European Polymer Journal 116 (2019) 134–143

Contents lists available at ScienceDirect

European Polymer Journal

journal homepage: www.elsevier.com/locate/europolj

Marine-inspired polymers in medical adhesion T

a a,b a,c,⁎
Diederik W.R. Balkenende , Sally M. Winkler , Phillip B. Messersmith
a
Departments of Bioengineering and Materials Science and Engineering, University of California Berkeley, Berkeley, CA 94720-1760, USA
b
University of California, Berkeley–University of California, San Francisco Graduate Program in Bioengineering, Berkeley, CA 94720, USA
c
Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA

A R T I C LE I N FO A B S T R A C T

Keywords: Medical adhesives that are strong, easy to apply and biocompatible are promising alternatives to sutures and
Bioinspired material staples in a large variety of surgical and clinical procedures. Despite progress in the development and regulatory
Tissue adhesion approval of adhesives for use in the clinic, adhesion to wet tissue remains challenging. Marine organisms have
Medical adhesive evolved a diverse set of highly effective wet adhesive approaches that have inspired the design of new medical
Mussel
adhesives. Here we provide an overview of selected marine animals and their chemical and physical adhesion
Sandcastle worm
Cephalopod
strategies, the state of clinical translation of adhesives inspired by these organisms, and target applications
Polymer biomaterials where marine-inspired adhesives can have a significant impact. We will focus on medical adhesive polymers
inspired by mussels, sandcastle worms, and cephalopods, emphasize the history of bioinspired medical adhesives
from the peer reviewed and patent literature, and explore future directions including overlooked sources of
bioinspiration and materials that exploit multiple bioinspired strategies.

1. Introduction have inspired. For a more general treatment of bioinspiration and

bioinspired materials development, the reader is referred to several
Medical adhesives that are easy to apply to seal wet tissues during excellent reviews [3–10]. Well-studied underwater adhesion specialists
surgery have enormous potential to replace invasive mechanical fixa- include the mussel, sandcastle worm, and octopus (Fig. 1) [11–14].
tions such as sutures and staples, or to provide fluid-impenetrable Basic science research has elucidated these animals’ highly-evolved wet
sealing of a suture line [1]. Most engineering and consumer adhesives adhesion mechanisms, and researchers have since incorporated these
exploit non-specific interactions (e.g. van der Waals), but these ad- chemical and physical wet adhesion strategies into medical adhesives.
hesive interactions are dramatically weakened in the presence of the Much of the work in mussel-inspired adhesion has focused on under-
high dielectric and ionic strength of physiological fluids [2,3]. Despite standing and mimicking the unusual adhesive proteins found in the
these challenges, a myriad of biological and synthetic adhesives have terminal plaque of the mussel byssus [15]. Sandcastle worms employ
been developed and approved for specific surgical procedures [4]. coacervate-forming protein adhesives to construct their sand grain
Clinically used tissue adhesives include fibrin, gelatin resorcinol, and dwellings [12]. Cephalopods, on the other hand, rely on anatomical
cyanoacrylates, all of which are considered to have shortcomings with features, in the form of suction cups, to adhere robustly onto wet sur-
respect to toxicity or mechanical performance [4]. They suffer from faces [14]. Moving forward, promising strategies in bioinspired ad-
poor adhesion or biocompatibility and fail to meet the requirements of hesives will likely involve incorporating multiple bioinspired elements,
many surgical procedures including sealing leaks in the lungs and for example mussel-inspired motifs together with a cephalopod-inspired
gastrointestinal system, fetal surgery, and most musculoskeletal repairs. suction cup microstructure or other combinations of chemical and
This unmet clinical need has motivated the development of synthetic physical adhesive strategies. Animals have evolved many strategies for
and bioderived adhesives, including polysaccharide and polyethylene adhering underwater, and incorporating these strategies into medical
glycol (PEG) based materials with improved adhesive strength and adhesives offers a tremendous opportunity to address unmet clinical
biocompatibility relative to clinically available formulations. challenges.
Here, our focus is on marine animals that firmly attach to biological
or mineral surfaces underwater and the medical adhesive materials they

⁎
Corresponding author at: Departments of Bioengineering and Materials Science and Engineering, University of California, Berkeley, 210 Hearst Mining Building,
Berkeley, CA 94720-1760, USA.
E-mail address: [email protected] (P.B. Messersmith).

https://doi.org/10.1016/j.eurpolymj.2019.03.059
Received 9 January 2019; Received in revised form 27 March 2019; Accepted 30 March 2019
Available online 04 April 2019
0014-3057/ © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
D.W.R. Balkenende, et al. European Polymer Journal 116 (2019) 134–143

Fig. 1. Underwater bioinspiration for medical adhesives. (a) Mussels strongly attach to underwater surfaces with a protein-based plaque and can withstand the strong
forces of crashing waves. Image was generously provided by and reused with permission from Gary McDonald. (b) The sandcastle worm builds tubular dwellings of
sand particles cemented together with adhesive proteins. Photo of a sandcastle worm (left, arrow) and a worm inside a tubular dwelling in construction. The
(untanned) white granules contain the coacervated and un-cured adhesive. Reproduced under the terms of the Creative Commons Attribution 4.0 International
License [7] Copyright 2016, John Wiley & Sons, Inc. (c) A common New Zealand octopus uses suction cups to reversibly adhere to diverse surfaces and can use this
attachment to move around its environment. Courtesy of the National Aquarium of New Zealand.

2. Mussel-inspired adhesion composition and protein sequence, recent research has shown that
other chemical and physical phenomena including iron crosslinking,
2.1. Biology of mussel adhesion phase inversion and temporospatial control during byssal thread fab-
rication are essential to overall mussel adhesion [11,27,28]. A funda-
Mussels secrete protein-based byssal threads to tether themselves to mental understanding of mussel adhesion has inspired many scientists
diverse underwater surfaces, including rocks, ships, and other organ- to improve the performance of medical adhesives [29].
isms. At the distal end of these threads, adhesive proteins form an ad-
hesive plaque that securely anchors the thread (and thus the mussel) to 2.2. Mussel-inspired tissue adhesives
the surface, allowing the mussel to withstand the high shear forces of
waves [15–22]. The mussel’s adhesive plaque is arguably the most well- 2.2.1. DOPA oxidation, crosslinking and interactions with tissue surfaces
studied marine bioadhesive (Fig. 2). A landmark 1981 paper from the In theory, a robust medical adhesive would form covalent interfacial
Waite lab identified a mussel adhesive protein in the byssus that had interactions with the tissue surface. Thus, many clinically approved
repetitive decapeptide sequences with a high concentration of 3,4-di- synthetic adhesives rely on reactive motifs (e.g. aldehyde, N-hydro-
hydroxypheny-l-alanine (DOPA), a post-translational modification of xysuccinimide (NHS) esters) that target lysine and cysteine residues
tyrosine. DOPA was hypothesized to mediate the high adhesion that are omnipresent at the surface of most targeted tissues [30]. In the
strength of these proteins [23]. Waite and colleagues went on to mussel and in mussel-inspired medical adhesives, DOPA facilitates wet
identify numerous other byssal proteins, each with a specific sequence, adhesion to the substrate. As an amino acid, DOPA has thus far only
biodistribution and function [22]. been identified in the proteins of marine adhesives, likely due to its
In particular, mussel foot proteins (mfps) found at the adhesive versatile reactivity which could interfere with organisms’ biochemical
interface have high DOPA content. Surface force apparatus measure- processes [11].
ments of extracted and recombinant mfps clearly demonstrated the In alkaline seawater or after the addition of a strong oxidant (e.g.,
contribution of DOPA to bioadhesion [21,24]. In another fundamental NaIO4), catechols convert to reactive o-quinone species and can cova-
study, single molecule force spectroscopy experiments demonstrated lently conjugate with tissue surfaces via many possible reaction path-
the high adhesion strength of an isolated DOPA amino acid, furthering ways (Fig. 3). A similar pathway in the bulk of the plaque leads to
the hypothesis that DOPA, specifically its catechol side chain, mediates protein crosslinking, thereby contributing to elastic properties of the
robust adhesion [25]. In the interfacial proteins with the highest DOPA mussel byssus [11]. Importantly for tissue adhesion and perhaps also
content, DOPA was often flanked by the positively-charged, nitrogen- for mussel adhesion, o-quinone is highly reactive towards tissue-bound
containing amino acids lysine and arginine [26]. Experiments with lysine and cysteine residues via nucleophilic addition or imine forma-
model siderophores (proteins that chelate iron) confirmed that catechol tion (Fig. 3) [31]. Although the exact reaction pathways are still under
and amino functional groups contribute synergistically to wet adhesion investigation, it is clear that DOPA can form covalent bonds with nu-
in a spatially-dependent manner [26]. In addition to amino acid cleophilic substrates.

Fig. 2. The mussel byssus. Mussels secrete many byssal threads to securely attach to underwater surfaces and withstand the high forces exerted by waves. During
formation of a byssal thread, glands along the mussel foot secrete a mixture of byssal collagens and mfps that self-assemble and solidify into the thread shaft and the
adhesive plaque. The core of the adhesive plaque consists of a porous complex coacervate with mfps with low DOPA concentrations (mpf 2, 4). Mfps at the adhesive
interface (mfp 3, 5, 6) have high DOPA content.

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Fig. 3. DOPA’s reactivity leads to multiple chemical pathways relevant to wet tissue adhesion. DOPA’s side chain, catechol (1), forms the highly reactive o-quinone
(2) intermediate upon (auto)oxidation with dissolved oxygen, a strong oxidant (e.g. NaIO4) or basic conditions. o-Quinone can then react with tissue pendent lysine
or cysteine residues to form covalent interfacial bonds via Michael-type addition (3, 4) or Schiff base formation (5). Alternatively, tanning of o-quinone also results in
polyphenol crosslinks (6), which contribute to the elastic properties of the byssus or synthetic wet adhesives.

In synthetic materials, DOPA or catechol is often used for both ad- progressed to clinical use. Later, Biopolymer Products of Sweden dis-
hesion (binding to substrates) and cohesion (crosslinking of the ad- closed in a patent the use of small, bioderived mussel adhesive dec-
hesive material), and there are several common strategies for oxidizing apeptides that were combined with charged polysaccharides (e.g. he-
or crosslinking DOPA. The formation of coordination bonds between parin, chitosan) and tested these as corneal adhesives [41,42]. For this
DOPA and Fe3+ has been extensively studied as a crosslinking and particular application, the use of strong oxidizers or aldehyde com-
toughening mechanism in the mussel byssus and in mussel-inspired pounds could be avoided, thus greatly increasing the biocompatibility.
materials [32,33]. However, for medical applications, iron should be The only remaining commercial outcome of this early work appears to
used with caution, since soluble iron salts may increase bacterial be Cell-Tak™, an extract of adhesive proteins from the mussel byssus
growth and result in localized or systemic infection [34–36]. Swelling is that is available for non-medical applications including attaching non-
an additional concern in iron-coordinated catechol gels; due to the adherent cells to surfaces for microscopy [43].
dynamic nature of metal coordination bonds, hydrogels that are only In subsequent efforts, the Yamamoto group synthesized numerous
crosslinked via metal-DOPA coordination may swell, causing the gel to polypeptides as mussel-inspired tissue adhesives [44–47]. For example,
dissipate [37]. Oxidizing agents such as NaIO4 are regularly used to the addition of tyrosinase (X-Tyr-Lys)n (X = Gly, Ala, Pro, Ser, Leu, Ile,
crosslink DOPA. However, when using such oxidizers with DOPA- or Phe) resulted in the post translational modification of tyrosine into
functionalized polysaccharides, aldehyde formation via oxidative car- DOPA and subsequent oxidative crosslinking [48]. Tissue adhesion
bohydrate ring opening is important but often overlooked as a side experiments on dry pig skin with concentrated solutions of the poly-
reaction in these studies. Indeed, relying only on oxidative aldehyde tripeptides showed a shear tissue adhesion strength of 11 kPa. In an
formation in polysaccharides is enough to establish good tissue adhe- elegant approach, Deming and colleagues copolymerized lysine- and
sion. This was exemplified by a study from the Elisseeff group in which DOPA-functionalized α-amino acid N-carboxyanhydride (NCA) mono-
methacrylated chondroitin sulphate was treated with NaIO4 and re- mers into high molecular weight random polypeptides
sulted in the carbohydrate ring opening to yield aldehyde motifs [38]. (> 100 kg mol−1) [49–51]. This material was used to prepare moisture
Upon UV irradiation, the methacrylate motifs form a covalent network resistant bonds to aluminum, steel, glass, and plastics. In a related pa-
and the aldehydes form interfacial bonds resulting in a horizontal shear tent, Deming and coworkers hinted at the potential biomedical ad-
adhesive strength of 46 kPa to cartilage. NaIO4 oxidation and Fe3+ hesive applications [52]. Taken together, early bioinspired research
coordination are ubiquitous in the mussel-inspired adhesives literature, efforts focused on precise mimicry of the polypeptides of the mussel
but the benefits and drawbacks of each approach should be carefully foot proteins and, while they informed future investigations, they were
considered in the context of the intended application. later replaced with efforts to develop materials with simplified designs.

2.2.2. Materials with mussel-inspired proteins and peptides 2.2.3. Catechol-PEG materials
As Waite and colleagues discovered and characterized the proteins After Deming’s influential work, the focus of the field of mussel-
responsible for mussel adhesion, research teams have been striving to inspired materials shifted towards designs in which only one or a few
develop synthetic versions of mussel glue. Early efforts involved ex- bioadhesive elements are used to enhance wet adhesion. These ap-
tracted mussel adhesive proteins intended for a range of applications proaches facilitate clinical translation but admittedly suffer from iso-
including ligament reconstruction, skin grafts and dental restoration lating one or more components (e.g. DOPA) from a complex protein
[39]. Extracting adhesive proteins from mussels proved to be im- adhesive. In an effort to obtain adhesive hydrogels, Lee et al. reported a
practical and expensive; thousands of mussels are needed to obtain even 4-arm PEG macromer that was end-functionalized with DOPA motifs
1 g of pure adhesive protein [10]. Therefore, a polymer with grafted (cPEG, Fig. 4a) [53]. The addition of an oxidizing agent (NaIO4) to a
DOPA-containing decapeptides was synthesized in an effort to mimic solution of this polymer led to rapid gelation and adhesion to tissue.
the high molecular weight of mussel adhesive proteins [40]. Tissue cPEG was tested as a tissue adhesive and showed a shear adhesion
adhesive experiments on bovine corneal tissue revealed a shear ad- strength of 35.1 kPa towards porcine dermal tissue, a five-fold im-
hesive strength of up to 32 kPa; however, unintended DOPA reactivity provement over fibrin glue (Fig. 4b) [54]. In the first in vivo use of
resulted in a short shelf life and large variation in observed adhesion cPEG, Brubaker et al. secured transplanted islets to the liver or epidi-
strengths [40]. Despite this early research effort, neither material dymal fat pad of diabetic mice with cPEG [55]. The material secured

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Fig. 4. Mussel-inspired adhesives for fetal surgery. (a) Chemical structure of DOPA functionalized branched PEG polymer (cPEG). (b) Insertion of a fetoscopic
instrument during fetal surgery. After removal of instrument, a small defect is left in the uterus and the amniotic sac (fetal membranes). The sac defect does not heal,
leading to postoperative complications including membrane rupture and preterm birth. (c) Histology of the fetal membrane (pink) shows that the mussel inspired
sealant (purple) successfully sealed a trocar-induced defect. Reprinted from [56], Copyright 2010, with permission from Elsevier. (For interpretation of the references
to colour in this figure legend, the reader is referred to the web version of this article.)

the islets in place in vivo for up to a year, with little evidence of in- to exploit peptide cleavage by tissue elastase in vivo [66]. In another
flammatory response or fibrotic capsule formation. Islet transplantation attempt to obtain degradable 4-arm PEG hydrogels, Zahid and cow-
with cPEG and in sutured controls led to normoglycemia, reversal of the orkers functionalized 4-arm PEG polymers with photocleavable ortho-
diabetic phenotype, in the mice. nitro substituted catechol groups [67]. After oxidative formation of the
Sealing of the amniotic sac after fetal surgery has been an important hydrogel, irradiation with UV light resulted in photocleavage of the
strategic focus for marine-inspired adhesives. Fetal surgery can correct crosslinks and hence debonding of the adhesive.
some severe congenital abnormalities like spina bifida and twin-twin One drawback of PEG-based hydrogels is significant swelling which
transfusion syndrome in utero, but to access the fetus, surgeons must has the potential for postoperative complications such as blocked
puncture the amniotic sac (fetal membranes) [57]. This fragile mem- nerves. To address swelling, Barrett et al. reported the synthesis of 4-
brane does not heal or withstand suturing, and can rupture, leading to arm polypropylene-PEG (Tetronic) functionalized with DOPA (cT) [68].
high risk of preterm birth (Fig. 4c) [57]. Common commercial tissue Subsequent oxidative crosslinking (NaIO4) yielded a hydrogel that
adhesives were unsuccessful in this application [58]; however, marine- displayed a shear adhesion strength of 49 kPa and an absence of swel-
inspired adhesives excel at sealing in wet environments and are well- ling due to a thermally induced hydrophobic transition of the PPO
poised to address this unmet clinical need. With collaborators at the domains. Interestingly, a comparative investigation between cPEG and
University Hospital Zurich, our group reported cPEG based hydrogels as cT as amniotic sealant did not reveal a significant difference in critical
a promising material to seal induced amniotic sac defects (Fig. 4d) burst pressure when sealants were used to seal a membrane that was
[56,59,60]. Ex vivo evaluation of the sealant showed a comparable inflated until rupture [58].
acute tissue toxicity response to fibrin sealants [56].
Nerites Corporation explored PEG-catechols as synthetic mussel- 2.2.4. Polysaccharide materials
inspired tissue adhesives for medical applications. In a comparative Polysaccharides are strong candidates for mussel-inspired mod-
study, the authors compared 4-arm PEG based adhesives functionalized ification because they have a range of modifiable substitutions such as
with a single DOPA motif, tetra DOPA sequences and short DOPA-lysine primary amines (e.g. chitosan) and carboxylic acids (e.g. alginate,
sequences, respectively [61]. Surprisingly, they did not observe a sig- hyaluronic acid) to derivatize with phenolic motifs [4,69]. In one ex-
nificant difference in tissue shear adhesion strength between adhesives ample with hyaluronic acid, Cho and Haeshin Lee formed hydrogels of
carrying a single DOPA versus tetra DOPA sequences. However, upon dopamine-conjugated hyaluronic acid oxidized with NaIO4 [70]. Al-
addition of short DOPA-lysine sequences, a marked increase in lap shear though these hydrogels could also be formed by photo crosslinking of
tissue adhesion strength was found, confirming the synergy between methacrylated hyaluronic acid, the authors showed that catechol was
DOPA and lysine. Lee and colleagues also developed a library of linear essential for the formation of an adhesive interface. While such DOPA
copolymers of polycaprolactone (PCL) and 4-arm PEG macromers in containing hydrogels did not show appreciable pull-off adhesion to liver
which two PEG-arms are functionalized with DOPA [62,63]. With tissue (1.4 kPa), the authors observed an adhesive strength of 48 kPa to
hernia repair as a target application, these functionalized PEGs were heart tissue. In a similar fashion, the Cho group formed hydrogels of
coated onto surgical meshes and biological scaffolds to form materials hyaluronic acid functionalized with aromatic triols in alkaline condi-
with high adhesive strengths [62]. The authors showed that adding an tions or after addition of NaIO4 [71]. Interestingly, rheological tack
oxidant is necessary to form a strong adhesive interface. In another tests were used to qualitatively show that alkaline conditions lead to
approach from the same team, unreacted NaIO4 was incorporated into higher adhesion strengths. This observation may indicate that adhesion
the polymer coating via a solvent casting process, rendering the patches of DOPA-containing materials is sensitive to the oxidation method and
immediately adhesive upon contact with tissue [62]. While strong suggests different oxidation method-dependent kinetics or reaction
oxidants such as NaIO4 are perceived as potential biotoxins, bio- pathways. Additionally, hyaluronic acid conjugated with dopamine was
compatibility studies showed acceptable cell viability (> 70% cell combined with thermo-responsive PEO-PPO-PEO (Pluronic) to prepare
survival per ISO standard 10993-1) [62]. On a cautionary note, cyto- a lightly crosslinked injectable hydrogel [72]. Upon increasing the
toxicity of mussel-inspired hydrogels was mainly attributed to the temperature to 37 °C, adhesive hydrogels were formed. Tissue adhesion
generation of H2O2 during oxidation of aromatic diols [64,65]. This experiments on mouse skin revealed a pull-off adhesion strength of
effect could be reversed with the addition of catalase to suppress oxi- 7 kPa.
dative stress. Another polysaccharide of high interest for medical applications is
To introduce degradability into PEG-catechol hydrogels, one can chitosan, a (partly) deacylated chitin that is commercially derived from
exploit linkers that are photo- or hydrolytically labile or that are sus- crustaceans. One important commercial medical application of chitosan
ceptible to enzymatic cleavage. Our group introduced di-alanine (Ala- films is hemostatic wound dressings (e.g. HemCon®) [73]. Taking ad-
Ala) as spacer in DOPA functionalized 4-arm PEG macromers in order vantage of the hemostatic ability of chitosan, Lee, Park, and colleagues

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prepared hydrogels by reacting catechol functionalized chitosan (Chi-C) 2.2.6. Polymethacrylate materials
with thiol endcapped Pluronic [74]. These hydrogels had a pull-off There is a large research effort to incorporate DOPA into poly-
adhesive strength of 15 kPa, and reduced blood loss when applied as a methacrylates to develop wet adhesives for engineering and tissue
hemostat. InnoTherapy is currently pursuing these materials commer- sealing applications. The Grubbs group prepared adhesive hydrogels by
cially [75,76]. To improve the mechanical properties of bioinspired reacting poly(dopamine methacrylamide (DMA) - NHS ester acrylate -
chitosan hydrogels, Hwang and colleagues synthesized pyrogallol- acrylic acid) with thiol end-functionalized three-arm PEG, revealing a
functionalized chitin fibers that formed adhesive hydrogels after oxi- shear adhesive strength of approximately 12 kPa towards porcine
dation with NaIO4 or chelation with Fe3+ [77]. In another innovation dermal tissue [90]. In a report from Kuroda and coworkers, poly(DMA-
from Lee and coworkers, oxidatively crosslinked Chi-C was drop casted methoxyethyl acrylate (MEA)) was tested as dental adhesive with and
onto needle shafts to form hemostatic needles [76,78]. Intravenous and without the addition of Fe3+ salts [91]. The authors observed especially
intramuscular injection into mice using these coated needles revealed a strong adhesive bonds to dentin in the presence of Fe3+, and the pre-
complete prevention of blood loss due to self-sealing of Chi-C. Likewise, sence of saliva during adhesive application did not significantly reduce
the same authors also coated cotton swabs with Chi-C [79]. Simply the bonding strength. In an elegant approach to render methacrylate
swiping coated swabs onto a bleeding wound reduced blood loss in both based polymers biodegradable, Agarwal and coworkers copolymerized
normal and coagulopathic (diabetic) mice. a mixture of 2-methylene-1,3-dioxepane, DMA and PEG methacrylate
Alginate, a polysaccharide found in certain bacterial biofilms and monomers, resulting in randomly distributed degradable ester bonds in
brown seaweed, is also a promising material for medical adhesives. the polymer backbone [92]. Tissue adhesion experiments on fresh
Upon addition of Ca2+, alginate will form weak hydrogels due to the porcine skin revealed a shear adhesive strength of 6 kPa, with a further
formation of ionic bonds. Inspired by the tanning of brown algae, increase to 8 kPa and 13 kPa after the addition of H2O2 or Fe3+ salts,
Bianco-Peled and colleagues oxidized a solution containing phlor- respectively.
oglucinol, alginate and Ca2+ to form adhesive hydrogels [80]. De- Polymethacrylates containing catechol were also used in a com-
pending on the concentration of each component, the authors observed bined mussel- and gecko-inspired adhesive material in which the wet
tissue shear adhesive strengths from 17 to 25 kPa. In a subsequent re- adhesive capabilities of the catechol were combined with the dry,
port, the same authors investigated the influence of alginate con- structural adhesive strategies used by many organisms including geckos
centration in combination with various phenolic compounds as a sea- [93–95]. Geckos’ impressive climbing abilities are due in large part to
lant using a burst device [81]. In such a device, a hole in a fluid-filled nanofibers on their foot pads that provide a large surface area for non-
chamber is covered with cellulose and the sealant. Then, the chamber is specific interactions like van der Waals forces. However, gecko feet, as
inflated and the pressure at which the sealant bursts is recorded. Con- well as many synthetic gecko-inspired materials, have limited adhesive
trary to their previous results, no significant difference in burst pressure abilities in wet environments as water disrupts these non-specific in-
was detected in the presence or absence of phenolic compounds. In teractions [93,96,97]. It is likely for this reason that geckos are less
addition, two of the polyphenolic compounds (epicatechin and morin) active during rainy weather [98]. To overcome the reduced wet adhe-
appeared to reduce the adhesive performance. sion of synthetic nanofibrillar-patterned materials, our lab reported the
To increase the tissue adhesive strength of alginate gels, Mooney first gecko- and mussel- inspired wet adhesive: nanopatterned PDMS
and coworkers prepared a family of double network hydrogels that coated with a DOPA-containing poly(DMA-co-MEA) [99,100]. In dry
contain alginate, Ca2+ and a second covalently crosslinked polymer conditions, adhesion was doubled compared to uncoated nanos-
such as poly(acrylamide) or NHS-crosslinked chitosan. These materials tructures, and in wet conditions, the coated samples could maintain the
adhered to diverse tissues [82]. In a control experiment using chitosan adhesive strength during 1000 contact cycles. The combination (na-
labeled with fluorescein, the authors observed significant tissue pene- nofibers and polymer coating) material exerted stronger adhesion
tration (30 μm), suggesting that mechanical interlocking of cationic forces in wet conditions than the gecko-inspired (nanofibers only)
polymers into tissue surfaces is at least partly responsible for the ad- material. This is one example of researchers combining multiple
hesive interfacial strength of these chitosan adhesives. bioinspired strategies to create materials to address challenging pro-
blems.

2.2.5. Gelatin-based materials

The use of DOPA or catechol to mediate adhesion in wet environ- 2.2.7. Materials for mucoadhesion
ments is usually considered to be mussel-inspired, but, to the best of our Mfps extracted from the threads and plaques of mussel byssal
knowledge, the first reported example of a marine-inspired medical threads were found to have mucoadhesive properties, but, at first, the
adhesive was actually inspired by the strong underwater adhesion of exact contribution of DOPA to this adhesion was unclear [39,101].
barnacles. Barnacle adhesive plaques had been found to contain tyr- Experiments with cPEG revealed significant mucoadhesion that could
osine and polyphenol oxidase enzymes that were hypothesized to be be attributed more definitively to catechol, since PEG alone is not
responsible for the strong interfacial adhesion [83,84]. Based on the mucoadhesive; this demonstrated DOPA’s ability to form effective in-
assumption that catechol-lysine crosslinks serve an essential role in terfacial bonds with mucosa [102]. Several other DOPA-containing
barnacle adhesion, the Erhan group reported the first marine-inspired materials have been tested for mucoadhesive properties. Cerruti and
medical adhesive – gelatin functionalized with aromatic diols [84,85]. colleagues infiltrated or conjugated chitosan with DOPA, hydrocaffeic
Adding polyphenol oxidase to a solution of functionalized gelatin re- acid or dopamine. These materials were mucoadhesive, and oxidation
sulted in a material that adhered to bone slices. However, protein was initiated upon contact with mucosa [103,104]. Likewise, Haeshin
analysis of barnacle adhesives subsequently showed an absence of Lee and coworkers observed increased gastrointestinal (GI) tract re-
DOPA [86], and Rittschof and Wahl reported that tyrosine and poly- tention due to mucoadhesive properties of Chi-C [105]. In addition to
phenol oxidase enzymes are connected to surface priming: eliminating DOPA-functionalized materials, oxidative coatings of polydopamine
marine biofilms before the establishment of permanent adhesion have also been evaluated. Sunoqrot and coworkers tested the mu-
[13,86–88]. Since the early barnacle-inspired work, Wang and cow- coadhesive properties of polydopamine coated mPEG-PCL nano-
orkers crosslinked DOPA-functionalized gelatin using Fe3+ or genipin, particles, targeting gastric mucosa for controlled drug release. Com-
resulting in an adhesive hydrogel [89]. Shear adhesion studies on moist pared to uncoated particles, the authors observed an increase in
porcine dermal tissue and cartilage showed an adhesion strength up to mucosal retention and a similar drug release profile [106]. Mussel-in-
25 and 194 kPa respectively. spired chemistries and materials are promising mucoadhesives and
poised to address many clinical mucosal adhesion challenges.

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3. Sandcastle worm inspired medical adhesives membranes of Yucatan pigs healed spontaneously, a phenomenon not
seen in human fetal membranes [114]. The complex coacervate glue
3.1. Chemistry of sandcastle worm adhesion was also tested for in utero spina bifida repair in a sheep model, but this
study showed fetal neuronal degeneration or necrosis [115]. While the
Sandcastle worms, Phragmatopoma californica, are small marine reasons for the negative response in this animal trial remain unclear,
worms that build their own underwater dwellings out of sand particles this body of work shows promise for the development of coacervate
that they cement together with protein coacervate glue that they ex- based injectable tissue adhesives.
crete (Fig. 1b) [7,12,27,107]. Coacervate formation is a thermo- Researchers have also taken inspiration from the mechanisms that
dynamically driven liquid-liquid phase separation in which oppositely sandcastle worms use to process their adhesive and its precursors.
charged (amino acids in) proteins are triggered to phase separate by a Before coacervate formation, the sandcastle worm stores the two op-
change in temperature, pH or ionic strength. The exclusion of water positely charged proteins in separate secretory granules inside its
during coacervation results in the formation of a concentrated macro- glands [12]. Because proteins are stored in granules, the proteins are
molecular liquid that can solidify into a porous solid [108]. The rapid stable at the acidic pH of the glands but destabilize upon contact with
formation of solid coacervates by marine organisms has been hy- seawater. This strategy is a practical approach to overcome high protein
pothesized to be triggered by injection of proteins from acidic storage viscosity and prevents premature coacervate formation inside the
glands into seawater (pH ∼ 8.1) while, simultaneously, Ca2+ and Mg2+ glands. Inspired by this secretion approach, a collaboration between the
ions coordinate with phosphorylated serine residues [109]. As the groups of Langer, Lin and Karp coated particles of a highly viscous
sandcastle worm constructs its dwelling, after initial coacervate for- polymer, poly(glycerol sebacate acrylate) (PGSA), in alginate, resulting
mation, the excreted adhesive is further slow-cured via oxidative DOPA in a low viscosity, injectable aqueous dispersion [116,117]. After in-
crosslinking [12]. While the proteinaceous cement of the sandcastle jection of the nanoprecipitate dispersion, positively charged protamines
worm contains DOPA residues (Fig. 1b), these reactive amino acids are were added, and the material rapidly coalesced. Formation of a solid
mainly indicated for cohesive protein crosslinking via polyphenol for- was achieved after rapid crosslinking of the viscous polymer using high
mation and DOPA-cysteine crosslinks. This suggests that the adhesive intensity UV irradiation (10 s, 380 mW cm−2). Tissue adhesion studies
interface mostly relies on non-specific interactions [12,109]. Inspira- onto epicardium tissue showed a pull-off adhesive strength of 14 kPa
tion from marine coacervate formation has led to the development of and cell viability studies indicated cytocompatibility. Commercial ap-
several medical adhesives. plication of PGSA is currently pursued by Gecko Biomedical with a
recent approval for clinical use in Europe.

3.2. Sandcastle worm-inspired materials

4. Adhesives inspired by cephalopods
Inspired by the proteins involved in complex coacervate formation
in sandcastle worms, Stewart and coworkers developed several complex
4.1. Anatomy of cephalopod adhesion
coacervate tissue adhesives. As an analog to the phosphorylated anionic
proteins of the sandcastle worm’s coacervate, the authors synthesized
Mussels and sandcastle worms secrete proteinaceous adhesives that
poly(monoacryloxyethyl phosphate-co-DMA). To mimic the cationic
are intended to form a permanent holdfast. However, in nature, as in
protein, gelatin was functionalized with primary amines (Fig. 5b)
the clinic, adhering reversibly or temporarily can be quite useful.
[110]. A fluid coacervate was observed upon addition of Ca2+ to an
Cephalopods, a class of mollusks that includes octopus, squid, cuttle-
acidic solution that contained both polyelectrolytes at low pH (Fig. 5c).
fish, and nautilus, adhere to underwater surfaces temporarily for nu-
Mimicking sandcastle worms’ adhesive secretion into basic seawater, a
merous purposes including prey capture, mating, camouflage, and lo-
shift to basic pH led to solidification of the synthetic coacervate. The
comotion [118]. As in gecko and sea star adhesion, most cephalopod
coacervated adhesive was well tolerated in vivo and adhered to bone in
adhesion is the result of anatomical features, like muscular suction
a rat model of craniofacial reconstruction [111]. To improve the ad-
cups, or suckers, that adhere reversibly to surfaces [14]. However, some
hesive strength, the same authors also prepared a double network hy-
species in four cephalopod genera secrete adhesives from epithelial
drogel that combined a complex coacervate consisting of poly(mono-
gland structures in different parts of the body to accomplish specially
acryloxyethyl phosphate-co-DMA) and poly(acrylamide-co-
evolved functions including camouflage (Euprymna), attaching to un-
aminopropyl methacrylamide) with a PEG diacrylate hydrogel [112].
derwater plants (Idiosepius), enhancing adhesion of the digital tentacles
While the presence of DOPA in sandcastle worm glue is hypothe-
(Nautilus), and improving mechanical adhesion (Sepia) [118]. The
sized to primarily serve a cohesive role, synthetic sandcastle worm-in-
biochemical makeup of these adhesives in each genus is still an active
spired materials can become adhesive to tissue when oxidized with
area of investigation, but early evidence suggests that they are com-
NaIO4. In collaboration with TissueTech, the Stewart group tested these
posed of carbohydrates or protein [118–120]. As the biochemistry of
adhesive hydrogels to seal defects after fetal surgery [56,113]. In an ex
these adhesives is elucidated, they may inspire synthetic mimics, but
vivo experimental setup, they demonstrated that complex coacervate-
thus far, most cephalopod-inspired tissue adhesives have mimicked the
coated fetal membrane patches outperformed uncoated patches in their
suckers that serve as muscular hydrostats to allow cephalopods to grasp
ability to withstand pressure when inflated with fluid. In an in vivo
objects and attach reversibly to underwater surfaces, including living
model of fetal membrane sealing in Yucatan pics, the same authors
tissue (prey) and irregular surfaces [14].
were unable to detect a difference in efficacy between a bioinspired
coacervate gel and a human amniotic membrane patch because the fetal

Fig. 5. Inspiration from the sandcastle worm. The

sandcastle worm connects sand grains to build
tubular dwellings. The load bearing bioadhesive
that connects sand particles consists of a complex
coacervate of highly phosphorylated anionic pro-
teins (Pc-3B) and cationic proteins (Pc-2).

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D.W.R. Balkenende, et al. European Polymer Journal 116 (2019) 134–143

Fig. 6. Octopus-inspired tissue adhesive patches. (a) It is hypothesized that Octopus vulgaris muscular hydrostats reversibly adhere to surfaces by compressing suction
cups, causing liquid to flow to the upper chamber, above the protuberance resulting in a low hydrostatic pressure. A vacuum is created in the lower chamber. Adapted
from [14]. (b) A simplified biomimetic suction cup patch showed wet tissue adhesion to a porcine heart. Reprinted with permission from [123] Copyright 2017
American Chemical Society.

4.2. Materials inspired by octopus suckers potential of suckerin and suckerin-inspired materials as bioadhesives
was furthered when Ding and colleagues produced recombinant suck-
Octopus arms are covered with suckers that serve as muscular hy- erin that could be crosslinked into gels and films across a range of
drostats. In Octopus vulgaris, there is an unusual small round protu- stiffnesses. When human primary fibroblasts, mesenchymal stem cells,
berance inside each flexible suction cup. It is hypothesized that com- or embryonic kidney cells were cultured on these suckerin materials,
pression of this protuberance against a surface leads to a spatial cells attached, were viable, and proliferated [129]. Together, this pre-
separation between water at the top of the chamber and at the surface, liminary work represents promising first steps towards biomedical ap-
effectively creating a vacuum that attaches the cup to the surface plications by demonstrating that suckerin materials are adhesive and
(Fig. 6a) [14,121,122]. Importantly, this type of adhesion is only strong cell compatible [128].
perpendicular to the surface. When a force in the plane of the surface is
applied, water can easily re-enter and eliminate the pressure difference. 5. Outlook
Pang and coworkers reported patterned surfaces that are inspired by
octopus suction cups [14]. The adhesive patches were prepared by re- Future research to develop bioinspired adhesives for clinical use
active molding of a polyurethane acrylate-based polymer into an in- may take inspiration from other sources, for example animals’ materials
verted silicon master. The authors compared various patterned geo- processing strategies, or may combine multiple adhesive strategies.
metries including perforated cylinders, cylindrical pillars, cylindrical These efforts should address the mechanical mismatch often found
holes and the vulgaris inspired sphere-in-cup architecture. In wet con- between tissue adhesives and target tissues. To achieve high tissue
ditions, the octopus inspired architecture outperformed other geome- adhesive strengths, it is essential to avoid a mechanical mismatch be-
tries. tween the tissue and adhesive. This mismatch exists in most commercial
Yang and colleagues also created sucker-inspired tissue adhesives tissue adhesives because the focus of development is usually on the
with a simplified cup architecture with no protuberance (Fig. 6b) [123]. formation of an adhesive interface rather than on the cohesive prop-
Silicon substrates were patterned with nanosucker geometries and erties of the adhesive itself. In nature, adhesive interfaces feature so-
tested on porcine epicardium tissue. Pull-off experiments showed the phisticated mechanical gradients to eliminate mechanical mismatch, for
patches had an adhesive strength of around 28 kPa on a wet glass example as found in the squid beak where the gradient of hardness and
substrate, and the patches maintained the initial adhesion strength for toughness from the tip of the beak to the underlying soft tissue spans
at least 80 min when submerged. Due to plastic deformation of PDMS, two orders of magnitude [130]. Squid beak gradients have inspired
the authors found that the suction cups showed a significant loss of synthetic mimics [131,132], and squid beak-inspired materials could
adhesion after 30 contact cycles. Patterned arrays of nanosuckers were address the unmet challenge in tissue engineering of adhering tissues
also used to develop a multilayer skin adhesive patch that could serve with different mechanical properties together, for example attaching
as a wearable temperature sensor [124]. Similar to observations of ligament to bone or tendon to muscle [133,134]. Developing adhesives
Pang, et al., the authors found that a cylindrical hole pattern only re- whose mechanical properties closely match those of the target tissue
sults in appreciable dry adhesion [14,124]. Taken together, octopus may necessitate development of different glue formulations for dif-
inspired patterned surfaces are an exciting new avenue of exploration ferent applications, but the improved adhesive performance would
for reversible tissue adhesive materials. likely be appreciable.
Another focus of future work should be to better understand pro-
4.3. Inspiration from squid sucker ring teeth cessing methods used by marine creatures to store, process, and deliver
the adhesive to the interface. Indeed, biomimicry of sandcastle worm
Like octopuses, squid also use suction cups on their tentacles to complex coacervate formation described above is an early example of
capture prey, but some squid species have a set of tough sucker ring this. However, further research into coacervate formation is necessary
teeth inside each sucker that they use to grip escaping prey. These to relate phase behavior to mechanical properties as a function of pH,
sucker ring teeth attracted attention from materials engineers after concentration, temperature and ionic strength. For most surgical pro-
Miserez and coworkers discovered that sucker ring teeth (SRT) were cedures it is desirable to prepare injectable formulations, which require
mainly composed of proteins, not chitin as previously suspected a combination of low viscosity and rapid setting kinetics to form a load
[125–127]. The authors showed that SRT proteins contain randomly bearing adhesive. An often-used strategy is injection of two solutions
oriented β-sheet nanocrystals dispersed in an amorphous matrix. This through a mixing chamber, one containing an adhesive polymer and the
protein structure gives SRT their relatively high elastic modulus [125]. other a (macromolecular) crosslinker. Notably, oxidative curing of
In the absence of covalent crosslinks, SRT proteins are readily soluble DOPA-containing proteins (e.g. mussel plaque, marine egg cases) is
and melt processable, which is distinctive for natural load bearing slow in nature. Slow oxidation combined with tissue penetrating
materials. Pena-Francesch and colleagues demonstrated that SRT pro- polymers may significantly increase (long term) interfacial adhesion via
tein (suckerin) extracted from squid SRT have promising tensile and lap mechanical interlocking and anchoring. Therefore, it may be desirable
shear adhesive strengths to various underwater surfaces [128]. The to combine rapid initial gelation with slow curing.

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Besides injectable formulations, tissue-adhesive patches are also has been achieved with this approach. Similarly, in the cases of sand-
valuable for medical applications. Gecko-inspired adhesive patches castle worm and cephalopod inspired materials, mimetic strategies that
cannot adhere in wet environments unless an adhesive coating is ap- utilize only the most essential adhesive elements may surpass more
plied or swellable amphiphilic blockcopolymers are used [135]. On the thorough mimicry attempts. This strategy also allows for the in-
other hand, octopus-inspired patches do not require such a coating corporation of additional chemical functionality. In fact, taking in-
[124]. Like the gecko inspired wet adhesive patches, adding a wet-ad- spiration from multiple biological sources, incorporating synergistic
hesive coating to octopus sucker-inspired patches may further improve elements inspired by the mussel, sandcastle worm, octopus, or other
their adhesion. Unlike in cephalopod adhesion, reversibility is not de- animals as yet unexplored, may give ample opportunity for future ad-
sired for most internal surgical applications, though it may be desirable vancement.
in treatment of skin wounds. One advantage of patch-based adhesives is In mimicking and taking inspiration from the ocean’s adhesives,
that the adhesive properties of patterned adhesive patches are largely researchers have developed materials with remarkable adhesion to wet
substrate independent. Thus, adhesiveness can, for the most part, be mammalian tissues. Moving forward, engineers developing novel ma-
decoupled from the bulk mechanical properties of the patch, improving terials are buoyed by basic science researchers, who are discovering and
material tunability. characterizing the wet adhesives of the natural world. This biological
Stimuli-responsive properties, including the ability to bond or de- understanding is paired with new breakthroughs from the lab bench,
bond on demand, may also be desirable in medical adhesives. Nitro- including new polymer synthesis strategies, nanofabrication techni-
catechols have been incorporated into mussel inspired materials, and ques, and crosslinking chemistries. In developing adhesives for the
these adhesives de-bond upon exposure to UV irradiation [67,136]. clinic, tissue wetness is an enduring hurdle. Researchers and clinicians
Another promising strategy to achieve de-bonding on demand in cate- alike should continue to turn to the seas, where this challenging pro-
cholic materials is to incorporate catechol-boronate chemistry, which blem has been solved many times over.
features a pH-dependent boronate ester bond. Thus, changes in pH can
be used to cycle a material between adhesive and non-adhesive states Acknowledgements
[137]. Other examples include the skin of many cephalopod species
which can respond to physical and chemical stimuli with a rapid change The authors acknowledge the National Institutes of Health
in color or texture [138]. Researchers have developed cephalopod skin- (1R01EB022031-01) for supporting this work. D.W.R.B. is grateful for
inspired materials for applications including films that change color support from the Swiss National Science Foundation early and ad-
when stretched, innovations towards the development of wearable vanced postdoc mobility grant (P2FRP2_165141 and P300P2_174468).
electronics, dynamic patterning, and materials that can change shape S.M.W. acknowledges the National Science Foundation (Graduate
and texture [138–140]. Phan, et al., expertly reviewed dynamic mate- Research Fellowship DGE 1752814) for support.
rials inspired by cephalopod skin [140]. Many such technologies have
the potential for eventual clinical translation to enhance tissue ad- Conflict of interest
hesives, especially those on the skin. Dynamic adhesives may be able to
report strain or respond to skin temperature, and materials that can de- The authors declare no competing financial interests.
bond on demand (e.g. after exposure to specific wavelengths of light)
may be valuable as, for example, adhesives to attach monitor leads to References
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