Perspective pubs.acs.org/JACS
Perspectives on Mussel-Inspired Wet Adhesion B. Kollbe Ahn* Marine Science Institute, University of California, Santa Barbara, California 93106, United States materials to biomimetic wet adhesives, despite an increased number of related scientific publications during the same period (more than 10,000 peer-reviewed mussel-mimetic research articles were published in the past decade alone, 2006−2016). In this Perspective, we address current challenges and opportunities in marine mussel-inspired adhesion by reassessing the significant advances in this field and correcting misconceptions of the biological material, while providing motivation and strategies for future research.
ABSTRACT: Nature employs sophisticated control of a structure’s properties at multiple length scales to achieve its wet adhesion. However, the translation of such structures has very often been missing in biomimetic adhesives; in turn, their performance is significantly limited as compared to that of biological adhesion, e.g., from mussels. In this Perspective, we overview the major breakthroughs in this field, highlighting the recent advances that demonstrate that holistic multiscale translation is essential to biomimetic design. We argue that the multiscale coordination of numerous key elements in the natural adhesive system is essential to replicate the strong, instant, and durable wet adhesion of the marine sessile organism.
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MUSSEL-MIMETIC MOLECULAR ADHESION The first polyphenolic proteins were identified in 1981,5 after extraction from the mussel’s foot, and the structure−property relationships of more than 20 mussel-, barnacle-, and sandcastle worm-derived adhesive proteins have since been reported.7,8,11−14 In all cases, these proteins have an unusually high amount of phenolic residuese.g., 3,4-dihydroxy-Lphenylalanine (Dopa), tyrosine, and phenylalaninepiquing the interest of the biochemistry and molecular biology communities.5,13−15 However, it has been challenging for biological scientists in their early studies to investigate the contribution of each protein to molecular interactions and/or nanoscale interfacial adhesion. Advances in nanoscience and materials characterization, including the development of the surface force apparatus (SFA)16 and atomic force microscopy (AFM) methods,16,17 led to increasingly interdisciplinary research thrusts and enabled measurement of the molecular interaction forces and energies of native adhesive proteins12 and their synthetic analogues.18 This mussel-mimetic research “boom” started in earnest in 2006, when AFM was used to measure the strong singlemolecule adhesion force of Dopa (or catechol) on both inorganic titania surfaces and organic primary amine surfaces via metal coordination19,20 and Michael addition,21 respectively.22 In the following year, simple dip-coating of dopamine as an analogue of Dopa in mfp’s onto various inorganic and organic surfaces was reported, opening the door to broad use and applications of catechol-functionalized materials such as polydopamine.23 These technological improvements, coupled with theoretical advances, led to a rapid expansion of our understanding of the molecular properties of biological adhesives. As a key example, the bond lifetime of the bidentate hydrogen bond of catechol was predicted to be 106-fold higher than that of the monodentate hydrogen bond using Bell theory, and the significant difference in binding energy between monoand bidentate bonds was experimentally confirmed using SFA.24 The prolonged lifetime of bidentate binding is an obvious advantage of catechol chemistry, but the diversity of
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INTRODUCTION The field of biomimetics involves the transformation of the concepts and design principles developed by nature into manmade technologies. Underlying this approach is the notion that a deeper understanding of the chemical, structural, and mechanical principles at play in natural materials will lead to better translation of desirable features to controlled synthetic systems that can then be optimized to address technological demands that current synthetic materials cannot meet. There has been a great demand on wet adhesion because hostile wet environments have presented an insurmountable challenge for dental, medical, and industrial applications. For example, as most synthetic adhesives, coatings, and sealants suffer deterioration and detachment in the presence of moisture, state-of-the-art dental restoration fails in several years due to the weak bonding between dental resin and tooth surfaces,1−3 and the irreversible loss of tooth tissues is inevitable during the replacement of the defective restoration. To overcome those challenges, the marine mussel byssal plaque has become a leading model for the biomimetic wet adhesion approach. Within the plaque, six major proteins with substantially different sequences, mussel foot proteins (mfp’s) 1−6, have been isolated and their chemical and mechanical properties investigated.4−8 Each mfp is found at a different location in the foot and byssus, and each is believed to play a distinct and important role, as shown in Figure 1.7,9,10 Moreover, each mussel plaque contains a space-spanning soft, foamy core that is penetrated by collagen fibers originating in the thread and bounded by an iron-rich cuticle. However, these compositional gradients and rich structural features have been largely ignored in designing and engineering biomimetic underwater adhesives. We argue that this lack of consideration of the multiscale, multiphase features of the byssus has slowed progress in translating the impressive performance of mussel © 2017 American Chemical Society
Received: December 21, 2016 Published: June 28, 2017 10166
DOI: 10.1021/jacs.6b13149 J. Am. Chem. Soc. 2017, 139, 10166−10171
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Journal of the American Chemical Society
Figure 1. Cartoon of mussel byssus and proposed model of mussel’s adhesion mechanism. (A) Schematic overview of a mussel. (B) Schematic of mfp delivery from different precursors under mussel’s foot. (B′) Mfp incremental secretion: step 1, acid; step 2, primers (mfp-3 and mfp-5); step 3, reducing agent (mfp-6); step 4, bulk adhesives (mfp-2 and mfp-4) and collagen; and step 5, coating proteins (mfp-1). (C) Schematic showing the distribution of major mfp’s and collagen in byssal plaque.
bonding strategies and reactions that are available25as shown in Scheme 1is also critically important. These include
Numerous mussel-mimetic studies have argued that catechol functionality is both necessary and sufficient for mussel-mimetic adhesion,46 and the use of functionalized synthetic polymers decorated with catechol groups has become ubiquitous. However, although there are numerous advantages in using catechol chemistry in synthetic adhesives and coatings, a more complex picture of the molecular interactions that optimize interfacial adhesion and cohesion in the natural material is emerging. First, catechols are very sensitive to pH, with oxidization to quinone dominating at pH above 5.5. This leads to loss of adhesion via hydrogen bonds to the oxide surfaces and chelate bonds to surface metal sites,26,45,47 but it can be used to trigger oxidative cross-linking.18,23,27,45 Coordination bonds18,48 and metal ion coordination20,48−50 also lead to enhancement of cohesion when pH increases from acidic (mono-complex) to basic (bis- and/or tris-complex). However, such pH-mediated bonding performance enhancements occur only when the pH is adjusted af ter the adsorption of the catechol-containing molecules onto surfaces.18,23,27,45,51−53 In other words, catecholic molecules must adhere to a substrate before oxidative or coordination-mediated curing can take place to obtain molecular adhesion to substrates. Oxidation of the surface-binding catecholic sites due to high pH in a bulk solution would render it unreliable for adhesion; therefore, control of pH levels and an ability to change pH in situ are critical to use oxidative cross-linking as a mechanism for adhesion/cohesion enhancement. In nature, the mussel acidifies the surface to pH ∼2 under its foot, ensuring reducing conditions during deposition of its adhesive proteins (Figure 1B’).54 It is only after the foot disengages that the pH equilibrates to that of seawater (pH ∼8), as recently demonstrated through the use of pH-sensitive dyes and live imaging via fluorescence microscopy.54 In contrast, biomimetic
Scheme 1. Examples of Mussel-Inspired Catechol Chemistry
bidentate hydrogen bonds,24,26−28 metal−ion coordination bonds,19,20 borate complexation,29−31 redox reactions,32−35 autoxidation (via Dopa−quinone coupling6,21,27), Michael addition (via quinone−amine coupling6,23,36), and dehydration reactions37−39 with the aid of a vicinal amine.38 The varied chemical interactions available through catechol chemistry thus provide an extremely a versatile platform to enhance the wet adhesive and cohesive performance26,27,38,40−44 of a wide range of natural and synthetic materials.
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SO CATECHOL = MUSSEL ADHESION? The extraordinary adhesive strength of mfp’s,12,45 coupled to the diversity of surfaces and bonding strategies, has led many to ask: Are catechol groups alone responsible for wet adhesion? How can catechol groups (easily oxidized) be intact? 10167
DOI: 10.1021/jacs.6b13149 J. Am. Chem. Soc. 2017, 139, 10166−10171
Perspective
Journal of the American Chemical Society dopamine coating techniques use simple dip-coating of surfaces into dopamine-containing aqueous solutions23 at pH values of ∼8−8.5; the surfaces are then soaked for several hours to allow the auto-oxidative cross-linking reaction to come to completion.23 This catecholic coating method (polydopamine) is similar to the strategy used by plants, for example, to protect damaged fruit from microbial attack, and it has been used in traditional processes to dye leather using tea and red wine.55,56 However, such coating efforts are somewhat different from mussels’ strategy, and perhaps not surprisingly, the mussel’s strong and instant wet adhesion has yet not been reproduced in synthetic materials using this approach, although this method has been utilized for many practical thin coating applications. 23,56,57 For the sake of more practical adhesive applications related to storage time of catechol-based materials, a few possible avenues for improvement of oxidation stability is also suggested through the use of protecting chemistry. For example, the biologically relevant boronyl-Dopa complex (seawater contains 0.45 mM of borate) is stable against oxidation at pH values of 7−8, but can still exchange with highaffinity sites on mica, although the adhesion is time-dependent (>5 min).29 This result could lead to important new technological applications of catechol-based adhesives at neutral to basic pH.31
Various synthetic approaches have been reported to incorporate catechol groups to polymer backbones to achieve bonding performance enhancement, as shown in Table 1. Table 1. Major Breakthroughs in Mussel-Inspired Synthetic Adhesives Compared to Mussels’ Bioadhesion and Questions for Future Studies
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IMPORTANCE OF THE MOLECULAR CONTEXT IN LOCAL ENVIRONMENTS A second aspect of the natural mussel adhesive materials that has been neglected in most synthetic approaches is the importance of molecular context to catechol-mediated adhesion. In other words, is catechol content the only important parameter, or does the local environment in which the catechol groups reside also play a role? Again, studies of natural mussel-derived proteins suggest that the mere presence of similar amounts of Dopa does not guarantee similar adhesive performance. In particular, mfp-1 and mfp-3, which contain similar Dopa content but have very different primary amino acid sequences, exhibit distinctive adhesive performance.12 In SFA measurements, it was found that mfp-1, which the mussel uses in coating the protective cuticle, only coated a single mica surface but did not contribute to bridging interactions unless vigorously sheared,12,58,59 whereas mfp-3 readily adhered and bridged between the two mica surfaces, consistent with its role in adhesive surface priming.6,12,27,52 In addition, simplified synthetic peptides containing key residues from mfp-5 showed very different adhesive properties despite their identical Dopa content; these differences were attributed to varying bridging abilities associated with peptide length.60 It was also shown that the length of the peptide is crucial in iron-mediated bridging between surfaces, and Dopa in a peptide sequence does not by itself mediate Fe3+ bridging interactions between peptide films.61 In addition to physical constraints (i.e., peptide length), neighboring side chains within the peptide sequence should also play important roles. The abundance and proximity of Dopa and lysine residues in many mfp’s have long suggested their synergistic role in adhesion. Recent work confirmed that vicinal lysine residues play a key role in removing hydrated cations from mineral surfaces, thus promoting catechol binding to the underlying oxide groups.38 These studies provide the clear messages that molecular catechol bonding, while important, is not solely responsible for strong adhesion and that numerous other important factors must be considered in order to mimic complex biological wet adhesion.12
Polydopamine methacrylamide-co-acrylate has become the most popular polymer backbone for mussel-mimetic polymers because acrylate polymer is one of the most common polymers and relatively easy to handle in a laboratory.22 However, to obtain wet adhesion, the polydopamine methacrylamide adhesive film must be prepared by dip-coating in ethanol followed by drying of the surface.22 Significant lap-shear bonding strength (shear bonding strength of adhesives tested on a single-lap-joint specimen) of catecholic polypeptide36 and polystyrene,62 respectively, has been reported, but those adhesives were cured in a dry hot oven, and dry shear strength was measured. More recently, studies were performed to replicate the underwater processing and wet adhesion of mussels’ biological adhesion using polyeugenol acrylate,26 chitosan/chitin,63 alginate,64 acrylic phosphate polyelectrolyte,65 acrylic carboxylate polyelectrolyte,43 and acrylic polyampholyte52 (Table 1). Interestingly, when the polymers were decorated with various functional groups found in mfp’s, the phase behavior (underwater processing) and wet adhesion were very similar to those which we have observed in the adhesive mfp’s.27,43,52,65,66 These recent studies suggest the importance of the local chemical environment in mimicking biological wet adhesion, and future studies have opportunities to investigate the essential influences of vicinity, side groups, backbones related to underwater processing, wet durability, and bonding performance (Table 1).
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STRATEGIES FOR PROCESSING AND DELIVERY Marine mussels generate structured threads and plaques with highly controlled composition and spatial gradients of various 10168
DOI: 10.1021/jacs.6b13149 J. Am. Chem. Soc. 2017, 139, 10166−10171
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a structured fluid, and the continuous inverted fluid phase can be subsequently solidified into a load-bearing porous material.43 This suggests that pH- or salt-triggered solidification in the mussel plaque is plausible.
components that are presumably important for the load-bearing properties of the byssus (Figure 1). The use of multiple, sophisticated, and carefully timed steps is common in synthetic adhesive processing (e.g., etching, priming, coating, curing, etc.) in order to enhance bonding performance.67−69 To date, however, only a small number mussel-mimetic adhesion studies have attempted to apply a surface priming step to improve bond performance, and more sophisticated means of process control have not yet been employed.27,70−73 One challenge to biomimetic translation is that the means by which a mussel achieves control of architecture and processing is poorly understood. It has been proposed that mussels deliver the adhesive precursors from individual reservoirs to the ventral groove of the mussel’s foot via a microfluidic system. This would allow the interfacial, bulk, and coating mfp’s to be incrementally secreted to the substrate in sequence (Figure 1B’), while also allowing spatiotemporal control of the local environmental conditions, including the pH, ionic strength, and redox potential.74,75 This mechanism would require fluidic delivery of a material that can rapidly coat a variety of surfaces but can then undergo cross-linking and hardening to form a loadbearing holdfast within minutes. Coacervates (formed by a type of fluid−fluid phase separation driven by the association of oppositely charged polyions at a pH where the mixtures are electrically neutral)76,77 demonstrate the requisite properties low viscosity to enable delivery, low surface energy to promote wettingand are thus suggested as the means of biological delivery of adhesive proteins in both mussels8,78 and sandcastle worms.14,79 In complex biological fluids, coacervation likely occurs via a sophisticated balance between anionic/cationic residues, counterions, and hydrophobic/noncharged hydrophilic residues, and thus depends on protein composition, salt concentration, and pH.14,41,52,77,78 The dense, viscous surfaceactive fluid (the coacervate) remains phase-separated from water, as shown in Figure 2, and can thus be delivered via sheath flow to the substrate, where it spreads easily with low interfacial energy (
