Introduction

Polymer microcapsules have drawn considerable interest for various applications, especially drug delivery, as they can encapsulate cargo (for example, therapeutics), and release them in a controllable manner. There exist two major strategies for preparing polymer microcapsules, namely template-free assembly and template-mediated assembly.1 Representative template-free methods are the self-assembly of polymersomes2 and polyion complex vesicles3 from block copolymers. In the template-mediated assembly method, which is the focus of this review, polymeric shells can be assembled via the sequential deposition of complementary polymers (layer-by-layer, LbL4, 5, 6, 7, 8, 9, 10, 11) around sacrificial template particles.12 Hollow polymer microcapsules can be obtained by selectively removing the template cores without disrupting the LbL-assembled polymeric shells. Despite the significant progresses in the field of LbL-engineered microcapsules, the manufacturing process inherently involves multiple alternating deposition steps of complementary polymers, rendering it time-consuming and labor intensive. To circumvent this limitation, we recently developed electrophoretic13 and immersive14 LbL techniques for simplifying and automating the capsule preparation processes. Recently, the one-step deposition of phenolic-based thin films has emerged as a rapid, simple and cheap alternative technology for template-mediated microcapsule preparation. This technique has opened up practical processing methods that researchers can readily access and explore to prepare a diverse range of functional materials.

Phenolic compounds are naturally occurring materials widely found in living organisms.15 The significant interest in phenolic compounds in recent years is attributed to their broad spectrum of chemical and biological properties. For instance, plant-derived phenolic compounds in tea and wine are major flavor determinants and are believed to have a number of pharmacological benefits on human health.16 Animals also take advantage of phenolics, as phenolic (L-3,4-dihydroxyphenylalanine)-containing proteins have a crucial role in the adhesive functions of mussel feet.17 From the engineering point of view, the stickiness, bio-based nature and metal-coordination capabilities, as well as antioxidant, anticarcinogenic and antibacterial properties of phenolic compounds, are attractive for developing biofunctional ‘green’ materials.18

In 2007, Lee et al.19 reported the formation of mussel-inspired multifunctional coatings on a wide range of substrates. The deposition of polydopamine (PDA) films takes place in one step on virtually any surface by simply dipping the object of interest into an aqueous solution of dopamine (DA). Although the molecular-level mechanism is still being elucidated,20 recent research suggests that non-covalent self-assembly and covalent polymerization both contribute to the PDA film formation.21 Recently, we reported the coordination-triggered deposition of tannic acid (TA)-metal films on a wide range of substrates.22 This deposition process is more rapid than that of PDA, and the obtained films can be disassembled at low pH. By depositing these phenolics on sacrificial particulate templates, hollow microcapsules with advanced functions can be assembled.

PDA capsules

Postma et al.23 first reported the template-mediated preparation of PDA capsules in 2009 (Figure 1). Sacrificial particulate templates (SiO2) were incubated in DA solution (10 mM tris(hydroxymethyl)-aminomethane (Tris)-HCl at pH 8.5), and the sacrificial SiO2 particles were subsequently removed by hydrofluoric acid. The diameter of the sacrificial templates (0.5–5 μm were used) directly translated to the size of the assembled PDA capsules. The thickness of the PDA shells varied with changing incubation time (ca. 10–20 nm). By simply repeating the deposition step, the thickness could be further increased in set increments. In 2009, Yu et al.24 also reported the preparation of PDA capsules, and examined their loading and release properties. Rhodamine 6G and methyl orange were used as model cargo and the effect of several parameters (pH, capsule size, shell thickness and solvent) on the loading and release kinetics were investigated.24, 25 DA-modified poly(L-glutamic acid) has also been self-polymerized and deposited on sacrificial particulate templates in a similar way to pure DA (Figure 2).26 The protease-triggered degradation of poly(L-glutamic acid)–PDA films was achieved and quantified by quartz crystal microgravimetry.

Figure 1
figure 1

PDA film engineering for template-mediated capsule preparation. (a) Schematic illustration of the preparation process. (b, c) Differential interference contrast microscopy (b) and transmission electron microscopy (c) images of the PDA capsules. Reprinted with permission from Postma et al.23 Copyright 2009 American Chemical Society. A full color version of this figure is available at Polymer Journal online.

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Figure 2
figure 2

Film assembly of DA-modified PGA on particles for capsule preparation. (a) Schematic illustration of the preparation process. (b, c) DIC microscopy (b) and TEM (c) images of the capsules. Reprinted with permission from Ochs et al.26 Copyright 2011 American Chemical Society. DA, dopamine; DIC, differential interference contrast; PGA, poly(L-glutamic acid); TEM, transmission electron microscopy. A full color version of this figure is available at Polymer Journal online.

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Liu et al.27 demonstrated the preparation of carbon capsules via the carbonization of PDA. First, the SiO2 particles were coated with PDA, then the PDA layer was carbonized at 800 °C and finally the SiO2 cores were removed by treatment with hydrofluoric acid (Figures 3a and b). By starting with Au@SiO2 core-shell particles,28 instead of SiO2 templates, carbon capsules encapsulating single Au nanoparticles were obtained (Figure 3c). These yolk-shell carbon capsules showed high catalytic activity and good recyclability in the reduction of 4-nitrophenol into 4-aminophenol.

Figure 3
figure 3

Carbon capsules prepared from the PDA precursor. (a) Schematic illustration of the preparation process. (b, c) Scanning TEM images of carbon capsules (b) and Au@C yolk-shell composites (c). Reprinted with permission from Liu et al.27 Copyright 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. PDA, polydopamine; TEM, transmission electron microscopy. A full color version of this figure is available at Polymer Journal online.

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Cui et al. showed that low-molecular-weight polydimethyldiethoxysilane oil-in-water emulsion droplets29 are favorable sacrificial templates for the preparation of PDA capsules,30 as these templates can be removed with ethanol (cf. SiO2 needs to be removed with hydrofluoric acid). Furtheremore, the diameter of these droplets can be readily tuned from hundreds of nanometers to several micrometers by changing either the condensation time or the concentration of the precursor dimethyldiethoxysilane. In conventional LbL assembly, the template particles need to be spun down after each deposition step to remove excess polymer; however, the polydimethyldiethoxysilane templates have a density lower than water and are difficult to spin down. Therefore, the one-step deposition process of PDA, without any need for intermittent centrifugation steps, allows the use of polydimethyldiethoxysilane emulsion droplets as sacrificial templates. The advantage of oil-in-water emulsion droplets is that hydrophobic cargo, such as magnetic Fe3O4 nanoparticles, fluorescent quantum dots (CdSe/CdS) or an anticancer drug (thiocoraline), can easily be preloaded into the emulsion before PDA coating (Figure 4).30 Wang et al. utilized alkane-in-water emulsions as templates for the preparation of PDA capsules,31 and it was found that the interfacial basicity of the droplets promoted the self-polymerization of DA.

Figure 4
figure 4

Schematic illustration of the PDA capsules prepared from an emulsion template and the loading of hydrophobic cargo. Reprinted with permission from Cui et al.30 Copyright 2011 WILEY-VCH Verlag KGaA, Weinheim. PDA, polydopamine. A full color version of this figure is available at Polymer Journal online.

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PDA films can be used as the basis for surface-initiated atom transfer radical polymerization.32, 33 Kohri et al.32 demonstrated the co-deposition of DA and atom transfer radical polymerization initiator-bearing DA onto polystyrene particles. 2-Hydroxyethyl methacrylate (HEMA) was polymerized to give a polyHEMA brush-functionalized PDA layer. The transparency of the films increased as the initiator-bearing DA fraction was increased. Colorless phenolic coatings are desired in some cases, as the characteristic black color of PDA can hinder some practical applications.18 The further functionalization of the polyHEMA-PDA capsules with fluorescent dansyl group was carried out in acetone in the presence of triethylamine. Ma et al.33 prepared dual-responsive capsules sensitive to pH and temperature changes using the surface-initiated atom transfer radical polymerization of 2-(2-methoxyethoxy)ethyl methacrylate (MEO2MA) and oligo(ethylene glycol) methacrylate (OEGMA) on the PDA base layer (Figure 5). The charge of PDA is dependent on the pH, while the poly(MEO2MA-co-OEGMA) has a lower critical solution temperature, which can be tuned by changing the molar fraction of OEGMA. Thus, the copolymer-functionalized PDA capsules exhibited dual-responsive loading and release of dye molecules (Rhodamine 6G and methyl orange).

Figure 5
figure 5

Schematic illustration of polymer grafting from PDA capsules via ATRP. Reprinted with permission from Ma et al.33 Copyright 2013 American Chemical Society. ATRP, atom transfer radical polymerization; PDA, polydopamine. A full color version of this figure is available at Polymer Journal online.

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Organic–inorganic hybrid capsules were prepared using PDA as a bioadhesive layer.34 First, the CaCO3 template particles were coated with protamine, which induced the hydrolysis and condensation of titania or silica precursor to form the second inorganic layer. These particles were finally capped with the third layer, PDA and the CaCO3 cores were removed with EDTA treatment. The PDA/titania capsules exhibited superior mechanical stability than the PDA/silica due to the strong coordination interactions between TiIV and the catecholic groups in PDA. DA-modified alginate was also used to construct LbL capsules based on the coordination with TiIV.35

PDA capsules were also used as a vehicle for drug delivery into living cells (Figure 6).36 The anticancer drug doxorubicin (Dox) was conjugated to a thiolated poly(methacrylic acid) through acid-cleavable hydrazone bonds. The thiol functionalities on thiolated poly(methacrylic acid) were used to immobilize this drug–polymer conjugate on the PDA shells based on the Michael addition (Figure 6a). The Dox release from PDA capsules was investigated at pH 7.4, 6.0 and 5.0, simulating the physiological pH in the extracellular space, subcellular endosomes and lysosomes, respectively. Although 85% and 40% of the encapsulated Dox were released at pH 5.0 and 6.0 over 12 h, respectively, less than 20% was released at pH 7.4. Cell viability assays using a cervical cancer cell line (HeLa) showed enhanced cytotoxicity of Dox-loaded PDA capsules, compared with free Dox under the same conditions, demonstrating the effectiveness of PDA capsules for drug delivery in living cells.

Figure 6
figure 6

Drug delivery using PDA capsules. (a) Schematic illustration of the preparation of PMASH-Dox-loaded PDA capsules. (b) Fluorescence microscopy image of the Dox-loaded PDA capsules. (c) Deconvolution microscopy image of the uptake of the PDA capsules (green) by HeLa cells. Reprinted with permission from Cui et al.36 Copyright 2012 American Chemical Society. Dox, doxorubicin; PDA, polydopamine; PMASH, thiolated poly(methacrylic acid).

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TA capsules

TA is a biodegradable phenolic compound of natural origin, which has a central glucose core connected with gallic acids through ester bonds at the hydroxyl groups of glucose (Figures 7 and 8). TA has a high spectrum of bioactivities such as antioxidant,37 antibacterial,38 anticarcinogenic,39 antimutagenic40 and antiviral41 properties. Through electrostatic or hydrogen bonding interactions, TA has been assembled via the LbL assembly method with poly(dimethyldiallylamide),42 poly(allylamine),42, 43, 44 poly(N-vinylcaprolactam),45, 46 poly(N-vinylpyrrolidone),45, 46, 47 poly(ethylene oxide),45 poly(N-isopropylacrylamide),45, 46 poly(2-n-propyl-2-oxazoline),48 FeIII ions49, 50 and proteins51 to form thin films. The first microcapsules based on TA were prepared by Shutava et al.42 via multistep LbL assembly in 2005.

Figure 7
figure 7

Schematic illustration of the preparation of polymersome-loaded LbL capsules. Reprinted with permission from Lomas et al.52 Copyright 2011 WILEY-VCH Verlag KGaA, Weinheim. LbL, layer-by-layer.

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Figure 8
figure 8

One-step assembly of FeIII–TA films. (a) Schematic illustration of the FeIII–TA film assembly. (b–d) DIC (b), AFM (c), (d) images of FeIII–TA capsules. Reprinted with permission from Ejima et al.22 Copyright 2013 American Association for the Advancement of Science. AFM, atomic force microscopy; DIC, differential interference contrast; TA, tannic acid; TEM, transmission electron microscopy.

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Lomas et al.52 used TA to construct polymersome-loaded multicompartment capsules (Figure 7). Polymersomes formed from poly(oligo(ethylene glycol) methacrylate)-block-poly(2-(diisopropylamino)-ethyl methacrylate) were incorporated into multilayers of TA and poly(N-vinylpyrrolidone). TA acts as an efficient hydrogen-bond donor for both poly(N-vinylpyrrolidone) and the POEGMA corona of the polymersomes. The polymersomes disassembled at low endocytic pH due to the pH-dependent nature of the PDPA block (that is, deprotonated at physiological pH and protonated at endocytic pH), hence the polymersomes could release a therapeutic cargo in a pH-dependent manner. The polymersome-loaded capsules showed the release of a plasmid DNA encapsulated within the polymersome subcompartments in response to the lowering pH from physiological to endocytic conditions.

Recently, we found that the instantaneous film deposition of TA occurred on a wide range of substrates, including inorganic, organic and biological substrates, triggered by TA complexation with FeIII ions (Figure 8).22 The formation of FeIII–TA films on particulate polystyrene templates was readily confirmed by the negative shift of the surface zeta potential relating to TA and the color change from white to dark blue relating to the complexation of Fe. After removing the polystyrene templates, highly uniform microcapsules were obtained (Figures 8b–d). The shell thickness was about 10 nm, as determined by atomic force microscopy height analysis. Analogous to LbL assembly, the thickness could be further increased by simply repeating the coating procedure. The mechanical properties of the FeIII–TA capsules were examined by atomic force microscopy force measurements. Young’s modulus (EY) of the D=3.6 μm capsules was 1.0±0.2 GPa, which is at the high end of the range observed for LbL polyelectrolyte capsules (0.01 to 1 GPa).53 The FeIII–TA capsules disassembled in a pH-sensitive manner, as coordination between FeIII and TA is pH dependent. The competitive chelation of FeIII (using EDTA) markedly accelerated the disassembly of the FeIII–TA capsules even at neutral pH, suggesting the main interaction between FeIII and TA is coordination bonding. It is noteworthy that the metal species chelated by TA are not limited to FeIII, as was demonstrated for other metals such as VIII, AlIII and GdIII.22, 54 Solutions of TA capsules prepared with various metals exhibited a wide spectrum of colors that depend on the metal species chelated;54 thus, where color matters, a judicious choice of metal can be made depending on the specific application. For metal–phenolic network films, the simple preparation, negligible cytotoxicity, pH-responsive disassembly profile and extendibility to various metals all provide a platform for the engineering and assembly of promising architectures useful for biomedical applications.

Summary

Recent advances in the preparation of microcapsules using phenolics have been reviewed herein. Phenolic microcapsules can be assembled via the multistep LbL assembly method or via one-step deposition methods. The sacrificial particles necessary for templating the phenolic films into microcapsules can be of varying composition (solid or liquid) allowing for the facile encapsulation of hydrophobic or hydrophilic cargo depending on the template particles used. By controlling the reaction conditions and by reapplying the films, the shell thickness of the microcapsules can be tuned between 10 nm to over 100 nm. Importantly, depending on the phenolic compound used, non-degradable or degradable capsules can be prepared, allowing for the release profiles of cargo to be specifically tuned. Similarly, the phenolic compound used also determines what further chemistries or modifications can be used to functionalize the capsules. The technical advancement of moving towards rapid, robust film deposition methods that phenolic compounds allow for is an important step toward realizing easy-to-prepare nanoengineered drug delivery vehicles with enhanced mechanical properties and stimuli-responsive abilities. As mussels use reversible metal–phenolic coordination for the self-healing of their feet, capsule shells with self-healing abilities could be developed in the near future for smart and adaptive systems, capable of releasing and encapsulating cargo in situ depending on concentrations of trace ions. Films prepared from phenolics other than DA and TA are expected to expand the functionality and applicability of phenolic-based microcapsules in the biomedical field.