Review Cite This: ACS Biomater. Sci. Eng. 2019, 5, 2708−2724
pubs.acs.org/journal/abseba
The Chemistry of Bioinspired Catechol(amine)-Based Coatings Qinghua Lyu, Nathanael Hsueh, and Christina L. L. Chai*
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Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543 ABSTRACT: Surface coatings are widely used for the protection of underlying materials from erosion or contamination by the external environment, with biomimetic organic coatings based on catecholamine chemistry gaining prominence in recent years. Such coatings have found use in the biomedical field, e.g., in diagnostics, implant manufacturing, and biosensing, with coatings based on polydopamine (PDA) being the most popular. This Review aims to summarize the chemistry of catechol(amine) coatings, in particular the adhesion and cohesion properties of catecholamine-based coatings. This will allow for the design and synthesis of new polymers and coating materials in a more rational manner, enabling the selection of parameters and conditions to precisely control the structure of the materials formed. Particular attention is paid to the formation mechanism, structure, and variables affecting the properties of PDA, which is the most widely reported catechol(amine) coating. The use of other catechol(amine) precursors to synthesize biomimetic coatings is also discussed. A summary of the different methods reported in the literature to effect specific chemical properties on catechol(amine) coatings will allow the reader to best choose the technique to tailor coating properties for specific applications. KEYWORDS: surface coatings, biomimetic, catechol, catecholamine, biomedical, polydopamine
1. BACKGROUND AND OVERVIEW Surface coatings are widely used for the protection of underlying materials from erosion or contamination by the external environment. Furthermore, advances in surface modification techniques have enabled control of surface properties including the ability to confer new functionalities onto surfaces. This feature is especially significant in some areas in the biomedical field, e.g., in diagnostics, implant manufacturing, and biosensing.1,2 For example, a precise control of bio-interfacial interactions between surfaces and the bio-environment is critical for the efficacy and safety of medical devices. Thus, versatile, convenient methods for controllable surface modifications have rapidly developed in the past decade.3 The modification of surfaces that are immersed in the aqueous environment is a particularly challenging problem. Underwater adhesion is a difficult process to effect due to the presence of a thin hydration layer that prevents the contact between a polymer and the surface. Modified surfaces are also prone to underwater degradation. Yet in nature, there are many examples of marine adhesives that are able to glue underwater surfaces with high strength and durability.4 The most celebrated example is the marine mussel foot proteins (MFPs). MFPs enable mussels to adhere to surfaces (e.g., intertidal rocks) with great tenacity,5 and studies have identified that 3,4-dihydroxyphenylalanine (DOPA), a hydroxylated tyrosine derivative, and lysine residues are critical for adhesion (Figure 1).6 Detailed studies have shown that the high DOPA content in MFPs originates from post-translational modifications of tyrosine residues catalyzed by the enzyme tyrosine hydrox© 2019 American Chemical Society
Figure 1. Components of mussel foot proteins that are responsible for surface adhesion: DOPA and lysine moieties.
ylase.7 It is also known that DOPA is a naturally occurring catecholamine that exists in human and some animals.8 More importantly, DOPA is the precursor to other catecholamines such as dopamine (DA), epinephrine, and norepinephrine (Figure 2), which are neurotransmitters that play critical roles in controlling health and well-being.9−11 Interestingly, some of these catecholamines, e.g., DOPA and DA, are also precursors to biomaterials, and these building blocks can undergo oxidative polymerization leading to materials that vary in structure and function, e.g., eumelanin and pheomelanin.12,13 Inspired by the astonishing adhesion ability of DOPA-rich mussel adhesive proteins, much effort has been devoted to the use of catechol(amine)s and their derivatives in the Received: February 26, 2019 Accepted: May 17, 2019 Published: May 17, 2019 2708
DOI: 10.1021/acsbiomaterials.9b00281 ACS Biomater. Sci. Eng. 2019, 5, 2708−2724
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Figure 2. Structures of various catecholamines.
construction of adhesive materials with specific functionalities for various applications, e.g., the extensively reported DOPAcontaining adhesive polymers and hydrogels.14−16 In 2007, Messersmith et al. reported that under mildly alkaline conditions, aqueous dopamine was able to form polymeric coatings on virtually all tested substrates.17 This landmark paper catapulted catechol-based coatings to the forefront of materials science, and interest has not waned even after 12 years. Intriguingly, other studies have shown that compounds containing both the catechol and primary amino groups can also be used to fabricate catechol/amine-based adhesive materials for surface modification.14,15,18−20 So far, a number of other excellent reviews have been written on related subjects; however, these reviews have focused on the role of the catechol group in synthetic coatings,15,20−24 the mechanism and role of MFPs in mussel adhesion,5,25−27 or the polymerization process and applications of polydopamine (PDA)-derived materials.28−30 This work aims to capture salient points from these diverse topics, summarizing the current state-of-the-art of catechol and catecholamine-based coatings from a chemistry-based perspective, hopefully in a manner relevant to a biomaterials audience. While it is not possible to cite all primary literature due to the huge volume of work published in this area, primary literature was selected in this Review on the basis of having representative procedures and protocols with interesting applications included, wherever possible. The authors apologize if any readers’ works have been inadvertently omitted in the interest of brevity. Particular emphasis is made on the similarity in pathways that allow for adhesion/cohesion in the formation and adsorption mechanisms of these coatings. The synthesis of coating materials is also categorized by the different strategies and approaches employed by various groups, allowing the reader to explore the topic in a thematic way. Some perspectives on future developments are also raised.
Figure 3. Typical interactions of catechols with different surfaces.
In terms of hydrophilic substrates, e.g., hydroxylated silica surfaces and hydroxylated alumina, or organic surfaces containing polar groups, e.g., carboxylic acid, catechols are proposed to interact with these surfaces mainly via hydrogen bonding. To understand the interaction of catechols with such surfaces in a moist environment, Mian and Ganz et al. carried out simulation studies using density functional theory (DFT) calculations.33 These studies indicate that the binding energy of the catechol moiety onto hydroxylated silica surfaces (2.4− 6.2 kcal/mol) was higher than that of a water molecule onto silica surfaces (0.6−1.98 kcal/mol). This indicates the catechol moiety can competitively displace the pre-adsorbed water layers from the silica substrate.34 On hydrophobic surfaces, e.g., polymeric substrates lacking polar groups, van der Waals forces and hydrophobic interactions between the phenyl ring of catechols and surfaces play an important role in the adsorption process. Such interactions are illustrated by a study reported by Levine et al. in which the adsorption of mussel-derived peptide adhesives onto wet organic surfaces was examined using theoretical modeling approaches and experimentally using single-molecule force spectroscopy (SMFS).35 In the case of hydrophobic substrates containing aromatic groups, such as polystyrene and carbon nanotubes (CNTs), π−π stacking interactions between the catechols and these aromatic-rich surfaces are proposed to prevail over other weak non-covalent interactions. In another study reported by Wang et al., it was found that catecholic compounds exhibited stronger adsorption onto CNTs in water as compared to the non-aromatic compound cyclohexanol.36 The adsorption of catechols onto metallic or metal oxide surfaces is mainly through coordination bonding. The interactions between catechols with titanium and titanium oxide have been widely studied due to the wide applications of titanium-related devices in the field of biomedical and energy.37−40 Messersmith et al. first demonstrated that the force between a single DOPA molecule and a Ti surface is ca. 800 pN based on atomic force microscopy (AFM) measurements.41 This is much higher than that of tyrosine molecule (ca. 97 pN), i.e., DOPA with one less hydroxy group. In a study reported by Das et al., the adhesion strengths of DOPA, tyrosine, and phenylalanine on TiO2 surface were compared using SMFS;31 it was found that adhesion decreased in the order DOPA (ca. 383 pN) > tyrosine (ca. 97 pN) > phenylalanine (ca. 69 pN). These observations explain the critical role of the catechol group in the strong adhesion onto Ti and TiO2 surfaces. In addition, both studies noted that the oxidized form of DOPA, i.e., the DOPA ortho-quinone,
2. ADHESION/COHESION CHEMISTRY OF CATECHOL(AMINE)-BASED COATINGS In general, a strong adhesive should possess two fundamental characteristics for adhesion: (i) interfacial adhesion for the adsorption of materials onto substrates and (ii) cohesion for the intermolecular attraction of materials to stick together. In this section, the chemistry related to adhesion and cohesion properties of catechol(amine)-based coatings is discussed. 2.1. Interfacial Adhesion of Catechol. The interfacial adhesion of catechol(amine)-based coating materials is thought to be due to its catechol moiety which can interact with different inorganic or organic surfaces.31,32 The attachment mechanism(s) of catechols are substrate-dependent, as displayed in Figure 3. 2709
DOI: 10.1021/acsbiomaterials.9b00281 ACS Biomater. Sci. Eng. 2019, 5, 2708−2724
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Figure 4. Contribution of cation−π interactions to adhesion and cohesion.
Scheme 1. Oxidation of Catechol and Subsequent Cross-Linking
Scheme 2. Reactions between Dopaquinone and Thiols (Cysteine and GSH)
protonated amines (Figure 4), which is one of the strongest non-covalent interactions in water.43,44 2.2. Oxidation Chemistry of Catechol(amines). In order to form a good coating, catechol-containing molecules not only adhere to the substrate’s surface but also can interact with one another to provide cohesive strength within the bulk material. Both non-covalent and covalent interactions can contribute to the cohesiveness of catechol-based adhesives. Covalent interactions are critically related to the oxidation chemistry of catechol(amines), which is an important mechanism for cross-linking. Catechols are prone to oxidation under one or two electron conditions. In the context of oneelectron oxidation, semiquinone radicals are formed, while in the two-electron oxidation reaction, the o-quinone will be formed.22,45 Generally, the redox potential decreases with increasing pH, due to the effect of deprotonation of the hydroxyl groups of catechol. The semiquinone radicals formed
exhibited weaker adhesion than non-oxidized DOPA. This is presumably because the quinone, lacking both catecholic hydroxyl groups, cannot efficiently form hydrogen bonds to the surface.31,42 In terms of organic substrates containing amino or thiol groups, catechols are believed to covalently attach to these substrates via Michael addition or Schiff base formation through the reaction of the amino or thiol functionalities with the quinone moiety derived from the catechols. However, the covalent interactions between catechols and these surfaces have not been well elucidated. The force between oxidized DOPA and amine-containing surfaces was found to be significantly increased by up to 2.2 nN as compared to that between DOPA molecules and inorganic surfaces, suggesting the formation of a covalent bond.41 In addition, for organic surfaces bearing primary amino groups, the aromatic ring of catechol can further form cation−π interactions with 2710
DOI: 10.1021/acsbiomaterials.9b00281 ACS Biomater. Sci. Eng. 2019, 5, 2708−2724
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ACS Biomaterials Science & Engineering Scheme 3. Reaction of Dopaminoquinone with Histidine
Scheme 4. Formation Pathways of DHI- and DHICA-Based Eumelanin
Scheme 5. Polymerization Pathways of DHI and the Structures of Possible Dimers
reactive intermediates that can undergo both intra- and/or intermolecular nucleophilic trapping to give adducts.53 Thiols are very good nucleophiles that are capable of rapidly trapping o-quinone to form the corresponding adducts, mainly via 1,6Michael addition. This addition reaction is not regioselective, but the C5 position of the o-quinone appears to be favored.54 For example, in the presence of tyrosinase, both cysteine55 and glutathione (GSH)56 can react with dopaquinone (Scheme 2), to give the corresponding C5-adducts as the major products with minor C2-adducts. A similar reaction also occurs between
during the oxidation of catechol can undergo aryl−aryl coupling reaction (Scheme 1).46,47 In natural systems, this type of quinone-mediated crosslinking between catechols can be facilitated by the presence of enzyme (e.g., tyrosinase and peroxidase) or metal ions (e.g., Fe3+), contributing to the hardening of the naturally occurring biomaterials (e.g., MFPs).6,48,49 Experimental studies have also demonstrated that the adjustment of the cross-linking reactions could be applied to improve the cohesiveness of the synthetic materials.50−52 The o-quinones formed from catechols are also 2711
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ACS Biomaterials Science & Engineering Scheme 6. Polymerization Pathway of DHICA and the Structures of Possible Dimers
cysteine and DOPA in the formation of MFPs, and the cysteinyl adducts are proposed to play important roles in the solidification of mussel proteins, e.g., via conjugation with other proteins and to maintain the redox balance.57 Another nucleophile capable of trapping the o-quinones of catechol is the amines.54 Primary amines can react with quinones through Michael addition or Schiff-base formation. These reactions have been proposed to occur in the formation of the MFPs, and thus the cohesiveness of MFPs is enhanced.58 However, the definitive role of the lysine residues is still unclear. Additionally, it has been reported that the Michael addition between amines and o-quinones is highly dependent on the pKa of the amines such that the lower the pKa value, the faster is the formation of the amino adducts.22 To illustrate the reactivity of amines, the histidine adduct found in insect sclerotized cuticles, is formed through the attachment of the imidazole nitrogen of histidine (pKa = 6.10) at the 6 position of o-quinones (Scheme 3), rather than the attachment via the α-amino group of histidine (pKa = 9.18).59 This has also been verified experimentally under chemical oxidation conditions.60,61 2.3. Polymerization Chemistry of DHI and DHICA. In addition to the intermolecular nucleophilic reactions described above, o-quinones of catecholamines can also undergo intramolecular reactions.62 In the biosynthesis of melanin/ eumelanin, an intramolecular nucleophilic addition of the amino group to dopaminoquinone or dopaquinone results in the formation of 5,6-dihydroxyindole (DHI) and 5,6dihydroxyindole-2-carboxylic acid (DHICA), respectively (Scheme 4).12 It is worth discussing the oxidative chemistry of DHI and DHICA in this subsection, as many catechol(amine)-derived coatings may cross-link in an analogous fashion. Several methods to approach DHI and/or DHICAbased coating materials are also reported, which are systematically described in section 4. The complex polymerization process of DHI/DHICA and the aggregation mechanism of the derived oligomers have been clarified in recent years, and more details can be found in these references.63−65 Briefly, both of these indoles can readily undergo oxidative polymerization reactions to form eumelanin under enzymatic oxidation conditions. The oxidative coupling of DHI under enzymatic control generally produces 2,2′, 2,4′ and 2,7′-dimer (Scheme 5, pathway A). In the presence of metal cations such as Ni2+, Cu2+, or Zn2+, the 2,2′-dimer (pathway B) is mainly produced.66−68 Other oligomers connected via 4,4′-, 7,7′-, and 4,7′-bonding are also likely to be formed (pathway C), although they have not been isolated and characterized due to the complex cross-linking patterns of DHI.69
Several theoretical studies have suggested that the oligomers derived via pyrrolyl-type bond, i.e., 2,2′-, 2,4′-, and 2,7′bonding can adopt planar conformations, whereas the linear DHI dimer through biphenyl-type bonds, i.e., 4 and/or 7 connection possess nonplanar backbones, exhibiting hindered rotation (atropisomerism) at the inter-ring bonds.70,71 Therefore, it has been proposed by researchers that the nearly planar oligomers, e.g., 2,4′- and 2,7′-dimer- have a tendency to form layered aggregates via π−π interactions, while the twisted conformation of 4,4′-, 7,7′-, and 4,7′-dimer formed in pathway C (Scheme 5) cannot generate π-stacked aggregates but supports the formation of amorphous aggregates. In the case of DHICA, the C2-position on the indole ring is blocked by the carboxylic acid group and limited bonding sites are available for oxidative coupling. Thus, the polymerization of DHICA mainly leads to the oligomers via 4,4′-, 7,7′-, and 4,7′-connections (Scheme 6).72,73 Similar to the above discussion on DHI-based oligomers through biphenyl-type bonds, these oligomers exhibit atropisomerism due to steric hindrance about the single bonds linking phenyl units.74,75 Therefore, the indole moieties in the oligomers derived from DHICA are dramatically twisted with respect to each other, and that the conformation of DHICA-based oligomers does not favor the formation of π−π stacked aggregates.70,71 2.4. Roles of Non-Covalent Interactions in the Curing Process. Besides the above covalent interactions, non-covalent interactions including interactions with metal ions, hydrophobic interactions, cation−π interactions, and hydrogen bonding, are also proposed to play important roles in the cohesion process of biomaterials and synthetic adhesives.76−79 Among these, the complexation between catechols and metal ions (e.g., Fe3+, Mg2+, and Ca2+) is the most studied and has been successfully used in the design and synthesis of adhesive materials.21 Ejima et al. reported that a solution of tannic acid and iron(III) chloride, adjusted to pH 8 with sodium hydroxide, was capable of almost instantaneously forming a FeIII-tannic acid film on various substrates; the thickness of the film was 20 nm after five deposition cycles.80 This coating was found to be non-cytotoxic and showed pHsensitive behavior, disassembling at low pH. Ejima et al. proposed that the FeIII cation acted as a cross-linker, chelating three tannic acid molecules per cation; this gives rise to a strong FeIII-tannic acid film.80 Yang et al. found that changing the order of addition of reagents had an effect on the growth profile and thickness of the FeIII-tannic acid films.81 Cation-π interactions have also been studied in recent years, e.g., the interactions between the protonated amines and phenolic rings, enhancing the cohesiveness of catecholaminebased adhesive materials, as demonstrated in Figure 4.82−85 For example, Israelachvili et al. demonstrated the synergistic 2712
DOI: 10.1021/acsbiomaterials.9b00281 ACS Biomater. Sci. Eng. 2019, 5, 2708−2724
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DA between 0.1 and 2 mg/mL, the maximal thickness of PDA coatings after 24 h increases linearly with increasing concentrations (i.e., 20−25 nm for 0.5 mg/mL, 25−30 nm for 1 mg/mL, and 40−50 nm for 2 mg/mL). At concentrations of DA above 2 mg/mL, the maximal thickness of PDA obtained in classical Tris buffer at pH 8.5 after 24 h of polymerization does not dramatically increase but reaches a constant value at ca. 40−50 nm. Based on these, most research groups employ 2 mg/mL (10 mM, pH 8.5, 24 h) of DA as a standard condition to prepare PDA coatings. However, the reasons underlying the self-limiting thickness of PDA coatings are still not well understood. Interestingly, the immersion of a PDA-coated substrate in a freshly prepared DA solution at pH 8.5 for 24 h can give an additional 40 nm thick coating. Thus, PDA coatings with a controllable thickness of up to hundreds of nanometers can be achieved by successively repeated immersions in freshly prepared DA solutions at pH 8.5.94 The pH can significantly affect the deposition and formation of PDA coatings.93 At acidic pH, no obvious polymerization of DA is observed even after 48−72 h. The oxidative polymerization of DA at neutral pH is much slower than at pH 8.5, and only 1−3 nm thick coatings are obtained after 24 h. This is likely because at higher pHs, the phenolic group (pKa = 9.5) of DA is deprotonated, and this can lower the redox potential and facilitate the oxidation of DA. Nevertheless, in the presence of oxidants such as NaIO4 and CuSO4, DA undergoes polymerization to produce thick coatings under acidic or neutral conditions.95 Ponzio et al. reported the use of NaIO4 at pH 5 to oxidize DA, which resulted in a more homogeneous coating with unprecedented superoleophobic properties,96 as compared to PDA coatings prepared under classical alkaline conditions. In the presence of CuSO4, PDA coatings with a thickness of above 70 nm can be achieved, and the UV−visible absorption spectrum of the coating displayed defined peaks at 320 and 370 nm, which were not observed in normal PDA films.97 Zhang et al. reported that the use of CuSO4/H2O2 triggers fast polymerization of DA and rapid deposition of PDA coating on surfaces and that the resulting PDA coatings exhibit better uniformity and stability as compared to the PDA coatings obtained using the conventional method (Tris buffer, pH 8.5, 24 h).98 The choice of buffer also affects PDA coating formation. The use of phosphate buffer can result in PDA coatings with a thickness of up to 100 nm, almost 2 times the thickness of PDA films prepared in Tris buffer (normally 40−50 nm). Interestingly, the choice of buffer also has an effect on the PDA particles produced, with larger PDA particles (500−600 nm) formed in phosphate buffer, compared to that in Tris buffer (
