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Invited Feature Article

Nanogels and microgels: From model colloids to applications, recent developments and future trends Matthias Karg, Andrij Pich, Thomas Hellweg, Todd Hoare, L. Andrew Lyon, Jérôme J. Crassous, Daisuke Suzuki, Rustam A. Gumerov, Stefanie Schneider, Igor I. Potemkin, and Walter Richtering Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.8b04304 • Publication Date (Web): 18 Apr 2019 Downloaded from http://pubs.acs.org on April 19, 2019

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Nanogels and microgels: From model colloids to applications, recent developments and future trends Matthias Karg,1* Andrij Pich,2,3 Thomas Hellweg,4 Todd Hoare,5 L. Andrew Lyon,6 J.J. Crassous,7 Daisuke Suzuki,8,9 Rustam A. Gumerov2,10 Stefanie Schneider,7 Igor. I. Potemkin,2,10,11 Walter Richtering,7* 1

Physical Chemistry I, Heinrich-Heine-University Duesseldorf, 40204 Duesseldorf, Germany; DWI-Leibnitz-Institute for Interactive Materials e.V., 52056 Aachen, Germany; 3Functional and Interactive Polymers, Institute for Technical and Macromolecular Chemistry, RWTH Aachen University, 52056 Aachen, Germany; 4Physical and Biophysical Chemistry, Bielefeld University, 33615 Bielefeld, Germany; 5Department of Chemical Engineering, McMaster University, Hamilton, Ontario L8S 4L8, Canada; 6Schmid College of Science and Technology, Chapman University, Orange, CA 92866, USA; 7Institute of Physical Chemistry, RWTH Aachen University, 52056 Aachen, Germany; 8Graduate School of Textile Science & Technology and 9 Institute for Fiber Engineering, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, 3-15-1 Tokida, Ueda 386-8567, Japan; 10Physics Department, Lomonosov Moscow State University, Moscow 119991, Russian Federation; 11National Research South Ural State University, Chelyabinsk 454080, Russian Federation. 2

ABSTRACT Nanogels and microgels are soft, deformable and penetrable objects with an internal gel-like structure that is swollen by the dispersing solvent. Their softness and the potential to respond to external stimuli like temperature, pressure, pH, ionic strength and different analytes make them interesting as soft model systems in fundamental research as well as for a broad range of applications, in particular in the field of biological applications. Recent tremendous developments in their synthesis open access to systems with complex architectures and compositions allowing for tailoring microgels with specific properties. At the same time state-of-the-art theoretical and simulation approaches offer deeper understanding of the behavior


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and structure of nano- and microgels under external influences and confinement at interfaces or at high volume fractions. Developments in the experimental analysis of nano- and microgels have become particularly important for structural investigations covering a broad range of length scales relevant to the internal structure, the overall size and shape and inter-particle interactions in concentrated samples. Here we provide an overview of the state-of-the-art, recent developments as well as emerging trends in the field of nano- and microgels. The following aspects build the focus of our discussion: Tailoring (multi-)functionality through synthesis; the role in biological and biomedical applications; the structure and properties as model system, e.g. for densely packed arrangements in bulk and at interfaces; as well as the theory and computer simulation.

INTRODUCTION Gels are three-dimensional, macromolecular polymer networks that are swollen by a solvent such as water in case of hydrogels. When their size is reduced to the colloidal regime these gels are typically referred to as nanogels for overall sizes below 100 nm and microgels for larger objects up to the micron range. Nano- and microgels combine typical characteristics of macromolecules, colloids and surfactants:1 Like macromolecules they are soft and respond extremely fast to changes in solvent quality by changes of their local conformation,2,

3

like

colloids they can crystallize at high volume fractions,4, 5, 6, 7, 8 and like surfactants they adsorb to interfaces and reduce the interfacial tension.9, 10, 11 The unique properties of functional nano- and microgels are mainly related to their dynamic, permeable, network-like architecture, their


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capability to swell in different solvents and their deformability. In view of numerous potential applications for such materials their custom synthesis becomes increasingly important. Several different synthesis methods to obtain nano- and microgels with controlled properties were reported in the literature. The free radical precipitation polymerization by far remains the most important technique for the synthesis of temperature-responsive microgels because of its versatility and flexibility. The precipitation polymerization offers several advantages compared to other techniques. It is typically performed in aqueous solutions at moderate temperatures (60 -80 °C). This relatively simple approach can be applied to a broad range of monomers and allows for the introduction of functional groups by the use of comonomers or via post-modification. Changing the morphology of microgels provides a different way of tailoring their properties. The compartmentalization of functional groups, e.g., in core/shell systems with different monomer compositions in the core and in the shell can be realized by a semi-batch precipitation polymerization process and leads to new swelling behaviors.12 A different approach plays with the mechanical properties of the components, e.g., by combining hard and soft components in hybrid core/shell nano- and microgels.13, 14, 15 The dissolution of a sacrificial core allows fabricating hollow microgels.16, 17, 18 With their excellent colloidal stability and the large specific surface area, nano- and microgels are important candidates for biological and bio-medical applications such as biocatalysis, sensing and drug delivery. In this perspective the practical clinical use and the identification of suitable therapeutics that can be loaded to and on purpose be delivered from nano- and microgels resemble current challenges, despite the actual in vivo testing. Their soft and responsive character is not only relevant to controlled release and interaction with soft tissues but renders nano- and microgels as perfect model systems to study soft interactions. In particular at


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high packing fractions pronounced differences in their structure and dynamic behavior in comparison to classical hard sphere colloids are observed in 2D and 3D that clearly result from their deformability and capability to interpenetrate.19 Crucial for the general understanding of soft objects in confinement is the role of softness on the structure and dynamics of dense dispersions. In this perspective theoretical considerations and computer simulations became essential for the general understanding of the internal structure of nano- and microgels during the last years.2, 20, 21, 22, 23, 24 With this article we want to highlight recent activities in the fundamental and application relevant research dealing with nano- and microgels. At the same time, we will discuss current challenges and future perspectives. This feature article is organized as follows: First we discuss aspects and developments in the synthesis of (multi-)functional nano- and microgels by precipitation polymerization followed by a discussion on systems for biological applications. Then we discuss recent works on densely packed nano- and microgels as well as their behavior at liquid/liquid and air/liquid interfaces. Finally, we address the theory and computer simulation of nano- and microgels.

SYNTHESIS OF (MULTI-)FUNCTIONAL NANO- AND MICROGELS The basis of all studies on microgels is of course synthesis and a lot of progress was achieved in this context. Two current reviews summarize extensively different synthesis methods to obtain tailored nano- and microgels.25, 26 Hence, here we will focus on the publications of the last two to three years and we will only highlight some recent advances in the synthesis of nano- and


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microgels. Due to the high number of works dealing with synthesis of nano- and microgels, the present chapter cannot provide a fully comprehensive overview, but will be rather selective.

In most cases the work-horse synthesis still is precipitation polymerization in aqueous solutions, sometimes using seeding approaches. Since the early works by Pelton et al.27 hundreds of publications describe the synthesis of nano- and microgels with controlled properties. The free radical precipitation polymerization remains the most widely used technique because of its versatility, flexibility and up-scaling possibility. This relatively simple method can be applied to a broad range of monomers from acrylamide (typical representative N-isopropylacrylamide (NIPAM)) or N-vinyllactam (typical representative N-vinylcaprolactam (VCL)) families and allows introducing functional groups by the use of comonomers such as acrylic acid (AA),28 dimethylamino ethylene methacrylate (DMAEMA),29 and acetoacetoxyethyl methacrylate (AAEM).30 Also seeds can be added leading to the formation of core/shell structures.31

Building blocks for microgel synthesis. The synthesis of nano- and microgels requires careful selection of the building blocks, that are monomers, cross-linkers and initiators in the case of precipitation polymerization. Copolymerization is a powerful tool to adjust the chemical structure and incorporate functional groups into colloidal polymer networks.32 Suzuki and coworkers synthesized copolymer microgels by precipitation polymerization using NIPAM, methacrylic acid (MA) and fumaric acid (FA).25 The obtained poly(N-isopropylacrylamide) (PNIPAM) microgels (reference sample), P(NIPAM-co-MA) (carboxylic groups localized in the


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core) and P(NIPAM-co-FA) (carboxylic groups localized in the corona) were used as seeds in polymerization of styrene. It has been shown that the distribution of carboxylic groups in the microgel structure controls the polymerization loci of styrene and consequently the morphology of the composite microgels (Figure 1). This example demonstrates that the control of the chemical functionalities in microgels achieved during precipitation polymerization allows fabrication of complex colloids by the follow-up polymerization or post-modification steps.

Figure 1. PNIPAM microgels with controlled distribution of carboxylic groups synthesized by precipitation polymerization were used as seeds for the polymerization of styrene to form compartmentalized colloids. Reproduced with permission from ref25 (Copyright 2017 Springer Nature Limited). The copolymerization of different monomers in a precipitation polymerization process is a powerful tool to fabricate microgels that can be specifically loaded with drug molecules and


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serve as cargo for the delivery and release applications. Ozbas and co-workers synthesized poly(acrylamide-co-N-vinylpyrrolidone-co-2-(diethylamino)ethyl

methacrylate)

(P(AAM-co-

NVP-co-DEAEMA)) copolymer microgels.33 The microgels were loaded with 5-fluorouracil (5FU) as a model drug. In vitro release profiles demonstrated that 5-FU release from P(AAM-coNVP-co-DEAEMA) microgels at pH 7.4 was much faster compared to pH 5.5 and pH 2.1 due to the increased solubility of 5-FU with increasing pH. This is a nice example for the rational combination of different functional comonomers in a microgel structure to control the loading and the release rate of the drug molecules in aqueous solutions. The post-modification of microgels is an important strategy to integrate chemical functionalities, which cannot be directly incorporated during precipitation polymerization. Yun-Yan and coworkers reported the synthesis of copolymer microgels by copolymerization of NIPAM and AA. P(NIPAM-co-AA) microgels synthesized with different contents of AA were post-modified by 4′-amino-benzo-12-crown-4-acrylamide

(B12C4)

mediated

by

1-ethyl-3-(3-

dimethylaminopropyl)carbodiimide (EDC) to obtain microgels modified with molecular recognition receptors capable of forming host-guest complexes with cyclodextrins (γ-CD).34 These microgels act as phase-transition actuators and adsorbents simultaneously exhibiting an isothermal γ-CD-induced volume change behavior because of the formation of host–guest γCD/B12C4 complexes. The authors demonstrated that the γ-CD concentration in aqueous solution could be determined by simply measuring the size of microgels at a certain temperature. Moreover, the microgels are promising for selective adsorption of γ-CD molecules. This might be useful for separation of cyclodextrins after enzymatic synthesis. Besides classical copolymerization approaches described above, recently many research groups

apply

successfully

reversible

addition-fragmentation

chain

transfer

(RAFT)


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polymerization to synthesize of nano- and microgels. RAFT polymerization is a versatile, controlled technique, which is tolerant to different monomers and can be performed with commercially available initiators in aqueous solutions. Exploiting this method Etchenausia et al. synthesized poly([2-(acryloyloxy)ethyl]trimethylammonium chloride) (PAETAC) reactive cationic polymers. These were subsequently used as stabilizers for the emulsion polymerization of poly(N-vinylcaprolactam) (PVCL) microgels.35 A series of monodisperse microgels with cationic PAETAC shells and reversible, temperature-triggered micro-phase separation driven volume transition were synthesized and characterized by dynamic light scattering (DLS) and small angle neutron scattering (SANS) The controlled incorporation of biological building blocks into nano- and microgels opening new perspectives for the design of materials for biomedical applications is still a big challenge. Li and co-workers synthesized PNIPAM microgels decorated with DNA using a onestep precipitation polymerization approach. In this work 5′-acrydite-modified nucleic acid strands were incorporated into the outer shell of PNIPAM microgels using a low-temperature redox-initiated radical polymerization approach to avoid damage of DNA at high temperatures. 36 The authors demonstrated that this approach allows design of DNAzymes that mimic the horseradish peroxidase (HRP) and glucose oxidase (GOx) and can catalyze efficiently chemical reactions in aqueous solutions. Leite et al. have achieved to decorate microgels with partly crystalline starch nanoparticles. This most-likely leads to a better biocompatibilty.37 The incorporation of nanoparticles into nano- and microgels is still an important research topic. It was shown that microgels can be loaded with nanoparticles, either by infiltration with small, inorganic nanoparticles38 or enzymes,39 the in situ reduction of metal nanoparticles40, 41, 42 or the loading of nanoparticles to the outer corona of microgels by e.g. electrostatic


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interactions.43,

44

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Hybrid gels combining the responsiveness of polymer networks and the

catalytic or optical properties of nanoparticles are adjustable building blocks for the design of new functional materials. A recent review by Din and co-workers summarizes available techniques for the fabrication of hybrid nano- and microgels pointing out existing and emerging applications in drug delivery, catalysis, diagnostic tools, sensors and actuators.26 Microgels with complex architectures. In the last decade the synthesis of microgels with complex architectures received considerable attention. Among different known microgel morphologies, core/shell45 or multishell46,

47

colloids were in focus of research. Temperature-

responsive microgels with core/shell morphology are interesting building blocks for the design of interactive coatings. Cors and co-workers reported surface coatings based on core/shell microgels with the core and shell made of two distinct polymers with a significant contrast in lower critical solution temperature (LCST) (Δ LCST= 23 K) (Figure 2).45 In their system, the microgel shell possesses the lower LCST, thus it shrinks first as temperature is increased and compresses the core. Inversely, by decreasing temperature, the core tends to swell first, but is hindered by the still collapsed shell. Using this effect and varying the cross-linker amount in the microgel core (Figure 2a,b) the authors demonstrated that the obtained microgel films exhibit a peculiar linear-swelling behavior similar to the behavior of microgels in aqueous solution (Figure 2c,d). Such microgel-based coatings with tunable mechanical properties are extremely interesting for cultivation of vertebrate cells and understanding of their adhesion, motility and differentiation. Simultaneously, the works by Richtering’s group reported on the synthesis of core/shell/shell and multishell microgels either with or without a solid silica core and two distinct shells made of the aforementioned polymers with the different LCSTs.46,

47

The authors

demonstrated that at the intermediate swelling state, the internal microgel structures disclose


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pronounced differences. In particular, the microgels with a collapsed inner and a swollen outer shell show similar density profiles with and without silica core, with a slight increase of the cavity size.46 In contrast, the microgels with a swollen inner and a collapsed outer shell47 showed a considerably stronger interplay of the two networks, resulting in shell interpenetration in the presence of the rigid core and a decrease of the void size in its absence. Meanwhile, independently of the collapse of the outer shell, the cavity and the structural integrity of the nanocapsules were preserved. Therefore, such microgels can be used as carriers for nanoparticles.


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Figure 2. (a) AFM image of well separated dry microgels on a silicon wafer used for the profiles in b. (b) Average height profiles for dry core/shell microgels determined from AFM height scans for different core cross-linker contents as indicated in the legend. (c) Schematic drawing of a microgel in suspension and an adsorbed microgel. (d) AFM image of a densely packed microgel layer deposited on a silicon wafer used for the ellipsometric measurements shown in e and f. (e) Ellipsometric measurements in water of the layer thickness d of core/shell microgels deposited on a silicon wafer for different core cross-linker contents as indicated in the legend, as a function of temperature. In (f), the curves are normalized to the high-temperature average (45−50 °C) dmin, allowing a comparison of the swelling properties. The data clearly reveal the linear change in thickness of these layers. The inset shows a zoom of the linear region with the respective linear fits. The AFM images were not yet published and the other plots in the figure were adapted or reproduced with permission from ref45 (Copyright 2017 American Chemical Society).

Advances in polymerization processes. The in situ monitoring of the polymerization processes is essential for the understanding of polymerization kinetics, microgel formation mechanisms


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and establishment of reliable protocols for the synthesis of functional nano- and microgels. Meyer-Kirschner et al. combined in-line Raman monitoring and model-based spectral evaluation achieving quantitative component prediction of monomers and polymers during the precipitation copolymerization process.48 In this work homo- and copolymer microgel syntheses based on VCL and NIPAM were monitored at reaction temperatures of 60–80 °C using turbidity and inline Raman spectroscopy. The calibrated mixture model reveals conversion of both monomers and describes the formation of both polymers. Knowledge of such effects is essential for production of microgels with tailored properties, since differences in monomer reactivity directly affect the distribution of monomer units within the microgels. In addition, compared to manual sampling and off-line analysis, in-line Raman monitoring provides a higher sampling rate, determining component fractions during microgel synthesis every 12 s. Continuous polymerization processes are required for the efficient up-scaling of nano- and microgel production. Recently Kather and co-workers reported the synthesis of extremely small, monodisperse, stimuli-responsive PVCL nanogels with a radius of 45 nm by surfactant-free continuous precipitation polymerization in a high-pressure confined impinging jet reactor.49 It was shown that high pressures, combined with high mechanical shear forces inside the reaction chamber, resulted in size reduction and improved the stabilization of microgel precursors leading to the formation of extremely small and uniform colloidal gels. Wolff and co-workers presented a new continuous synthesis process applicable to the fabrication of temperature-responsive microgels (see Figure 3).50 In this study the size, size distribution, and temperature-responsive behavior of microgels synthesized by the continuous process are compared to microgels synthesized using conventional batch processes.


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Figure 3. Schematic representation of continuous microgel synthesis process. Comparison of hydrodynamic radii of PVCL microgels at 20 °C synthesized under flow and batch conditions (a) and calorigrams and conversions over time for PVCL microgels synthesized under batch conditions (b). Each radius symbolizes the mean radius of three independent syntheses. Reproduced with permission from ref50 (Copyright 2018 American Chemical Society). PVCL and PNIPAM microgels obtained in this work by surfactant-free continuous synthesis are systematically smaller, while the actual size depends on the premixing of the reaction solutions. However, by the use of a surfactant, the size difference between microgels synthesized by batch and continuous protocol diminishes, resulting in equal-sized microgels. Moreover, the temperature-induced swelling/deswelling of microgels synthesized under continuous flow conditions was similar to that of their analogues synthesized using the batch polymerization process. The main advantage of the developed continuous microgel synthesis method is the combination of flexible precipitation polymerization conditions and possible up-scaling.


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Despite the many opportunities to synthesize tailored nano- and microgels offered by precipitation polymerization, some of the main challenges for microgel synthesis still remain. 25, 45

The precise control of size and size distribution for nano- and microgels becomes difficult

especially when charged monomers are employed in precipitation polymerization. The flexible variation of the chemical structure in nano- and microgels is not always possible due to the different reactivity and solubility of monomers. Different reactivity of monomers and crosslinkers on one hand and limited choice of analytical methods able to provide direct evaluation of the network topology on the other hand limit the possibilities to tailor the internal structure and morphology of nano-and microgels. Finally, new approaches for the efficient colloidal stabilization in water and organic solvents as well as model-based sustainable production technologies are required to open new application possibilities for functional nano- and microgels.

NANO- AND MICROGELS FOR BIOLOGICAL APPLICATIONS Nano- and microgels with a broad range of compositions and sizes have been applied to address a range of challenges in biology and biomedical engineering, in each case leveraging one or more of the unique properties of such colloidal gels to create technologies difficult to replicate with other types of materials. Bioactive Nano- and Microgels. The high specific surface area, low non-specific adsorption, and high aqueous colloidal stability of nano- and microgels have attracted interest in their application in various bio-catalytic, sensing, and affinity binding applications. In particular, recent developments in this area are primarily focused on using the highly hydrated environment


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inside nano- and microgels to stabilize the sensing unit and/or enhance mass transfer between the analyte(s) and the sensing unit(s), with the small macroscopic dimensions and high water contents of nano- and microgels offering particular benefits. Bio-Catalysts: While the concept of using microgels to protect enzymes is well-established,51, 52 several recent papers have described new approaches to fabricate nano- and microgels directly in the presence of enzymes to maximize loading while preserving enzyme stability by avoiding high temperature and radical-rich processes. For example, Zhou et al. reported the ordered selfassembly of amyloid fibrils into microgels for efficient enzyme stabilization53 while Pich’s group reported the fabrication of biohybrid nanogels based on direct cross-linking of poly(Nvinylpyrrolidone-co-N-methacryloxysuccinimide), enzymes, and amine-containing synthetic polymers in an inverse emulsion that exhibited tunable activity based on cross-link density.54 Microgels have also been applied to create biomimetic catalysts for biomass conversion reactions. For example, Sharma et al. reported the formation of inverse emulsion microgels based on butyl acrylate, ethylene glycol dimethacrylate, and the pentadendate ligand VBdpdpo that, when activated by copper, induced 38-fold enhanced glycosyl transfer rates relative to a low molecular weight analogue.55 Biological Sensors: Most reported applications of microgels as sensors take advantage of the potential of analytes to either change the swelling state of individual microgels (detectable via size change) or the inter-particle spacing of a microgel network (detectable by refraction changes) upon binding to microgels. Serpe’s group has reported extensively on using microgel etalons, tightly packed microgel layers sandwiched between two gold layers, for such purposes.56 As one representative practical example, anti-progesterone antibody-functionalized PNIPAM microgels cross-link upon exposure to progesterone, inducing shrinkage of the microgel layer


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and thus a reduction in the distance between the two gold layers; this alters the reflectance spectrum from the etalon to enable visual quantification of progesterone concentrations as low as 0.28 ng/mL.57 Glucose sensing has also been a long-targeted application of microgels, with systems having been reported to work via enzymatic (e.g. glucose oxidase58) or apo-enzymatic (i.e. enzyme fragments that allow for binding but not conversion59) pathways, biomimetic protein binding (e.g. concanavalin A60), and/or small molecule chemical equilibria (e.g. phenylboronic acid)-based mechanisms.61 Particular attention has been paid to phenylboronic acidfunctionalized microgels given their glucose binding equilibrium-induced changes in microgel ionization, resulting in tunable changes in microgel swelling,62, 63 microgel net charge,64 and/or (as more recently proposed) microgel transition temperature65 in response to glucose concentration changes, although their lack of direct specificity to glucose can be a challenge for in vivo use. Significant challenges however do persist in driving large-scale transitions over the physiologically-relevant glucose concentration ranges and detecting such changes reliably in complex biological media. Improving the specificity of the sensing entity while at the same time engineering the network structure to generate swelling responses over the application-specific analyte concentration range offer potential for further improvements moving forward. Integrating other types of read-outs into nano- and microgel-based sensors also offers additional opportunities to improve the sensitivity of the responses. For example, Sigolaeva et al.66 fabricated an amperometric biosensor based on a temperature- and pH-sensitive poly(Nisopropylacrylamide)-co-(3-(N,N-dimethylamino)propylmethacrylamide)

(poly(NIPAM-co-

DMAPMA) microgels loaded with the enzyme butyrylcholinesterase (BChE) and deposited on a surface of graphite-based screen-printed electrodes (SPEs) premodified with MnO2 nanoparticles. The developed amperometric biosensor uses butyrylthiocholine as BChE


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substrate, with subsequent MnO2-mediated thiocholine oxidation at a graphite-based SPE. This sensor

enabled

precision

detection

of

organophosphorus

pesticides

(diazinon(oxon),

chlorpyrifos(oxon)) in aqueous samples (with detection limits of 6 × 10-12 M and 8 × 1012

respectively) with minimized interference from extraneous (nonanalyte) substances (e.g. ions

of heavy metals).

Affinity Binding/Biological Scavenging: The dynamic nature, high mass transport potential, and facile functionalization of nano- and microgels make them highly attractive as scavengers and/or concentrating platforms for analytes of interest. Shea’s group has done particularly impactful work in this area by using empirical screening to design microgels with remarkably high specific affinities to a variety of biological targets, exploiting the ease of fabricating copolymer microgels based on PNIPAM via precipitation polymerization to create screenable microgel libraries.67 For example, by copolymerizing (hydrophobic) tert-butylacrylamide and (anionic) acrylic acid (AA) with NIPAM, highly specific binding of melittin (the principal component of honey bee venom) was achieved such that the microgels could effectively detoxify mice in vivo.68 In contrast, copolymerization of NIPAM with AA with pentafluorophenyl acrylamide demonstrated high specific deactivation of the lytic activity of the peptide phenol-soluble modulin 3.69 High affinity interactions have been successfully engineered between microgels and targets ranging from small molecules to proteins,67 including in some cases thermoresponsive “catch-andrelease” activity to effectively recover scavenged biomolecules after binding.70

Affinity binding of microgels can also be applied in more biomedically-oriented applications, either to promote coalescence or to scavenge low-concentration biomolecules. As an example of


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the former, ultra-low cross-linked (ULC) microgels decorated with fibrin-binding motifs have been applied as platelet mimics for hemostasis.71 The surface-displayed fibrin ligands act to coalesce and stabilize a nascent clot while the low modulus of the microgel allows for conformationally flexible, multivalent binding, enabling these microgels to contract clots in much the same way as activated platelets.72 As an example of the latter, Jans and co-workers showed that glycan-functionalized polyethylene glycol microgels exhibited a high binding efficiency (Kd ≈ 0.5 to 1 μM) to lectins, enabling effective collection and concentration of such proteins.73

Drug delivery. The tunable porosity, composition, colloidal stability, and elasticity of nano- and microgels have long been recognized to have significant benefits for facilitating drug delivery in various applications.74, 75 Recent efforts have focused on resolving challenges associated with the practical clinical use of microgels as delivery vehicles as well as expanding the scope of therapeutics that can be effectively delivered using microgels. Degradability: The lack of degradability of conventional thermoresponsive nano- and microgels limits the potential of such materials for in vivo use, prompting recent efforts in the fabrication of degradable analogues of thermoresponsive microgels. Dynamic covalent bonding offers an appealing strategy and has recently been applied by several groups for drug-loaded microgel fabrication (Figure 4). Hoare’s group reported an all-aqueous approach for fabricating degradable PNIPAM76 and poly(oligoethylene glycol methacrylate) (POEGMA)77-based microgels in which a solution of oligomeric hydrazide-functionalized pre-polymers is heated above its LCST to create stable nanoaggregates that are subsequently cross-linked into nanogels (interestingly, with apparently uniform cross-link densities78) via the addition of an aldehyde-


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functionalized oligomer via dynamic hydrazone bonding. Pich’s group reported a complementary approach using hydrazone chemistry to fabricate poly(N-vinylcaprolactam) microgels by cross-linking the ketone groups of the comonomer diacetone acrylamide with the small molecule cross-linker adipic acid dihydrazide,79 while Haag’s group reported the use of a similar nanoaggregate pre-assembly technique to form microgels based on photocross-linked vinyl ether acrylate-functionalized poly(vinyl alcohol).80

Figure 4. Emerging strategies for fabricating degradable well-defined microgels for drug delivery: (a) thermal pre-aggregation of hydrazide-functionalized PNIPAM followed by hydrazone cross-linking with aldehyde-functionalized PNIPAM. Reproduced with permission from ref76 (Copyright 2015 American Chemical Society); (b) hydrazone cross-linked inverse emulsion poly(caprolactone) microgels. Reproduced with permission from ref79 (Copyright 2017 Wiley); (c) photocross-linking degradable linkage-tethered acrylates within pre-formed nanoaggregates. Reproduced with permission from ref80 (Copyright 2017 Elsevier).


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Other strategies that do not use dynamic covalent cross-linking have also been reported. For example, Sung et al. prepared semi-interpenetrating networks of a NIPAM/acrylamide copolymer in a genipin-cross-linked gelatin microgel that showed both thermoresponsiveness and enzymatic degradation,81 while Wang et al. prepared microgels by copolymerizing NIPAM with acrydite-modified cancer-targeting aptamers and single-stranded DNA that could be reversibly cross-linked by adding a complementary linker DNA sequence.82 Additional investigations as to the long-term fate of these degradable/dynamic cross-linked microgel networks in vivo need to be conducted to confirm that these approaches do lead to ultimate clearance without inducing any chronic inflammation or toxicity challenges. Delivering Macromolecular Therapeutics: While most papers describing drug delivery with microgels have focused on small molecules, there is emerging interest in developing protein or polynucleotide-based therapeutics that are increasingly important in clinical applications. Protein delivery is particularly attractive in that the mesh size and highly hydrated internal structure of microgels offers potential not only to deliver but also to stabilize the activity of proteins. Microfluidic production of larger microgels has been most widely investigated given that the use of microfluidics can facilitate the incorporation of various in situ-gelation chemistries that can better preserve protein activity. For example, Garcia’s group reported the fabrication of starPEG-based microgels by cross-linking maleimide-terminated star-PEG with a dicysteinemodified matrix metalloproteinase-cleavable peptide to create inflammation-responsive microgels that could release active growth factors for promoting in situ vascularization,83 while De Laporte’s group described a double emulsification strategy to fabricate aqueous protein solution core/photopolymerized six-armed acrylated poly(ethylene oxide-stat-propylene oxide) shell microgels that offer tunable hydrolytic degradability and protein release.84 Malmsten’s


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group has shown similar benefits of microgels in peptide delivery, in particular demonstrating the use of anionic poly(ethyl acrylate-co-methacrylic acid) microgels to load and subsequently release cationic anti-microbial peptides to create active anti-fouling biomaterial surfaces.85, 86 The facile functionalization of nano- and microgels coupled with their potential for dynamic size changes is also attractive in the context of their use for the delivery of genetic material. Lyon’s group pioneered the use of PNIPAM-based microgels for delivery of siRNA by physically adsorbing the siRNA into the microgels from solution,87 while Nuhn et al. developed cationic nanogels for delivery of siRNA to tumors.88,

89

Incorporation of labile cationic groups in

microgels that can be protonated between physiological pH and lysosomal pH is of particular interest to exploit the proton sponge effect to enable cytoplasmic DNA/RNA delivery, essential for effective transfection. For example, Deshpande et al. have recently combined microgel-based delivery with more conventional polyelectrolyte complex formation by using anionic thermoresponsive microgels as platforms for poly(ethylene imine) adsorption, demonstrated to enhance both endosomal escape of the RNA complexes and the capacity of the microgels for RNA loading.90 Promoting Bioavailablity: Microgels offer attractive properties to address the transport challenges associated with therapeutic nanoparticles in vivo. In particular, the high hydration and low non-specific protein adsorption to microgels can enhance the circulation lifetime of intravenously injected nanoparticles; short circulation times are a key barrier to effective targeted nanotherapies. While substantial prolongation in circulation times have been observed with both PNIPAM and in particular POEGMA-based microgels,91 zwitterionic microgels based on the precipitation polymerization of sulfobetaine methacrylate have been recently demonstrated to show particularly extended circulation half-lives (~30-35 hours) and improved tumour


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localization (10% of injected dose) relative to competitive nanoparticles,92 although further improvements are necessary to further enhance the degree of tumor localization for practical application. The switchable hydrophobicity of PNIPAM-based microgels demonstrated by Yurdasiper et al. to promote microgel penetration both through and into the skin also suggest potential uses of microgels as effective dermal or transdermal drug delivery vehicles that warrant further investigation.93 On-Demand Release: Various self- or externally-activated drug delivery approaches using microgels have been reported in which on-demand phase transitions in thermoresponsive microgels and/or localized microgel de-cross-linking are applied to drive pulsatile drug release, which is increasingly of clinical interest to enable chronotherapy of drugs and/or personalized local therapies that can be dynamically adjusted as the patient’s needs change. Microgels or microgel nanocomposites that can effectively actuate ex vivo signals have been of particular interest, as nano- and microgels are among the few functional materials that can effectively perform such actuation while also offering significantly faster response speeds relative to corresponding bulk smart materials due to their smaller dimensions. Among key recent examples, Alejo et al. polymerized a POEGMA-based microgel shell around hollow gold nanocapsules that could be photothermally heated using near-IR irradiation to enable pulsatile anesthetic release.94 Hoare’s group reported microgel/injectable hydrogel/magnetic nanoparticle nanocomposite formulations in which the application of an alternating magnetic field generated heat to induce microgel swelling and thus pulsatile drug release,95 and Hang et al. described hyaluronic

acid-based

nanogels

functionalized

with

7-N,N-diethylamino-4-

hydroxymethylcoumarin that could be reversibly photocross-linked and photocleaved upon UV irradiation to facilitate light-promoted localized microgel degradation.96 In vivo (pH,


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temperature, etc.) signals can also be applied for disease site-specific triggering of drug release; such strategies are particularly well-suited to microgels given their tunable surface and swelling properties. For example, Mo’s group entrapped acid-activatable hyaluronidase inside hyaluronic acid-based microgels that can be activated upon contact with acidic endosomal compartments to degrade the microgel and thus promote intracellular-specific drug release.97 However, improving the ratio of drug release between the on and off states, necessary for most clinically-relevant applications, remains challenging to do with nano- and microgels given their inherent porosity and water contents (even in the “collapsed” state),. Engineering Multi-Drug Release: Emerging microgel structures and composites have also been applied to both facilitate and control release of multiple therapeutics to enable synergistic drug therapies. Core/shell microgels have attracted particular interest in this context. For example, Brown’s group reported that a densely cross-linked PNIPAM-core/loosely cross-linked PNIPAM-shell microgel could enable two-stage delivery of tissue plasminogen activator (tPA) (a large molecule loaded primarily in the loosely cross-linked shell) and the ROCK pathway inhibitor Y-27632 (a small molecule hypothesized to penetrate into the densely cross-linked core98). Alternately, Richtering and colleagues demonstrated both experimentally and theoretically (see the Chapter on Theory and Computer Simulation for a more detailed discussion) the potential of core/shell charge compartmentalization to enhance uptake but slow release of macromolecular therapeutics of the same charge as the core but the opposite charge to the shell.99 Microgel composites offer additional promise to further tune release kinetics by (1) using microgels as building blocks for bulk hydrogels, taking advantage of the differential partitioning and diffusion of drugs within and between the embedded or cross-linked microgels100 or (2) combining microgels with other types of delivery vehicles enabling co-


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delivery of multiple classes of drugs. As a recent example of the former, Burdick and colleagues cross-linked mixtures of different norbornene-functionalized microgels and adamantanefunctionalized hyaluronic acid with cyclodextrin-grafted HA,101 achieving highly tunable drug release and degradation according to the cross-linking density of the microgels used. As recent examples of the latter, Rogach’s group created multi-compartment alginate-based microgel beads via electrospraying that could deliver otherwise incompatible drugs at individually tunable release rates102 while Town et al. applied the in situ thermoaggregation of poly(NIPAM-coallylamine) microgels to co-entrap solid drug-loaded nanoparticles inside microgel aggregates to enable sustained release of poorly soluble drugs over four months.103 Cell and Tissue Engineering. Microgels have been widely applied in the context of cell-based therapeutics as well as, increasingly, as building blocks for bulk cell scaffolds. In both these contexts, precise engineering of the mechanics and interfacial chemistry of the microgels is essential to preserve high cell viability while also (at least in tissue engineering applications) promoting desirable cell responses such as proliferation and differentiation. Cell Delivery: Large microgels have long been used to encapsulate cells for in vivo delivery. In this context, the microgel is simply a carrier that can provide sites for cell adhesion as well as (via porosity control) regulate what nutrients and/or cells can access the encapsulated cells. The key attribute of microgels used in this application is that their cross-linking chemistry must be highly cytocompatible and ideally bio-orthogonal with biomolecule cross-linking chemistry; the widely-used alginate-calcium cross-linking strategy is popular given that it offers such benefits. Non-alginate microgels based on PNIPAM104 and on poly(2-oxazoline)105 have also recently been demonstrated as effective cell carriers for even sensitive neuronal cells, although cationic modification is typically required to achieve desired cell adhesion and may induce inflammatory


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issues in vivo. Cell delamination can also be triggered from the PNIPAM-based microgels by cooling the microgels and exploiting the hydrophobic-hydrophilic phase transition.104 Enzymatic cross-linking approaches that produce more stable microgels than alginate-calcium gels but avoid free radical polymerization processes have also been recently reported. For example, microgels based on dextran-tyramine (cross-linkable via horseradish peroxidase/H2O2) maintain ~20% and ~35% higher cell viability post-encapsulation while sustaining cell viability four times longer compared to alginate-Ca2+ and UV photopolymerized PEG-diacrylate respectively.106 Combinations of such in situ-gelation chemistries with high-throughput synthesis strategies including microfluidic processing,107 surface wettability-guided assembly on a patterned interface,108 or 3D droplet bioprinting109 offer particular promise to create cell loaded-microgels with optimal compositions. Tissue Engineering Scaffolds: Relative to conventional bulk hydrogels, tissue scaffolds based on microgels can offer advantages in terms of their (1) enhanced mechanics (tunable both within and between the microgels); (2) tunable multiscale pore size distributions (controllable on both an intraparticle and inter-particle length scale); (3) higher internal surface areas (providing more adhesion sites for cells); and (4) potential for coupling cell growth/infiltration with drug delivery. Several recent papers have demonstrated these benefits with a range of different cell targets. Zhou et al. reported the assembly of thiol-ene cross-linked PEG-diacrylate microgels into networks by adding tunable amounts of 8-arm PEG-vinyl sulfone to engineer the bulk hydrogel modulus to optimally promote the activity of Schwann cells.110 Similar cross-link densitydependent in vivo cell infiltration was also demonstrated using Burdick’s supramolecularly cross-linked hyaluronic acid-based microgels.101 Alge’s group reported photoinitiated click cross-linking of norbornene-functionalized PEG microgels with PEG-dithiol that substantially


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promoted mesenchymal stem cell (MSC) spreading and mechanosensing based on the combination of the microgel-induced microporosity and lower inter-particle cross-link densities.111 Conventional poly(NIPAM-co-acrylic acid) microgel-based substrates were shown by Wu’s group to stretch MSCs and induce the expression of several osteogenesis-related genes in 2D culture, even in the absence of external signaling.112 Finally, Douglas and co-workers created microgel-fibrin hybrids containing microgel-filled pores that were permissive to cell infiltration due to low microgel shear moduli despite the bulk modulus of the materials being relatively “stiff” (kPa scale), enabling surgical handling113 (Figure 5). In all these cases, the use of microgels as a scaffold building block offered specific mechanical or transport benefits that improved cell responses relative to those observed with bulk hydrogels. Microgel networks have also been applied biologically for non-viable tissue replacements, primarily by exploiting the unique viscoelastic mechanics that can be engineered into such materials by independently manipulating microgel and bulk gel cross-linking chemistries and densities. For example, Saunders’ group described the use of methyl methacrylate/methacrylic acid/ethylene glycol dimethacrylate/glycidyl methacrylate microgels that could self-cross-link via epoxy ring opening that reproduced the mechanical properties of intravertebral discs better than conventional bulk hydrogels,114 materials now being evaluated for clinical translation.


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Figure 5. Incorporation of ultra-soft microgels enhances cell infiltration in dense fibrin ECMs compared with fibrin-only controls. Reproduced with permission from ref113 (Copyright 2017 National Academy of Sciences).

Microgels can also be used in a tissue engineering context as both a building block and a biofunctional unit. For example, Haag’s group demonstrated that combining the controlled release functionality (delivering bone morphogenic protein-2) with the cell encapsulation functionality of Michael addition-cross-linked poly(vinyl alcohol)-based microgels enhanced the osteogenic differentiation of encapsulated MSCs.115 Alternately, De Laporte’s group fabricated anisotropic magnetic microgels functionalized with cell adhesive peptides that, upon magnetic alignment of the bioadhesive and anisotropic microgels inside a fibrin-based hydrogel, induced effective alignment of both fibroblasts and neurons coupled with a reduction in fibronectin production.116 Such examples of exploiting multiple functional benefits of microgels in a single application are particularly attractive to develop moving forward, clearly differentiating the potential benefits of microgel-based scaffolds from other developed tissue engineering scaffolds.


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While microgels are highly promising in all these biomedical applications, it must be emphasized that relatively few of the microgels described have been tested in vivo in animal models (much less proceeded to clinical trials). The described emerging activities around designing nano- and microgels with improved degradability, prolonged circulation times, and cell-compatible chemistries are all positive steps toward enabling such translation, but the thorough in vivo validation of such strategies is a critical next step to support further work in this area.

STRUCTURE AND PROPERTIES OF DENSELY PACKED NANO- AND MICROGELS Though the phase behavior and dynamics of model hard spheres are rather well understood, spheres interacting with a soft interaction potential exhibit a much more intricate behavior. Hereby, understanding the influence of this softness on the structure and dynamics of dense dispersions and its repercussion on, for instance, the rheological properties is of tremendous interest for a large community from fundamental physicists to formulation engineers.117 Microgels constitute possible candidates as models for soft colloids due to their ambiguous nature between hard spheres, polymers and surfactants.1, 118 In particular, responsive microgels, which properties can be tuned as function of the temperature have been widely employed to reach high volume fractions, 𝜁, through temperature quench. These systems are extensively investigated with respect to their intriguing structural and dynamic properties as discussed in recent reviews.119, 120 The focus of many researchers has now turned to understanding their behavior at high volume fractions beyond close packing, where microgels will have to change their size and conformation due to the increasing osmotic pressure. Most microgels polymerized by precipitation


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polymerization present a fuzzy sphere structure consecutive to the faster consumption of the cross-linkers with respect to the monomers.27,

121,

122

Consequently, they exhibit a

polymer/colloid duality emerging from the combination of their cross-linked core and fuzzy corona ending with dangling chains. Due to their internal structure and softness, microgels can interpenetrate, deswell and deform/facet at high 𝜁, as illustrated in Figure 6A. A large experimental effort has been currently undertaken to resolve the structure of densely packed microgels using either neutron scattering (Figure 6B)123,

124, 125, 126, 127

or super-resolution

microscopy (Figure 6C).128 Although conventional small-angle x-ray (SAXS) and neutron (SANS) scattering techniques provide useful information on the structural properties of the dense microgel dispersions, it remains difficult to decouple unambiguously the form factor from the scattering profile.123 Contrast variation neutron experiments in mixtures of deuterated microgels, d-µgels, and hydrogenated microgels, h-µgels, were therefore carried out to measure exclusively the form factor as a function of 𝜁 (Figure 6B). So-called tracers (Tr)124,

125, 126, 127

and zero-

average contrast experiments (ZAC)124, 125, 126 performed on “neutral” PNIPAM microgels, i. e., synthesized without addition of charge moieties, with different degrees of cross-linking. On one hand, h-µgels are dispersed in an excess of contrast matched d-µgels in Tr experiments. On the other hand, ZAC experiments124,

126

rely on an approximately 50/50 (by number) mixture of

ideally, identical except from their scattering contrast, h-µgels and d-µgels measured in a D2O/H2O mixture satisfying that the scattering contrast of d-µgels is the invers of the hydrogenated microgels d-µgels. Under such conditions, the inter-particle contributions to the scattering intensity related to the structure factor cancel each other allowing to measure the average form factor of the two microgels, only.124,

126

Note that the scattering contrast is

relatively unsensitive to the degree of deuteration of the particles for x-rays, which motivates the


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use of SAXS for the determination of the structure factor. Combining SAXS and SANS, thus presents a very efficient way to characterize conformational and structural changes in dense microgel dispersions.124, 125, 126, 127

Figure 6. A) Possible scenarios for dense microgel dispersions including interpenetration, deswelling and deformation. B) Summary of normalized microgel size measured from ZAC or Tr experiments for two different degrees of cross-linking (5 mol%:126, 2.5 mol %:124). Deswelling measured on 5 mol% -cross-linked tracer hollow microgels127) and on larger fluorescent microgel using dSTORM are shown for comparison. Reproduced with permission from ref128 (Copyright 2017 AAAS). C) 2 color dSTORM experiments of labelled microgels measured at high 𝜁. Reproduced with permission from ref128 (Copyright 2017 AAAS). D)


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Simulation snapshot of hollow and full microgels at high 𝜁. Reproduced with permission from ref127 (Copyright 2018 AIP Publishing). E) In silico synthesis of microgels. Reproduced with permission from ref20 (Copyright 2009 Wiley).

Figure 6B summarizes the results from different studies, performed with different degrees of cross-linking (2.5 mol% and ~ 5 mol%126) as well as for tracer hollow microgels dispersed in full d-µgels (5 mol%).127 The radius of the particles measured as a function of 𝜁, 𝑅(𝜁), has been normalized for comparison by the radius measured at lower 𝜁, 𝑅0 . No significant change within the microgel size was measured for 𝜁 ≤ 1 indicating that the microgels mostly interpenetrate in this regime. At higher 𝜁, the observed deswelling becomes more significant for softer particles. While these experiments provide new insights in the conformation of microgels at high 𝜁, they remained highly challenging as both h-µgels and d-µgels have to exhibit similar size, structure and interactions. This requires some adjustments of the synthesis conditions, which are usually set by using different degrees of cross-linking for the two types of microgels. Differences in properties between h-µgels and d-µgels can be traced back to the comparison of Tr- and ZACexperiments, where a slight difference in softness may lead to deswelling at much larger 𝜁 (with “harder” tracer particles)124. A similar effect is illustrated by the tracer hollow microgels exhibiting a much more pronounced deswelling when immersed within full d-µgels with a similar cross-linking127. It is worthwhile noting that even “neutral” microgels are usually charged, considering that they are synthesized using charged initiators and sometime surfactants. The contribution of these charges to the osmotic deswelling and structural properties of the microgels still remained largely unexplored at the exception of a recent study on binary mixtures of microgel particles presenting interesting self-healing properties125. Conversely, this effect has been much more studied for so-called ionic microgels co-polymerized for instance with


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polyacrylic acid (PAA), which exhibit in their deprotonated state a significant decrease of their size at relatively low 𝜁 as shown for instance by microscopy129 and light130, 131, 132 and neutron133 scattering. Direct stochastic optical reconstruction microscopy (dSTORM) was recently applied to microgels,128,

133, 134, 135, 136

allowing for the super-resolution imaging of the conformation of

labelled particles in dense dispersions.128 Two-color dSTORM experiments performed on “neutral” 5 mol% cross-linked microgels clearly evidence a sequence of interpenetration, deswelling and faceting with increasing 𝜁 (Figure 6C)128. The extent of each of these processes could further be quantitatively determined from image analysis.128 The corresponding evolution of 𝑅(𝜁)⁄𝑅0 shown in Figure 6B, is in good agreement with SANS results measured on smaller particles with comparable cross-linking.126, 128 In comparison, conventional confocal microscopy experiments performed on larger and more homogeneous microgels evidenced a pronounced osmotic deswelling and later faceting of the microgels, what was put in the perspective of the osmotic pressure increase at higher concentrations.137 These two examples illustrate that differences within the microgel microstructure and chemical composition may lead to completely different conformations at high 𝜁. In this context, super-resolution microscopy offers unprecedented possibilities to study microgels in situ, in particular if one considers its possible combination with other techniques probing the local structural organization and dynamics of the particles such as conventional confocal microscopy.119, 128, 138, 139, 140 The new accessible length scales will probably allow determination of the local molecular dynamics at the polymeric chain128, 133, 134 or cross-linker136 level at high 𝜁 in the future. However, microgels have to be specially modified to allow for the grafting of the blinking agent, which can change their physical properties and the distribution of fluorophores will only reflect the polymer density


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profile of the particles at the cost of a large synthetic effort to adjust its distribution within the particles. In addition, the sample has to be sufficiently arrested in respect to the long acquisition time usually only allowing for the dispersion investigation at very high 𝜁 unlike SANS for which fluid samples can be measured. Due to their complex nature, the link between the particle microstructure and their structural organization at high 𝜁 remains most of the time complex. In order to capture the properties of the microgels at diverse length scales, more advanced simulation models have been implemented as shown for instance for tracer hollow microgels on Figure 6D127 and the ‘in silico” synthesis of microgels in Figure 6E.20, 141 The latter approach illustrates the current trend to develop coarse grained models at the monomer and cross-linker scales, that are able to capture both the microstructure and structural rearrangement at reasonable computational costs. Again, these models remain coarse and do not necessarily include all the molecular interactions or the large ensemble of particles necessary to explain the collective behavior of the dense dispersions. When compared to experiments, they can however provide a very powerful way to capture the nature of the interactions between the microgels.141 The softness of microgels has direct consequences on the collective dynamics of the dispersion, which has attracted a large interest in the investigation of their glass transition as illustrated by a recent study142 comparing diverse colloids143, 144, 145 including microgels146, 147 in the form of an Angell plot (Figure 7A).148,

149

The normalized long time relaxation, 𝜏⁄𝜏0 , 𝜏0 being the

relaxation time of non-interacting particles, is plotted as a function of 𝜁 ⁄𝜁𝑔 , where 𝜁𝑔 is the volume fraction at the glass transition. Hereby, the so-called fragility criteria, initially describing glass-forming liquids and amorphous solids,148 has been extended to soft colloids in order to


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illustrate the profound influence of the softness on the collective long time dynamics.142,

146

Interestingly, following this definition, “hard” colloids have a “fragile” behavior due to the abrupt increase of 𝜏⁄𝜏0 approaching 𝜁𝑔 , whereas soft colloids are defined as “strong” in respect to their ability to accommodate their conformation and more densely pack at high 𝜁. The different lines shown in Figure 7A corresponds to the proposed model accounting for volume regulation of compressible colloids to maintain osmotic equilibrium.142 These results illustrate the need for a detailed in situ characterization of the dispersions and the intrinsic difficulty to characterize 𝜁 for soft microgels stemming from the dependence of their size, shape and interaction on the number density.120, 142 Considering that 𝜏⁄𝜏0 roughly scales as the zero shear viscosity, the interaction potential is as well reflected by the rheology of the dispersions and more particularly by the evolution of their linear viscoelastic properties in the vicinity and beyond 𝜁𝑔 . Within the arrested region, the elasticity increase is usually captured by the elastic modulus plateau, 𝐺′𝑃 (𝜁). Both quantities are of the same order of magnitude for emulsion particles.149 Conversely, when comparing the evolution of the osmotic pressure, Π(𝜁), with the shear modulus 𝐺′𝑃 (𝜁) for microgels, both quantities exhibit a similar trend but have to be rescaled assuming a rescaling factor, 𝐺′𝑃 (𝜁)⁄Π(𝜁) ~10−3 − 10−2 .150, 151, 152, 153 Accordingly, even if the osmotic pressure may be one of the main drivers to describe the microgel deswelling, the dynamical behavior and rheological properties of dense microgel dispersions are certainly far more complex. The increase of 𝐺′𝑃 (𝜁) at high 𝜁, was first considered assuming an inverse-power law potential stressing the difference of softness between microgels having different degrees of cross-linking.123 However at much higher 𝜁 the power law scaling fails and 𝐺′𝑃 (𝜁) may increase more steeply to finally flatten again at much higher 𝜁

131, 150, 151, 152, 153

as shown for example in Figure 7C for “soft” and “hard”


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microgels.153 Note that this is usually observed when 𝐺′𝑃 (𝜁) is spanning several decades as for dense emulsion dispersions.149

Figure 7. A) Angell plot for various colloidal systems with different softnesses. The solid lines are predictions from a model accounting for volume regulation of compressible colloids to maintain osmotic equilibrium. Modified and reproduced with permission from ref.142 (Copyright 2017 American Chemical Society). B) Schematic representation of a microgel considering a core/corona model. C) Linear viscoelastic shear modulus measured for a soft ionic microgel (top left) and a highly cross-linked microgel (top right). The predictions in the limit of incompressible core (dash-dotted line) and of no corona (dash-double dotted line) are also reported. The plots in the bottom left and right illustrate the corresponding model predictions for the relative compression of the core (full line) and of the corona (dashed line). Modified and reproduced with permission from ref.153 (Copyright 2010 American Physical Society).

Different types of interaction potentials were tested within a most of the time limited range of 𝜁, using for instance effective hard sphere123 and brush153, 154 models and power-law, harmonic or Hertzian potentials.139, 140, 141, 155, 156, 157 Among them, Monte Carlo simulations using an Hertzian potential were offering a good description of the pair correlation function of neutral microgels at moderate 𝜁, but, fail for larger 𝜁.139, 140, 141 In the densely packed regime, large deformations are not supposed to be accurately described with a Hertzian and the potential beyond contact should reflect for instance the fuzziness of the particles.141 This is inspiring the development of new


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models considering a multishell approach.153,

155

An example of which is a core/shell model

consisting of an elastomeric core surrounded by a polymer brush as schematically shown in Figure 7B. The inner elastomeric core and the polymeric brush were here described via mean field Flory-Rehner and Alexander-de Gennes theory, respectively.153 Considering that at equilibrium the osmotic pressure of the core, Π𝑖𝑛 , is equal to the one of the shell, Π𝑏𝑟 , the lines in Figure 7C present the fits from the model and the corresponding relative evolution of core and brush dimensions.153 Besides the increasing number of studies on ultra-dense dispersions, it remains in general unclear how the stress builds up when the particles overlap and/or build up contacts. A large theoretical effort has been engaged to unveil the nature of the jamming transition.119, 138, 158, 159, 160, 161, 162 Here, one of the main parameters is the number of contacts between particles and its evolution through the jamming transition.158, 159, 160, 161, 162 The major scaling could be confirmed for large slightly deformable athermal systems.163, 164, 165 The term athermal refers to particles for which the Brownian motion is becoming negligible, which is the case for instance for foams and granular materials. However, for Brownian systems, even a finite temperature has an important impact on the jamming transition.158, 160, 161, 162 One major difficulty is then to “disentangle”161 glass and jamming transition160,

161, 162

considering that glassy dispersions tend to become

athermal in respect to the dramatic slowing down of their dynamics at high densities.161 Therefore, understanding the jamming transition for soft thermal systems, assuming that they could jam, has become one of the major challenges within the soft matter community. Although recent jamming studies were investigating PNIPAM microgels,131, 156, 157, 162 one may wonder on what is really defining the notion of “contact” for such particles. Further on, the eventuality that


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microgels may interpenetrate and its impact on the local dynamics, i. e., the “athermality” of the dispersion has still to be explored. Unlike well-established colloidal “hard sphere” models, such as poly(methylmethacrylate) (PMMA) particles that are synthesized with almost standardized synthesis conditions,118 microgels are far more versatile in terms of structure and chemical composition. Trying to unify the properties of these particles is extremely challenging and comparing two different microgels turns out many times in comparing pears and apples. The recent trends in literature illustrate that conclusions on the nature of their interactions can only be drawn at the cost of great experimental efforts to thoroughly characterize changes of their microstructures at different densities, temperature and ionic strength. Recent exciting advances in experimental techniques and simulations are providing new insights on their complex structural behavior at high 𝜁 offering the possibility to develop more accurate physical models. Finally, we believe that when the glass transition of soft microgels has been one of the main foci in the field of dense microgel dispersion, its evolution aims towards the jamming transition of soft interpenetrable and deformable soft materials.

NANO- AND MICROGELS AT AIR/LIQUID AND LIQUID/LIQUID INTERFACES Nano- and microgels strongly adsorb to air/water and oil/water interfaces due to a significant reduction in interfacial tension. Different from conventional rigid microspheres, such soft microspheres can deform at interfaces. It was found that depending on the cross-linking density, i.e. the softness of the particles, pronounced lateral deformation leads to a stretching of the microgels covering a larger interfacial area as compared to their bulk dimensions.166 The degree


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of stretching typically increases with decreasing cross-linker density, i.e. with decreasing softness. The Suzuki group has systematically investigated the unique drying behavior of aqueous droplets containing microgels (Figure 8a).167,

168, 169, 170

They have discovered that i)

lightly-cross-linked PNIPAM microgels immediately adsorb at the air/water interface when drops of dilute suspensions are deposited on polystyrene substrates, ii) the adsorbed microgels arrange themselves at the air/water interface as a function of time, and iii) the ordered microgels can be transferred onto other solid substrates.167 They have also investigated the effects of the size, degree of cross-linking density, and chemical composition of the nano- and microgels on their adsorption kinetics and revealed that the size (92-2257 nm) is not crucial for this phenomenon, albeit that other parameters affect the behavior significantly.170 For example, the adsorption of the microgels at the air/water interfaces decelerates substantially with increasing hardness of the PNIPAM microgels (Figure 8b,c). The faster adsorption of softer microgels has tentatively been assigned to the deformation of the microgels at the air/water interfaces. The deformation of individual PNIPAM-based microgels was investigated using a fluorescence microscope equipped with a high-speed camera.169 The deformation dynamics were monitored on unexpectedly large microgels (6.3 μm) that had developed. The spherical microgels were highly deformed at the air/water interface, and their size increased up to 20 μm within a second (Figure 8d).169 In the same paper, it was demonstrated that highly deformed microgels at the air/water interface deformed even further at the interface upon evaporation of the droplets, which resulted in decreasing center-to-center distances of the microgels. A similar behavior (Figure 8a) was also observed for other soft microgels such as poly(N-isopropyl methacrylamide)- and poly(acrylamide)-based microgels, albeit that these


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move slightly at the air/water interface.170 On account of this difference, the ordered structures of these microgels could not be transferred onto other solid substrates upon complete evaporation of the water. This result suggests that the hydrophilicity (or hydrophobicity) also plays a crucial role when the microgels are assembled at the air/water interface. The impact of other factors such as the charge density of the microgels should also be investigated systematically in order to clarify the whole picture of soft and deformable microgels at such interfaces. Recently Maestro et al. studied the behavior of PNIPAM microgels at air/water interfaces as a function of temperature using a combination of ellipsometry and particle tracking based microrheology.171 They found a significant decrease in the lateral as well as the vertical dimensions of the microgels at the interface when the temperature is increased from below to above the LCST. Furthermore, microrheology revealed a structural transition from a solid-like, densely packed layer of microgels below the LCST to a liquid-like film above the LCST due to the pronounced decrease in microgel size.


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Figure 8. (a) Self-organization of microgels during the evaporation of microgel suspensions. (b) Optical microscopy images of soft (N1) and hard (N8) microgels adsorbed at air/water interfaces. (c) Normalized number, NN, of microgels adsorbed at the air/water interface as a function of the normalized time, TN. (d) Deformation of microgels at the air/water interface. Reproduced with permission from refs167, 170 (Copyright 2012 and 2018 American Chemical Society) and ref169 (Copyright 2018 Royal Society of Chemistry). Apart from the spontaneous self-adsorption of microgels at the curved air/water interface of droplets deposited on a solid support, microgels can also be spread directly at flat oil/water interfaces using careful injection with a pipette or microsyringe. In order to study the localization and dimensions of microgels at water/n-hexane interfaces, Geisel et al. used freeze-fracture shadow-casting cryo-SEM (FreSCa) to image the particle laden interface.172 They found that microgels possess an almost two times larger diameter at the interface in comparison to their bulk diameter. Furthermore, the authors determined very small protrusion heights to the oil phase


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indicating that the majority of the particles is located in the aqueous phase. From studies in bulk dispersion it is already known that microgels typically feature a pronounced core/shell structure with a higher cross-linked core due to a faster consumption of the cross-linker during the synthesis via precipitation polymerization.121, 122 In the work of Geisel et al. FreSCa revealed that such a core/shell structure is also detectable when the particles are spread at liquid/liquid interfaces. This core/shell structure was found to strongly influence the 2D microstructure of the microgels when the available area per particle at the interface is reduced by compression in a Langmuir trough.173 First, at low surface coverage, a transition from a gas phase with large interparticle distances to a hexagonal crystalline phase with microgels in shell-to-shell contact was observed when the accessible area was reduced by compression. Further compression led to an isostructural phase transition to a hexagonal crystalline phase with microgels in core-to-core contact. Apart from purely organic microgels that possess an internal core/shell like structure due to the cross-linker distribution, the occurrence of two defined length-scales was also observed in compression isotherms of core/shell microgels with rigid, inorganic cores and various thicknesses of a soft hydrogel shell.174 At high enough compressions the core/shell microgels arrange in hexagonally packed aggregates with inter-particle distances significantly smaller than their equilibrium bulk dimensions indicating a compressed state of the hydrogel shell. At low compressions, the particles arrange in clusters with shell-to-shell contacts. In contrast to purely organic, sub-micron sized microgels without inorganic cores, these clusters of microgels were already found at very low surface coverage, i.e. a randomly ordered gas phase was not observed. This clustering behavior could be attributed to attractive capillary interactions that result from a local deformation of the liquid/liquid interface. A comparable phase behavior, including the


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clustering at very low surface coverage, was also found for larger, micron-sized microgels without rigid inorganic cores.175 This interesting and complex phase behavior of core/shell microgels (either with inorganic nanoparticle cores or with a pronounced cross-link gradient) was studied in detail by a direct comparison of the bulk and the interface behavior using silica/PNIPAM core/shell microgels.176 In this study particles with a core diameter of 351 ± 16 nm and overall hydrodynamic diameter of 1028 ± 10 nm (swollen state of the shell, 20°C) were used. The microgels possessed excellent colloidal stability in bulk without noticeable aggregation for a broad range of volume fractions. Interestingly experiments at the water/n-hexane interface provided a different picture. Figure 9 shows the results of compression experiments performed in a Langmuir trough. The microstructures of the respective monolayers at different surface pressures  are depicted by the representative SEM images (A-F). The latter images were obtained from samples produced by transferring the particle monolayers from the interface onto a silicon wafer. Small values of  were measured for a broad range of low packing fraction, i.e. high values of specific area per particle Ap. In this regime the SEM images (A, B) revealed a two-dimensional network of percolating aggregates. Large voids between the aggregates are clearly visible and highlight the low average surface coverage. When the monolayer was compressed and the surface coverage was increased, the voids decreased in size until a homogeneous monolayer of microgels in shellto-shell contact was formed (C). Again due to the lateral deformation of the hydrogel shells at the interfaces the average inter-particle distance in this uniform monolayer is larger than the bulk hydrodynamic diameter. Further compression led to a significant increase in surface pressure and the corresponding microstructure of the monolayer revealed local clustering of particles into aggregates with significantly smaller inter-particle distances, approximately half the value of the


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distance of particles in shell-to-shell contact (D). When the available area was further reduced another transition was observed visible by a kink of the surface pressure at a value of Ap close to unity. At this stage the clusters of densely packed particles had grown to a critical size and additional compression caused the clusters to move closer together reducing the average interparticle distance in between individual clusters (E, F). Thus the distance previously assigned to the shell-to-shell contact reduced continuously.

Figure 9. Compression isotherms of silica/PNIPAM core/shell microgels at a hexane/water liquid/liquid interface along with representative SEM images (A-F) recorded from samples at various surface pressures. The surface pressure  as a function of specific area Ap is shown for compression experiments performed with different initial amounts of a 1.37 wt% dispersion (red squares: 20 L, green circles: 50 L, blue triangles: 110 L). The scale bars in the SEM images correspond to 2 m (top row) and 10 m (right column). Reproduced with permission from ref176 (Copyright 2018 American Chemical Society).


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Honold et al. made use of the attractive capillary interactions at low surface coverage to obtain highly ordered, freely-floating monolayers of plasmonic core/shell microgels at air/water interfaces.177 In contrast to the previously described compression experiments in a Langmuir trough, the latter monolayers were not confined between two barriers. Conveniently the freelyfloating monolayers could be transferred from the air/water interface onto solid, glass supports while maintaining their microstructures. The authors have applied this approach to core/shell particles whose initial gold nanoparticle cores were selectively overgrown with either gold or silver to produce core/shell particles with spherical, plasmonic cores with diameters between 20 and 100 nm. Since the inter-particle distances at the air/water interface was determined by the balance of attractive capillary forces and steric repulsion between the laterally deformed, relatively thick hydrogel shells, all monolayers showed similar average inter-particle distances independent of the core size or material. This allowed for the fabrication of plasmonic monolayers with nearly identical surface coverage, i.e. number of particles per area, and finely tuned plasmonic properties due to the variation in core size and composition. Interestingly Volk et al. have shown that the lateral shell deformation of uniform and densely packed monolayers of core/shell microgels at air/water interfaces depends strongly on the time the particles spend at the interface.178 A freely-floating monolayer of these microgels with initial average inter-particle distances corresponding to the bulk hydrodynamic diameter extends its overall dimensions and thus increases the inter-particle distance as a function of time because of the lateral shell deformation. Although the location of nano- and microgels and their deformation at liquid/liquid and air/liquid interfaces has been recently quantified by different experimental studies, the influence of softness controlled by, e.g. the extend of cross-linking, as well as the influence of parameters like


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charge density on their structural and time-dependent interfacial behavior have only been barely touched. We believe that the stability and dynamics at such interfaces and the resulting microstructure will strongly depend on the microgel architecture with important implications for example for emulsion stabilization and the use of nano- and microgels in soft nanolithography. Recent developments in experiment and simulation provide important information on their complex behavior in terms of structure and dynamics at interfaces covering packing fractions from the dilute, non-interacting state to densely packed films of highly deformed particles.

THEORY AND COMPUTER SIMULATION OF NANO- AND MICROGELS Single microgel particles. Theoretical and computer simulation studies of nano- and microgels have been rapidly developing during the last years. A major aspect of these studies 2, 20, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189

is to show how the chemical composition and various

external stimuli (such as the solvent quality,181, 183 temperature,2, 20, 180, 184, 187 pH,99, 179, 182, 188, 189 ionic strength186, 188 and light183) affect the structure of single neutral2, 20, 184, 185, 187 and charged99, 181, 182, 183, 186, 188, 189

microgel particles.

One method to obtain information on the swelling behavior of polymer microgels is analytical calculations, which is based on the minimization of the free energy of the microgel system179,

180, 181, 183, 185

, taking into account different contributions to the free energy as e.g.

network elasticity, electrostatic interactions, excluded volume, chain entropy. Many of the analytical calculations do not take into account the finite size of the microgels, but treat the microgels as if they were macroscopic and homogeneous. For charged systems this means for example neglecting the possibility of counterions leaving the microgel. Often this is a good


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approximation, but the validity of this approximation depends on quantities like the size of the microgel, the microgel concentration and the salt concentration. Not only microgel swelling, but also their internal structure has been investigated theoretically. Internal phase separation (a region of strongly stretched subchains in the center of the particle and the dense skin at the periphery) as an effect of the interplay of subchain elasticity and electrostatic interactions has been predicted in good agreement with experimental findings.181 In computer simulations of nano- and microgels, a general approach lies in the use of coarse-grained bead spring models in which one bead represents a group of atoms. For the topology in most cases an ideal “diamond-lattice-like” network with tetra-functional cross-links and polymer subchains of equal lengths is chosen.2, 183, 186, 188, 189 In contrast to simulations of macroscopic hydrogels, in which it is sufficient to simulate a small portion of the gel with periodic boundary conditions, it is necessary here to simulate the complete microgel. This allows to account for radial inhomogeneity and for non-uniform counterion radial distribution in the case of charged networks. The drawback here is the computational cost which strongly limits the size of the simulated microgels especially for charged systems.2, 183, 186, 188, 189 An alternative way to the diamond lattice for creating a polymer network is the random (yet uniform) distribution of the cross-links within a sphere with the subsequent connection of the cross-linkers by polymer chains of different lengths.71,

184

Finally, a microgel model can be prepared in silico by

mimicking the actual polymerization process.20 Even though the last method possibly results in a more realistic description of a polymer network, the use of the first two architectures does reproduce the experimentally observed swelling and collapse behavior reasonably well. For instance, the simulations of the collapse of microgels with both ideal2 and random184 networks reveal that the shrinking of particles starts from the periphery and then propagates to the center.


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For the modelling of charged polymer networks, we need to distinguish between simulations of strong polyelectrolytes181, 183, 186 carrying a fixed number of charges with fixed positions along the polymer chains and weak polyelectrolyte networks, in which the monomers can be protonated or deprotonated and thus be either in a charged or in an uncharged state. Weak polyelectrolyte microgels respond to changes in the pH by a change in their linear charge density along the polymer chain as well as with a change in the gel volume. The simple approach of varying the number of permanent positive and negative charges in a polyampholyte microgel linearly with pH, leads to a pH dependence of the microgel radius of gyration, which agrees qualitatively well with experimental findings (Figure 10a). 182 However, since for weak polyelectrolytes the ionization usually is not linear and does not only depend on the pH of the bulk solution, but also on the electrostatic potential at the locations of the ionizable groups (or in other words on the local pH)179 the charging/uncharging of the ionizable groups needs to be considered explicitly in order to calculate the pH dependent degree of ionization. This was done in studies of pH-dependent ionization and swelling behavior of weakly charged microgels under salt-free conditions189, 190 (Figure 10b) and in the presence of salt.188


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Figure 10. (a) The size of polyampholyte microgels as the function of pH obtained from DLS measurements (upper curves) and MD simulations (lower curves); the different colors of the curves correspond to different fractions of anionic and cationic groups. DLS: ca. 5% (black), 10% (brown), 14 % (dark orange), 16% (light orange), 20% (olive). MD simulations: 5% (black), 10% (red), 20% (orange); the inset images are the simulation snapshots of microgels at the different pH values; (b) degree of ionization αgel of microgel particles for various simulation cell lengths L as the pH is varied; the protonation/deprotonation has been explicitly accounted for in the Monte Carlo simulation; the black dashed line represents the theoretical titration curve of the isolated acid monomer at infinite dilution. Reproduced with permissions from ref.182 (Copyright 2015 American Chemical Society) and ref.189 (Copyright 2018 Royal Society of Chemistry).

Microgels of complex architecture. The growing variety of synthesized colloidal networks requires the studies of their properties by theory and computer simulations.46, 47, 71, 184, 191, 192, 193, 194, 195, 196, 197,

Along with the microgels with homogeneous structure discussed

previously, particles with composite,46, 71, 193, 197 core/shell,47, 184, 194 multi-shell,46, 47 hollow,193, 198 branched,195 interpenetrating networks (IPN),199 special architecture192,

197

and, finally, with

sliding cross-links196 have been investigated. Often, simulation studies and experimental results are combined in joint and complementary research projects.46, 47, 71, 193 In particular, the density profiles of multi-shell nanogels obtained from molecular dynamics simulations show nice agreement with the profiles obtained from SANS measurements46, 47 (Figure 11a). On the other hand, due to simplifications of the structure of the polymer networks as well as the interactions, the description of real swelling/deswelling processes by these models may be limited.47


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The simulations can also provide the concept of new microgel systems, such as artificial swimmers based on a bilayer network192 and particles with sliding cross-links possessing an enhanced swelling ability and deformability,196 or discover the new features of the existing systems. It was found that in copolymer core/shell particles the core could reveal unusual swelling behavior: apart from the conventional core/shell conformation, one can observe an “inverted core” and “patchy surface” morphology.184,

194

Also, the obtained phase diagram187

allows to tune the internal morphology of the microgels by varying the shell volume fraction and interaction strength between polymer chains. In the case of IPN microgels it was shown that they can form classical core/corona structures, shell/corona structures, and core/shell/corona structures, depending on the subchain length and molecular mass of the system.199 The other interesting effect shown in simulations is the formation of a long chain of magnetic nanoparticles inside of microgels at strong dipolar interactions regardless of the distribution of particles in the polymer network and its degree of cross-linking.197 Concentrated microgel suspensions. When talking about the recent theoretical and simulation studies21, 22, 23, 127, 200, 201 of microgel suspensions at higher packing densities, we can distinguish two different approaches at different levels of coarse graining. In the first approach the network particles are modeled as compressible, soft, spherical colloidal particles that interact via an elastic Hertz pair potential while their internal structure is ignored.21, 200, 201 Simulations of neutral200 and ionic21 suspensions, showed very good consistency between calculated and experimental thermal and structural properties. Another study dealt with microgel ordering caused by external electric fields,201 and excellent agreement between the theory, simulation and experiment was achieved. Nevertheless, we should point out that the choice of such elastic interaction potential is largely phenomenological, as the Hertzian soft repulsion was derived for


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the case of non-penetrable spheres, while real microgels are able to interpenetrate.140 On the other hand, the validity of use of modified (multi-Hertzian) potential has been proved as the most suitable one for reproducing the interactions between homopolymer core/shell microgels in concentrated suspensions.141, 155 In the second approach, which is mostly implemented in simulations, the structure of the polymer network is explicitly accounted for,22,

23, 127

and the intermolecular interactions are

modelled as the superposition of interactions between microgels segments. Several notable results were achieved from these studies. It has been shown that the interactions between the ideal microgels can be described neither with the Hertzian potential nor with the soft sphere potential in the wide range of the center-to-center distances, and a modified version of Hertzian potential was proposed.22 In case of charged particles, it was revealed that the electrostatic forces between microgels can be approximately derived from a Yukawa-like potential.23 Finally, in case of concentrated dispersions it was found that hollow microgels possess the alternative mechanism to respond to the compression (the polymer subchains are pushed and rearranged within the cavity) while the regular microgels can only adapt to the squeeze by deswelling, interpenetration or faceting.127 Overall, one might consider the last approach in modelling of microgel suspensions as the preferable one since it allows to estimate the structural dynamics of the particles. Unfortunately, the existing computational limitations still restrain the maximum number of molecules in the simulated systems. Therefore, the choice of the simulation approach will depend on the scale of the investigating physicochemical effects (unstructured spheres and finite-sized networks at the upper and lower mesoscale limits respectively).


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Microgels in multiphase systems. In addition to the theoretical and computer simulation studies of microgels in the bulk solutions, the scientific interest is also represented by the systems, which can demonstrate the effectiveness of soft colloidal particles in the potential applications (namely, the emulsion stabilization, biphasic catalysis, responsive membranes and drug delivery). These systems include microgels at liquid-liquid24, interfaces196,

203

193, 195, 202

and solid-liquid

and the uptake/release of guest molecules by microgels of various

architechture.46, 99, 185, 204 Simulations of hollow microgels revealed that these macromolecular objects maintain their cavity while being adsorbed at the liquid interface.193 Further studies demonstrated that both the interfacial adsorption rate and the deformation of network particles increase with the decrease of cross-linking density.24 In the case when microgels have the same compatibility with two immiscible liquids, it was shown that such liquids can be partially or fully mixed within the microgels situated at their interface (Figure 11b).202 Later on, it was found that blockcopolymer-based amphiphilic microgels have a higher stabilization efficacy in comparison with the respective linear diblock copolymers, and the equilibrium microgel monolayer at the liquid interface will be either uniform or nanostructured.195 As it was already mentioned, the particles containing physical bonds (sliding cross-links) are predicted to be more deformable in comparison with the particles containing only chemical bonds, which was demonstrated by the adsorption analysis of such microgels onto a solid surface (Figure 11c).196 Apart from this, for the porous solid surfaces it was shown that adsorbed microgels can reversibly enter and exit the pores upon collapse and swelling, respectively.203 Considering the interactions between colloidal networks and guest molecules, a multishell nanogel-based drug container concept was proposed: by varying the permeability of


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different parts of the network, one can load the fully swollen nanogels with drug molecules and then collapse the inner shell, which locks the guest molecules while the swollen outer shell provides a colloidal stability of the container. An additional mechanism can be realized in case of charged systems. Here, the simulations of polyampholyte core/shell microgels demonstrated that the presence of an anionic shell allows the release of negatively charged molecules due to the electrostatic interactions. Meanwhile, the presence of an additional shell prevents the aggregation of charged microgels and creates a stable microgel–polyelectrolyte complex.99 We summarize that both in theoretical and simulation studies microgel models on different levels of coarse graining and with a strong predictive power have been created and validated by comparison to experimental findings. While for the analytical theories, the main challenge often lies in the complexity of the mathematical formalism and necessary simplifications, the main limitation for the simulations are the high computational costs. However, the continuing growth of computational power together with the improvement of computational algorithms suited for calculations on GPU processors will make simulations of microgels with a higher level of molecular detail and/or larger size accessible in the future. Also, an overview of the proceedings on the theory and simulations of microgels can be found in the recent work.99, 205


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Figure 11. (a) Radial density profiles of PNIPAM/PNIPMAM multi-shell nanogels with silica core at T = 40 °C (upper row) and at T = 20 °C (lower row) obtained from SANS measurements (left column) and MD simulations (right column); the rightmost images are the snapshots of core/shell/shell and hollow-shell/shell particles; Reproduced with permission from ref.46 (Copyright 2016 Springer Nature Publishing AG) (b) left: Density profiles within (solid lines) and outside (dashed lines) the microgel; grey, red and green lines correspond to volume fractions of microgel monomer units, water and oil, respectively; right: simulation snapshots representing the conformation of single microgel particle at liquid interface (top image) and its interior (bottom image); Reproduced with permission from ref.202 (Copyright 2016 American Chemical Society) (c) left: snapshots of the adsorbed sliding and chemical microgels; right: fraction of


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adsorbed microgel beads depending on the adsorption strength parameter for sliding and chemical microgels. Reproduced with permission from ref.196 (Copyright 2018 Royal Society of Chemistry).

CONCLUSIONS AND OUTLOOK Nano- and microgels are unique soft colloidal systems with fascinating properties that distinguish them clearly from classical colloids as, e.g. rigid nanoparticles, micelles or polymers. The combination of being deformable, penetrable while still having a stable structure that enables compartmentalisation makes them suitable as model soft matter systems as well as for applications in various fields, in particular in the broad area of biological applications. As nanoand microgels can adapt size and shape according to their environments, details of the chemical composition and architecture are very important. That creates challenges on the one hand for synthesising custom-made microgels, often with structures of growing complexity and on the other hand for the analysis the final products. In recent years, there has been tremendous progress in many fields of microgel research and there is a clear trend towards even more complex systems. It is obvious that a closer link between different communities will be important for further progress. Concerning the synthesis of microgels with controlled spatial distribution of functional moieties – which can be small functional groups or even biological building blocks – protocols have been mostly developed on lab-scale. Very recently aspects of process engineering have been addressed, which is important to achieve synthesis routines that allow producing larger quantities with high reproducibility of product properties. This will have strong impact on their use in biological applications. In the latter context, actual in vivo testing of nano- and microgels will be


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an essential next step towards clinical use. The potential of upscaling, controlling and predicting synthesis strategies has even reached computer simulations, which allows for synthesising nanoand microgels in-silico and for modelling of batch and continuous polymerisation processes. The experimental investigation of the structure of microgels on a broad range of length scales requires sophisticated techniques that rely on an appropriate "contrast". The above-mentioned development of microgel synthesis facilitates defined labelling of microgels, be it in terms of selective deuteration for neutron scattering employing contrast variation or the incorporation of dyes for super-resolution fluorescence microscopy. These techniques provide information on size, shape and structure of microgels and are now more and more used to study not only the behavior of isolated microgels but how they are affected by confinement. Interfaces, as well as high concentration of microgels – or other colloidal objects – will affect the microgel and can lead to deswelling, interpenetration and / or faceting. Predicting the behavior of microgels under such conditions by theory or simulations is still a challenge but there are already examples where simulations can guide synthesis. It is obvious that theoretical descriptions of complex microgels need to take into account details of the "microgel chemistry". The open question about the contribution of ionic species, e.g. originating from the initiator, to the osmotic pressure and thus microgel swelling is an important example. On the other hand, designing microgels for specific applications needs to consider the consequences of the softness of microgels; here theoretical and simulation studies provide relevant inputs. The continuing growth of computational power and the improvement of computational algorithms will allow for even more detailed investigations in the future.


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We hope that this feature article helps identifying the relevant concepts that govern microgel behaviors and stimulates further collaboration across disciplines.

AUTHOR INFORMATION Corresponding Authors *Address correspondence to [email protected] (Orcid-ID: 0000-0002-6247-3976) and [email protected] Biographies Matthias Karg is currently full professor in the Institute of Physical Chemistry I of the Heinrich-Heine-University Düsseldorf (Germany). He studied chemistry and finished his diploma in 2006 and his PhD in physical chemistry in 2009, both at the Technical University Berlin (Germany). Afterwards he spent two years as a postdoctoral research fellow of the Alexander von Humboldt foundation at the University of Melbourne (Australia). In 2012 he started as a junior professor in the Physical Chemistry department of the University of Bayreuth (Germany). His current research interests cover aspects from colloid and interface science, soft matter and plasmonic materials. Andrij Pich studied chemistry at the State University Lvivska Polytechnika (Ukraine) and obtained his PhD at the Dresden University of Technology and Institute of Macromolecular


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Chemistry and Textile Chemistry as a Fellow of the Collaborative Research Centre ‘‘Reactive Polymers’’ in 2001. Afterwards he was a postdoc at the University of Toronto and completed his Habilitation at the Dresden University of Technology in 2008. He was appointed as a professor for Functional and Interactive Polymers at RWTH Aachen University in 2009. In 2019 he was appointed as a professor for Functional Biobased Polymers at Maastricht University. He received the Georg-Manecke-Award of the German Chemical Society (GDCh) in 2007. In 2009 he received a Lichtenberg-Professorship-Grant funded by the VolkswagenStiftung. Since 2010 Thomas Hellweg is full professor for physical and biophysical chemistry at Bielefeld University. From 1996 to 1998 he was postdoc at the Centre de Recherche Paul Pascal (Pessac, France) and subsequently at the physics department of the Technical University of Chemnitz. In 2001 he joined the Stanski-Laboratory of the Technical University of Berlin as an assistant professor. In 2007 he became associate professor for the physical chemistry of colloids at Bayreuth University. His research focuses on the structure and dynamics of soft matter with an emphasis on smart microgels and association colloids. Todd Hoare is an Associate Professor, University Scholar, E.W.R. Steacie Memorial Fellow and Canada Research Chair in Engineered Smart Materials (Tier 2) in the Department of Chemical Engineering at McMaster University. He received his Ph.D. degree from McMaster University, with a focus on engineering smart microgel morphologies, and held a post-doctoral fellowship at the Massachusetts Institute of Technology before becoming a faculty member in 2008. He specializes in designing hydrogels and microgels with targeted “smart” properties, with a focus on controlling the nanostructures of hydrogel-based materials to engineer the performance of those materials in a variety of drug delivery, tissue engineering, environmental,


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and agricultural applications. He has received the 2016 Early Investigator Award from the Canadian Biomaterials Society and the 2010 John Charles Polanyi Prize in Chemistry. Andrew Lyon is the Founding Dean of the Fowler School of Engineering at Chapman University. He received his BA degree from Rutgers College (1992) and his MS (1993) and PhD (1996) degrees from Northwestern University. Prior to his current role, he served as Dean of the Schmid College of Science and Technology at Chapman University from 2014-2018. Before arriving at Chapman, Dr. Lyon spent 16 years at the Georgia Institute of Technology as a member of the Chemistry & Biochemistry faculty, directing a research program aimed at creating new types of biomaterials for regenerative medicine applications. He is the recipient of the NSF CAREER, Beckman Young Investigator, Research Corporation Research Innovation, and Camille Dreyfus Teacher-Scholar Awards, an Alfred P. Sloan Fellowship, and the National Fresenius Award. Jérôme J. Crassous is a junior professor at RWTH Aachen University, Germany. He received his PhD in Physical Chemistry in 2009 from the University of Bayreuth, Germany. After two postdoctoral appointments, one in Switzerland at the University of Fribourg at the Adolphe Merkle Institute, and the other one in Sweden at Lund University in the Department of Physical Chemistry, where he was latter employed as a researcher, he joined the faculty at RWTH Aachen University in 2018. His research interests are centered on the use of microgels as model systems for the investigation of dense colloidal dispersions and responsive self-assembly processes. Daisuke Suzuki obtained his PhD from Keio University (2007), before he went on to conduct postdoctoral studies at the University of Tokyo (2007-2009) as a JSPS research fellow (PD). He started his independent research career at Shinshu University in 2009 as a tenure-track Assistant Professor, where he was promoted to Associate Professor in 2013. His current research is


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focused on the design, synthesis, and assembly of soft hydrogel and elastomer microspheres. His awards include the SPSJ Award for outstanding papers in Polymer Journal (sponsored by ZEON), and the Award for Encouragement of Research in Polymer Science from the Society of Polymer Science (Japan). Rustam A. Gumerov received his M.Sc. in physics from Moscow State University in 2013 and Ph.D in physics in 2017 under the supervision of Prof. Igor I. Potemkin. Currently, he works as a researcher in the Physics Department at the University. Also, he is a visiting scientist at DWI Leibniz Intitute for Interactive Materials. His research interests focus on computer simulations and theory of polymer and soft matter systems. Stefanie Schneider studied chemistry at the Carl von Ossietzky University of Oldenburg, Germany. For her Ph.D. thesis under the supervision of Per Linse, she joined the Department of Physical Chemistry at Lund University, Sweden. She returned to Germany for a postdoctoral stay at the Research Center Jülich and is now working at the RWTH Aachen University, Germany. Her main research interest is the molecular modeling and simulation of polymer systems. Igor I. Potemkin studied physics at the Lomonosov Moscow State University (MSU) and completed his Ph.D. degree at the MSU under the direction of Sergey V. Panyukov on the theory of microphase segregation in random multiblock copolymers. Then he joined the group of Alexei R. Khokhlov (MSU), where developed theories of associating polyelectrolyte and liquidcrystalline polyelectrolyte solutions, thin films of block copolymers and comb-like macromolecules, interpolyelectrolyte complexes and ionic liquids. He is a professor at the Lomonosov Moscow State University since 2010. His current interests are related to the theory


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and computer simulations of various polymer systems including microgels, block copolymers, polyelectrolytes, etc. Walter Richtering studied chemistry at the universities of Bochum and Freiburg and obtained his PhD with Prof. Burchard at the University of Freiburg. Afterwards he joined the University of Massachusetts as Feodor-Lynen Fellow of the Alexander von Humboldt Foundation. He was appointed Professor for Physical Chemistry at Kiel University in 2000 and to the chair of Physical Chemistry at RWTH Aachen University in 2003. 2003 he received the Liesegang award. In 2016 he was appointed as associated leading scientist at the DWI-Leibniz-Institute for Interactive Materials. He is coordinator of the collaborative research centre 985 “Functional Microgels and Microgel Systems”.

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Conflict of Interest The authors declare no competing financial interest. ACKNOWLEDGMENT This article was inspired by contributions to the Adaptive Nanogels symposium at the 255th ACS National Spring Meeting in New Orleans, USA, March 18 to March 22, 2018. Parts of this work were funded by the Emmy Noether programme through DFG KA3880/1-1 (to M.K.). R.A.G. and I.I.P. acknowledge the Russian Science Foundation, project No. 15-13-00124, and the Government of the Russian Federation within Act 211, Contract No. 02.A03.21.0011.


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Financial support from the Deutsche Forschungsgemeinschaft (DFG) within the SFB 985 “Functional Microgels and Microgel Systems” to J.J.C., A.P., I.I.P., W.R. & S.S. is gratefully acknowledged. T.H. acknowledges funding by the DFG grants HE2995/5-1 and HE2995/6-1.

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