Nicolas
Sanson
a and
Jutta
Rieger
*b
aLaboratoire de Physico-chimie des Polymères et Milieux Dispersés, UMR 7615 UPMC-CNRS-ESPCI, Ecole Supérieure de Physique et de Chimie Industrielles ESPCI, 10 rue Vauquelin, 75231, Paris Cedex 05, France
bLaboratoire de Chimie des Polymères, UPMC Univ. Paris 6 and CNRS, UMR 7610, 4 place Jussieu, Tour 44-54, 75252, Paris Cedex 05, France. E-mail: jutta.rieger@upmc.fr; Tel: +33 1 44275137
First published on 26th April 2010
This review compares conventional and controlled radical polymerization techniques and processes in preparing nano-/microgels. Special focus is made on the synthetic parameters that allow controlling their size, morphology, composition, and structural homogeneity.
![]() Nicolas Sanson | Nicolas Sanson completed his PhD in 2005 under the supervision of Corine Gérardin and François Fajula at the ENSC of Montpellier. He started a postdoctoral position with Prof. Eugenia Kumacheva at the University of Toronto, where he was introduced to the field of microgels. Subsequently, he worked as a postdoctoral fellow at the CRPP (Bordeaux) with Virginie Ponsinet. Since 2007, he is assistant professor at the University Pierre et Marie Curie (UPMC, Paris) and his research occurs at the ESPCI. His research focuses on assemblies of nanoparticles induced by stimuli-responsive polymers and on synthesis and characterization of microgels. |
![]() Jutta Rieger | Jutta Rieger is currently a CNRS researcher at the University Pierre et Marie Curie (UPMC, Paris). She completed her PhD at the University of Liège (Belgium) and CERMAV (France) under the supervision of Professors Robert Jérôme and Rachel Auzély-Velty in 2005. After briefly working in 2006 for Macopharma at ICMMO (France), she received a FNRS fellowship for a research project on stimuli-reponsive nanogels in collaboration with Dr Christine Jérôme. In 2007 she joined Professor Bernadette Charleux's group (UPMC) where her research focuses on the synthesis of functional self-assemblies by controlled radical polymerization in homogeneous or heterogeneous media. |
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Fig. 1 Evolution of the number of publications on nanogels/microgels since 1950. (Source: SciFinder Scholar, Keywords: “microgels” and “nanogels”. For 2009, the number of papers registered until October 2009 is plotted.) |
First syntheses were all performed in organic solvents at high dilution. Since then significant advances in the synthetic pathways (polymerization techniques and processes) have been made (cf. Section II), that allow not only tuning the chemical composition of those crosslinked polymer particles but also their size, morphology and functionality (cf. Section III). In the age of green chemistry today's syntheses tend to use environmental friendly processes, mainly aqueous heterogeneous polymerization processes.
Numerous groups have focused on the development of “smart” or “responsive” microgels that undergo structural or morphological changes such as volume transition in response to (environmental) stimuli such as pH, temperature, ionic strength, solvent, light, magnetic fields, enzymatic activities, or ligand binding. They pave their way towards new materials that not only have tunable dimensions, but also differ in the material's properties such as wettability, permeability, refractive index, flexibility, and viscoelasticity. Within the class of stimuli-responsive polymers, the most common responsive polymer is poly(N-isopropylacrylamide) (PNiPAm), which is a thermo-responsive polymer that undergoes a coil-to-globule transition in aqueous media at ∼32 °C, i.e. at its “lower critical solution temperature” (LCST). When those chains are crosslinked in a polymer network, the responsivity appears as a volume collapse arising from the expulsion of the solvent (water). This transition temperature is thus referred to as a “volume phase transition temperature” (VPTT), which is generally close to the LCST of the corresponding linear polymer. In the last decade, multiresponsive materials that are sensitive to multiple stimuli and show a more complex transition behavior have received increasing interest.4,5 Hydrophilic, hydrophobic, neutral or charged monomers can be introduced that allow the preparation of combined temperature–pH, amphoteric or double temperature-sensitive microgels.6–8 Furthermore, functional/reactive groups have been incorporated regioselectively in their core or in their shell and they are then available for the attachment (bioconjugation) of bioactive compounds, such as ligands or enzymes.9 Such functionalized nano-/microgels pave the way towards bioresponsive materials that enable—for instance—targeted and/or triggered drug delivery. In addition, certain functional groups may promote the complexation of metal ions/nanoparticles opening the door to a large spectrum of new sophisticated applications, e.g. the template-based fabrication of hybrid materials or separation and purification technologies.10,11
In addition to the intrinsic properties of the nano-/microgels given by the nature of the polymers/materials that they are composed of, their dimension and geometry are of crucial importance. Depending on the application, dimensions in the nanometre or in the micrometre range are targeted. Especially, optical applications based on the assembly of colloids in a lattice structure are very demanding in relation to size distribution (polydispersity). Microgels with polydispersity factors lower than 10%12,13 are generally required when photonic applications are targeted, such as their use as photonic crystals or sensors,14 or when they are used as model systems for fundamental studies in colloidal physics.6,15 In addition to the control over the size and size distribution of spherical gel particles, today's efforts tend to control the synthesis of nano-/microgels of more complex architectures, such as core–shell structures,16,17 hollow,18 or non-spherical, di- or trimeric structures.19–21 In Section III.1 and 2, the synthetic strategies to reach control over size/size distribution and morphology are discussed.
The applications of nanogels/microgels are manifold. For biomedical applications, hydrogel particles containing mostly water are especially interesting. Indeed, they may possess good biocompatibility, as the high water content results in low interfacial tension. However, supplementary studies on cytotoxicity and immunogenicity are still required. The potential application of nanogels/microgels as carrier systems relies primarily not only on their tunable size, their high loading capacity, thanks to their interior network structure, but also on their high stability (compared to micelles) and responsiveness to environmental factors (such as pH, ionic strength, light and temperature).22–24 Moreover, they possess large surface area allowing multivalent bioconjugation. Specific ligands have been introduced on the surface of nanogels allowing their accumulation in targeted tissues. The decoration of their surface by biocompatible polymers is also possible. It has for instance been demonstrated that poly(ethylene glycol) (PEG) coatings prolong considerably the circulation time of polymeric nanoparticles in the blood stream.25 Finally, the presence of such long stabilizing polymer chains at their surface may impart nano-/microgels with high stability and prevent them from aggregation.
Apart from the applications mentioned above other important fields are sensing,17 molecular imprinting,26 their application as emulsifiers or stabilizers in complex coatings, or their use as nanoreactors capable of modulating the catalytic activity of metal nanoparticles. The variety of applications makes clear the need for reliable and straightforward synthetic strategies towards the controlled synthesis of these complex materials. In contrast to existing reviews,7,24,27–32 this review is limited to syntheses pathways based on radical crosslinking copolymerization (RCC) of vinylic monomers with di- or multivinyl crosslinker (one-batch addition). In the following part, we will compare different polymerization processes and oppose synthetic strategies based on conventional radical polymerization (RP) to controlled radical polymerization (CRP) techniques. Depending on the targeted morphology, properties and application of the colloids, the limits and advantages/disadvantages of each technique are highlighted. Star polymers prepared in two steps by the arm-first or core first method,29i.e. polymer chains that are crosslinked at a central point and do not possess a gel-like core structure, and nanogels that are obtained in several steps through crosslinking of preassembled morphologies, are not discussed in this review. Consequently, core crosslinked (CCL) micelles33 and shell crosslinked (SCL) micelles34,35 where either the core or the shell of preformed amphiphilic block copolymer micelles is crosslinked through organic chemical reactions—such as amidification—are beyond the scope of this review.
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Fig. 2 Schematic presentation of the crosslinking reactions in conventional and “controlled”/“living” radical polymerization systems. (Reprinted with permission from D. Taton, in Macromolecular Engineering: Precise synthesis, materials properties, applications, ed. K. Matyjaszewski, Y. Gnanou and L. Leibler, Wiley, Weinheim, 2007, vol. 2, ch. 8, pp. 1007–1056.) |
Finally, a smart strategy to reach nano-/microgels instead of macrogels (at quite high monomer conversion/concentration) relies on the limitation of the primary chain length by using high amounts of initiator or chain transfer agents.51 For the same purpose, controlled polymerizations, such as living ionic polymerizations52,53 or controlled/“living” radical polymerization (CRP)29 (cf. Section II.2), have been applied and their potential in the synthesis of well-defined/functional nanogels/microgels has been demonstrated.
Since the nineties, the beneficial effect of CRP has been demonstrated for the synthesis of branched polymers and especially macrogels prepared in homogeneous conditions (i.e. in the bulk or in solution).42,43,65–72 As schematized on the top of Fig. 2, in a conventional non-living RCC polymerization mechanism intramolecular crosslinking dominates at low conversions (at the left side) leading to the formation of dense/nodular “microgel domains” and a heterogeneous structure of the final macrogel (at the right side).29,65,73 In contrast, when CRP techniques are applied the kinetics is considerably slower than in conventional RP and dormant polymer chains have time to diffuse and relax before being reactivated to propagate. Consequently, crosslinking points are more homogeneously distributed within the networks—assuming equivalent reactivity of the monomer and crosslinker—as lately demonstrated by combined experimental and simulation data.74 It was demonstrated that for controlled radical crosslinking copolymerizations (cRCC) the number of primary (linear) chains is essentially determined by the concentration of control agent; their chain length and molar mass distribution depend directly on the monomer/control agent ratio.29,72,73,75–78 These experimental data were recently supported by Monte Carlo simulations based on a dynamic lattice liquid (DLL) model. They provide indeed a useful tool to understand the influence of various experimental parameters (such as dilution, monomer/control agent ratio and crosslinker concentration) on the onset of gelation.79
CRP techniques have thus successfully been applied to the controlled synthesis of nano-/microgels, i.e. networks which are limited in size and molar mass. Indeed, when nanogels were synthesized by ATRP or RAFT/MADIX in the presence of degradable crosslinker,29 such as disulfide-based di(meth)acrylate crosslinker,9,80–82 di(ethylene glycol) di(methacryloyloxy)ethyl ether,83 or N,N′-(1,2-dihydroxy ethylene) bisacrylamide84 degradation of the crosslinking points resulted in individual polymeric chains with quite narrow molar weight distribution and molar masses were close to those of the corresponding linear polymers prepared in equivalent conditions but in the absence of crosslinker.76,77,80–83 These experiments clearly demonstrate the effect of CRP on nano-/microgel formation. Applying CRP techniques, their synthesis can be carried out at much higher monomer and crosslinker concentration (or stopped at higher monomer conversion) as gelation is retarded.41–43,79 It is indeed possible to synthesize low molar mass branched polymers in solution at monomer concentrations as high as 20 wt% in the presence of up to 10 mol% crosslinker.76,85 Thanks to the living character of CRP, chain extensions can be performed after addition of a second monomer batch.75,85,91 Controlling the sequence of addition of (several) monomers or crosslinker, the structural composition and morphology of the nanogels/microgels can be controlled and a large variety of architectures becomes accessible (cf.Fig. 3 and Table 1). The use of functional initiators further allows the incorporation of functionalities in the core or at the surface of nano-/microgels, which are available for (bio)conjugation reactions (Fig. 3). Today the implementation of especially ATRP9,29,86,87 but also NMP68,88,89 and RAFT90–94/MADIX85 to the synthesis of nano-/microgels is well established (cf. Section III). It should also be noted that cRCC in heterogeneous (mostly aqueous) conditions45,46 has raised particularly interest for the reasons explained in Section II.1.
Structural features | Conventional crosslinking radical polymerization (RCC) | Controlled radical crosslinking polymerization (cRCC) |
---|---|---|
Size/polydispersity | Parameters that influence size and size distribution are: (a) amount of crosslinker and initiator; (b) process of polymerization; (c) for heterogeneous aqueous polymerization processes: amount of surfactant/charged initiator, presence of a soluble comonomer, temperature, stirring speed. | Parameters that influence size and size distribution are: (a) crosslinker/CRP initiator (RAFT agent) and monomer/ CRP initiator (RAFT agent) ratios; (b) process of polymerization; (c) see (c) in RCC. |
Highly monodisperse dispersions can be reached by heterogeneous polymerizations processes. | It is possible to reach well-defined nanogels in heterogeneous polymerization processes in the absence of surfactant using soluble or charged macroinitiators/macroRAFT agents that act as stabilizer and control agents. | |
Polymerization in homogeneous conditions must be performed in high dilution (small amounts of monomer and crosslinker) or stopped at low conversion in order to avoid macrogelation. | High solids content (up to 20%) can be reached. | |
Chain extension with a second monomer batch is possible. | ||
Architectures | Importance of the process of polymerization. | Importance of the process of polymerization. |
Core and shell crosslinked structures by multistage seeded polymerizations where the core and the shell are not covalently linked with each other and composed of a network structure. | Chain extension with a second monomer batch is possible ⇒ hairy shell or core might be composed of two different types of polymers. | |
Multilayered microgels by multistage (precipitation) polymerizations. | Anisotropic gel particles are accessible by the formation of block copolymers. | |
Hairy nano-/microgels where the hairy shell is formed by a macromolecular comonomer. | Hairy nano-/microgels where the core is covered by covalently linked polymer chains using macromolecular CRP initiators or macroRAFT agents. | |
Hollow nano-/microgels by removal of a degradable core from core–shell nano-/microgels. | Hollow hairy nano-/microgels (nanocapsules) are accessible in one step in heterogeneous polymerization conditions. | |
Hollow microspheres by inverse (mini)emulsion RCC. | ||
Surface functionalization | Utilization of soluble functional comonomers in heterogeneous RCC. | Utilization of soluble functional (macro)initiators or (macro)RAFT agents in heterogeneous cRCC. |
Functionalization of the core | Copolymerization with functional comonomers. | Copolymerization with functional comonomers (enhanced homogeneity). |
ω-Chain end functionalities through the use of appropriate CRP initiators or RAFT agents. |
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Fig. 3 Synthetic approaches for the preparation of nano-/microgels of different morphologies and functionalities via conventional and controlled radical crosslinking polymerization. |
In the following part (Section III), we will discuss the synthetic parameters that allow one to tune the morphology, structure and size of nano-/microgels. Examples for both conventional radical crosslinking polymerization (RCC) and controlled radical polymerization (CRP) will be given and the different structures that are accessible by each technique are highlighted in Fig. 3 and in Table 1.
It is thus important to find synthetic approaches that allow tuning the size, architecture of the resulting particles while maintaining narrow particle size distribution (low polydispersity factors). The first and most important parameter that affects the dimensions of the resulting gel particles is the process of polymerization (heterogeneous/homogeneous) which is mainly determined by the solvent used. As described in Section II.1, network formation is fundamentally different in homogeneous conditions compared to heterogeneous ones and the resulting nano-/microgels differ in size, structure and properties. In solution, i.e. in homogeneous conditions, their molar mass essentially depends on the concentrations of the compounds: lower monomer concentrations yield gels of smaller dimensions (the formation of macroscopic gels can be avoided), as the probability of intramolecular crosslinking (loop formation) increases. At very low concentrations only “self-crosslinked molecules”, i.e. branched polymers are formed.44,95 The size of the macrogels can also be reduced by using decreased crosslinker concentration or enhanced initiator concentrations.75,76,96,97 As described before, chain transfer agents, e.g. thiols, and CRP control agents, i.e. NMP-/ATRP initiators or RAFT agents, have shown to allow the formation of low molar mass branched polymers instead of (macroscopic) gels by decreasing the molar mass of the primary chains.
Several authors studied the influence of the solvent in which RCC is performed.98–100 It was concluded that the dimensions of the resulting particles depend on the solubility of both the monomers and the polymers. Indeed, as the solvent properties change (temperature must also be considered), interfacial energies and the mechanism of the particle formation are modified. For instance, Kim et al.100 performed syntheses of PNiPAm nanogels either in water or in a water/THF mixture at 50 °C, i.e. above the LCST of PNiPAm in water. Gel particles obtained in the solvent mixture were bigger than those obtained in water (500 vs. 70 nm). The fundamental difference accounting for the variation in size must be found in the solubility of the growing polymer chains. With increased solubility, phase separation will be postponed and the critical length of the polymer chains at the phase separation becomes longer resulting in bigger colloidal gels. In a similar study, Stucky et al. performed surfactant-free RCC of methyl methacrylate (MMA) either in water (i.e. in emulsion conditions) or in 25 wt% acetone/water mixture. Here, bigger particles were obtained in water compared to the acetone/water mixture. This must be attributed to a different nucleation mechanism due to the difference in monomer solubility. In the solvent mixture, MMA is more soluble which might contribute to an enhanced number of nucleation seeds leading to smaller particles.99
In such heterogeneous polymerization conditions, particle stabilization must be considered. In fact, stability is given by repulsive electrostatic, electrosteric or steric interactions between particles generally provided by a surfactant. Under certain conditions, stable nano-/microgels can be prepared by surfactant-free emulsion or (aqueous) precipitation polymerization.32 Particles of low size distribution might be obtained, but their size is generally larger than in the presence of surfactant as an aggregation step generally occurs during particle growth. In surfactant-free aqueous heterogeneous polymerization, particles are stabilized by the charges provided by the initiator, such as ammonium persulfate (APS), potassium persulfate (KPS) or 2,2′-azobis(amidinopropane) dihydrochloride (V50). The particle size might slightly be diminished through the use of large amount of initiator. Typically, stable gel particles smaller than 300 nm could be achieved by aqueous precipitation polymerization of NiPAm in the presence of high amount of initiator,6 but their average size is generally larger compared to that of particles prepared in the presence of ionic surfactants.31 Apart from the initiator or the surfactant concentration, a third parameter may contribute to particle stabilization and affect the particle size. Actually, stabilizing (charged) comonomers, such as acrylic acid, may be employed in aqueous heterogeneous RCC.101 This approach does not only allow to tune the size of the particles (by changing the co-monomer/monomer ratio102) but also to impart additional functionalities or responsivity to the nanogels.
In addition, the application of CRP techniques to crosslinking polymerization in heterogeneous conditions opened up new surfactant-free synthesis pathways towards autostabilized hydrogel particles of very small dimensions. Indeed, the use of soluble or charged macromolecular CRP initiators (macroinitiators) or macromolecular RAFT agents (macroRAFT agents) allows small nanoparticles to be prepared in the absence of conventional surfactant.103,104 Such nanogels are (electro)sterically stabilized via a polymeric corona provided by the soluble macromolecular control agent (see Fig. 3). By changing the length and the nature (e.g. charged polymers vs. neutral polymer) of the stabilizing macromolecular control agent, nanogels of different dimensions could be obtained91 at rather high solids content.88,92 It should also be mentioned that in such heterogeneous conditions the stirring quality/speed, the application of microwave power99 and temperature are additional important parameters that impact the particle size and its distribution. It had been shown that a decrease of the temperature to 60 °C increased the particle size to 1.5 µm due to a prolonged nucleation stage.105 Further decrease of the temperature to 50 °C leads to less stable particles with an excessive amount of coagulum formed instead of monodisperse colloids. In order to achieve large >2 µm size PNiPAm microgels Lyon et al. performed the aqueous dispersion polymerization of NiPAm using a programmed temperature ramp from 45 to 65 °C (30 °C h−1) during the nucleation step. 2.5 to 5 µm large stable microgels could be afforded.106 It is proposed that initially, because of the slow decomposition rate of the thermal initiator, low nuclei concentrations are obtained and higher propagation rates (compared to initiation) favor particle growth in these particular conditions. The temperature ramp then compensates a decrease in propagation rate (because of monomer consumption) and maintains it approximately constant.
The particle size distribution (polydispersity) was shown to be intimately related to the process and kinetics of particle formation. It has been shown, that a short nucleation stage favors the formation of monodisperse samples,96,107 meaning that all particles are formed at low overall monomer conversion, and over most of the polymerization, particle growth dominates the kinetics instead of particle nucleation. Whereas nonliving dispersion polymerizations normally afford monodisperse particles, dispersion CRP—where the propagation kinetics is slowed down—often yields broad particle size distributions.46 Indeed, in a CRP system the nucleation stage is prolonged because high molar mass polymer is not formed instantaneously as it is in a nonliving system, resulting in broad particle size distributions. This issue has been overcome using a “two-stage”/seed strategy, whereby the control agent (RAFT agent) and the crosslinker were added after completion of the nucleation stage, resulting in monodisperse spherical micron-sized particles.108 It is in order to shorten the nucleation stage, that thermally initiated RCC of NiPAm in aqueous media is generally conducted at 70 °C, that is much higher than the LCST (∼32 °C). This relatively high temperature will not only induce rapid phase separation (as soon as the initiator adds some monomers), but also leads to an accelerated decomposition of the thermal initiator and thus induces a shorter nucleation period.
In addition to solvent and temperature effects, the influence of the crosslinker reactivity has also been studied, both experimentally99 and by Monte Carlo simulations.74 For instance, Stucky et al.99 studied the heterogeneous RCC of MMA in acetone/water mixture. It was found that the crosslinker of the lowest kp led to the biggest particles. They were indeed significantly bigger than reference particles prepared in the absence of crosslinker and the increase in dimension was attributed to the occurrence of interparticular crosslinking. In contrast, in the presence of N,N′-bismethylene acrylamide (MBA), i.e. the crosslinker of the highest reactivity, the particle size corresponded to that of the model particles meaning that interparticular crosslinking was prevented. Due to its high reactivity, MBA is indeed by far the most frequently employed crosslinker for the aqueous RCC of NiPAm, and leads to monodisperse particles possessing a gradient in crosslink density (from the core to the shell) because of difference in monomer reactivity.31 In order to foresee the structure of microgels, consumption of monomer and difunctional monomer can be calculated applying copolymerization kinetic models and the distribution of crosslinker and/or functional groups can be predicted.109,110 Actually, the homogeneity of crosslink distribution, i.e. the homogeneity of the polymer network, is an important issue of (hydro)gel particles that will influence their swelling properties and their mechanical properties. Generally, homogeneous networks are targeted where the crosslinking points are homogeneously distributed throughout the objects. As explained in part II.2, CRP methods may favor the formation of more homogeneous networks due to the mechanisms and kinetics that are inherent in them—assuming similar reactivity of the monomers and the crosslinker. To overcome reactivity issues, semi-continuous processes (semi-batch or starve-fed monomer feed strategies) can be applied where a crosslinker of enhanced reactivity is gradually added during polymerization.110,111
In emulsion or precipitation polymerization, it appears to be difficult to prepare microgels that have a completely uniform structure. In these heterogeneous conditions, not only differences in reactivity ratios between monomers and crosslinker but also differences in solubility (hydrophilicity/hydrophobicity) must be considered: for instance, when a hydrophilic monomer is copolymerized with a less hydrophilic (i.e. quite hydrophobic) crosslinker the formation of first crosslinks creates hydrophobic centers, and then partitioning of the crosslinking agent in these hydrophobic domains results in hydrogels with inhomogeneous distribution of crosslinks. Inverse miniemulsion polymerization might be a better method for achieving a uniform comonomer concentration as the polymerization mechanism does not involve diffusion between phases.32
Richtering and others studied in detail the internal structure of double thermosensitive core–shell microgel (synthesized by a two-step precipitation polymerization in the presence of surfactants) where the core and the shell are composed of two different temperature-responsive polymers, namely N-isopropylacrylamide (NiPAm) and N-isopropylmethacrylamide (NiPMAm) possessing LCSTs of ∼32 °C and ∼45 °C120 respectively.121 Dynamic light scattering (DLS) and differential scanning calorimetry (DSC) revealed that they exhibited two distinct VPTT that corresponded to the LCST of the core and the shell polymer.122 Their internal structure, such as the volume ratios between the core and the shell (giving access to the thickness of the shell) and the crosslinker density of the shell, were extensively studied by dynamic light scattering (DLS) and small angle neutron scattering (SANS).123–125 For PNiPAm core/PNiPMAm shell microgels the swelling behaviour was mainly governed by the thickness and the crosslinker density of the shell and it was found that the core and the shell influence each other. A suitable universal analytical form factor based on the radial scattering length density distribution of core–shell microgel was introduced allowing the internal structure of microgel with a diffuse and/or sharp interface to be described. For the reverse system, PNiPMAm core/PNiPAm shell, at an intermediate temperature between the LCST of the two polymers, the size of the core–shell microgel is smaller than that of the core alone indicating that the PNiPAm shell in its collapsed state restricts the swelling of the core. The swelling kinetics of core–shell microgels which is an important parameter in the comprehension and development of responsive materials have also been studied by light scattering methods, 1H NMR, differential scanning calorimetry,126 fluorescence spectroscopy127 or laser-induced temperature transition measurements.128
To the best of our knowledge, no papers have been reported where controlled radical crosslinking polymerization was applied to the synthesis of core and shell crosslinked microgels where both the shell and the core possess a hydrogel-like structure.
Commonly, hairy nano-/microgels are prepared by conventional radical crosslinking polymerization (RCC) in heterogeneous conditions in the presence of stabilizing macromonomers (macromonomer approach) (Fig. 3). The latter are necessarily soluble in the continuous phase as they will form a stabilizing “shell” around the crosslinked core. For instance, PNiPAm microgels coated by a PEG shell were prepared by aqueous radical precipitation polymerization in the presence of poly(ethylene glycol) methacrylate macromonomers.130,131 At temperatures above the LCST of PNiPAm, the PNiPAm core collapses but no particle aggregation occurs as the macromonomer remains soluble and contributes to the stabilization of the microgel. Other groups used the same PEG macromonomer for the synthesis of hairy PEGylated microgels based on different monomers such as 2-(diethylamino)ethyl methacrylate (DEA),132,133 2-(diisopropylamino)ethyl methacrylate (DPA)132 and vinylpyridine (VP).134–140 For the surfactant-free synthesis of microgels in dispersed media, the use of macromonomers as reactive polymeric stabilizer allows to reach higher solids content (up to 7% compared to ∼1 to 3% for syntheses performed in the absence of surfactant and macromonomers) and better colloidal stability. The combination of macromonomers and charged surfactants allows the synthesis of microgels at very solids content.132 In addition to neutral macromonomers, such as PEG, charged (polyelectrolyte) macromonomers have also been used.132,141 Poly(2-vinylpyridine) microgels stabilized by cationic poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) chains were synthesized in this way. As expected, the pH was shown to be a critical parameter for the synthesis and for the physico-chemical properties of the microgels. Due to the difference of pKa between the polymers in the core and in the shell, P2VP/PDMAEMA microgels can be consequently considered as double pH-sensitive microgels.
The main disadvantage of the macromonomer approach using heterogeneous polymerization processes is the presence of residual macromonomer in the continuous phase. One way to tackle this problem is the use of azo-macroinitiators that decompose thermally, such as PEG–NN–PEG. In addition, the application of controlled radical crosslinking copolymerization (cRCC) techniques such as ATRP,100 RAFT91,92 or NMP88,89 has proved to be a very straightforward approach to reach hairy nanogels at high solids content (Fig. 3). For instance, PEGylated thermosensitive nano-/microgels were directly synthesized by ATRP or RAFT using reversible PEG macroinitiators (e.g. poly(ethylene glycol bromoisobutyrate))100 or PEG macroRAFT agents.92
Charleux and co-workers proposed an elegant surfactant-free approach to reach very small thermosensitive poly(N,N′-diethylacrylamide) (PDEAm) nanogels that are coated by a pH-responsive polymer brush of poly(acrylic acid); in a one-pot synthesis DEAm was copolymerized with MBA in the presence of a poly(sodium acrylate) (PNaA) SG1-based macroalkoxyamine that plays the role of both the macroinitiator and stabilizer. When the crosslinker was introduced from the beginning (one batch conditions), macrogelation was observed with ≥3% of crosslinker. In contrast, when the crosslinker was not added at the beginning of the polymerization but only in a second stage, nanogels could be obtained at high solids content (up to 20%) and with high amounts of crosslinker (up to 9%). Using NMP but in homogeneous conditions in DMF, Hawker et al. reported the synthesis of PEGylated poly(N,N-dimethylacrylamide) (PDMA) star nanogels comporting reactive N-hydroxysuccinimide (NAS) groups that are available for bioconjugation. Here, the crosslinked PDMA core is coated by a “double shell” composed of a PEG-b-P(DMA-co-NAS) block copolymers.89 RAFT has also been used for the direct synthesis of hairy nano-/microgels. Hydrosoluble poly(N,N-dimethylacrylamide) (PDMAm)92 or poly(ethylene glycol)-b-poly(N,N-dimethylacrylamide) (PEG-b-PDMAm)92 macromolecular RAFT agents were used that made possible the preparation of stable sub-100 nm thermosensitive gel particles in a surfactant-free aqueous dispersion polymerization process. For both examples, a minimum chain length for the stabilizing (macroRAFT) agent was necessary in order to avoid the formation of aggregates or macrogelation at high solids content. Indeed for short macroRAFT agents, the forming nanogels were not sterically stabilized enough and aggregation occurred during polymerization yielding in interparticle crosslinking and the formation of heterogeneous dispersions.
Many groups in different application fields and especially in the biomedical prepare hairy nano-/microgels by conventional radical precipitation polymerization—via the macromonomer approach—because of the easiness of this technique. However, controlled radical crosslinking polymerization (cRCC) allows the synthesis of stable hairy gel nanoparticles at high solids content (up to 20%) without the necessity of using surfactants, as reversible macroinitiators/macroRAFT agents may play the double role of polymerization controlling agent and colloidal stabilizers. Indeed, such conditions open the way to large scale productions and thus industrial applications.
Similar to the synthesis of core and shell crosslinked microgels (illustrated in Fig. 3) they can be prepared by two-step precipitation polymerizations using degradable crosslinkers for the synthesis of the core. A common method consists in preparing first degradable cores (composed of PNiPAm) that are synthesized by RCC using for instance N,N′-(1,2-dihydroxy ethylene) bisacrylamide (DHEA) as degradable crosslinker. The next step consists in the polymerization of a crosslinked hydrogel-like shell around the collapsed core (i.e. at a temperature above the LCST of NiPAm) using non-degradable crosslinkers, e.g. MBA or DVB. Then, the (degradable) core–crosslinker is cleaved, e.g. by NaIO4 in the case of DHEA, yielding short polymer chains that can diffuse out of the remaining shell in its swollen state at T < LCST. Hollow PNiPAm microgels (microcapsules) are thus obtained. Apart from thermosensitive PNiPAm18 hollow microgels, double-sensitive glucose- and thermoresponsive poly(N-isopropylacrylamide-co-phenylboronic acid)146 poly(NiPAM-PBA) microcapsules have also been synthesized with the same templating process.
An original approach based on interfacial polymerization was developed by Deng and Sun for the synthesis of hollow PNiPAm microgels.147 They were synthesized in inverse emulsion in the presence of surfactants as shown schematically in Fig. 4. The polymerization was initiated at the oil/water interface by using a redox initiation system containing benzoyl peroxide in the oil phase and tetraethylenepentamine in the aqueous phase. As the polymerization is carried out above the LCST of PNiPAm, the forming polymer chains collapse and confine at the interface. Thermosensitive microgels of several microns (however, with a broad size distribution) were prepared and the hollow structure with a wall thickness of ca. 100 nm was confirmed by freeze-fracture microscopy (Fig. 4).
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Fig. 4 One step synthesis of poly(N-isopropylacrylamide) hollow microgels via interfacial polymerization with an inverse emulsion polymerization approach. (Reprinted with permission from ref. 147.) |
Finally, miniemulsion,148 microfluidic devices149 and membrane emulsification150 can also be used for the synthesis of monodisperse hollow microgels. In the two last approaches large microgels are obtained, where monomer and crosslinker are confined in the aqueous droplets while photoinitiator is located in the continuous oil phase. Then, polymerization initiated by UV-irradiation occurs at the oil/water interface. With microfluidic processes, the size of hollow microgels can be modulated from 50 to 80 µm depending on the surfactant content and the flow rates of the water and oil phases. Smaller capsules could be reached by combining miniemulsion polymerization processes with CRP. Thanks to the use of a PEO ATRP macroinitiator, Matyjaszewski et al. synthesized recently hairy nanocapsules made of crosslinked poly(butyl methacrylate) surrounded by a poly(ethylene glycol) corona.151 Similarly, Schork et al. used a PEO macroRAFT agent to reach thermosensitive PNIPAm nanocapsules in inverse miniemulsion, but in the absence of crosslinker.152
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