Bio‐inspired adhesive hydrogel for biomedicine—principles and design strategies

Abstract The adhesiveness of hydrogels is urgently required in various biomedical applications such as medical patches, tissue sealants, and flexible electronic devices. However, biological tissues are often wet, soft, movable, and easily damaged. These features pose difficulties for the construction of adhesive hydrogels for medical use. In nature, organisms adhere to unique strategies, such as reversible sucker adhesion in octopuses and nontoxic and firm catechol chemistry in mussels, which provide many inspirations for medical hydrogels to overcome the above challenges. In this review, we systematically classify bioadhesion strategies into structure‐related and molecular‐related ones, which cover almost all known bioadhesion paradigms. We outline the principles of these strategies and summarize the corresponding designs of medical adhesive hydrogels inspired by them. Finally, conclusions and perspectives concerning the development of this field are provided. For the booming bio‐inspired adhesive hydrogels, this review aims to summarize and analyze the various existing theories and provide systematic guidance for future research from an innovative perspective.

In this review, we summarize the principles and design strategies of bio-inspired adhesive hydrogels in the context of biomedicine.We systematically categorize the bioadhesion mechanism into structure-related and molecule-related types, each containing several specific principles, shown as Graphical Abstract.Besides, the corresponding design criteria of bioadhesive hydrogels inspired by these principles are introduced.Finally, we discuss the current achievements, challenges, and future development of this field.With this, we aim to provide a concise yet systematic description and critical thinking of bio-inspired hydrogel for biomedicine.This review also focuses on nascent research results and undetermined viewpoints in this field and attempts to propose more innovative perspectives.We believe that this paper would trigger more discussions about biological adhesion principles and biomimetic material design strategies, ultimately promoting the development of the field.

| STRUCTURE-RELATED ADHESION
In nature, various structure-related strategies have evolved on the surface of biological adhesion organs. 74ccording to whether the adhesion comes from the interface, and whether it is related to the fluid medium, we divide the common ordered structure-related bioadhesion strategies into three main categories: direct interface interaction-related, interface fluid mechanicsrelated and negative pressure-related.0][81][82] The second type, the adhesion force originated from interface fluid mechanics is mainly reflected in the considerable capillary force or Stefan adhesion brought by the ordered structure (Figure 1G-I). 20,83,84Since excessive interfacial water often has a negative effect on adhesion, interface fluid mechanics-related strategies may also include those structures favorable for water drainage. 9,21The third type, negative pressure-dependent adhesion is often based on a suction cup-like structure (Figure 1J-L).Interestingly, it does not originate from the interface where adhesion occurs.The adhesion force is essentially determined by the pressure difference inside and outside a negative pressure chamber.The force occurs at the interface between the negative pressure structure and the external fluid and is transferred to the

Key points
� The bioadhesion mechanism of bio-inspired adhesion hydrogels are categorized systematically into structure-related and moleculerelated types.� The corresponding design criteria of bioadhesive hydrogels inspired by these principles are introduced.� This review also focuses on the nascent research results and undetermined viewpoints in this field and attempts to propose more innovative perspectives.
adhesive interface. 85In this section, we introduce classical structure-related bioadhesive mechanisms and the strategies for the construction of corresponding bioinspired hydrogels.

| Direct interfacial interaction
As mentioned above, direct interfacial interaction-related adhesion structures mainly correspond to two effectsmechanical interlocking and van der Waals forces.Examples of mechanical interlocking in nature organisms include mayfly larvae, thorny-headed worms (Acanthocephala) (Figure 1A,B), cockleburs, etc., 38,39,79,86 which tend to have barb-like or similar structures.Biological organs with such structures can plunge into the matrix for a firm anchoring.Especially in some species, this structure can have dynamic responsiveness.For example, Pomphorhynchus laevis can expand a bulb of proboscis after the insertion of the thorn-like structure.When the mechanically interlocked structure expands after insertion, it exerts a greater force with the matrix like an expansion bolt, further strengthening the anchorage. 87he mechanical interlocking strategy has inspired the construction of many adhesive hydrogels for medical use, mainly microneedle patches.Yang et al. reported a swellable double-layer microneedle adhesive (Figure 2A). 63Before contacting with water, the smooth needles can be easily inserted into the tissue in a dry and hard state.By absorbing water in tissues, a rapid increase in the cross-sectional area occurs, achieving local tissue deformation and subsequent interlocking, and thus providing adhesion.As the hydrogel swells, the soft microneedle tip can be removed without significantly damaging the tissue or causing the microneedle to break during rigid removal.Besides, Zhang et al. fabricated a mechanically interlocking hydrogel microneedle patch with a multi-layered structure by step-by-step mold replication (Figure 2B). 62The interlocking structure can make the microneedle tightly anchored to the surface of the tissue.
Another type of direct interfacial interaction is the substantial Van der Waals force provided by hairy structures of hierarchical branches of some reptiles and insects. 89Among them, the most widely studied gecko toe has a complex multi-level structure from macroscale to nanoscale, including lamellae, setae, branches, and spatulae (Figure 1C-F). 43Such hierarchy in structure enables the spatulae to match the roughness of a surface to be adhered, increasing the effective contact area and resulting in considerable van der Waals forces.In addition, geckos can effectively adhere and peel by changing the angle between the toe and the surface to be adhered. 80,82ccording to the latest research, the contribution of forces such as acid-base interactions in gecko adhesion has also been proposed. 90However, van der Waals forces are still considered to be the main source of adhesion.][93][94] For gecko-inspired hydrogels, the adhesive structures are abstracted as arrays of columns of various types, which are usually prepared by template methods.Interestingly, an "array + coating" design paradigm has been implemented to construct patches that combine the high van der Waals forces of gecko-inspired arrays with other adhesive properties of hydrogel surfaces. 95Mahdavi et al. utilized photolithography and reactive ion etching to prepare silicon templates with arrays of concave pillars of various shapes.A prepolymer is then perfused and crosslinked, resulting in a gecko-inspired column array.The array surface was further modified with oxidized dextran (DXT) coating for covalent adhesion to tissues.Zhou et al. improved this "array + coating" paradigm. 96A thermally responsive adhesive macromolecule p(DMA-co-MEA-co-NIPAm) was coated with an array of mushroom-shaped F I G U R E 2 Bio-inspired artificial hydrogel with direct interface interaction-related structures.(A) Mechanical interlocking of a double-layer microneedle via hydrogel swelling.Reproduced with permission. 63Copyright 2013, Springer Nature.(B) Sting-inspired hierarchical microneedle array with mechanical interlocking-mediated adhesion.Reproduced with permission. 62Copyright 2021, Elsevier.(C) Gecko-inspired hydrogel patch.The thermally responsive hydrogel back sheet realizes controllable attachment and detachment.Reproduced with permission. 88Copyright 2021, American Chemical Society.
pillars with enlarged heads.The hydrophilic-hydrophobic transition of this coating is controlled by temperature.Excessive interfacial water can lead to failures of such as van der Waals forces on the surface of the gecko array.Similarly, the artificial array adhesion behavior is controlled by temperature-controlled water contact angle transition.Zhang et al. imitated the peeling behavior of geckos on previous research basis. 88The controllable peeling of the patch was achieved by integrating a thermally responsive bending hydrogel on the back sheet of the patch (Figure 2C).

| Interfacial fluid mechanics
In the presence of interfacial fluids, a class of bioadhesive surfaces relying on capillary force and Stefan adhesion is summarized.[97][98][99] The footpads of tree frogs have a hierarchical structure (Figure 1G-I).Epithelial cells present an array of polygon prisms, with the prisms spaced from each other forming channels.Through the channels, mucus may diffuse and excess interfacial water can be drained.Similarly, the feet of flies have brush-like bristles, whose tip secretes a viscous liquid when contacted. 98,100,101Such liquids on the interfaces form numerous liquid bridges at the interface, thus providing the adhesion force that can be attributed to capillary force and Stefan adhesion. 45,46The capillary force is formed by the attraction of the liquid to the surface and the cohesion of the liquid.Theoretical calculations reveal that when the total liquid volume remains unchanged, the capillary force increases significantly with the increase of the number of liquid bridges, which also explains part of the reason for the huge capillary force of the multilayer structure. 102Stefan adhesion occurs when two surfaces with fluid at the interface are separated from each other.It is a type of adhesion that is positively related to the viscosity of the liquid, the speed of interfacial separation, etc.Therefore, the highly viscous mucus has provided a considerable contribution to Stefan adhesion. 20,1037][108] Rao et al. used the template method to construct a class of hexagonal facet arrays with interconnecting grooves (Figure 3A). 104When the hydrogel contacts with an adhered surface, the interfacial water is drained from such grooves, and the interface forms a F I G U R E 3 Bio-inspired adhesive hydrogel with interfacial fluid mechanics-related structures.(A) Clingfish disc-inspired hydrogel with hexagonal arrays.When the hydrogel is in contact with the substrate, the groove drains rapidly.The dynamic bonds of the hydrogel bond to the matrix and dissipate energy when breaking.The hexagonal facets are separate from each other, which prevents crack propagation.Reproduced with permission. 104Copyright 2018, Wiley-VCH.(B) Bio-inspired hydrogel patch.Microarrays of hydrogels absorb water and maximize capillary adhesion forces.Reproduced with permission. 107Copyright 2018, The Royal Society of Chemistry.
good contact.The matrix of the hydrogel was designed based on dynamic bonds.The high energy dissipation when broken endowed the hydrogel with good adhesion and toughness.In addition, the segmented hexagonal facet.also prevented the continuous propagation of cracks at the interface.Bo et al. constructed similar interconnecting grooved hexagonal facets using thermally triggered shape memory hydrogels. 105Under thermal triggering, the hexagonal column structure of the hydrogel was transformed into a flat structure that was not conducive to adhesion, and accordingly, the adhesion strength decreased to 15.4% of the initial value.Meng et al.'s work is not limited to the patterned surface itself but focuses more on the interaction between the pattern and the fluid at the interface. 106The effects of different temperatures, heights of hexagonal columns, and viscosity and surface tension of the interfacial fluids on the adhesion behavior were studied.Finally, the optimal conditions for realizing low separation distance, high adhesion, and high friction were obtained.Yi et al. adopted the principle that hydrogels coupling with a microarray structure could generate huge capillary and van der Waals forces to produce reversible and strong adhesion on dry, wet, and underwater surfaces (Figure 3B). 107

| Negative pressure
Negative pressure is a non-interfacial effect.Many species maintain adhesion at the interface through negative pressure.4][35] Some micro/nanostructures common on the surface of the adhesive organs have the effect of consolidating the seal and enhancing the friction.Adhesion by suction often occurs at a wet interface, which is related to the maintenance of the negative pressure by water in the cavity and interface.On non-wettable surfaces or other scenarios prone to cavitation, the fail of water in tension may result in the fail of negative pressure adhesion. 35,85,109Interesting recent studies have revealed that two chambers can be identified when the suction cup adheres to a substrate, including an acetabular chamber and an infundibular chamber.][112] The multilevel fine structure and muscle-driven contraction patterns allow for strong adhesion at various interfaces while being reversibly detachable.4][115] The continuous exploration of the principle will lead to the emergence of more versatile microstructured medical hydrogels.
The structures that produce negative pressure adhesion in nature have inspired hydrogels with various types of suction cups or cavity structures.The preparation methods involved include the template method, 66,68,116,117 3D printing, 118,119 liquid or air trapping, 67,112,120,121 etc. Fu et al. used the lithography technology to construct a mold with suction cup structures, and finally fabricated a patch. 68Lee et al. developed an advanced 3D microprinting technique based on two-photon polymerization to construct heterostructures (Figure 4A). 118The formed hydrogel suction cup was composed of PEGDA on the outer wall and pNIPAM spherical protrusions inside.pNIPAM is a class of thermosensitive hydrogels that can generate heat-triggered shrinkage.Such temperaturesensitive shrinkage of the spherical protrusions resulted in a change in the effective suction area, which enabled the patch to have a higher adhesion at 27°C relative to that at 45°C.Similarly, Ko and colleagues coated pNIPAM hydrogels on elastomeric microcavity pads made of PDMS to mimic the contraction behavior of octopus suckers (Figure 4B). 117The smart adhesive pad exhibited thermally controllable adhesion, which was high at 35°C and low at 22°C.Baik et al. developed a series of "air-trapped" methods. 112,120They used air bubbles to controllably form gas-liquid interfaces in an array of holes to prepare suction cups with concave columns with spherical protrusions inside. 112Cai et al. prepared suction cup structures based on an assembly of colloidal particles in droplet templates. 67The resulting sucker-shaped microspheres containing self-assembled nanoparticles (NPs) were obtained through the fast water extraction process in the droplets.
At the end of the discussion of the main bioadhesion structures, it is worth mentioning that in nature, especially underwater, the forces corresponding to each structure do not appear alone.For example, the adhesion of octopus sucker actually involves multiple mechanisms, including capillarity, friction, and negative pressure, while the contribution of the capillary force in gecko toes' adhesion behavior is still controversial. 34,35,82,91,111This review can only relate specific structures to their primary mediated effects.For bio-inspired structure-related artificial adhesive hydrogels, the design is often not only inspired by a single organism or limited to a single effect.Therefore, the strict imitation of nature is difficult and somewhat unnecessary in the application aspect.The soft and wet properties of hydrogels make it difficult to be shaped into precise micro-nano structures identical as that of the adhesive organs in natural organisms.However, the unique features of hydrogels such as swelling and temperature response also endow the artificial adhesion materials with more flexible design and more functional potentials, making it possible to surpass natural materials in terms of controllability and adhesion ability.

| MOLECULE-RELATED STRATEGIES
According to the spatial scales and characteristics of molecule-related bioadhesion strategies in nature, we classify them into four categories: sticky groups, complementary pairing, molecule-network interaction, and phase behavior.Generally speaking, the spatial scale varies from small to large, sticky groups and complementary pairing can occur within a few molecules, while molecule-network interaction requires macromolecules and their networks, and phase behavior can even be observed at the micrometer scale. 21,26,47,553]127,128 Such adhesion is often nonspecific, which means that materials with similar groups can adhere to a wide range of surfaces.Molecular complementary pairing-derived adhesion is F I G U R E 4 Bio-inspired artificial hydrogel with suction cup-like structures generating negative pressure for adhesion.(A) An octopusinspired hydrogel patch.The wall of the sucker is a PEGDA hydrogel and the internal protruding structure is composed of pNIPAM hydrogel.Reproduced with permission. 118Copyright 2022, The Authors, published by Wiley-VCH.(B) Intelligent adhesive pad with suction cupinspired microcavity structure.The adhesion is temperature sensitive.Reproduced with permission. 117Copyright 2016, Wiley-VCH.

F I G U R E 5
Molecule-related adhesion strategies in nature, including their action forms, typical biological examples, and principles.(A) Mussel adhesion.Reproduced with permission. 47Copyright 2017, American Chemical Society.(B) Some common interaction paradigms of catechol chemistry.Reproduced with permission. 122Copyright 2021, Wiley-VCH.(C) Microscope image of bacteria with adhesins.The scale bars are 5 μm.Reproduced with permission. 123Copyright 2016, American Chemical Society.(D) Scheme of bacteria with charged adhesins.Reproduced with permission. 123Copyright 2016, American Chemical Society.(E) Molecular structure of adhesin.Reproduced with permission. 124Copyright 2013, American Chemical Society.(F) Cell adhesion on a surface mediated by receptor-ligand interaction. 125Copyright 2018, Elsevier.(G) Nucleobase complementary pairing.(H, I) Entanglement and topohesion.Reproduced with permission. 26Copyright 2020, Wiley-VCH.(J) Liquid-liquid phase separation by coacervation.Reproduced with permission. 21Copyright 2021, Wiley-VCH.(K) Sandcastle worm adhesives' phase transitions.Reproduced with permission. 126Copyright 2013, American Chemical Society.(L) The calcified interface between various tissues and bone.Reproduced under terms of the CC-BY license. 25Copyright 2020, The Authors, published by Springer Nature.
supposed to be more specific.In organisms, it is mainly manifested as receptor-ligand interactions (Figure 5F) and complementary pairing of nucleobases (Figure 5G). 125,129,130Hydrogels inspired by this tend to adhere to specific surfaces.In the molecule-network interaction scale, entanglement (Figure 5H) and topological adhesion (topohesion) (Figure 5I) are discussed together.These processes involve molecular chains and the interactions with the adhered network. 56,57,59,131,13233][134][135] Similar to the previous chapter, various biological molecular-related adhesion principles and corresponding artificial adhesion strategies of hydrogels are discussed.

| Molecules with sticky groups
,136,137 Taking the most widely studied mussels for example (Figure 5A), they secrete a liquid-state protein-based glue called mussel foot protein (mfp).Further investigation reveals that the catechol group in 3,4-dihydroxyphenyl-lalanine is an important sticky group. 50The diverse interaction forms of catechol groups not only provide adhesion for the adhesive interface but also provide cohesion for the adhesive itself.These two effects together contribute to the adhesion.9][140][141] Besides, the quinone structure after being oxidized can covalently react with -NH2, -SH, and other groups through Schiff base, Michael addition, or react with itself by dopa quinone coupling. 139,142Of course, the actual mussel adhesion in nature involves more complex factors, including controlled changes in pH, redox, etc., 143,144 far from just the action of catechol chemistry.The coacervation and solidification of mussel adhesives are also as important and will be specifically described in Section 3.4.
Small molecules containing catechol-like groups such as dopamine (DA) and tannic acid (TA) are widely introduced in artificial mussel-inspired adhesive hydrogels.Due to the wide range of chemical reaction forms, there are a variety of methods for introducing these groups.154][155][156] Doping and soaking are the easiest ways to non-covalently introduce monomeric molecules.For example, Ahmadian et al. added TA directly to a gelatin solution. The hydroxl groups of TA are hydrogen donors, while the amino and carboxyl groups of gelatin are hydrogen acceptors.The two compositions formed abundant hydrogen bonds and then physically cross-linked to form a non-toxic Gelatin-TA hydrogel (Figure 6A).145 Chen et al. developed a method of polymerization lyophilization conjugation.146 PEGDA hydrogels were first prepared and lyophilized and then soaked in a TA solution.Due to the high flexibility of the PEGDA molecule and its high affinity to tannins, the gel showed good mechanical properties and underwater adhesion.
Covalent graft of DA can be achieved via the reaction of the amino group of DA with the carboxyl group in the side chain of macromolecules. 70,711][152] For example, Zhou et al. oxidized hyaluronic acid (HA) to generate aldehyde groups.Then the aldehyde group reacted with the amino group of DA to obtain DA-modified HA.The catechol in the DAHA molecule can be cross-linked by NaIO 4 , which enabled rapid formation of hydrogels with strong adhesion (Figure 6B). 151n addition, DA, TA, and other molecules can be combined with various inorganic non-metallic and organic compounds or self-polymerized to form nanomaterials. Doping of such nanomaterials will also enhance the hydrogel adhesion.Han et al. synthesized PDA nanoparticles by oxidative self-polymerization of DA.The PDA nanoparticles were then directly incorporated into a PNIPAm pregel and cured.The obtained hydrogel had good cell-tissue adhesion ability (Figure 6C). 153Feng et al. obtained PPy-PDA nanoparticles by copolymerization of pyrrole (Py) and DA.The nanoparticles were then incorporated into PNIPAm hydrogels to obtain NIR-tunable adhesion. 154Han et al. inserted DA into clay nanosheets in order to protect them from oxidation.Acrylamide monomers were further incorporated to form a composite hydrogel that exhibited broad, durable, and reproducible adhesion. 155Jia et al. used silver ions and TA to obtain TA-Ag nanozymes via in situ reduction.The phenolic hydroxyl group of TA promoted its uniform incorporation into a polyacrylic acid hydrogel.The nanozyme in the hydrogel network maintained the balance of dynamic redox between phenol and quinone, thereby ensuring the stability of the hydrogel adhesion. 156It is worth mentioning that catechol chemistry can be incorporated not only in a homogeneous way but also heterogeneously through surface coating, which also provides more ideas for the construction of adhesive hydrogel materials. 159,160onspecific sticky groups of microorganisms are also worth investigating.In order to achieve permanent adhesion to non-biological surfaces under various complex conditions, various microorganisms have developed a series of universal non-specific adhesins (Figure 5C-E).2][163][164] Several species of marine bacteria such as Caulobacterale have charged molecules on their holdfast that allow them to attach to surfaces. 161ncreasing the expression of the polysaccharide deacetylase has demonstrated an adhesion enhancement effect. 162,163Such nonspecific adhesin-mediated adhesion has also inspired biomimetic design. 157,165Inspired by the positively charged polysaccharide intercellular adhesin (PIA) in biofilms, Han et al. grafted chitosan to have similar structure and composition with natural PIA as a source of adhesion (Figure 6D). 157][168] Jiang et al. adopted a modular genetic strategy to design recombinant protein hydrogels incorporating Mefp-3 and Mefp-5 from mussels (Figure 6E). 158The final obtained protein-based hydrogel had good adhesive strength.Another interesting example is the combination of the adhesion domains of mussel Mefp with the abilities of environmental perception, migration, and adhesin secretion of microorganisms by which a multifunctional adhesive "living glue" was prepared. 167

| Molecular complementary pairing
There are a lot of specific molecular complementary pairing phenomena in organisms such as base complementary pairing and receptor-ligand interaction.These interactions can also contribute to bioadhesion and inspire material design.The mechanism of specific adhesion of cells is particularly instructive in the design of biomaterials.The specific adhesion of cells to cells or substrates is mediated by multiple receptor families, such as immunoglobulin superfamily, cadherins, and the widely studied integrins (Figure 5F). 125,129,169,170A representative example is the interaction between integrin and short peptide Arg-Gly-Asp (RGD). 169,171,172RGD F I G U R E 6 Bio-inspired artificial hydrogels with sticky groups.(A) Adhesive hydrogel prepared by direct mixing of gelatin and TA.Reproduced with permission. 145Copyright 2021, Wiley-VCH.(B) Hydrogel prepared by covalent grafting of dopamine on hyaluronic acid through Schiff base reaction.Reproduced with permission. 151Copyright 2020, American Chemical Society.(C) PDA-NPs/PNIPAM hydrogel with simultaneous adhesion and temperature sensitivity.Reproduced with permission. 153Copyright 2016, American Chemical Society.(D) Dual bacterial biofilm-and mussel-inspired hydrogel.Reproduced with permission. 157Copyright 2020, The Authors, published by Elsevier.(E) Adhesive hydrogel combining mussel adhesion mechanism and genetic engineering technology.Reproduced with permission. 158Copyright 2022, Wiley-VCH.
groups presenting on the surface of a matrix have been proved to promote cell adhesion.Cadherins are another well-known class of cell adhesion molecules that mediate mechanical adhesion between cells. 173However, the current research on this type of adhesion and the materials inspired by it is often at the molecular and cellular level, which is not the same as the various macroscopic tissue adhesion mentioned above. 174,175It is promising and exciting to mediate tissue-specific adhesion behavior of biomedical adhesives by applying the principles of cell adhesion to the macroscopic level.
Inspired by such effects, the introduction of specific cell adhesion molecules or fragments into materials is a means of promoting cell adhesion.7][178] For example, Chakraborty et al. used the principle of supramolecular self-assembly to construct RGD-based hydrogels.Due to the existence of RGD fragments, the cells seeded on it were easy to adhere to the surface and connect with each other and spread. 176Sun et al. used synthetic biology to directly introduce fragments such as RGD to design cell adhesion proteins. 179agahama et al., took inspirations from biological tissues and designed a cadherin-mediated "living hydrogel" system (Figure 7A). 180Specifically, individual modified living cells were covalently linked to the hydrogel network via bioorthogonal reactions and cells adhered to each other via cadherin-mediated adhesion.The resulting hydrogels can form good adhesion and show self-healing ability.The same team also verified selective adhesion properties of similar "living hydrogels" to different substrate surfaces mediated by cell adhesion. 183nother interesting and instructive biocomplementary pairing effect occurs in nucleobases.Nucleobases include adenine (A), thymine (T), guanine (G), cytosine (C), and uracil (U), which are important components of nucleic acids.There are pairing interactions between bases based on hydrogen bonding, including G-C and A-T (A-U in RNA) (Figure 5G).This mediates pairwise binding of biological macromolecules, such as DNA and RNA. 1305][186] Liu et al. covalently introduced five nucleobases A, T, G, C, and U into PAAm hydrogel. 116All nucleobase-containing hydrogels exhibited better adhesion than pure PAAm hydrogels.Abundant molecular recognition interactions between the hydrogels and solid surfaces, including hydrogen bonding, π-π stacking, metal complexation, hydrophobic interaction, etc., were considered as contributing factors.
F I G U R E 7 Bio-inspired artificial hydrogels with molecular complementary pairing.(A) Materials and cells are modified to form biological tissue-inspired hydrogels through bioorthogonal reactions and its adhesion behavior depended on cadherin-mediated specific cell adhesion.Reproduced with permission. 180Copyright 2021, American Chemical Society.(B) The introduction of adenine and thymine into the hydrogel drives its adhesion behavior.Reproduced with permission. 181Copyright 2017, American Chemical Society.(C) The designed oligonucleotides form a dendritic-structured linker through complementary base pairing, which is further cross-linked with polyethylenimine-modified black phosphorus quantum dots to form an adhesive hydrogel.Reproduced with permission. 182Copyright 2021, Wiley-VCH.

LI ET AL.
Such adhesion behaviors are somehow nonspecific due to the presence of hydrophobic molecules, metal atoms, benzene rings, etc., commonly found on the substrate surface in related experiments.Other studies have used the specific hydrogen bonding pairing of A-T and G-C to enhance the self-adhesion of the hydrogel network and achieve self-healing (Figure 7B). 181,184In addition to the introduction of nucleobase groups, single-stranded oligonucleotides have been used as building blocks to construct dendrimer-like DNA-linker through hybridization, which were soon cross-linked with a cationic polymer to form DNA-based hydrogels (Figure 7C). 182

| Molecule-network interactions
The molecule-network interactions discussed here mainly include entanglement (Figure 5H) and topohesion (Figure 5I).In the mucus secreted by organisms in nature, these effects are commonly found. 26,52,187,188Physically, both entanglement and topohesion can occur at an interface without any functional groups.Entanglement refers to the diffusion of polymer chains at the interface of two pre-existing networks and physical entanglement with both networks, which results in strong adhesion.Such adhesive interfaces can be slowly separated.At the microscopic level, the polymer chains are slowly pulled out of the network at the adhesion interface during the separation process. 189,190This type of adhesion has been likened to an unknotted suture. 26The topohesion theory was mainly proposed by Suo et al. 22,26,131,132 The initial stage of formation is the same as that of entanglement, yet topohesion arises from the formation of a third network after diffusion and entanglement. 22,191What's more, the polymer chain diffused at the interface needs to be cross-linked in situ to form a third network, which is entangled with the two previous networks.This usually results in a stronger adhesion than simple entanglement. 26It is worth mentioning that some studies have used similar principles, such as diffusing monomers at the interface and in situ cross-linking to form networks. 192,193 Cohesion is another interesting point of view to describe the interaction of a third network between two surfaces.These correlative perspectives are expected to develop further along with the topohesion theory. 194,1957][198] For example, Chen et al. used covalently polymerized PEGDA networks and diffusible hydrophilic linear PEG molecules to form double-network hydrogels (Figure 8A).The PEG chains in the PEGDA network can penetrate target surfaces and form entanglements, thereby generating adhesion. 196There are also studies that involve the use of nanomaterials to obtain hydrogels with abundant entanglements and strong adhesion. 199In addition, controllable entanglement can be achieved through exerting ultrasound or electric field on the polymer and tissue matrix to control adhesion. 200,201nspired by the pH-triggered adhesion of mussels, Yang et al. added chitosan solution (pH = 5) at the interface of two layers of PAAm hydrogels (pH = 7).Chitosan gradually diffused and entangled to the two layers of PAAm.With the homogenization of pH, the chitosan itself gradually formed a third network via hydrogen bond cross-linking and finally resulted in high adhesive energy (Figure 8B). 22

| Phase behaviors
Many bioadhesion systems are dominated by phase behaviors that involve complex phase separations, phase transitions, etc. 55,58,61,133,202 Sandcastle worms and mussels secrete adhesives underwater.During the adhesion process, the adhesive is stable underwater without dispersion and can be applied to a substrate surface even when subjected to destructive currents. 55The related effect is so-called coacervation (Figure 5J). 55,133Coacervate is an aqueous phase rich in macromolecules, typically oppositely charged polyions.Coacervation is the phase separation of coacervate out of a dilute, equilibrium phase.The relevant molecular interactions that lead to coacervation include long-range electrostatic forces as well as short-range hydrogen bonding, hydrophobic interactions, etc. 57 Coacervation makes the adhesives to not be easily dispersed in the external liquid, and thus plays an important assisted role in underwater adhesion. 55In addition, this process is also accompanied by solidification, that is, liquid-solid phase transition of the adhesives that makes the adhesion firm (Figure 5K). 55,126,203nother common type of phase transition related to bioadhesion is biomineralization, a process in which organisms generate solid-phase biominerals with the help of ions through the influence of organics. 58Cartilage and tendon can firmly adhere to bone surfaces through a mineralized transition layer (Figure 5L). 25,204,205The inter-binding forces provided by biomineralization between organic and inorganic matter allow the formation of hybrid materials that can be used for adhesion. 202nspired by the coacervation and solidification behaviors of sandcastle worms and mussel adhesives, various types of water-stable, nondispersing hydrogel adhesives have been designed. 134,135,206The most common strategy is to use electrostatic forces between polyanions and polycations.Shao et al. used polyanions containing phosphate and catechol and polycations with amine groups.When the two compositions mixed with each other, a dense coacervate formed.A subsequent covalent cross-linking process dominated by catechols resulted in firm underwater attachment. 206Dompé et al. grafted pNIPAM chains in polyelectrolytes to form a coacervate with thermal-responsive phase transition ability.This made it injectable at room temperature while forming a hydrogel at body temperature, thus being favorable for underwater adhesion (Figure 9A). 134n addition to conventional coacervation formed from oppositely charged molecules, Kim et al. used two polyelectrolytes of the same charge, by which the πcation interactions overcome electrostatic repulsion to generate an adhesive coacervate. 1358][209] Besides, biomineralization also inspires studies on the adhesion of hybrid hydrogels. 59,210hang et al. devised a robust and universal strategy to build stable adhesions between hydrogels and various substrates, inspired by biomineralization at the cartilage-bone interface (Figure 9B). 59Cation and anion pairs that can form solid minerals (e.g., calcium ions and phosphates) were introduced in the hydrogel and matrix, respectively.When the hydrogel came into contact with the matrix, ions diffused at the interface, forming mineral nanoparticles.The nanoparticles can bind to polymer chains on both sides of the surface, leading to adhesion.
At the end of the discussion in this chapter, it is worth noting that bioinspired adhesion strategies can incorporate theoretical models at multiple levels.For example, in some strategies inspired by biomineralization, inorganic particles generated at the interface bind to the networks on both sides, in a way that is similar with topohesion. 59,211Another example is that the adhesion on a surface provided by some coacervate systems still depend on sticky groups, coagulation, etc. 134,209 Besides, some bioinspired adhesions require systematic exploration.For example, the interesting specificity of nucleobasedependent adhesion to various surfaces are still looking for further experiments. 116,186Moreover, the exciting combination of adhesion theory and biotechnology and the research on adhesion of cell-loaded "living" hydrogels have enriched the field of bio-inspired adhesion, although much endeavor is still to be made. 179,180,212

| CONCLUSIONS AND PERSPECTIVES
Study on biological adhesive phenomena has come a long way, and the design of biomimetic hydrogels involves multidisciplinary efforts.For example, the study of adhesion structures and molecules in nature has promoted the generation of a series of hypotheses. 20,21,109he experimental verification and simulation help to shape the theory of adhesion. 85,102,213The combination of advanced technologies from fields such as materials science facilitate the design and construction of bio-inspired adhesive hydrogels.In this long and extensive development process, progress always continues and discussion remains accompanied.Typical examples include the exploration on gecko toes' adhesion from different perspectives 91,93,94 and the expansion of the adhesion theory with the emerging understanding on coacervation [55][56][57] and topohesion, 22,131,132 etc.This article divides bio-inspired adhesion strategies into structure-related and molecule-related, which is supposed to be a relatively comprehensive and systematic F I G U R E 9 Bio-inspired artificial hydrogels with phase behavior-associated adhesion mechanisms.(A) Temperature-sensitive coacervate formed by pNIPAM-grafted oppositely charged polymers for underwater adhesion.Reproduced with permission. 134Copyright 2019, The Authors, published by Wiley-VCH.(B) Cartilage-inspired adhesion through the interaction of mineral NPs and the network.Reproduced with permission. 59Copyright 2022, Wiley-VCH.
classification.In structure-related adhesion, the classification revolves around the origin of the adhesion, that is, whether the adhesion arises from direct interfacial interactions, is fluid-mediated, or does not even originate from the interface (e.g., negative pressure).These adhesion theories are still being updated as research on natural biological structure progresses.In molecule-related adhesion, the classification mainly relies on the scale at which the force is applied with their unique characteristics-from chemical groups to molecules, networks, and phases.Theoretical models may be derived from a single effect, for example, topohesion without any sticky groups or catechol chemistry that does not involve any network interactions, both of which have been shown to result in appreciable adhesion. 26,214However, situations in nature are often complex and some natural phenomena simultaneously involve coacervation, sticky groups, phase transitions, topohesion, etc., such as sandcastle worms and mussels.Accordingly, biomimetic strategies for creating adhesive hydrogels can also include several contributing factors.
Disciplines such as material science and engineering have played an important role in the process of converting the adhesive theories into design principles for the fabrication of bio-inspired adhesive hydrogels.6][217] For example, the temperature-sensitive material PNIPAm has been integrated with structures inspired by geckos, tree frogs, and octopuses or chemically by the introduction of musselinspired catechol groups, resulting in temperaturecontrolled adhesion behavior. 117,118,134,1531][222] We are confident to see that bio-inspired adhesive hydrogels are not just blunt imitations of natural strategies, but combine the unique advantages of various advanced materials and technologies.It is believed that with the development of materials science and other fields, biomedical hydrogels that perfectly meet the requirements of safety, robustness, appropriateness, and controllability will be developed.

AUTHOR CONTRIBUTIONS
Luoran Shang and Wenzhao Li conceived the idea; Wenzhao Li, Luoran Shang, and Xinyuan Yang wrote and revised the manuscript.Puxiang Lai assisted with the scientific discussion of the article.