cells, tissues or organs from one individual into a part of the body or another individual to replace the lost function of the original part. Depending on the transplanted material, it can be divided into cell, tissue and organ transplantation. During surgical transplantation, biocompatibility issues between the graft and the patient often cause a series of complications in the patient's body, which in turn lead to the failure of transplantation treatment.⁶⁰ Among them, the most common problem encountered in transplant surgery is immune rejection, which can easily cause a series of adverse biological reactions in the body, leading to an increase in the mortality rate of transplant patients.⁶¹ Currently, various immunosuppressive drugs are mainly used clinically to suppress the patient's immune system's rejection of the transplant. Although these immunosuppressants suppress the patient's body's rejection of the implant, they also downregulate the activity of the immune system, causing the patient's immunity to decline after surgery and putting them at the risk of complications associated with infections.⁶² In addition to the biocompatibility issues related to biological reactions mentioned above, implant surgery often leads to safety issues related to material reactions. During the surgical transplantation process, it is usually necessary to fix the implant to a specific part of the patient's body or to close the wound created during the transplantation process after surgery. These surgical operations require the participation of biological materials related to fixation. Currently, surgical sutures and other materials are mainly used clinically to perform the above-mentioned functions of implant fixation or wound suturing.⁶³ However, due to their design defects, these materials are prone to causing postoperative complications related to material reactions during application, resulting in the failure of transplantation treatment.^64,65 Alternatively, the introduction of adhesive hydrogels in the field of surgical transplantation has brought new hope for transplantation therapy.

Currently, in the field of bone transplantation, artificial bone can utilize a limited tissue cells to repair large-area tissue defects, and provide theories and methods for achieving structural reconstruction and functional regeneration of bone tissue.⁶⁶ However, artificial bone still has certain biocompatibility defects during its application. Specifically, after artificial bone is implanted into the surgical site, it usually causes adverse biological reactions, such as inflammation, at the implant site due to factors such as incomplete adhesion with the tissue interface and mismatch between the degradation rate and the growth rate of new bone, which may cause delayed healing, peri-implant infection, poor bone integration and other postoperative problems.⁶⁷ The application of adhesive hydrogels may be able to cleverly solve the biocompatibility-related issues in this application field. As shown in Wu's research results, giving the implant a certain tissue adhesion ability can promote the close fit between the implant and the surrounding biological tissue interface, thereby significantly reducing the inflammatory response and fibrosis degree in the implant area, which effectively promotes tissue repair and regeneration (Fig. 3A).⁶⁸ In particular, for bone transplantation, the use of adhesive hydrogel can form a good integration between the implanted bone and the surrounding tissue interface, which prevents serious adverse biological reactions caused by excessive friction between the implanted bone and the surrounding bone tissue, greatly improving the biocompatibility of artificial bone transplantation treatment. For example, the results of the work of Li and her research team showed that the adhesive hydrogel-assisted bone transplantation treatment regimen displayed a significant reduction in the inflammatory response and the formation of fibrotic tissue around the implant. In addition, the formation of new bone has been significantly promoted, indicating that the assistance of adhesive hydrogel can greatly improve the problem of insufficient biocompatibility of bone transplantation treatment and promote the repair and functional reconstruction of bone defects.⁶⁹ As mentioned above, although the application of adhesive hydrogels in bone transplantation can optimize the biocompatibility of implants and thus promote the repair and regeneration of bone defects, this can only be achieved under certain conditions, that is, the adhesive hydrogel needs to tightly adhere the artificial bone to the defect site without gaps, which emphasizes the adhesion principle of adhesive hydrogels. Considering that bone tissue contains not only organic components, such as collagen, but also inorganic components represented by hydroxyapatite, which is significantly different from other tissues, the adhesive hydrogel in this application direction needs to be able to interact with both organic and inorganic components to form adhesion (Fig. 3B).⁷⁰ Bai et al. presented us with a very clever design. The adhesive hydrogel could interact with the organic and inorganic components in the bone tissue at the same time and form a tight and firm adhesion through molecular interactions, including hydrogen bonds and other interactions, with the bone tissue, thereby assisting in the fixation of the implant in the bone defect (Fig. 3C). The results showed that the use of the adhesive hydrogel can greatly reduce the immune rejection and inflammatory response after implantation, assist in the formation of new bone, promote structural regeneration and functional reconstruction of bone repair, and meet the requirements of the biocompatibility principle and adhesion principle of the adhesive hydrogel for bone transplantation treatment.⁷¹

Fig. 3 Adhesive hydrogels for bone tissue repair. (A) Schematic of adhesive hydrogel design for bone tissue application. Considering the biocompatibility issues of bone transplantation, the assistance of adhesive hydrogels can probably improve the treatment effect. Adapted with permission from ref. 68. Copyright 2024, Springer Nature. (B) Schematic of the components of bone tissue. (C) Schematic of adhesive hydrogel design for bone tissue application. Considering the special composition of bone, adhesive hydrogels should have the ability to form adhesion with the organic and inorganic parts simultaneously. Adapted with permission from ref. 71. Copyright 2020, Wiley. (D) Schematic of adhesive hydrogel design for bone tissue application. Considering the potential for severe biocompatibility-related complications caused by microbial infection in bone transplantation, adhesive hydrogels should have excellent antibacterial properties. Adapted with permission from ref. 74. Copyright 2025, Elsevier.

Apart from the biocompatibility issues inherently associated with the biomaterial design in bone transplantation, complications of microbial infections resulting from the surgical process are significant issues that cannot be overlooked in bone transplantation therapy.⁷² Microbial infections not only cause independent infection issues but also significantly exacerbate and alter the immune response of organisms to bone implants, leading to more severe consequences than mere immunological rejection.⁷³ Specifically, microbial infections amplify inflammatory responses, disrupt immune homeostasis, exacerbate bone destruction, and inhibit the formation of new bone, ultimately resulting in a series of biocompatibility-related problems, such as implant loosening, persistent pain, and functional impairment. Therefore, endowing bone adhesive hydrogels with anti-infective properties, which could brilliantly avoid microbial infections and support the bone repair process, is also an indispensable consideration. Here, Chen displayed an ordinary but effective solution. They developed an adhesive hydrogel through a supramolecular assembly strategy based on polyphenols, polypeptides and clay nanosheets (Fig. 3D). The catechol and guanidinium groups inside the adhesive hydrogel grafted it with strong bioadhesion and simultaneously conferred excellent antimicrobial properties and charming immunoregulatory. In addition to the osteogenic differentiation-promoting capability of the clay nanosheets, the fabricated adhesive hydrogel could firmly adhere to bone tissue, positively regulate the inflammatory microenvironment and accelerate bone regeneration.⁷⁴

4.2 Muscle tissue repair

The primary function of muscle tissue is contraction, which enables muscle tissue to propel the body into motion, maintain posture, and drive circulation.⁷⁵ Muscle tissue is composed of muscle cells (or muscle fibers). There is a small amount of connective tissue, blood vessels and nerves between muscle cells. Muscle cells are in the shape of long fibers, also known as muscle fibers. The cell membrane of muscle fibers is called sarcolemma, and the cytoplasm is called sarcoplasm. Many myofilaments are arranged parallel to the long axis of the cell in the sarcoplasm. They are the main material basis for the contraction and relaxation function of muscle fibers.⁷⁶ According to the location, structure and function, muscle cells can be divided into three types: skeletal muscles (or striated muscle), smooth muscles and cardiac muscles. Among them, skeletal muscles are distributed in the trunk, limbs and other parts, are innervated by somatic nerves, are controlled by consciousness, contract quickly and powerfully, and get easily fatigued.⁷⁷ Smooth muscles are mainly distributed in the viscera and blood vessel walls, innervated by visceral nerves, not controlled by consciousness, are automatic, and can automatically produce excitement and contraction without nerve innervation. Myocardium is mainly distributed in the heart wall and exists at the proximal end of large blood vessels. It is innervated by visceral nerves, contracts slowly, has rhythm, and lasts for a long time, and is not easily fatigued.⁷⁸ Thus, the three muscle tissues have different fundamental requirements for adhesive hydrogels during the process of tissue damage repair due to their different physiological functions and physiological microenvironments.

Although muscle tissue has lifelong regeneration capabilities, when a large amount of muscle tissue is lost (i.e., volumetric muscle loss), the muscle tissue's regeneration capacity is overwhelmed, causing skeletal muscle to form a large amount of scar tissue due to excessive fibrosis, seriously interfering with its physiological functions, such as tissue contraction.⁷⁹ Although adhesive hydrogels can effectively treat this type of tissue damage, this also has certain prerequisites, that is, adhesive hydrogels need to have good fatigue resistance and be able to adhere tightly to the muscle defect during tissue repair to provide mechanical support for the long-term mechanical load of skeletal muscle. On this basis, adhesive hydrogels need to further promote the repair and regeneration of muscle tissue.⁸⁰ Consequently, Quint et al. adopted a very unique in vivo printing strategy to treat skeletal muscle injuries caused by volumetric muscle loss (Fig. 4A). They loaded LAPONITE® nanoclay containing vascular endothelial growth factor into gelma bioink and printed it in situ at the defect site of muscle tissue to form a hydrogel scaffold with strong adhesion properties. The adhesive hydrogel would continue to release vascular endothelial growth factor at the defect site of skeletal muscle, promote muscle recovery, reduce fibrosis, enhance metabolic response, and improve muscle tissue repair.⁸¹ However, considering that the cross-linking network is solely formed by covalent interactions, which lack the characteristic of energy dissipation, it is recommended that this approach could further introduce non-covalent interactions, such as hydrogen bonds, to further improve the fatigue resistance of the adhesive hydrogel.⁸² This amelioration enables the adhesive hydrogel to better withstand the mechanical load caused by movement during the repair process and prevent stress damage that may lead to treatment failure.

Fig. 4 Adhesive hydrogels for muscle tissue repair. (A) Schematic of adhesive hydrogel design for skeletal muscle tissue application. Considering the rapid contraction and relaxation of skeletal muscles, adhesive hydrogels should contain excellent fatigue resistance. Adapted with permission from ref. 81. Copyright 2021, Wiley. (B) Schematic of adhesive hydrogel design for cardiac muscle tissue application. Considering the pathological microenvironment of cardiac muscle, adhesive hydrogels should contain biological activities to improve the tissue microenvironment. Adapted with permission from ref. 86. Copyright 2024, Wiley.

For the other two types of myocardial muscle and smooth muscle innervated by visceral nerves, since their physiological functions and surrounding environment are quite different from skeletal muscle, when adhesive hydrogels are applied to repair defects in these two types of muscle tissues, extra attention should be paid to the multifunctional principle of hydrogels (especially the properties related to promoting tissue repair). Taking myocardial tissue as an example, myocardial infarction is a very classic type of disease loss in myocardial tissue damage, which can lead to adverse ventricular remodeling and even heart failure.⁸³ In the pathological environment of myocardial infarction, due to the limited proliferation capacity of adult cardiomyocytes, necrotic myocardial tissue cannot recover spontaneously, so additional biomaterial treatment strategies are needed to assist in the repair of myocardial damage, thereby accelerating the treatment of myocardial infarction.⁸⁴ In such a clinical application context, adhesive hydrogels not only need to have excellent wet tissue adhesion properties and good fatigue resistance but also need to have good biological activity to promote myocardial repair. The design of Sun et al. provided a good reference. They used methacrylated polyglutamic acid and hydroxypropyl chitosan as adhesive hydrogel substrates, loaded two functional complexes inside the substrates, and thus prepared hydrogel patches for the treatment of myocardial infarction. In actual application, the hydrophilic molecular chains in the adhesive hydrogel enable it to quickly absorb and remove water molecules on the tissue surface and form stable adhesion through multiple hydrogen bonds or electrostatic interactions between the carboxyl and hydroxyl groups in the hydrogel and the amino groups from the tissue. Subsequently, the loaded 3-acrylamidophenylboronicacid/rutin complexes can further induce the cross-linking of the adhesive hydrogel while removing advanced glycation end products in the pathological microenvironment, simultaneously improving the performance of the hydrogel and protecting myocardial cells. Another hypoxanthine-loaded and N,N′-bis(acryloyl)cystamine crosslinked-methacrylate dhyaluronicacid nanogel could continuously release to induce M2 polarization of macrophages and exert its anti-inflammatory effect. Through the combination of the aforementioned substances, the adhesive hydrogel patch can firmly adhere to the site of myocardial infarction, reduce inflammatory response, myocardial damage and cardiac fibrosis, and promote the recovery of cardiac function.⁸⁵ Lee et al. provided another simple and effective solution, which loaded tissue-specific cardiac decellularized extracellular matrix into a coatable adhesive hydrogel (Fig. 4B). The adhesive hydrogel (with the assistance of recombinant tyrosinase) generated wet adhesion in situ through phenolic chemistry-based multiple interactions between the catechol groups it contained and the tissue. Although harnessing the tissue-specific cardiac decellularized extracellular matrix to mitigate tissue fibrosis and promote angiogenesis, it also prevented adhesion formation, effectively facilitating the treatment of myocardial infarction and the regeneration of cardiac tissue.⁸⁶

4.3 Gastrointestinal tissue repair

Gastrointestinal tissue constitutes part of the human digestive system. The digestive system consists of the digestive tract (gastrointestinal tract) and digestive glands. Its fundamental physiological functions include the intake, transportation, and digestion of food, the absorption of nutrients, and excretion of waste.⁸⁷ The digestion and absorption of food provide the body with the necessary substances and energy. The process by which food is broken down into small molecules with simple structures that can be absorbed by the digestive system is termed digestion, which can be categorized into physical (mechanical) digestion and chemical digestion. The process by which these small molecules enter the bloodstream and lymph through the mucosal epithelial cells of the digestive system is referred to as absorption. For unabsorbed residues, the digestive system excretes them in the form of feces through the large intestine.⁸⁸ The gastrointestinal tract is the main place where digestion and absorption are performed. Its internal physiological environment is complex and variable, ranging from the acidic environment of the stomach to the alkaline environment of the intestines, coupled with the peristaltic movement of the gastrointestinal tract and the rich and diverse microbial flora.⁸⁹ Although this complex physiological microenvironment is conducive to the performance of the physiological functions of the digestive system, under pathological conditions, it seriously impedes the normal process of tissue repair, posing a huge challenge for the repair of the gastrointestinal system.

Take gastric perforation as an example. Gastric perforation is one of the most urgent diseases in the abdomen. Severe gastric perforation can lead to acute inflammation and microbial infection in the gastrointestinal tract. The current conventional clinical treatment is to use sutures made of biodegradable polymers to seal the wound to assist in perforation treatment. However, similar to transplantation therapy, the use of sutures has the risk of causing tissue damage, aggravating inflammatory reactions and other adverse reactions.⁹⁰ In contrast, adhesive hydrogels have great medical advantages in sealing gastric perforation to promote tissue healing due to their good biocompatibility. However, considering the acidic microenvironment of the stomach and the influence of gastrointestinal motility, how to meet the requirements of gastric perforation for the adhesion principle of adhesive hydrogels is the first factor to be considered in hydrogel design.^91,92 In this regard, Chen et al. provided a design strategy. They developed an acid-resistant adhesive hydrogel consisting of an acid-resistant hydrogel matrix and an adhesive polymer brush layer (Fig. 5A). In detail, through protonation and hydrophobic interactions of the matrix components, the acid-resistant hydrogel matrix can resist gastric acid erosion and excessive swelling of the hydrogel matrix, thus preventing the rapid decline of hydrogel performance caused by the acidic tissue microenvironment. Simultaneously, the adhesive polymer brush layer provided a stable bioadhesive interface through multiple chemical bond connections. The synergistic collaboration between the robust cohesion of the matrix and the superior adhesion on the interface provided a stable adhesive interface, thereby reducing the inflammatory response and fibrosis of the defect site and promoting the tissue repair process.⁹³ Besides, this instance also provides an effective method for addressing the serious swelling and unrobust mechanics of PEG-based adhesives. Similarly, by introducing the hydrophobic crosslinked chains into the PEG-based adhesive, An et al. prepared an adhesive hydrogel with anti-hydration, excellent toughness and high wet state adhesion. The hydrophobic cross-linked chains inside restricted the movement of molecular chains and hindered the intrusion of water molecules, implying their feasibility in addressing the excessive swelling behaviors and unstable mechanics of commercial PEG-based adhesives.⁹⁴

Fig. 5 Adhesive hydrogels for gastrointestinal tissue repair. (A) Schematic of adhesive hydrogel design for stomach tissue application. Considering the acidic microenvironment of the stomach, adhesive hydrogels should have the ability for acid tolerance. Adapted with permission from ref. 93. Copyright 2022, Wiley. (B) Schematic of adhesive hydrogel design for intestinal tissue application. Considering the alkaline microenvironment of the stomach, adhesive hydrogels should have the ability for acid tolerance. Adapted with permission from ref. 97. Copyright 2024, Elsevier.

Severe ulcerative colitis is another typical gastrointestinal disease that includes inflammatory bowel disease, with the main clinical manifestations of intestinal epithelial barrier destruction and bleeding. Tissue repair of this disease requires rapid hemostasis at the wound site and rapid reconstruction of the mucosal epithelium, that is, there is a specific demand for the adhesive properties of the adhesive hydrogel and the multifunctionality related to treatment.⁹⁵ However, considering the alkalinity, high humidity, and high dynamics of the tissue in the colitis microenvironment, forming stable adhesion on the tissue surface to assist in the treatment of the disease and tissue repair is still a major clinical challenge.⁹⁶ In this regard, Peng et al. put forward their insights and designed an orally administrable in situ forming hydrogel. The precursor of the fabricated hydrogel, which was composed of a dopa-rich silk protein matrix and inflammation-responsive nanoparticles, had the property of forming phase separation in the presence of intestinal fluid. When encountering the inflammatory microenvironment characterized by the presence of metalloproteinases, the precursor would undergo a gelation transformation behavior and form stable adhesion on the inflammatory site, thus sustaining exercise functions in situ and ameliorating the deteriorating tissue microenvironment (Fig. 5B). During the tissue application process, the liquid-state hydrogel precursor could migrate across the intestinal surface through intestinal peristalsis, thus allowing the arrival at the inflammatory site. Subsequently, it could quickly transform into an adhesive hydrogel, achieving rapid hemostasis and long-term retention. During the stable adhesion stage, it can also alleviate inflammation at the injured site, thereby promoting tissue repair and functional reconstruction.⁹⁷ Mao et al. provided another adhesive hydrogel design, which was composed of gelatin modified with o-nitrobenzaldehyde, and can firmly bind to the amino groups on the surface of the intestine through a Schiff base reaction to form a biophysical barrier. The barrier formed by the adhesive hydrogel can not only effectively protect the damaged intestinal epithelium from the stimulation of external metabolites and harmful bacteria but also relieve the inflammatory response at the wound site and provide a favorable environment for cell migration and proliferation to promote intestinal repair and regeneration.⁹⁸

4.4 Neural tissue repair

The functions of various organs and systems of the human body are directly or indirectly under the regulation and control of the nervous system. The nervous system serves as the predominant regulatory system for the entire body.⁹⁹ The human body is a complex organism. The functions of various organs and systems are not isolated but are interconnected and mutually restricted. Moreover, the human body lives in a constantly changing environment, where changes in the environment affect various functions within the body at any time. This necessitates that the functions within the human body undergo continuous, rapid, and perfect regulation to enable the body to adapt to changes in both internal and external environments. The primary system responsible for this regulatory function is the nervous system, which belongs to connective tissue.¹⁰⁰

From the above, we can observe the importance of nervous tissue to the normal life activities of the human body. Many diseases related to nerve tissue often interfere with the signal transmission of the nervous system, thereby affecting the execution of physiological functions in our organisms. For example, the peripheral nerve injury, it is a catastrophic damage to the nervous system, leading to loss of sensory, motor function, and even lifelong disability.¹⁰¹ Peripheral nerve damage mainly causes sensory, motor and nutritional disorders in the area innervated by the nerve for various reasons. In clinical medicine, the gold standard for peripheral tissue repair is autologous nerve transplantation. However, multiple problems (the poor match between nervous donor and acceptor, the limited donor source) seriously affect the implementation of clinical treatment plans and make it difficult to repair nerve tissue.¹⁰² Therefore, scientists are working to find effective alternatives to promote the repair of damaged neural tissue while solving clinical application problems. There are currently two difficulties in the treatment of peripheral nerve injury repair: first, during the repair process, it is necessary to guide the directional arrangement of regenerated neurons to achieve the regeneration of the natural structure of the nervous system and the reconstruction of physiological functions; second, before the nervous system is completely repaired and regenerated, a certain amount of exogenous intervention is required to replace the damaged nervous system to perform its physiological functions, thereby maintaining the normal progress of human life activities.¹⁰³ Both of the above points highlight the specific need for the multifunctional principles and adhesive principles of adhesive hydrogels, that is, adhesive hydrogels should have the properties of promoting tissue repair and guiding the directional arrangement of newborn neurons. In addition, they need to have strong adhesion and electrical conduction capabilities to assist in the conduction of electrical signals in the damaged nervous system, which is used to maintain the electrophysiology of the nervous system during tissue regeneration.¹⁰⁴ To cope with this situation, Bu et al. proposed a strategy to design a polyethylene glycol-based adhesive hydrogel. The adhesive hydrogel contained succinyl units, which gave it controllable dissolution properties and adhesion by reacting with the amino groups in the nervous tissue. In addition, the tissue adhesive contained lithium ions, which can improve axonal regeneration and promote the recovery of tissue electrophysiology. The results of the performance evaluation showed that the adhesive hydrogel had good adhesive properties and could significantly shorten the time for reconnection of severed nerve ends compared with clinical treatment options. Subsequent histological, electrophysiological and behavioral results showed that the connected nerves presented low levels of fibrosis, inflammatory response and muscle atrophy, as well as strong nerve axon regeneration and physiological function recovery, and had good nervous tissue repair properties.¹⁰⁵ Cai et al. provided another unique multiple design. By combining a natural double network hydrogel and a neurotrophic concentration gradient, they developed a graphene-based nerve guide catheter for the repair of nerve defects (Fig. 6A). First, the graphene-based nerve catheter was encapsulated in a gelatin-based dual cross-linking hydrogel matrix and partially immersed in a solution of neurotrophic factors so that the trophic factors were distributed in a gradient. Then, in the actual application process, a layer of silk protein-based adhesive hydrogel tape, which could form adhesion by reacting with the amino groups, was added between the nerve catheter and the damaged nerve tissue to achieve stable bioadhesion of the catheter to the damaged nerve site, thereby assisting the function of the nerve catheter. Before the damaged nerve regenerates, the conductive properties of the graphene-based nerve catheter can assist the normal electrophysiological function of the nerve. During this period, the gradient distribution of neurotrophic factors can guide and accelerate the growth of neurons and promote the repair of nerve tissue. The results of in vivo experiments indicated that during the whole process of implantation, the electrophysiological function of the nerve can be performed normally, and the conductivity of graphene combined with the gradient distribution of neurotrophic factors (through chemotaxis) can promote axon extension, myelin regeneration and angiogenesis, thereby better promoting the repair of nerve damage.¹⁰⁶

Fig. 6 Adhesive hydrogels for neural tissue repair. (A) Schematic of adhesive hydrogel design for neural tissue application. Considering the physiological function of neural tissue, adhesive hydrogels should have the ability of conductivity to assist the function of damaged neural tissue. Adapted with permission from ref. 106. Copyright 2022, Wiley. (B) Schematic of adhesive hydrogel design for nerve tissue application. Considering the physiological function of neural tissue, adhesive hydrogels should have the ability to promote tissue repair and guide the directional arrangement of newborn neurons. Adapted with permission from ref. 112. Copyright 2022, the American Chemical Society.

Traumatic spinal cord injury is another serious disease of neural tissue defect, which can lead to severe fibrosis in the defect site. The scar tissue formed seriously hinders cell infiltration and axon regeneration in the lesion site, resulting in failure of neural tissue repair and severe functional impairment of the limbs below the spinal cord injury segment.^107,108 The key to treating this type of nerve defect is similar to that of peripheral nerve defects, which requires intact contact and good integration between the implant material and the host tissue.¹⁰⁹ In addition, the implant material needs to create a conductive local microenvironment by simulating the extracellular matrix of the nerve tissue to promote nerve regeneration.¹¹⁰ In this regard, Xiao and his team developed a biomimetic hydrogel with highly complex characteristics for nerve regeneration after spinal cord injury. The adhesive hydrogel was composed of dihydroxyphenylalanine-grafted chitosan and polypeptides, which achieved cross-linking and formed adhesion with the tissue interface through various molecular interactions, such as hydrogen bonds, covalent bonds, and Π–Π stacking. Upon application at the spinal cord defect site, the adhesive hydrogel could stably connect two severed nerves, significantly promoting immune response modulation and axon regeneration. It also facilitated the formation of axons and synapses associated with various neurotransmitters and myelin regeneration, ultimately enhancing functional recovery after a spinal cord defect.¹¹¹ Chen et al. proposed another solution. They designed and prepared a directional collagen fibrin hydrogel with stretchability, adhesion and release of specific factors (stromal cell-derived factor-1α and paclitaxel, Fig. 6B). The adhesive hydrogel formed adhesion by establishing hydrogen bond interactions with various functional groups on the tissue surface, thereby achieving close contact between the hydrogel and the nerve section. Subsequently, the directional fiber structure in the hydrogel simulated the structural characteristics of the natural spinal cord, guiding axon growth and nerve regeneration from a bionic perspective, and supplemented by the sustained release of the encapsulated factors, jointly promoting the differentiation and regeneration of neurons and accelerating the repair process of nerve defects.¹¹²

4.5 Corneal tissue repair

The cornea is the transparent part of the outer layer of the eyeball, with a thickness of 0.5–1 mm. It has a refractive effect and is an important component of human visual function.¹¹³ Structurally, the cornea is composed of avascular collagen-rich matrix tissue (Fig. 7A). Many characteristics of the corneal matrix, such as the lack of blood vessels inside, the specific arrangement of the matrix collagen fibers and the scarcity of matrix cells, together contribute to the transparency of the corneal tissue.¹¹⁴ Anatomically, the cornea is in a special physiological environment, and its surface is covered with a tear film. The structural composition of the tear film from the outside to the inside is the lipid layer, water layer, and mucin layer (Fig. 7A). As an ocular surface barrier, while playing the physiological functions of antibacterial and ocular surface lubrication, the tear film also gives the cornea a unique physiological environment, so the cornea is always in a moist tissue environment containing a large amount of proteins, ions and other substances.¹¹⁵

Fig. 7 Adhesive hydrogels for corneal tissue repair. (A) Construction and microenvironment of corneal tissue, with requirements of corneal tissue regeneration. Schematic diagram of adhesive hydrogel design for corneal tissue application. (B) Considering the physiological function of corneal tissue, adhesive hydrogels should contain high transparency in the visible light region. Adapted with permission from ref. 11. Copyright 2022, Elsevier. (C) Considering the tissue microenvironment of corneal tissue, adhesive hydrogels should have the ability to form long-term wet adhesion in the corneal tissue microenvironment under pathological conditions. Adapted with permission from ref. 120. Copyright 2025, Wiley. (D) Considering the construction of corneal tissue, adhesive hydrogels should have the ability to suppress scar formation and neovascularization and promote tissue regeneration. Adapted with permission from ref. 125. Copyright 2023, Elsevier.

However, corneal diseases caused by ocular trauma and bacterial and viral infections have become the second largest blinding eye disease in my country. The main treatment for this type of disease in clinical practice is corneal transplantation.¹¹⁶ Corneal transplantation is a treatment method that replaces the patient's existing diseased cornea with a normal cornea to restore vision or control corneal lesions, thereby improving vision or treating certain corneal diseases. However, there are many problems with corneal transplantation in clinical practice, which lead to the risk of various postoperative complications, such as adverse biological reactions, including immune rejection similar to bone transplantation, as well as corneal donor shedding and microbial infection caused by material reaction.¹¹⁷ Apart from the adverse biological reactions caused by immune rejection, the current clinical problem of insufficient biocompatibility of corneal transplantation treatment is mainly caused by surgical sutures (especially after the postoperative suture removal stage).¹¹⁸ Specifically, before the sutures are removed after surgery, corneal transplant treatment is prone to graft detachment due to loose sutures; after the sutures are removed after surgery, due to the risky wound closure method of the surgery (it is necessary to create a tiny incision in the normal corneal tissue to provide mechanical support to fix the donor to the cornea), there is a risk of secondary trauma to corneal tissue and microbial infection. These biocompatibility problems caused by sutures can easily lead to the failure of corneal transplant treatment.¹¹⁹ In contrast, the adhesive hydrogel is easy to operate, has little tissue trauma, and can provide a tissue microenvironment similar to the extracellular matrix to promote tissue repair. It can be used as a favorable alternative to sutures for corneal transplantation treatment to significantly improve biocompatibility. As shown in the research results of Zhao et al., compared with the clinical surgical suturing method, sutureless corneal transplantation involving adhesive hydrogel had a better therapeutic effect. However, considering the physiological function of the cornea, the adhesive hydrogels require additional well-performed optical properties (Fig. 7B). Altogether, the treatment with the support of transparent adhesive hydrogel achieved an extraordinary result: the epithelialization of the cornea was accelerated, the structural composition of the corneal stroma was highly similar to that of normal corneal tissue, and there was no scarring or neovascularization.¹¹ Although the application of adhesive hydrogels in corneal transplantation has greatly improved the biocompatibility of this treatment, the application process may still cause related problems and lead to treatment failure. This requires us to design adhesive hydrogels more carefully. Specifically, we need to design adhesive hydrogels according to the characteristics of the corneal tissue microenvironment (the cornea after surgical transplantation is in a damaged state, and its tissue microenvironment contains a large amount of water molecules and substances, such as proteases) to prevent adhesion failure and related biocompatibility problems caused by material reactions, such as swelling and enzymatic hydrolysis. Zhao et al. provided a good example. When designing the adhesive hydrogel for sutureless corneal transplantation, they considered the high water content of the corneal tissue microenvironment and the presence of proteases. By enhancing the cross-linked density inside the adhesive hydrogel, they reduced the exchange of substances between hydrogels and the surrounding tissue microenvironment, thereby imparting the adhesive hydrogel with low swelling and anti-enzymatic properties to better assist the regeneration and repair of corneal tissue and improve the efficacy of corneal transplantation treatment (Fig. 7C).¹²⁰ Simultaneously, the design adhesive hydrogel is also an effective substitute for GRE glue by replacing the highly toxic formaldehyde monomer in the composition with the excellent biocompatible adhesive polymers, such as oxidized dextran.

In addition, there is another major problem that cannot be ignored in corneal transplantation treatment, that is, the shortage of human (or animal) corneal donors currently used in clinical practice. According to statistics, the current supply-demand ratio of corneal transplant donors in clinical practice is about 1 : 70, which means that the serious shortage of donors makes it difficult to carry out corneal transplantation treatment more generally.^121,122 In this case, adhesive hydrogel also has unique advantages. After functionalizing the adhesive hydrogel with therapeutic substances, it can perform the adhesive function and serve as a functional scaffold for corneal repair in sutureless corneal transplantation treatment.^123,124 However, in such a type of adhesive hydrogel design, considering the natural features of the cornea (such as avascular properties), adhesive hydrogels need to be given the function of inhibiting scar formation and preventing neovascularization. As shown in the work of Sun et al., after functionalizing the thermosensitive hyaluronic acid-based adhesive hydrogel with therapeutic exosomes, the adhesive hydrogel can first form an adhesive scaffold through thermosensitivity-mediated in situ gelation (in the form of physical interlocking) in corneal treatment, then promote the repair of damaged cornea by slowly releasing the exosomes loaded inside to promote corneal epithelialization, and inhibit scarring and neovascularization (Fig. 7D).¹²⁵ Another example is the research work by Yazdanpanah and his team, which functionalized the porcine decellularized extracellular matrix into an adhesive hydrogel for corneal repair treatment. The adhesive hydrogel underwent in situ gelation to cross-link within the damaged cornea, forming an adhesive scaffold whose adhesion was formed by physical interlocking. Moreover, leveraging the high similarity between the scaffold and the natural corneal components, an appropriate tissue microenvironment was provided for corneal repair, thereby accelerating the corneal regeneration process by promoting the migration of peripheral cells towards the scaffold, which ultimately achieved corneal repair.¹²⁶ Through the analysis of the above examples, it is not difficult to observe that compared with being used as sutures for corneal transplantation treatment, when used as a transplant donor, the adhesive hydrogel not only needs to have good biocompatibility and adhesion but also needs to have certain biological activity (i.e., the principle of multifunctionality), such as accelerating corneal tissue epithelialization and inhibiting inflammatory reactions, scars and neovascularization, to promote corneal repair and regeneration.^127,128 Therefore, when designing adhesive hydrogels, the four design principles of adhesive hydrogels should be ranked in order of importance based on the characteristics of the tissue microenvironment of the application scenario and the role and function that the hydrogel should play in it as a design consideration.

4.6 Liver tissue repair

The liver is an organ in the human body mainly responsible for metabolic functions.¹²⁹ For instance, it participates in vitamin metabolism, hormone metabolism, etc., and also secretes bile for fat digestion in the small intestine and detoxification functions.¹³⁰ Besides, it could produce coagulation factors that are of great significance in preventing severe bleeding. Apart from the liver's functional features, in terms of its structural characteristics, it is also a specific soft organ that possesses a high moisture content in the body, with an extremely moist tissue surface.

The functional performance and structural properties of the liver make tissue repair extremely difficult. Considering the functional features of the liver, which has the ability to store blood and produce clotting factors, liver damage is often accompanied by severe tissue bleeding.¹³¹ Besides, clinical liver bleeding usually has symptoms of abnormal coagulation, which could be attributed to increased fibrinolysis, anticoagulant substances and decreased platelet count with abnormal functions.¹³² On this basis, the structural characteristics of the liver further increase the difficulty of tissue hemostasis and repair of liver bleeding. In detail, the soft tissue characteristics of the liver make it an incompressible organ that cannot withstand the mechanical closure of surgical sutures and staples.¹³³ What is more, the high moisture properties and the abundant surficial water of the liver are also serious obstacles to liver wound closure. Thus, tissue damage repair in liver hemorrhage has extremely stringent performance requirements for adhesive hydrogels. The fabricated adhesive hydrogels should contain a rapid adhesion formation ability to quickly achieve wound closure and inhibit wound bleeding, in addition to strong wet adhesion properties to overcome the interference of the moisture microenvironment. Moreover, Yang et al. provide a marked example. They developed an injectable hydrogel with a rapid and robust adhesive for non-compressible hemorrhages of visceral organs (Fig. 8A). In detail, the adhesive hydrogel was constructed based on ε-polylysine and poly(ethylene glycol) derivatives, which achieve gelation and generate tissue adhesion through the formation of amide bonds. It could take a fast gelation transformation within 30 s and form strong and robust adhesion on the tissue surface even after an extra 24 h of immersion in PBS, presenting significant potential for the tissue treatment of liver hemorrhage. In addition to its biodegradability and antibacterial properties, the fabricated adhesive hydrogel holds significant clinical potential in the closure of various tissue wounds.¹³⁴ Besides, considering the dysfunctional coagulatory behavior observed in liver hemorrhage mentioned above, as well as the urgent necessity for rapid hemostasis, the fabricated adhesive hydrogels should possess supplementary pro-coagulation ability to support the hemostasis.¹³⁵ Du et al. developed an effective method for the design of pro-coagulate adhesive hydrogel. They established a pro-coagulate ability-containing adhesive hydrogel based on the combination of hydrophobic modified chitosan and oxidized dextran (Fig. 8B). Through Schiff base reaction, hydrophobic interactions and electrostatic interactions, it could perform a gelation transformation and adhere to tissue firmly. Further, the hydrophobic interactions and electrostatic interactions could synergistically promote the coagulation process on the bleeding wound probably by recruiting coagulation-related substances, including platelets, fibrinogen, and thrombin, to the wound site, thus achieving rapid hemostasis and wound closure.¹³⁶

Fig. 8 Adhesive hydrogels for liver tissue repair. Schematic of adhesive hydrogel design for liver tissue application. (A) Considering the structural characteristics of liver tissue as non-compressible soft tissue with a high water content and an extremely moist tissue surface, adhesive hydrogels must possess the capability to rapidly form strong and stable wet adhesion in a hydrated microenvironment. Adapted with permission from ref. 134. Copyright 2024, Wiley. (B) Considering the physiological functions of the liver in producing coagulation factors and storing blood, liver injury is typically accompanied by abnormalities in coagulation function and severe hemorrhagic symptoms. This necessitates that adhesive hydrogels contain excellent pro-coagulation capabilities to assist in liver hemostasis. Adapted with permission from ref. 136. Copyright 2019, Elsevier.

4.7 Lung tissue repair

The lung is an integral component of the respiratory system, serving as the primary site for gas exchange between the organism and the external environment.¹³⁷ The most distinctive feature of the lung is the significant variation in air pressure changes and their frequency within it due to changes in human behavior in daily life.¹³⁸ For instance, the respiratory patterns during rest and deep breathing during physical activity exhibit substantial differences in both the depth and frequency of respiration at different moments.

Pulmonary perforation, also known as pneumothorax, can be induced by various factors, such as external injuries, and its primary symptoms include alveolar rupture and respiratory distress resulting from the failure of pulmonary pressure regulation.¹³⁹ In severe cases, it may even lead to death due to respiratory failure. Herein, timely occlusion of pulmonary perforation is extremely crucial for the treatment of lung tissue injury caused by trauma. However, considering the irregular pressure variations in lung tissue caused by changes in respiratory status, the adhesive hydrogel should contain good mechanical properties and fatigue resistance to tolerate the disordered pressure change.¹⁴⁰ Liu et al. developed a half-dry adhesive based on silk fibroin and poly(acrylic acid), as presented in Fig. 9A. The half-dry property of the adhesive hydrogel, along with its strong liquid adsorption ability, enables strong adhesion on wet tissue surfaces. Besides, the special β-sheet fold structure attributed to the silk fibroin remarkably strengthened the mechanical property of the adhesive hydrogel. Accompanied by other molecular interactions and chain entanglement, the resulting adhesive hydrogel possessed excellent tough bulk strength and could perfectly withstand the irregular pressure changes inside the lung tissue, thus supporting the tissue repair process of the lung.¹⁴¹

Fig. 9 Adhesive hydrogels for lung tissue repair. (A) Schematic of the adhesive hydrogel design for lung tissue repair. Considering the irregular pressure variations in lung tissue caused by changes in respiratory status, the adhesive hydrogel should have good mechanical properties and fatigue resistance to withstand disordered pressure change. Adapted with permission from ref. 141. Copyright 2022, Wiley. (B) Schematic of adhesive hydrogel design, in which the adhesive hydrogel is composed of an adhesive layer and a tough hydrogel part. The adhesive layer could help in creating robust adhesion, while the tough hydrogel provides the ability of energy-dissipation and anti-adhesion. Adapted with permission from ref. 147. Copyright 2022, Wiley. (C) Schematic of a Janus adhesive hydrogel design, which was fabricated through electrostatic interactions. The produced hydrogel simultaneously contained the carboxyl surface responsible for adhesion formation and an electrostatic shielding surface that resists tissue adhesion. Adapted with permission from ref. 148. Copyright 2022, Wiley.

Apart from the mechanical property requirement of lung tissue repair towards adhesive hydrogel, another essential performance is also in urgent need, namely, the anti-adhesion property, which could avoid the detrimental adhesion between lung and chest cavity and ensure the normal repair and regeneration process of the lung.¹⁴² Similarly, although the currently designed adhesive hydrogels have great advantages in the tissue repair process, most of them also share common drawbacks that cannot be ignored, namely, the lack of consideration for adverse adhesion, which is prone to cause detrimental adhesion between damaged tissue and other normal tissues during the application stage, particularly in cases involving wound closure and tissue repair.^143–145 Such a phenomenon may result in tissue dysfunction and influence normal metabolism and life activities, causing biocompatibility problems. To deal with such a complicated problem, adhesive hydrogels are required to have two surfaces with different properties. One side is an adhesion layer with adhesion ability, which can form an intact connection with damaged tissue to produce adhesion; the other side is an anti-adhesion layer without adhesion properties, which is used to prevent adhesion between tissues and resist invasion and infection of microorganisms.¹⁴⁶ Cintron-Cruz et al. developed a simple but effective adhesive hydrogel design, as shown in Fig. 9B. They split the adhesive hydrogels into two parts: the adhesive layer and the tough hydrogel layer. The adhesive layer was composed of chitosan, which could form strong adhesion with the biological tissues through physical entanglement. Further, the tough hydrogel layer, which is composed of alginate and polyacrylamide, was covered on the adhesive layer to act as an anti-adhesion layer to prevent adhesion between different tissues. Besides, the tough hydrogel layer had great energy dissipation ability, which could support the long-lasting adhesion of the adhesive hydrogel.¹⁴⁷ In addition to the above methods, Cui et al. also presented a classic design scheme for a double-sided specific adhesive hydrogel, namely, Janus hydrogel, as shown in Fig. 9C. They formed a gradient-changing adhesion hydrogel by unilaterally immersing the negatively charged carboxyl-containing hydrogel into a solution of cationic oligosaccharides using the principle of electrostatic interaction. Using the one-sided dipping method, one side of the hydrogel was in a non-adhesive state due to the electrostatic interaction between the carboxyl groups and the free amino groups, which could effectively prevent adhesion between different tissues, while the other side was rich in negatively charged carboxyl groups and could exclude tissue surface water and interact with the tissue strongly through electrostatic interaction and hydrophobic interaction, thereby creating an adhesion hydrogel that can be used for internal tissue repair and simultaneously prevent tissue adhesion during the healing process.¹⁴⁸

5. Summary and prospects

Ideal adhesive hydrogels should have good biocompatibility, strong tissue adhesion, highly adaptable tissue specificity and multifunctionality in biomedical applications. However, for the examples mentioned above, currently existing adhesive hydrogels merely focus on the partial performance requirements of biomaterials from tissue repair and lack an overall comprehension of the tissue specificity under different pathological conditions, which leads to an insufficient clinical treatment effect. In this regard, based on a comprehensive consideration of the aforementioned design principles, it is imperative to propose higher requirements for the design of future adhesive hydrogels, namely, high tissue adaptability, balanced integration of diverse characteristics, establishment of monitoring and evaluation systems, and confirmation of clinical translational feasibility (Fig. 10). In detail, high tissue adaptability requires that the adhesive hydrogels be personalized customization according to the physiological functions, anatomical structures, and components of the targeted tissues, as well as the pathological microenvironments in which they reside. After delineating the therapeutic objectives of tissue adaptability, the balanced integration of diverse characteristics requires that adhesive hydrogels, during the preparation phase, must achieve a comprehensive and balanced integration of various performance indicators based on the features of tissues and diseases, thus obtaining an optimal structure-function integrated design that maximizes therapeutic efficacy. On this basis, it is necessary to further monitor the changes in the interaction between adhesive hydrogels and the tissue during the therapeutic process, and to conduct in-depth research on its core mechanisms to provide a comprehensive evaluation of its efficacy, which is urged by the demand for the establishment of monitoring and evaluation systems. In the subsequent confirmation of clinical translational feasibility, the development of scalable preparation techniques, optimization of the preparation process, and maintenance of the integrity of the structure and function of the adhesive hydrogel while expanding production are of higher order to meet the clinical translation requirements. In the aforementioned complex preparation process, artificial intelligence (AI) can serve as a highly potent tool to assist in the design of adhesive hydrogels, such as organizing the characteristics of tissue damage and optimizing performance integration, thereby achieving the goal of promoting tissue repair and regeneration more effectively. Achieving the higher design requirements of future adhesive hydrogels with the collaborative assistance of AI could effectively help to overcome the current shortcomings and provide a new benchmark for the development of next-generation adhesive hydrogels, thereby providing better therapeutic effects.

Fig. 10 Roadmap for the future design of adhesive hydrogels. Based on the comprehensive consideration of the design principles, higher requirements, namely, high tissue adaptability, balanced integration of diverse characteristics, establishment of monitoring and evaluation systems, and confirmation of clinical translational feasibility, are imperative for the design of future adhesive hydrogels. Besides, with the collaborative assistance of AI, development of next-generation adhesive hydrogels with enhanced efficacy and tissue regeneration and repair promotion is anticipated.

Author contributions

Zhuhao Tan: investigation, conceptualization, writing – original draft, writing – review & editing. Li Ren: funding acquisition, project administration. Wenjing Song: conceptualization, supervision, writing – review & editing, funding acquisition, project administration.

Conflicts of interest

The authors declare no conflict of interest.

Data availability

All the data are available from the author.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (52173123, 12432008), the Guangdong Scientific and Technological Project (2021A1515010878).

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