Bioinspired synthetic wet adhesives: from permanent bonding to reversible regulation

Journal Pre-proof Bio-inspired Synthetic Wet Adhesives: from Permanent Bonding to Reversible Regulation Shuanhong Ma, Yang Wu, Feng Zhou PII:

S1359-0294(19)30094-9

DOI:

https://doi.org/10.1016/j.cocis.2019.11.010

Reference:

COCIS 1322

To appear in:

Current Opinion in Colloid & Interface Science

Received Date: 1 October 2019 Revised Date:

21 November 2019

Accepted Date: 27 November 2019

Please cite this article as: Ma S, Wu Y, Zhou F, Bio-inspired Synthetic Wet Adhesives: from Permanent Bonding to Reversible Regulation, Current Opinion in Colloid & Interface Science, https:// doi.org/10.1016/j.cocis.2019.11.010. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.

Bio-inspired Synthetic Wet Adhesives: from Permanent Bonding to Reversible Regulation Shuanhong Ma1, Yang Wu1, Feng Zhou1* Dr. S. Ma, Dr. Y. Wu, Prof. F. Zhou 1. State Key Laboratory of Solid Lubrication Lanzhou Institute of Chemical Physics Chinese Academy of Sciences Lanzhou 730000, China

Corresponding author：Feng Zhou; Email: [email protected];

Abstract: (100-120 words) Nowadays, robust underwater adhesives products are highly demanded both in industrial and biomedical field. Meanwhile, study of the underwater adhesion mechanism of natural organisms under fluid environment is necessary, which provides inspiration for engineering adhesive materials that can be used in wet environment. Scientists are committed to discovering the unique adhesion mechanisms of proteins adhesives for natural organisms. Especially, recent understanding of wet adhesion mechanisms provides designable inspiration for developing novel synthetic underwater adhesives with high performance by employing Dopa-based and coacervate-enabled strategies. Although pursuing robust interface bonding in these years, controlling the wet adhesion state with reversible/switchable feature is the latest goal for developing intelligent biomimetic adhesives, which implies important applications in multiple fields.

1. Introduction Some of the natural organisms, such as mussel, sandcastle worms and barnacle, can firmly bond to the wet surfaces upon encountering harsh trial in water or humid surroundings [1-3]. The secretion responsible for such considerable wet adhesion is based on their use of adhesive proteins with unique molecular structure. For example, current research results indicate that 3,4-Dihydroxyphenylalanine (Dopa) in mussel foot proteins (Mfps) is the core for achieving high interfacial bonding strength of mussel [4-6], based on various types of interface interactions. Complex coacervate mechanism has been found to play a key role in the generation of the natural underwater bioadhesive for sandcastle worms, based on the mixture of oppositely charged polycationic and polyanionic proteins residues at physiological pH condition [7, 8]. The complicated intermolecular interactions among different types of proteins without any Dopa residues are proposed as the main contribution for permanent attachment of barnacle against various foreign surfaces during most of their lifespan [9], even though the exact mechanism is still worthy of further investigation. Direct extraction of natural adhesive proteins from organisms seems to be a good choice for realizing their commercial applications [10], but this task is highly challenging because of cumbersome separation process and limited adhesives amount. Especially, nowadays robust underwater adhesives products are highly demanded both for engineering [11] and biomedical fields [12]. Meanwhile, the frequent seal-failures events in engineering occur due to the broken of the used underwater adhesives. Under this necessary background, a hot research wave for designing and developing strong and robust underwater synthetic adhesives [13-19], inspired from of natural organisms, has been raising in the field of biomimetic materials. Based on this, natural underwater proteins adhesives have been systematically studied including their chemistry components, physical existing state, interface interaction and bulk solidification mechanisms, as the inspiration for developing novel synthetic adhesives or improving the performance of current adhesives of wet setting. Even so, underwater adhesive performance for many kinds of synthetic bio-inspired adhesives is still poor and needs to be improved. Furthermore, developing reversible underwater synthetic adhesives to realize rapid attachment/detachment behavior on-demand manner to target surfaces is also a challenging task. Here, we provided a mini review on the design of underwater synthetic adhesives, inspired by natural organisms. We first briefly described the current research progress of underwater adhesion mechanisms for natural proteins adhesive from mussel and sandcastle worms. Then, we discussed how these adhesion mechanisms of natural proteins serve inspiration for the rational design of permanent underwater adhesive materials based on novel biomimetic strategies and wonderful synthetic chemistry methods. Subsequently, we gave a short introduction for developing reversible underwater synthetic adhesives with switchable feature beyond nature. Based on these above contents, we also roughly summarized the current biomedical application situation of Dopa-functionalized synthetic adhesives, including as tissue-adhesives, hemostatic materials, drug release carrier, and tissue-repair materials. Finally, we analyzed and pointed out some key issues and challenges which enable to the

synthesis of reliable bio-inspired underwater synthetic adhesives. 2. Understanding the Adhesion Mechanism of Natural Cases When it comes to underwater adhesion, mussels, sandcastle worms and barnacles are the true experts which can firmly attach onto wet rocks under dynamic and turbulent environments. Over the past decade, extensive progress has been made for understanding basic wet adhesion mechanisms for those robust interfacial adhesion of marine organisms based on their diverse protein molecules, through the elegant strategies of catechol chemistry [15], supramolecular chemistry [20], polyelectrolyte complex [21] and other routes. Mussels are famous for its excellent ability to attach their byssus to diverse substrates in complex wet environment, such as high humid, alkaline and high ionic concentration [3]. The remarkable molecular feature of adhesive proteins is assigned to be related with interfacial underwater adhesion of mussels [1]. Figure 1a shows the distribution state of major mussel foot proteins of mussel byssal plaque. Meanwhile, Mefp-1 which is highly positively charged with high Dopa content of ~ 13 mol.%, is the first mussel proteins obtained and studied, exhibiting good interface binding ability and cross-linking property [22], along with excellent corrosion resistance [23]. Mfp-3 and Mfp-5 located at the contact interface are believed to be key components responsible for the interfacial adhesion against various substrates. Figure 1b shows the sequence of Mfp-5, including cationic, aromatic, Dopa-based and anionic fragments. Figure 1c shows the sequence of Mfp-6 with abundant Cys (C), Arg (R) and Lys (K), Gly (G) and Tyr (Y). Correspondingly, Dopa has been considered as the key residue to improve the mussel wet adhesion [24], while the cysteine thiols in Mfp-6 can eliminate O2 by reducing it to water to prevent the transition from Dopa to quinone [25]. The possible forces involved in the adhesion process between Mfps and substrates are extensively investigated [26-28], including electrostatic interactions, cation–π interactions, hydrophobic interactions, hydrogen bonds, π–π stacking, and ions-coordination. For example, the important contribution of hydrophobic residues in Mfp-3 and Mfp-5 has commonly been investigated. The research results indicate that hydrophobic residues, along with Dopa hydrogen bonds, commonly play two important roles in mussel wet adhesion. One role is that they provide a micro-environment to prevent Dopa from oxidation along with hydrophobic interactions to strengthen attachment on the substrate [29, 30]. The other role is that they can overcome the hydration layers on a substrate, which facilitates the approach of protein chains [31]. In addition to hydrophobic force, positively charged residues, such as lysine and arginine, can also remove the hydration layer from the adsorbed salt ions on the rocket surfaces to facilitate the access of Dopa group [32]. Furthermore, interaction between Dopa and cationic residues is also found to facilitate interface adhesion based on the formed hydrogen bond and coordination bond [33]. This corresponding mechanism in mussel adhesive proteins has also been well proved by experimental mean in synthetic copolymers system. For example, recent work by Dobryden and coworkers showed that the synergistic contribution of cationic and catechol anchoring groups of natural proteins-analogs, is important for the

extraordinary wear-resistant property of bio-inspired copolymer adhesion materials [34]. Such work is extremely useful for developing functional coatings with robust interface combination for wide applications. Also, Han et al. [35] reported a novel, facile, robust, and substrate-independent anchoring strategy based on a cationic amine-modified catechol ligand. The experimental result showed that interface bonding capacity of amine-modified catechol ligand to hydrophilic substrate was obviously improved as compared to those conventional and widely used catechol systems. Such robust binding ability can be attributed to the synergistic effect of cationic amine and catechol based on the analysis result of single-molecule force spectroscopy, which is highly desirable in materials science and surface engineering. Even though these above interaction forces in mussel adhesion have been extensively investigated, little was related about the contribution of negatively charged residues, such as phosphoserine and carboxylate groups. As expected, such molecular residues may coordinate with metal ions to enhance the catechol-mediated interface wet adhesion. Finally, the complex synergistic interaction mechanism among diverse protein residues to contribute underwater adhesion is still not clear. Sandcastle worms are another type of marine organisms in the ocean that can secret under water adhesive proteins [7]. They can build artificial architecture of tubular shells by adhering sand grains and mineral particles together with self-secreted proteins adhesive (Figure 1d). In detail, the proteins adhesive is composed of two types of oppositely charged proteins: the positively and negatively charged proteins (Figure 1e). Pc-3B is a representative of the negatively charged proteins with numerous phosphoserine residues, while Pc-2 and Pc-5 are positively charged proteins [1, 8]. Correspondingly, numerous Dopa residues are also found in both types of proteins as that in mussel proteins. Coacervation, as one typical liquid-liquid phase separation process [36], from oppositely charged proteins based on the electrostatic interaction force plays a key role during the formation of the sandcastle glue [7]. Finally, the coacervates, Dopa residues, and metal ions (such as Mg2+ and Ca2+), are believed to synergistically contribute to the strong underwater adhesion of sandcastle worms [14, 37]. However, it is believed that coacervation may also play a more widespread role in the underwater adhesion for other kinds of marine organisms. For example, Yarger and Stewart et al. discovered that the caddisfly larvae glue has a balanced ratio of positive to negative charges, similar to that of sandcastle worms [38]. Although proposed adhesion mechanisms have been commonly recognized as for underwater adhesion of several marine organisms, detailed information regarding: how the proteins adhesives keep balance between dynamic wetting to contacted surfaces and their increasing mechanical modulus, how proteins residues spontaneously solidify at the interfaces in seawater environment, and how coacervate-enabled underwater adhesion achieves sufficient cohesion, are still not clearly understood. All of these details are crucial for developing functional bio-inspired synthetic wet adhesives.

Figure 1. Typical wet adhesion mechanisms of mussel and sandcastle worms along with corresponding proteins sequences. (a) Schematic of the mussel byssal plaque showing the distribution of major mussel foot proteins, (b) Sequence of Mfp-5 from Mytilus edulis and (c) sequence of Mfp-6 from M. californianus (adapted from the study by Waite et al. [3]). (d) Photos showing the considerable ability of sandcastle worms to build tubular shells by gluing grains of sand and other mineral particles together with the self-made adhesive glues, and the secreted glue can bind glass beads together, (e) sequence of polyanionic Pc3B, the serine residues (S) are more than 95% phosphorylated on the hydroxyl side chain and the tyrosines (Y) are hydroxylated into Dopa residues, and sequence of polycationic Pc2, the structures of histidine (H) and lysine (K) residues with amine sidechains (adapted from the study by Stewart et al. [7]). 3. Recent Progress in Preparation of Synthetic Bio-inspired Wet Adhesives Natural underwater adhesion mechanisms provide inspiration for engineering bio-inspired or biomimetic adhesive materials that can perform in water or high-moisture surroundings. Current adhesives design system can be well assigned into two types: mussel proteins-inspired Dopa-based adhesives and sandcastle worm glue-inspired coacervate-enabled adhesives, based on unique molecular feature of Dopa residues and the presence of typical coacervation phenomena in the diverse adhesive components of marine organisms. Meanwhile, in order to adapt more complicated and harsh serving conditions, engineering reversible or switchable adhesive is still a challenging topic in this field. The ultimate goal of bio-inspired design is to develop functional synthetic adhesives materials with desirable applications in biomedical and engineering field. The following sections will clarify

different synthetic adhesive materials separately. 3.1. Dopa-inspired Design of Synthetic Underwater Adhesives Since the seminal discovery of its unique working mechanism in multi-components of adhesive proteins residues of marine species, 3,4-dihydroxy-L-phenylalanine (DOPA) groups are commonly used to guide the synthesis of functional wet adhesives with remarkable underwater bonding tenacity. In details, the design of bio-inspired synthetic adhesives commonly focuses on Dopa-containing or Dopa analogue-containing copolymers, peptides, and recombinant proteins [39-41]. Among, synthetic copolymer adhesives containing Dopa groups with improved interface bonding than control polymers, is mostly favored by chemists. For example, Wilker group has prepared catechol containing copolymers adhesive of poly [(3,4-dihydroxystyrene)-co-styrene] by copolymerizing styrene and 3,4-dimethoxystyrene [9, 42, 43]. As expected, the Poly(catechol-styrene) adhesive shows good interface bonding strength of ~ 5.5 MPa upon employing aluminum as interacted substrate under a shearing mode (Figure 2a). Meanwhile, it is found that bonding strength is highly associated with catechol content, cross-linking degree and molecular weight of the copolymer. Surprisingly, the adhesion strengths of such kind of copolymer can up to ∼11 MPa after cross-linking either in the presence of metal ions or upon oxidation [44], the bonding performance is the highest in current biomimetic adhesive system and can rival with commercial products. Especially, the interface adhesion strength is found to be stronger in salt water than deionized water, which implies its universality in more complex and harsh watery environment. Similarly, Messersmith research group has designed mussel-mimetic PEG hydrogel by the cross-linking of catechol group with branched and linear poly (ethylene glycol) (PEG) with the assistance of an oxidation agent [45]. The as-prepared hydrogel shows remarkable tissue adhesion ability for potential surgical and biomedical applications [46]. Inspired by the “one-two punch” synergistic interplay between abundant catecholic Dopa and lysine residues in mussel foot proteins, Maier et al. [33] have designed a synthetic analog of cyclic Trichrysobactin (CTC) (a natural bacterial catechol siderophore), as Tren-Lys-Cam (TLC) adhesive molecule which is a good platform to explore molecular synergies in bio-adhesion (Figure 2b). The synthetic TLC analogs exhibit desirable adsorption and adhesion ability as the natural CTC siderophore, with robust adhesion energies (Ead>15 mJ/m2) to mica surface under a wide pH range. The responsible mechanism for such robust adhesion is that cationic groups can expel or displace the adsorbed hydration salts, which is beneficial for the approach of the catechol groups to substrate surfaces. So, for the first time, the synthetic TLC adhesive molecules have been used to explain why wet adhesion is robust for natural mussel in harsh environment, such as high salt, pH, and hydration condition. Moreover, the authors indicated that 2,3-dihydroxy catechol in the TLC molecules showed better oxidation resistance compared with bare Dopa. This work suggests a new design principle for development of future bio-inspired synthetic polymers adhesives.

Inspired by strong wet adhesion mechanism of mfp-5 films and the coacervation process of mfp-3, Kollbe Ahn et al. [47] have synthesized low-molecular-weight catecholic zwitterionic molecules by modifying charged zwitterionic surfactant with catechol groups (Figure 2c). The as-synthesized mfp-mimetic zwitterionic adhesive homologues exhibit very strong and spontaneous bonding to diverse surfaces, and can self-assemble into ulta-thin glue layer. The surfactants exhibit very strong adhesion (~50 mJ/m2) and retain the ability to coacervate. Especially, they exhibit important application potential as an adhesive for nanofabrication. Finally, the design of current molecules enables to the understanding of synergistic working mechanism of natural mussel proteins and gives inspiration for developing high-performance bio-inspired synthetic wet adhesives by combining catechol chemistry, hydrophobic & electrostatic interactions. Even though easily achieving strong interface bonding, most synthetic polymer glues are hydrophobic and needed to disperse in organic solvents to form flowable sol. In addition, the biocompatibility of the synthetic polymers adhesives is also need to be improved with considering biomedical applications. Based on this, extensive researches have focused on the chemical modification of adhesive moieties (or groups) onto backbones of the natural or synthetic biomacromolecules. Among, the catechol moiety with superior wet adhesiveness, has been chemically grafted onto the backbones of a series of biomacromolecules, including chitosan (Chi-catechol) (Figure 2d) [48, 49], hyaluronic acid (HA-catechol) [50], and alginate (Alg-catechol) [51, 52]. As a result, chemical tethering of catechol groups to these backbones can dramatically improve their wet adhesiveness, which greatly expands the biological application of these materials. In the past 15 years, a lot of studies have aimed at developing biomacromolecules-based wet-resistant adhesives. Among them, chitosan-catechol is one kind of promising adhesive material for biomedical application. The introduction of catechol group onto chitosan backbone dramatically improves its solubility along with enhanced wet adhesiveness. Over the past 10 years, the chitosan-catechol adhesive has received widespread attention in biomaterial science [53], including as wound healing patches, tissue sealants, and hemostatic materials. For example, Lee research group has found that catechol conjugation takes obvious increase of mucoadhesion as for high molecular weight chitosan [54]. Compared with un-modified chitosan, chitosan-catechol can realize unprecedented long-lasting adhesion on the intestinal mucosal layer and acts as an excellent candidate for mucosal drug delivery polymeric platforms. More functionalities and applications for chitosan-catechol would be discussed in section 5. In addition to using chemical strategies towards synthetic copolymers or modified-biomacromolecule wet adhesives, proteins-based wet adhesives are also developed [55]. For example, Zhong et al. [39] have developed a modular genetic strategy for preparing functional amyloid adhesives, based on the integration of amyloid protein CsgA (the major protein component of E. coli biofilm) with Mfp-3/5 (major interfacial adhesive proteins from mussels) (Figure 2e). The mixture of such two kinds of proteins with different monomer ratios results in the appearance of hierarchically co-assembled fibrous bundles. Meanwhile, the researchers state that the

resulted copolymer fibers possess the highest wet adhesion strength among all of the proteins-based underwater adhesives reported thus far. Furthermore, the copolymer fibers also exhibit improved tolerance against oxidation compared with single Mfp-3/5.

Figure 2. Mussel-inspired synthesis of underwater adhesives. (a) Photograph of a marine mussel adhere onto a glass sheet with adhesive plaques (left), and mussel proteins-inspired synthetic underwater adhesive of poly[(3,4-dihydroxystyrene)-co-styrene] (right) (adapted from the study by Jenkins et al.[9]). (b) Structure of Tren-Lys-Cam (TLC), as a synthetic small molecular adhesive analog of the natural siderophore structure of Cyclic Trichrysobactin (CTC) (adapted from the study by Maier et al. [33]). (c) Structure of mfp-5 proteins-inspired zwitterionic biomimetic small molecules adhesive (adapted from the study by Ahn et al. [47]). (d) Chemical structure of bio-inspired synthetic adhesive of chitosan-catechol. (e) Synthesis underwater adhesives by recombinant protein techniques. In detail, in vitro copolymerization of the CsgA-Mfp3 and Mfp5-CsgA monomers results in hierarchically co-assembled structures, with the two adhesive domains externally exposed on the amyloid cores (adapted from the study by Zhong et al. [39]). 3.2. Coacervate-inspired Design of Synthetic Underwater Adhesives In addition to the great progress of Dopa-based synthetic adhesives, many researches have been focusing on developing functional wet adhesives inspired from the coacervate mechanism of natural organism. Meanwhile, complex coacervation plays a key role in the formation of wet adhesion glue of the sandcastle worm, based on the interactions from oppositely charged proteins, plus calcium and magnesium ions at physiological pH [7, 17, 56]. This natural mechanism commonly provides good inspiration for developing biomimetic underwater adhesive.

For example, inspired by the natural sandcastle worm glue, Stewart research group has developed synthetic polyacrylate adhesive which contains negatively charged phosphate, positively charged primary amine, and sticky catechol side chains, followed by molar ratios similar to natural components [57]. In typical case, the bio-inspired protein analogs are prepared by the free radical polymerization for obtaining two kinds of random copolymers (Figure 3a1-3a2). Meanwhile, the copolymer of polyamine analog possesses 10~20 mol% amine side chains and 80~90 mol% neutral filler subunits, while the copolymer of polyphospho-Dopa analog has 50~70 mol% phosphate side chains and 10–20 mol % catechol side chains. Very interestedly, fluid mixture of each kind of polyelectrolyte analog together induces obvious phase-separation along with the appearance of complex coacervates at a neutral pH condition (Figure 3a3). Correspondingly, the coacervate could easily adhere onto the surface of a glass piece with desirable shape under water without dissolving into the water (Figure 3a4). Finally, this kind of adhesive material is used to glue bone specimens, and the interface bonding strength can be around ~40% of the commercial cyanoacrylate adhesives. Similarly, Cha et al. [58] have designed complex coacervates by mixing positively charged adhesive proteins (fp-151 or fp-131) with negatively charged hyaluronic acid (HA). The experimental result indicates that the bulk adhesion strength of the coacervate is much stronger than the sole Mfps. Furthermore, in order to improve the interface bonding strength, the researchers in the same group introduce the other kind of polymer network within coacervate network, by mixing monomer of polyethylene glycol diacrylate (PEG-dA) into the formed coacervate phase [59]. As a result, the maximum shearing strength of the coacervate network with the assistance of secondary cross-linking network can be up to ∼1.2 MPa. Very importantly, such kind of monomer-integrated coacervate also shows sharp shear thinning behavior (Figure 3b), and exhibits very important medical applications. In addition, coacervates-inspired mechanism is also used to develop bulk soft adhesive materials. For example, Park et al. [60] have reported an injectable coacervate-enabled hydrogel material, which forms through electrostatic interaction between catechol conjugated hyaluronic acid (HA-DN) (negatively charged) and lactose modified chitosan (positively charged). Furthermore, a physically stable and interpenetrating hydrogel material is well prepared after through catechol cross-linking and cyclization, and such kind of bio-inspired coacervate hydrogel possesses injectable property and exhibits long-term stability in water environment. Gärdlund et al. [61] have used polyelectrolyte complexes (PEC) as a wet-adhesion agent for different pulps in production of fine paper. The experiment result shows that adding PEC can significantly increase the tensile strength of the sheet, providing a good guidance for manufacturing strong paper with a high bending stiffness. Based on the urgent application requirements of coacervate-enabled adhesives in the underwater sealing engineering, the focus of this kind of material changes from water-based system to organic system. Waite research group has reported one kind of novel coacervate adhesives, based on the formed microporous structures by polyelectrolyte mixture via solvent exchange[21]. In typical case, the researchers have

synthesized two different kinds of polyelectrolytes, one is copolymer of poly(acrylic acid) functionalized with catechol (PAAcat), and the other one is a quaternized chitosan that is ion-paired with bis(trifluoromethane-sulphonyl)imide (Tf2N-) (QCS-Tf2N). Subsequently, QCS-Tf2N and PAAcat are dissolved in DMSO together and then the mixture is injected onto substrate surfaces underwater (Figure 3c). Meanwhile, the DMSO-water exchange induces strong electrostatic interaction, phase inversion, and rapid formation of complex catechol-rich polyelectrolytes, resulting in fast (~25 s) and robust (Wad>2 J m-2) adhesion against a variety of substrates under water, including plastics, glasses, metals, and biological materials. Such kind of bio-inspired wet adhesive can be applicable to fluidics and micro/nano structures in the future.

Figure 3. Sandcastle worm glue-inspired synthesis of underwater adhesives. (a) Adhesive-complex coacervates inspired by the sandcastle worm glue. (a1) Synthetic poly (phosphodopa) analog of the highly phosphorylated Pc3 protein, (a2) synthetic polyamine analog of the polybasic Pc1 protein, (a3) photography of pipettable complex coacervate of the mixed synthetic copolymer analogs, and (a4) photography of fully submerged application of the adhesive complex coacervate (adapted from the study by Stewart et al. [56]). (b) Photo showing coacervate-enabled synthetic adhesive with typical shear thinning behavior, assisted with secondary cross-linked by polyethylene glycol diacrylate (PEG-dA) monomer (adapted from the study by Kaur et al. [59]). (c) Molecular structures of polyanionic and polycationic polymers along with balanced counter ions, and the process for synthesizing sandcastle worm glue-inspired underwater adhesive based on the solvent exchange strategy (adapted from the study by Zhao et al. [21]). In detail, QCS-Tf2N and PAAcat are dissolved in DMSO and the mixture is extruded onto a glass slide immersed in water. After setting

25 s in water, adhesion to substrate can withstand water blasting. 4. The Design Principle to Maximize the Interface Bonding Strength of Bio-inspired Synthetic Wet Adhesives Even though a series of catechol-containing biomacromolecules or copolymers have been designed to mimic the structure and functionality of natural proteins adhesives for achieving robust bonding to substrate surfaces under wet settings, realizing effective bonding on structured surfaces or maximizing the interface bonding strength still face a big challenge. Commonly, the quantitative evaluation of the interface bonding strength of bio-inspired synthetic adhesives can be realized by employing either an overlap shearing mode or a normal separation mode at macro test scale, defined as bond failure energy. Correspondingly, we believe that there are two key factors determining the strength of bond failure energy: one is the viscoelastic feature of the bulk adhesives themselves (cohesion), while the other one is interfacial interaction strength between the polymer molecules chains and contacted surface (interface adhesion). The entire adhesion strength is the unity of bulk cohesion and interface adhesion. Meanwhile, adhesives with high cross-linking modulus is advantageous for producing strong cohesive strength (effective resistance to internal motion of polymer chains), but it is not conducive to dynamic wetting of the structured contacted surface, so it is impossible to achieve sufficient adherence under low preload condition. In this case, strong adhesion must be assisted by applying external high preloads, which highly limits its extensive use in the field of biomedical. In contrast, adhesives with low cross-linking modulus is advantageous for dynamically wetting of the structured contacted substrates (rapid transport of polymer chains toward target surfaces), but it is not conducive to produce strong cohesive strength, and it is easy to pull the adhesive itself apart during the testing process while the real interface bonding strength can’t be accurately obtained. In this case, a large amount of adhesive residue will remain on the target surfaces. As a result, designing bio-inspired synthetic underwater adhesives with high performance requires addressing a key issue: that is finding a good balance between cohesion (elastic behavior) and dynamic bonding interactions (viscous flow). For the first time, Washburn research group systematically investigates the relationship between viscoelastic properties of the copolymers adhesives and their wet/dry adhesion behavior [62]. In a typical case, a series of lightly cross-linked poly(DMA-co-MEA) copolymers samples are synthesized by employing solvent-free, microwave-assisted polymerization technique with divinyl group agent (EGDMA) as crosslinker. Compared to those samples without cross-linking, the cross-linked poly (DMA-co-MEA) copolymer with 0.001% EGDMA exhibits the strongest adhesion under wet settings. However, under dry conditions, poly (DMA-co-MEA) copolymer without EGDMA cross-linking shows the highest adhesion. Subsequently, the relationship of adhesion with mechanical/rheological properties of the copolymers is investigated in detail. The experimental result indicates that the synthesized poly (DMAco-MEA) copolymers with 0 and 0.001% lightly cross-linking degree can be an ideal material for pressure-sensitive adhesive. For the first time, this work clearly

clarifies how to effectively control the interfacial bonding strength of the DMA-based copolymers adhesives through changing the corresponding viscoelasticity but without affecting the amount of adhesion groups. Based on our humble understanding of bio-inspired synthetic wet adhesives, future development of such kind of materials should focus more on the study of bonding strength rather than just staying at some fancy conceptual level. Regulating the chemical components is still one of the key ways to obtain the best glues. In addition, in order to realize good balance among components, mechanical property and wet adhesion strength, we suggest that bio-inspired copolymers adhesives can integrate with soft materials (for example hydrogels) to construct layered adaptive system or be cooperated with structured materials to maximize the interface bonding strength under water. 5. The Appearance of Reversible Bio-inspired Wet Adhesives Even though great progress has been made for scientists to understand the remarkable wet adhesion mechanisms of marine organisms and a series of bio-inspired synthetic underwater adhesives through imitating the natural catechol chemistry and polyelectrolyte complex strategies have also been developed, the resulted interface bonding is commonly designed for permanent and non-reversible. However, in some cases of surface engineering, we commonly hope that the adhered surfaces can be separated on-demand manner. So the question is that how to design intelligent materials with switchable adhesive ability beyond nature in wet settings. That means novel underwater wet adhesives materials with dynamic bonding and de-bonding capability are urgently needed. In the past few years, the development of reversible wet adhesives has gradually got considerable attention. Meanwhile, temperature-sensitive wet adhesives have received considerable attention among all reported wet adhesives system. For example, Zhao et al. [63] have reported a new method to prepare bio-inspired underwater adhesive, which enables the reversible, tunable, and fast regulation of the wet adhesion on diverse surfaces. In typical case, their reversible wet adhesive is synthesized by combining the mussel-inspired catechol chemistry, host–guest molecular assembly mechanism, as well as the responsive polymer, allowing for tuning the interfacial hydration degree by changing the bath temperature in an on-demand manner (Figure 4a). Meanwhile, such reversible adhesion is robust and durable (Figure 4b), especially available in complex liquid environments, such as metals ions solution, salt solution and wide range of pH media. Based the similar design principle, our group has synthesized one kind of thermo-responsive copolymer adhesive of poly(dopamine methacrylamide-co-methoxyethyl-acrylateco-N-isopropyl acrylamide) poly(DMA-MEA-NIAAm) and then decorates it onto structured poly(dimethylsiloxane) (PDMS) pillar arrays to engineer a novel underwater gecko-like adhesive (TRGA) [64]. The as-engineered TRGA can generate underwater high adhesion above the lower critical solution temperature (LCST) of the copolymer, yet low adhesion below the LCST of the copolymer. The TRGA can be applied to various substrates, especially for rough surfaces, realizing robust and reversible

adhesion cycles. Subsequently, intelligent TRGA smart to near-infrared (NIR) laser radiation can be well designed by in situ integrating the Fe3O4 nanoparticles into the pillars. As a result, we find that the intelligent TRGA can be successfully used for rapid and reversible remote control over adhesion so as to capture and release heavy objects underwater. Finally, we assemble the intelligent TRGA onto the tracks of a mobile device for realizing controllable movement underwater and wet environment. Beyond the bio-inspired design from sandcastle worm glue, Kamperman et al. [65] have reported one kind of thermo-responsive wet adhesive by mixing two oppositely charged copolymers solutions, namely poly(acrylic acid)-grafted-poly(N-isopropylacrylamide) (PAA-g-PNIPAM) and poly(dimethylaminopropyl acrylamide)-grafted -poly(N-isopropylacrylamide) (PDMAPAA-g-PNIPAM). The as-synthesized adhesive exhibits a typical fluid state with injectable feature at room temperature. However, after increasing the temperature above the lower critical solution temperature (LCST) of PNIPAM, the fluid state changes into a non-flowing gel state. Meanwhile, the as-synthesized wet adhesive can be applied to different surfaces regardless of their charge along with thermo-responsive attachment/detachment behavior. In addition to temperature-responsive underwater adhesive, the development of moisture or water sensitive reversible adhesives also has got great attention. Inspired from the corn, Wilker research group has designed one kind of new underwater adhesive by combining the positive attributes of poly (lactic acid) (PLA) and mussel adhesive chemistry to create catechol-containing copolymers [66]. The experimental results indicate that the interface bonding strength of the as-synthesized adhesive material can be comparable to that of several commercial glues. Importantly, interface bonding could be controllable, and the adhered substrates can gradually separate away based on the mild hydrolysis feature of PLA. This new kind of bio-inspired copolymer adhesive gives inspiration for developing intelligent underwater adhesives, for which are capable of replacing permanent adhesives materials. Recently, inspired by the dynamic adhesion mechanism of snail which can firmly adhere onto the substrates surface under dry condition while becomes movable in wet condition, Yang’s research group has synthesized an reversible, robust and smart adhesive based on the shape-adapting and shape memorizing poly(2-hydroxyethylmethacrylate) (PHEMA) hydrogel [67]. As shown in Figure 4c, the soft hydrogel adhesive shows low near-surface elastic modulus of ∼180 kPa under hydration state and can adapt to the target surface by low-energy deformation, while it exhibits high elastic modulus of ∼2.3 GPa under drying state, analogous to the behavior feature of the epiphragm of natural snails. As a result, the adhesion strength or state can be dynamically changed by rapid hydration and dehydration of the PHEMA hydrogel. Importantly, such kind of reversible adhesion is applicable to both flat and rough target surfaces. Similar mechanism is also used for preparation of hydrogel-based reversible adhesive by Jeong’s research group [68]. . Even though scientists have got great progress for the development of reversible synthetic wet adhesives, obtaining large switching difference value of adhesion strength under external stimuli is still difficult. Recently, Wang et al. [69] have

designed a reversible underwater glue based on dynamic change of its bulk strength by taking advantage of dynamic covalent bonds and hygroscopic polymer backbone (Figure 4d). The as-prepared glue can realize smart response to photo- and thermal stimuli under water, exhibiting tunable adhesion strength from 606.7 ± 30.3 (high adhesion state) to 50.5 ± 7.4 kPa (low adhesion state) on a series of materials surface (Figure 4e). Meanwhile, the responsible mechanism for high adhesion state can be analyzed as below: hygroscopic and hydrophilic glue with desirable fluid state can spontaneously spread over the surfaces and absorb interfacial water. For the first time, this work has realized maximum value transition of wet adhesion strength, which is extremely instructive for developing high-performance smart underwater adhesives used for transportation device, military, and some other relevant fields.

Figure 4. Bio-inspired reversible adhesives. (a) Schematic drawing shows molecular structures used for synthesizing the thermo-responsive underwater adhesive based on the host–guest molecular recognition strategy and (b) working mechanism of reversible interfacial adhesion when the local temperature of the water bath is below and above the LCST (adapted from the study by Zhao et al. [63]). (c) Schematic diagram shows epiphragm-like adhesion mechanism for a PHEMA gel, where shape conformability in the wet state followed by interlocking upon drying facilitates

adhesion. Upon rehydration, the wet hydrogel adhesive pad returns to its original un-deformed configuration and can be easily self-detached from the target substrate (adapted from the study by Cho et al. [67]). (d) Schematic diagram shows working mechanism of photo-responsive underwater reversible adhesive (anthracenyl-functionalized polyethylenimine) (anth-PEI) and (e) tunable underwater adhesion occurs on different substrates (adapted from the study by Wang et al. [69]). 6. Simple Introduction of Application for Bio-inspired Synthetic Wet Adhesives The most interesting application of bio-inspired synthetic wet adhesives is focusing on biomedical field [53, 70, 71]. The key purpose for developing bio-inspired synthetic wet adhesives is to address the realistic problem that most current adhesives exhibit poor adhesion against tissue or skins surface due to the presence of body fluid. Meanwhile, one of important applications of synthetic wet adhesives is to be used as sealing and bonding materials based on their considerable tissue-adhesion property. Chitosan-catechol is one kind of most outstanding and representative cases of these synthetic wet adhesives, as effective hemostatic materials. For example, Ryu et al. [48] have developed injectable and thermo-sensitive chitosan/Pluronic composite hydrogels which are used for tissue wet adhesives and hemostatic materials. In typical case, chitosan conjugated catechol side chains as the backbone is cross-linked with pluronic F-127 copolymer to engineer temperature-smart synthetic adhesive. The as-synthesized adhesive is in a typical viscous solution state at room temperature but becomes a solidified gel state in response to body temperature at physiological pH condition. This temperature-responsive feature of synthetic adhesive enables it strong combination with soft tissues and mucous layers along with considerable hemostatic properties. As expected, such kind of bio-inspired adhesive can be an ideal candidate as drug delivery, tissue adhesives, and antibleeding materials. As for bleeding problems after syringe needle removal, the same group has developed a haemostatic hypodermic needle which can effectively prevent bleeding after tissue puncture [72]. In details, the surface of the syringe needle is decorated with lightly cross-linked chitosan-catechol biomacromolecule coating (Figure 5a). Upon inserting tissue, the coating is rapidly wetted by the tissue fluid, and then changes from a solid state to soft gel state to realize in situ sealing of punctured sites. As a result, the decorated needle can realize complete prevention of blood loss with extending time by employing haemophiliac animal models (Figure 5b-5c). Finally, the researchers observe 100% survival in haemophiliac mice following syringe puncture of the jugular vein. Inspired from the above research work, our research group has developed one kind of novel thermo-responsive wet adhesive as named Chitosan-Catechol-poly (N-isopropyl acrylamide) (Chitosan-Catechol-pNIPAM)[73]. The as-synthesized Chitosan-Catechol-pNIPAM exhibits a reversible sol-gel transition behavior when temperature is cycled below and above its lower critical solution temperature (LCST), along with dynamic switching between lubrication and wet adhesion state on various materials (Figure 5d). Based on these excellent features, Chitosan-Catechol-pNIPAM can be used as smart excipient to realize controllable attachment/detachment on the surface of skin by employing simple heating/cooling

process (Figure 5e). Furthermore, the MTT cells experiment verifies its good biocompatibility. Finally, the responsive Chitosan-Catechol-pNIPAM adhesive is coated onto the surface of syringe needles, the functionalized needles exhibit low friction when inserting it into the tissue but instant haemostasis after removing the needles from punctured sites of mouse veins (Figure 5f). In addition to be used as functional hemostatic materials, bio-inspired synthetic wet adhesives can also be used as novel drug delivery systems. Among, chitosan-catechol synthetic adhesive is very suitable as an adhesive depot for drug delivery systems [74, 75], because of its good biocompatibility and excellent tissue wet adhesion capability. For example, Lee et al. have found that the release of human-insulin from chitosan-catechol muco-capsules can sustain for as long as 4 h, while insulin released from unmodified chitosan muco-capsules reaches a maximum in just 30 min [54]. Finally, the researchers believe that chitosan-catechol system will be an excellent candidate for mucosal drug delivery polymeric platforms. Also, chitosan-catechol synthetic wet adhesive can be used in the field of tissue engineering as cartilage repair materials based on its state transition from soft gel state to solid 3D networks [76]. Furthermore, chitosan-catechol material exhibits the possibility to be used as biosensor for redox-active detection of bacterial metabolites[77]. Messersmith’s research group has developed adhesive hydrogels based on the cross-linking of catechol with tetra functional branched and linear poly (ethylene glycol) (PEG) [45], the adhesive hydrogels can be used as surface coatings for antifouling [78], anti-bacteria as for biomedical and industrial applications. Compared with Dopa-based synthetic copolymers adhesives, coacervate-inspired wet adhesives also present potential application as functional materials. For example, Stupp et al. [79] have developed coacervate-based membranes materials based on the strong electrostatic interactions between the oppositely charged biomacromolecules, while Mata et al. have developed a robust membrane based on co-assembly of polypeptide (ELP5) and peptide amphiphile (PAK3) [80]. All of these functional membrane materials show potential applications in tissue engineering.

Figure 5. Synthetic chitosan-catechol (CHI-C) biomacromolecule as tissue adhesion and hemostatic material. (a) SEM images of CHI-C coated needle and corresponding EDS analysis of surface chemical components, (b) haemostasis in the jugular veins of a factor VIII-deficient haemophilia mouse model following intravenous injections with bare needles (top) and the coated needles (bottom), and (c) blood loss from haemophilic mice as a function of time (adapted from the study by Shin et al. [72]). (d) Optical photographs showing the solution states of Chitosan-Catechol-pNIPAM, 20 °C is flow sol state and 40 °C is cross-linked gel state, (e) photographs of demonstrative process showing the dynamic attachment/detachment of Chitosan-Catechol-pNIPAM coated PVA hydrogel dressing over the skin upon heating and cooling, and (f) photographs of the in vivo haemostasis tests based on the needles coated/uncoated with Chitosan-Catechol-pNIPAM in a mouse femoral vein (adapted from the study by Xu et al. [73]). 7. Conclusion and Outlook Firstly, this mini review simply summarizes several typical wet adhesion mechanisms of natural marine organisms, such as mussel, sandcastle worms and barnacle. Subsequently, the authors indicate that how the scientists develop novel preparation methods and strategies in order to synthesize bio-inspired synthetic wet adhesives with strong interface binding ability, based on the current understanding of natural wet adhesion mechanisms. Furthermore, some of recent progresses on reversible underwater synthetic adhesives are discussed with considering future application requirement as intelligent adhesives in wet setting. Finally, the biomedical application of bio-inspired synthetic underwater adhesives is selectively summarized for their use as tissue adhesives, hemostasis materials, drug deliver, and tissue repair materials. Based on our superficial understanding, we underline that future bio-inspired synthetic wet adhesives should take into account those issues below: (1) although a series of mechanisms responsible for underwater wet adhesion of natural proteins for several marine organisms have been well revealed, how those anionic groups contribute to underwater adhesion still remains largely unknown and which requires further exploration in the future; (2) what’s the exact source of force for in situ and fast solidification of natural proteins adhesives to various types of wet surfaces? (3) how to obtain an optimal balance between viscous flow (resistance to interface energy dissipation) and elastic behavior (resistance to internal energy dissipation) for the synthetic polymers, which is still the key design principle to maximize the interface bonding strength; (4) the development of intelligent underwater reversible adhesives (the next generation of adhesive materials) based on the biomimetic design principles is still a hot topic and key challenge in this field, especially for realizing high adhesion difference value switching from lubrication state to high adhesion state (Figure 6); (5) could we or how to precisely control the molecular weight of synthetic polymers wet adhesives in massive production beyond laboratory level? Which is a key problem limiting their real application; (6) long-term stable storage of the catechol-based biomimetic adhesives is still a problem with considering the fact that

catechol groups are easily oxidized, which needs to be solved; (7) the development of high-performance underwater adhesives that can work on highly hydrated wet & slippery surface is indeed an urgent task in the future; (8) considering the real application of different kinds of synthetic adhesive materials in future, standardization should be built to compare the interface bonding forces of different adhesion systems from diverse measuring techniques (SFA, AFM or macro test). Overall speaking, although most of the synthetic underwater adhesives have not realized immediate applications in biomedical and industrial fields, they indeed have significantly enhanced our understanding of the underlying mechanisms of natural wet adhesion. Upon clearly solving these above issues, we believe that scientists can finally obtain a more comprehensive picture about bio-inspired underwater synthetic adhesives and explore their real application both in military and non-military fields in future.

Figure 6. Suggested design concept for future development of bio-inspired underwater adhesives: reversible/switchable synthetic adhesives. The figure shows that the interface state switching from high adhesion/high friction/attachment case to low adhesion/lubrication/detachment case. In details, external stimuli induce the dynamic change of the interface hydration from the conformation switching of responsive molecular chains, along with the corresponding exposure of the catechol groups.

Conflict of interest statement Nothing declared.

Acknowledgements This work was supported by the National Key Research and Development Program of China (2016YFC1100401), National Natural Science Foundation of China (51705507, 51605470), and Young Elite Scientists Sponsorship Program by CAST (2017QNRC0181). Dr. S.H Ma thanks to the project of Western Young Scholar “B” of Chinese Academy of Sciences.

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Robust underwater adhesives products are highly demanded both for industrial and biomedical field.




Understanding the interface bonding mechanism for robust wet adhesion of natural organisms is proceeding.




Novel natural proteins-based adhesives & synthetic polymer adhesives are urgently needed.




Optimal balance between interface interaction and cohesion of synthetic adhesives.




Future direction: reversible underwater synthetic adhesives beyond nature.

Conflict of interest statement Nothing declared.