The Present and Future of Biologically Inspired Adhesive Interfacesand MaterialsCarrie E. Brubaker*,,,, and Phillip B. Messersmith*,,,,,,#

Biomedical Engineering Department, Materials Science and Engineering Department, Chemical and Biological EngineeringDepartment, and the Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois 60208, United StatesThe Institute for BioNanotechnology in Medicine and #the Robert H. Lurie Comprehensive Cancer Center, NorthwesternUniversity, Chicago, Illinois 60611, United States

ABSTRACT: The natural world provides many examples ofrobust, permanent adhesive platforms. Synthetic adhesiveinterfaces and materials inspired by mussels of genus Mytulishave been extensively applied, and it is expected thatcharacterization and adaptation of several other biologicaladhesive strategies will follow the Mytilus edulis model. Thesecandidate species will be introduced, along with a discussion ofthe adhesive behaviors that make them attractive for syntheticadaptation. While significant progress has been made in thedevelopment of biologically inspired adhesive interfaces and materials, persistent questions, current challenges, and emergentareas of research will be also be discussed.

INTRODUCTIONAdhesion across multiple length scales is integral to survival inthe natural world. Significant efforts have been undertaken bothto characterize the broad array of adhesive mechanisms utilizedby biological organisms in their natural environments, and tomimic such adhesive performance through synthetic platforms.These activities are carried out with the expectation thatbiologically inspired adhesives and coatings should findbeneficial and lucrative applications in medicine, technology,and industry. Furthermore, simplified synthetic mimics ofbiological adhesives facilitate better understanding of thesystems from which they are derived, by allowing systematicanalysis of adhesion parameters. In this Perspective, we willdiscuss the seminal findings and current status within the areaof biologically inspired adhesive interfaces and materials,specifically those that are nonreversible and intended forpermanent bulk and/or interfacial adhesion. We will introducealmost one dozen organisms that have inspired syntheticadhesive materials, or are expected to yield such materials in thenear future. As such, promising emergent research areas andapplications of biologically inspired adhesive interfaces andmaterials will be addressed throughout our discussion.Common experience tells us that adhesives and water do not

mix: bandages fall off during bathing and household glues donot work underwater. Therefore, it is unexpected and intriguingthat so many biologically inspired synthetic adhesives andcoatings are motivated by organisms inhabiting aquaticenvironments. Extensive research efforts have permittedsufficient characterization of the adhesive mechanisms utilizedby marine mussel species such as Mytilus edulis to engineermussel-inspired adhesive interfaces, coatings, and sealantmaterials. While many questions remain to be answered, the

path by which characterization of marine mussel adhesion hasled to innovative synthetic adhesives represents a model fordevelopment of adhesive materials inspired by organisms suchas the sandcastle worm (Phragmatopoma californica), barnacle,caddisfly larvae, and others. This underscores the first thematicsection of this Perspective, namely, the central importance ofcharacterizing candidate species. The remaining sections willaddress novel adhesive platforms, hybrid systems, and potentialapplications of nonreversible biologically inspired adhesiveapproaches. In addition to introducing approaches presentlyunder development, current challenges and future directionswill be emphasized, including basic research questions thatremain to be answered.

CHARACTERIZING AND MIMICKING NATIVEADHESIVES

Prior to developing engineered, biologically inspired adhesiveinterfaces and materials, it is necessary to identify an organismof interest and initiate the process of characterizing its adhesivemechanisms. The exploration of Mytilus edulis, its relatives M.californianus and M. galloprovincialis, and other fresh- and salt-water mussels, has progressed over many, many years.1,2

Subsequently, these efforts have yielded a broad array ofsynthetic mimics and derivatives, to be highlighted here; theapproach now represents a reliable model for understanding thenative systems and engineering biologically inspired materials,as follows. Attachment and adhesion by the organism are firstobserved in the native environment. Thereafter, upon isolation

Special Issue: Bioinspired Assemblies and Interfaces

Received: January 4, 2012Published: January 5, 2012

Perspective

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of sufficient quantities of putative adhesive secretions, analyticaltechniques in chemistry and biochemistry are harnessed tocharacterize the macromolecular (i.e., protein and/or poly-saccharide content) and molecular components of the material(i.e., amino acid sequence, post-translational modifications), aswell as addressing the role of trace components such as ionicspecies and metals. Additional topics to address include pH- orredox-dependent behaviors, and in the case of heterogeneoussecretions, the role of intermolecular interactions in adhesiveperformance. Where possible, a broad range of analyticaltechniques should be brought to bear on the unique adhesivemechanisms employed by biological organisms. As exemplifiedin the case of studies on native mussel glue, furthercharacterization by physical techniques such as atomic forcemicroscopy (AFM), surface forces apparatus (SFA), quartzcrystal microbalance (QCM), scanning electron microscopy(SEM), rheology, and mass spectrometry provide furtherinsight into the fundamental behavior of secreted biologicaladhesives.Engineered adhesive interfaces and materials inspired by

nature typically evolve in parallel with characterization of thenative platforms. As summarized in several excellent recentreviews,36 the mussel byssus is composed of a collection ofthreads terminated by adhesive plaques. It represents theinterface with the underlying substrate and is fabricated frommacromolecular components represented by several proteinfamilies: mussel foot protein (mfp)-1 through -6, and thepreCOLs. Early in the development of mussel-inspired adhesivematerials, Yamamoto and colleagues utilized N-carboxyanhy-dride (NCA) solution-phase polymerization and covalent cross-linking of 10-mers to generate mfp-1-mimetic polypeptides.7,8

As mfp amino acid sequences were further elucidated,recombinant mfp protein production was performed inSaccharomyces cerevisiae9 and Escherichia coli.10,11 One challengeof recombinant platforms is faithfully recapitulating the nativemfp post-translational modifications, which are known to play acentral role in the adhesive behavior of the byssal terminalplaque. For example, mfp-3 and mfp-5 are concentrated at theplaque/substrate interface and contain 2030 mol % 3,4-dihydroxyphenylalanine (DOPA),12,13 implicating this aminoacid in the robust interfacial adhesion demonstrated by theplaque. Other post-translational modifications identified inmfp's include phosphoserine, hydroxyarginine, and dihydrox-yproline.4 Optimization of recombinant mussel adhesiveproteins has been proposed as an affordable method for scalingup production of mussel-mimetic and other protein adhe-sives.14 Recently, the first example of recombinant mfpproduction in eukaryotic insect cells was achieved, permittingin situ post-translational modifications.15 Whether throughrecombinant or fully synthetic platforms, the ability to scaleaffordably provides a significant challenge in the area ofadhesive interfaces and materials. Additionally, the musselbyssus is a complex and heterogeneous macromolecularmicroenvironment composed of a handful of proteins withunique composition. It will be important to determine theimpact, if any, of interprotein reactions, and how theseinteractions may be reconstituted in a synthetic approach.For example, Waite and colleagues have proposed that thiolspresent in mfp-6 can reduce oxidized (quinone) DOPA in mfp-3 back to the catechol form, improving mfp-3 interfacialadhesion to inorganic substrates.16

DOPA is generated via hydroxylation of tyrosine by theenzyme tyrosine hydroxylase, to yield a post-translationally

modified amino acid that presents a dihydroxybenzyl, orcatechol, moiety. Following secretion of the proteinaceousbyssal adhesive precursor solution, DOPA catechol oxidation toquinone occurs at the alkaline pH of seawater, or possibly byredox or enzymatic mechanisms. DOPA is a potent effector ofinterfacial adhesion, as both the unoxidized and oxidized(quinone) forms of DOPA catechol demonstrate covalent andnoncovalent bonding capabilities with a broad range of organic,inorganic, and metallic substrates.17 For example, character-ization of DOPA catechol interaction with Ti by singlemolecule force spectroscopy identified a reversible, noncovalentbond strength of several hundred piconewtons.18 Further,DOPA-quinone covalently couples with primary amines viaMichael or Schiff reactions.19 Indeed, general reactivity tonucleophiles such as thiols and imidazoles is surmised, andidentification of 5-S-cysteinylDOPA in the mussel byssussupports this hypothesis.20 Promiscuity of substrate adhesionlikely represents a valuable performance characteristic of nativeadhesives, and one that should be emphasized in the design ofsynthetic engineered catechol-containing materials.In addition to general substrate adhesion, another remarkable

characteristic of DOPA and its catechol is structural simplicity:DOPA and DOPA analogues are small and easily incorporatedinto materials destined for adhesion to a wide variety ofsubstrates. As such, catechol-containing small molecules andpolymers have been applied in numerous platforms as adhesiveinterfaces and materials. For example, surface-anchored,catechol-presenting initiator species have been utilized forsurface-initiated polymerization techniques, including atomtransfer radical polymerization (ATRP),21 ring-opening meta-thesis polymerization22 (ROMP), and reversible additionfragmentation chain transfer (RAFT) polymerization;23 pro-posed applications of the surface-initiated approach includeengineering of surfaces demonstrating excellent protein and cellfouling resistance.24,25 Using the graft to technique, foulingresistance of modified surfaces has also been explored withcatechol-modified poly(ethylene glycol) (PEG) polymers,26,27

peptoid oligomers,28 and DOPA-containing mfp-1-mimeticpeptides.29 Substrate-independent catechol adhesion wasexploited in efficient layer-by-layer (LbL) assembly ofcatechol-modified poly(ethylenimine) and hyaluronic acidpolymers on Au, SiOx, and poly(methyl methacrylate)substrates.30 Photopolymerized DOPA-containing block co-polymer hydrogels have shown good adhesion to Ti in anaqueous environment,31 and DOPA modification impartsimproved mucoadhesive properties to physical gels derivedfrom thermosensitive block copolymers.32 In addition to thesemussel-inspired adhesive interfaces generated on ideal orhomogeneous surfaces, oxidatively cross-linked branched PEGsterminally modified with DOPA-mimetic 3,4-dihydroxyhydro-cinnamic acid have shown robust, nontoxic adhesion to humanfetal membrane ex vivo33 and to murine adipose tissue invivo.34 The finding that this catechol-PEG (cPEG) adhesivehydrogel remains intact and adherent to underlying tissue 1year following implantation34 highlights an important concernregarding the long-term stability of the adhesive materialsdescribed in this and subsequent sections. Namely, as noveladhesive interfaces and materials are inspired from mussel andother candidate species, it will be necessary to address both thelifetime of adhesive performance, and the environmental orbiological mechanisms of adhesive failure, especially inmaterials destined for commercial use.

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Progress achieved in the characterization and mimicry ofmarine mussel adhesion is just one example of biomimeticefforts underway. Here we introduce other organisms currentlyunder investigation; it is anticipated that the development andevolution of mussel-inspired adhesive interfaces and materialswill serve as a model for engineering analogous platformsinspired by these organisms. The sandcastle worm Phragma-topoma californica has also inspired adhesive materials. Thispolychaete generates its tubelike shelter by gluing togetherenvironmental inorganic particulate matter. Pc-1 and Pc-2 aretwo basic protein components of sandcastle worm cementdisplaying significant lysine and DOPA content.35 The acidicprotein Pc-3 is a family of protein variants containing 6090mol % serine, much of which is phosphorylated.36 In thepresence of divalent cations Mg2+ and Ca2+, simultaneoussecretion of these highly polar proteins is thought to result incomplex coacervation followed by pH-dependent hardeninginto a porous glue.37,38 Synthetic amine-presenting Pc-1 andphosphate- and DOPA-presenting Pc-3 mimics have beenprepared; when mixed, these polymers generate a surface-adherent and water immiscible complex coacervate, whichdemonstrated in vitro bonding performance over severalmonths between samples of bovine cortical bone.39 MixingPc-3 analogue and an amine-presenting modified gelatinpermitted thermally triggered coacervation at 36 C and pH7.4.40 These sandcastle worm mimetic adhesives have beenstudied in the repair of rat craniofacial defects.41 Sandcastleworm cement provides a wealth of synthetic adhesive designparameters to explore, including polymer charge density, pH-dependent behaviors, divalent cation concentration, andtemperature. Complementary DNA (cDNA) sequencing froman adhesive gland library42 and morphological analysis of thesandcastle worm adhesive system43 will provide new insightsinto engineered coacervate mimics.44 Like the sandcastle worm,the caddisfly larva is another aquatic organism that builds itstube-shaped shelter from environmental particulate matter,using a secreted silk-like adhesive glue. This silk adhesivecontains a (SX)n repeat unit in which half of the serines arephosphorylated and a significant portion of their paired aminoacids are basic.45 As in mussels and sandcastle worms, it appearsthat phosphate plays a valuable role in interfacial adhesion andmay provide a mechanism for promoting interfacial adhesion ofsynthetic materials on metallic surfaces.Barnacles attach to marine surfaces by secreting an insoluble

multiprotein adhesive complex at the interface of their ventralsurface and the underlying substrate. A combination ofhydrophobic interactions/aggregation, enzyme-dependent pro-tein cross-linking, and disulfide bonding is likely responsible forthe chemical nature of barnacle adhesion and cohesion, whereasno spectroscopic evidence for DOPA has been found.4648

Nanoscale globular protein domains and amyloid structureshave been observed in native barnacle adhesive,4951 andputative barnacle adhesive proteins Cp19k, Cp20k, Cp52k, andCp68k have been sequenced: their amino acid content supportsthe role of hydrophobic interactions and hydrogen bonding ininterfacial adhesion.4,52,53 In Balanus improvises, adhesivechemical content and mechanical stiffness are substrate-dependent,54 providing an intriguing design challenge forbarnacle-inspired adhesives. In the future, successful mimics ofbarnacle adhesion may chart the path toward incorporation ofamyloid-mimetic structural components, although their reticentsolubility presents a technical challenge. As in barnacleadhesion, it was recently determined that oyster adhesion

relies upon a hybrid, biomineralized secretion containingcalcium carbonate bound within a cross-linked protein matrix.55

Both of these organisms may inspire organicinorganiccomposite adhesive materials.Two relevant nonaquatic species have recently been

identified as candidates from which biologically inspiredadhesive mechanisms may be derived: the Australian frog ofgenus Notaden and gastropods such as snails and slugs.Whereas Notaden bennetti secretes a yellow-colored, protein-based tacky adhesive only upon provocation, many gastropodsachieve adhesive locomotion on a thin layer of sticky mucus onwalls and ceilings, even upside-down. Frog glue is a proteinhydrogel that contains hydroxyproline but lacks DOPA.56 Thenative glue has undergone mechanical testing, as well as invitro, ex vivo, and in vivo analyses of performance andtoxicity.5760 Looking ahead, once sequences are available,recombinant frog glue protein could offer a route to avoid thecytotoxic effects of trace nonprotein compounds found innative frog glue. Gastropod pedal mucus contains both proteinand polysaccharide components, and its intriguing nonlinearrheological properties have been explored.61 Thus theengineering of gastropod-mimetic adhesive substrates permit-ting locomotion along the interface presents very interestingresearch questions.As described in this section, a remarkable effort has been

invested in the identification, characterization, and mimicry ofadhesive-producing organisms, toward the goal of generatingnovel materials and platforms for adhesion. Nevertheless, thereis much fodder for future research efforts. For example, there ispresent debate about the role of metal ions such as Fe3+ inintra- and intermolecular protein cross-linking in the musselbyssus. Surface forces analysis has confirmed that Fe3+ plays arole in mussel foot cohesion,62 the basis of this mechanicaleffect being attributed to metal chelation by DOPA catecholand formation of coordination complexes,63,64 or covalentcross-linking.65 Given the fundamentally different mechanicalbehavior that arises from covalent versus coordination cross-linking,66 more thorough examination of these mechanisms willpermit the engineering of Fe3+-containing polymer platformswith interesting adhesive or mechanical properties. Asintroduced above, it will be worthwhile to further explore therole of amyloid in barnacle adhesion and determine whetherthis structural model might be incorporated into barnacle-inspired adhesive materials. The central importance of post-translational modifications in some of the systems introducedhere presents a challenge for preparing recombinant proteinmimics; polymer and polysaccharide engineering should also beemphasized. Lastly, several other species deserve morethorough characterization. As yet there is only a singlepublication that posits a role for microbial exopolysaccharidesas adhesive materials;67 further expansion of these efforts couldlead to new opportunities for natural and engineeredpolysaccharides as adhesives. Indeed, close attention must bepaid to research in the basic biological and biochemicalsciences, as biologically inspired research efforts may only beperformed on a foundation of basic understanding.

REDUCTIONIST AND HYBRID SYSTEMSEven the most sophisticated of the biologically inspiredsynthetic materials described above are simple compared tocomplex natural adhesives. However, sometimes even the mostprimitive biologically inspired material can provide powerfulresults, as can previously unimagined combinations of

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otherwise disparate adhesive strategies. Again we turn to themarine mussel for representative examples. While the presenceof DOPA in the mussel byssus was known relatively early on,68

subsequent elucidation of the primary amino acid sequences ofmfp-3 and mfp-5 revealed that a significant percentage of theDOPA amino acids in these two proteins are flanked by basicresidues such as lysine.12,13 Given that mfp-3 and mfp-5 localizeto the interface between the mussel terminal plaque and theunderlying substrate, it was hypothesized that combiningDOPA and Lys residues in synthetic polymer platformswould facilitate good interfacial adhesion.69 A dramaticallysimplified mimic of the catechol and amine rich mfp-3 and mfp-5 proteins exists in the form of dopamine (DA) and relatedsmall molecule catecholamines. Under basic conditions, DArapidly polymerizes in a process similar to the biologicalproduction of melanin. Polydopamine (pDA) adheres to anastounding array of substrates: a wide range of polymers,metals, inorganics, and even non-adherent substrates such aspoly(tetrafluoroethylene) (PTFE).70 Promiscuous pDA adhe-sion has revolutionized surface modification and adhesion atthe interface, as pDA serves as a primer for further surfacemodifications. In the last year, pDA has been utilized tofunctionalize Au surfaces for neural interfaces,71 to conjugatebone morphogenetic protein 2 (BMP2) onto TiO2 nano-tubes,72 for endothelial cell growth on pDA-coated electrospunpoly(caprolactone) nanofibers,73 and for precise spatial controlof cell adhesion and patterning,74 just to highlight the variety ofpotential substrates and applications. pDA coatings have evenbeen used to encapsulate and modify the entire surface of yeastcells, with excellent cell survival.75 One of the challenges thatmust be addressed in this field revolves around the robustnessof pDA coatings: although pDA modification permits broadsubstrate modification and a variety of functional properties,experience in our group has shown that pDA coatings aresusceptible to mechanical abrasion. Ultimately, the stability ofthese coatings will have a direct impact on the extent to whichsurfaces modified by interfacial adhesion will be utilized inmedical, consumer, or industrial applications.Another exciting aspect of synthetic, biologically inspired

adhesive materials is the potential for hybrid systems, includingthose that combine contrasting biological adhesive strategies.For example, in addition to the nonreversible interfaces andmaterials emphasized in this Perspective, a significant body ofwork has explored reversible adhesives inspired by fibrillarbiological adhesives such as those employed by the gecko.76 Ina hybrid approach, mussel-mimetic coatings have been appliedon gecko architectures to promote reversible adhesion to arange of substrates in both dry and wet conditions.77,78 There isremarkable potential for (bio)functionalization of nanoscalematerials; recently, iron oxide nanoparticle surfaces have beenmodified with small molecule catechol-derivatized clickableanchors,79 and pDA coatings have been used to immobilizefunctional enzyme.80 LbL assembly of clay and branchedDOPA-presenting PEG yielded a nanocomposite mimic ofseashell nacre.81 Climbing ivy (genus Hedera) produces anadhesive that contains nanoparticles,82,83 and it is anticipatedthat ivy-inspired composite adhesive materials will evolve as thisorganism is more thoroughly characterized.

EXPANDING POTENTIAL APPLICATIONSThanks to the broad range of surface modification approachesalready achieved by mussel-inspired coatings and adhesives, andthanks to the promise of other biological organisms currently

under investigation, the potential applications of biologicallyinspired adhesive materials are constantly expanding. Onemajor area of interest is the use of coatings in biological ormedical applications. For example, a suspension of native mfps-1, -2, and -3 dissolved in 5% acetic acid (Cell-Tak) iscommercially available as an in vitro cell attachment promoter;similarly, Kollodis, Inc. provides commercial recombinantfusion mussel foot proteins. Catechol-presenting smallmolecules and macromolecules, as well as pDA-mediatedsurface coatings, may be utilized to promote or prevent cellularadhesion on materials or surfaces relevant to the biomedicaldevice industry. For example, coatings of mfp polypeptidemimics permit stent endothelialization,84 hyaluronic acid andrecombinant mfp coacervates promote osteoblast proliferationon Ti,85 and pDA coatings facilitate mammalian cell adhesionon atypical materials such as PTFE.86 For fouling prevention,Au surfaces coated with catechol-presenting zwitterionicpolymers show excellent resistance to fibrinogen and lysozymedeposition,87 urinary stents coated with catechol-presentingPEG-based polymers effectively resist E. coli deposition invivo,88 and DA-modified heparin deposited on polyurethaneinhibited blood coagulation and platelet adhesion.89 In medicalimaging applications, iron oxide nanoparticles modified viaDOPA or DA have been utilized for targeted magneticresonance imaging (MRI),90,91 and Au nanoparticles coatedwith DOPA-conjugated heparin have been applied for liver-specific computed tomography (CT) scanning.92 Mussel-inspired adhesive interfaces have also expanded intobiotechnology applications: pDA-mediated coatings have beenexplored as novel surfaces for protein capillary electro-phoresis,93 and catechol-presenting copolymers have beenutilized as anchoring substrates for preparation of DNAmicroarrays.94

It is envisioned that the species addressed in this Perspectivewill also provide biologically inspired, high-performanceadhesive interfaces with important military or industrialapplications. Barnacles are notorious marine foulers, whoseattachment to boat hulls decreases naval cruising speeds andincreases fuel and cleaning costs.95,96 Ironically, the same routesutilized to characterize barnacle adhesion and identify futureadhesive materials may permit the design of surface-adherentnonfouling coatings to prevent barnacle attachment. Indeed,the finding that silicones disrupt barnacle adhesive curing97

could point the way toward synthetic, silicone-presentingadhesive coatings for marine fouling resistance. In anapplication relevant to industrial processing and environmentalconcerns, bisphosphonate-linked DA surfaces have been testedfor removal of uranyl ions from water,98 and other heavy metalremoval platforms are sought. The capability of pDA toincrease interfacial adhesion has been applied in compositematerials; for example, pDA-coated clay has been utilized forreinforcement of epoxy resin.99 Mussel-inspired coatings easilymodify polymer membranes: pDA coatings increase hydro-philicity and improve the performance of reverse osmosismembranes,100 and a poly(DOPA) coating permits heparinmodification of a common hemodialysis membrane (PVDF)for improved blood compatibility.101 Although this selection ofcurrent applications is by no means exhaustive, these highlightsare provided to demonstrate the array of potential uses forbiologically inspired adhesive interfaces and materials soughtfrom novel candidate organisms.

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CONCLUSIONSWhile mussel-mimetic materials have dominated the area ofbiologically inspired wet adhesive platforms, similar effortsshould also be focused on candidate species enjoying a lesserdegree of characterization, such that new families of novelmaterials may develop. These organisms may providealternatives to DOPA as a strategy around which to inspiresynthetic adhesives. Important discoveries are in the near futurefor other types of post-translationally modified amino acids, forpolysaccharide-based systems, for adhesion that depends ondiscrete structural units, and for multivalent or hybridplatforms. With the advent of nanoscale analytical techniquescomes the necessity for more thorough characterization ofadhesion at the nanoscale. These efforts will also contribute tobetter understanding of adhesive lifetime and adhesive failure,which will subsequently demand improved design and synthesisof molecules engineered to mimic biological adhesion. Thereexists a great deal of promise in this area of research, fordeveloping adhesive interfaces and materials with pertinentbiomedical, (bio)technological, industrial, consumer, andmilitary applications.

AUTHOR INFORMATIONCorresponding Author*Tel: +1 847 467 5273. Fax: +1 847 491 4928. E-mail: philm@northwestern.edu (P.M.); carrie.brubaker@epfl.ch (C. B.).

Present AddressLaboratory for Regenerative Medicine and Pharmacobiology,Institute of Bioengineering, School of Life Sciences, EcolePolytechnique Federale de Lausanne, CH-1015 Lausanne,Switzerland.

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