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Perspective pubs.acs.org/Macromolecules

Polymer Interfaces: Synthetic Strategies Enabling Functionality, Adaptivity, and Spatial Control Christopher Barner-Kowollik,*,†,‡,§ Anja S. Goldmann,†,‡ and Felix H. Schacher*,∥ †

Preparative Macromolecular Chemistry, Institut für Technische Chemie und Polymerchemie, Karlsruhe Institute of Technology (KIT), Engesserstr. 18, 76128 Karlsruhe, Germany ‡ Institut für Biologische Grenzflächen, Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany § School of Chemistry, Physics and Mechanical Engineering, Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia ∥ Institute of Organic and Macromolecular Chemistry (IOMC) and Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, 07743 Jena, Germany ABSTRACT: Polymer interfaces are ubiquitous in Nature and technology. Equipping artificial polymer-based interfaces with highly defined functions requires advanced macromolecular chemistry and powerful chemical tools. In this Perspective, we explore the nature of anisotropici.e., spatially resolved polymer interfaces prepared via top-down and bottom-up approaches with selected examples from the recent literature. These range from self-assembly driven systems based on single polymer chains and block copolymers to lithographic encoding able to span wide spatial dimensions of patterning. Based thereon, we formulate the in our opinion required advances in polymer chemistry that will contribute significantly to preparing the next generation of structured interfaces. Among others, this includes the to-date limited orthogonality of parallelly executed ligation reactions as well as limits in λorthogonally addressable pericyclic ligation chemistry. Finally, we propose some long-term visions for not yet existinghowever currently soughttechnology that could drive interactive and adaptive polymer interface construction to new levels. These include the spatially resolved encoding of interfaces with molecular precision and the introduction of programmable properties to interfaces of varying shape and chemical complexity.

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MOTIVATION AND TERMS OF REFERENCE The precision design of functional interfaces is arguably one of the key technologies relevant for almost all areas of science, as interfaces not only are found in every man-made device but also are the basis of life itself. From membrane systems in biological cellular structures to advanced touch and pressure responsive surfaces, interfaces enablein the widest sensecommunication between different parts of a system or, even more general, the inside of a system and its surroundings. Synthetic polymer chemistry plays a key role in the synthesis, understanding, emulation, and adaptation of naturally existing and artificial interfaces. Interestingly, Nature uses polymer chemistry and subsequent macromolecular self-assembly for interface design, and many synthetic processes take inspiration from Nature. In this Perspective, we will discuss somein our viewinteresting contributions of polymer chemistry to spatially resolved polymer interface design (i.e., interfaces that contain structural features on different length scales), outline existing challenges, and provide a possible vision for future interface design. Importantly, we note that we do not include interfaces that are functionalized with polymer chains in their entirety or are © XXXX American Chemical Society

completely consisting of polymeric material without anisotropy. Clearly, our selection of current examples is to some extent subjective, yet we nevertheless attempt to provide a view and perspective for the field of polymer chemistry that we hope is of use for all polymer chemists. In the following, a spatially encoded interface is considered as a point of chemical interaction and information exchange often a surfacethat allows for the execution of a particular function within its environment via its chemical functionality. Given the vastness of the field and the possible factors that affect interface design, we initially define our terms of reference as they relate to our definition of a polymer interface as well as its f unctionality, adaptivity, and spatial control. We define a polymer interface as a several nanometer- to micron-sized macromolecular system that can be constituted of a single polymer or an array of assembled polymer chains on a two- or threedimensional support structure. Interface formation can occur Received: March 30, 2016 Revised: May 31, 2016

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DOI: 10.1021/acs.macromol.6b00650 Macromolecules XXXX, XXX, XXX−XXX

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Scheme 1. Polymer Interface Design To Implement Functionality, Adaptivity, and Spatial Control via Both Bottom-Up (SelfAssembly Driven) and Top-Down (Externally Forced) Approaches

Our approach to providing future directions to these terms of reference isafter providing selected examplesto identify the in our opinion most important developments necessary to further advance polymer interface design. Clearly, our list of selected examples has no claim to completeness but merely serves to identify emerging trends and derive existing challenges.

using bottom-up (grafting-to, grafting from, (directed) selfassembly) or top-down strategies (e.g., microcontact printing, direct laser writing, etc., Scheme 1). This includes examples where one single functionality is anisotropically distributed across the polymer interface as well as combinations of different (orthogonal) functional groups with spatial control (also refer to the definition below). The title qualifiers were selected with care: (i) Functionality: The encoding of chemical information within or onto the interface is the basis of every responsive or self-directed action an interface can execute. Examples include variable sets of chemical reactions, such as polymerization processes. Clearly, imparting structured chemical information onto surfaces needs to proceed via fast, mild, and preferably ambient temperature chemistries, and we will provide a brief overview of these as they relate to polymer science. (ii) Adaptivity: Interfaces areif they not designed as barriers onlyactively interacting with their environment and thus need to be able to adapt to one or more trigger signals from the outside or contain chemistry that can direct further actions on its surface. Trigger signals can, for example, provoke a reaction on the surface of the interface to transmit information, store information on the interface, or change the properties of the interfaces to switch its interaction mode with the environment. In addition, the concept of adaptivity goes beyond the concept of externally triggered adaptivity and must in the futureas we will submit below also entail the concept of programmed adaptivity from within the interface itself. (iii) Spatial control: The ability not only to impart function globally onto an interface (or within an interface) but also to provide well-defined areas with disparate functions on an as high as possible level of spatial resolution critically defines the interface’s function. We herein restrict ourselves to structured interfaces featuring spatially resolved chemical information. To achieve the above-defined interface qualifiers shown in the middle of Scheme 1, the noted top-down and bottom-up approaches can be envisaged. The latter rely on intermolecular driving forces within a specifically encoded macromolecule, whereas top-down approaches employ external measures to force a specific interface geometry or chemistry.

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STATE-OF-THE-ART: SELECTED EXAMPLES In the following section, we will explore selected key synthetic methods for the (reversible) functionalization of polymeric materials and, with that, polymer interfaces and details of how spatial control of chemical functionalities and thus interface response can be achieved. In addition, we will showcase examples of imparting interfaces with switchable properties for planar (2D) as well as spherical surfaces, including approaches that draw inspiration from the solution properties of polymers. In the context of this section, we will identify some current synthetic limitations, which then lead into a section that discusses the required chemical advances to allow for a step change in future interface properties. The past decades witnessed steady progress regarding the applicability of reversible deactivation radical polymerization (RDRP) techniques to monomers or monomer combinations previously not accessible. Clearly, this is a result of constant improvement of the individual techniques to be less prone to impurities, more robust against the presence of traces of oxygen or water functional groups, and able to operate under milder conditions or even in dispersed systems.1,2 Especially radical polymerization with “living” characteristics such as atom transfer radical polymerization (ATRP)3,4 or reversible addition− fragmentation transfer (RAFT)5,6 shows exceptional functional group tolerance and is thus frequently used to equip interfaces with functional polymers as well as for spatially resolved polymer self-assembly in solution or in the solid state ideally without the need for additional protection/deprotection steps.7 Today, polymer chemists can exploit a versatile toolbox of reliable polymerization techniques to prepare materials of defined composition, precise architecture, and adjustable molar mass or dispersity. Certainly, in many cases a trade-off B


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Figure 1. Example of a polymer interface consisting of a single chain nanoparticle that has been assembled into an anisotropic shape to generate a defined catalytic pocket for a hydrogenation reaction. Note that the particles show statistical dispersion of the catalytically active sites due to the employed polymerization method. Top: Ru-segmented terpolymer. Bottom: supramolecular single-chain folding of terpolymers in water affording a compartmentalized catalytic pocket for the hydrogenation of ketones. Reproduced with permission from ref 39.

new level. It can be envisioned that both bottom-up and topdown approaches will tremendously benefit from such advances, e.g., by combining block copolymer self-assembly with sequence-defined segments toward direct access to structurewithin-structure materials with internal hierarchy. The currently available array of advanced chemistries allows for the construction of arguably the smallest possible functional interface, i.e., the “surface” of folded single polymer chains. Natureundeniably the master of single chain folding employs such constructs as enzymes and proteins that offer a specific geometry and surface chemistry to, for example, catalyze specific reactions or achieve unmatched substrate selectivity. Synthetic polymer chemistry is not anywhere near such precision, yet notable advances have been made to spatially distribute chemical functionality within and on single chain nanoparticles that are formed by forcing single macromolecules into defined geometries.31−37 This can be realized by the attachment of functional groups or orthogonal (reversible) binding motifs at specific positions along the polymer chain.38 These in our view smallest structured single chain interfaces would strongly benefit if constituted of monodisperse sequence defined macromolecules by allowing the precision shaping their geometries, making all geometries identical without statistical dispersion. Typical examples of this smallest form of interfacial interactions in the realm of single chain nanoparticles are their use as catalysts. For example, we36 and the team of Meijer39 have recently employed metal containing single chain nanoparticles to catalyze organic reactions, in the case of the Meijer group even with a defined catalytic pocket and thus surface design (Figure 1). A further very elegant way to encode spatially resolved information (or, more precisely, different functional groups or material properties) on interfaces can be realized directly by using block copolymers as interface building blocks in bottom-up driven self-assembly processes. Whereas these materials have been regarded as rather exotic for some decades, today an increasing number of research groups are exploring block copolymers in different environments. Here, at least two chemically unlike monomers are arranged in a sequential manner, and the material features the properties of all involved monomer units. Typically, the synthesis of block copolymers occurs in sequential one-pot reactionshowever, often the

regarding the latter two variables is required: while ionic polymerization methods often allow access to higher molar masses, narrower dispersities, and still offer unmatched endgroup fidelity, they are accompanied by a drastically increased experimental effort and limited functional group tolerance. In addition, it is possible to specifically position almost any chemical functionality at defined locations along a polymer chain, including both chain terminieither by using suitably functionalized initiators or termination agentsor within the side chain.8−10 Even more, targeting the junction between the individual blocks of block copolymers allows for an exact positioning of specific functional groups and with such systems can, for instance, subsequently be used to attach the block copolymers to planar or nanoparticle surfaces as “Ybrushes”.11,12 If a desired functional group cannot be directly introduced during polymerization, subsequent postpolymerization modification can present an alternative.13−15 Whereas postfunctionalization in general has been used since the early days of macromolecular chemistry, today’s flexibility and functional group tolerance in polymer synthesis open up entirely new avenues for exploiting highly efficient and orthogonal chemistries with and along polymer chains. Current directions are, e.g., the simultaneous introduction of two functionalities (double modification)16,17 or the adaption of multicomponent reactions.18,19 Regardless of all aforementioned progress in polymer synthesis or functionalization, a key remaining current challenge in designing precision macromolecules for interface design is the inherently statistical character of polymers grown from or tethered to interfaces. Ideally, the polymer strands on the surface should be monodisperse with a defined positioning of each individual monomer unit along the chain. To improve this, a strong drive to sequence controlled macromolecules can be identified within the polymer chemistry community.20−26 This includes both multiblock copolymers, which still show statistical variations and only fuzzily defined block segments, and sequence defined macromolecules, which are perfectly monodisperse and feature an exact positioning of each monomer unit.24−30 However, it is obvious that especially the latter case is synthetically much more difficult to access. Both classes have not yet been employed in interface design to any significant extent, thereby opening a clear opportunity to increase precision to a C


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Figure 2. Block copolymer self-assembly in thin films. (A) AFM phase views and their associated 2D fast Fourier transform images of thermally annealed well-ordered out-of plane cylinders of PDMSB49-b-PMMA17 thin layers with a periodicity of approximately 13.8 nm having trenches of different width: (a) 500 nm and (b) 230 nm. Scale bars: 100 nm. Reproduced with permission from ref 56. Copyright 2015 John Wiley and Sons. (B) SEM images of PDMS microdomains from PS-b-PDMS block copolymers templated by post arrays with various heights. Scale bars: 50 nm. Reproduced with permission from ref 46. (C) PS-b-PEO block copolymer self-assembly on sapphire (α-Al2O3) substrates with size regimes from 13 down to 3 nm. Scale bars: 100 nm. Reproduced with permission from ref 50. Copyright 2009 AAAS.

block-polydimethylsiloxane (PS-b-PDMS),46 poly(lactic acid)block-PDMS (PLA-b-PDMS),47 oligosaccharide-block-poly(trimethylsilylstyrene) (MH-b-PTMSS), 48 or poly(1,1dimethylsilacyclobutane)-block-poly(methyl methacrylate) (PDMSB-b-PMMA).49 In addition, the use of prepatterned substrates can further decrease feature sizes in block copolymer self-assembly, as could be shown by Russell and co-workers for PS-b-PEO features on sapphire (α-Al2O3) substrates with size regimes from 13 down to 3 nm (Figure 2).50 Whereas many other examples could be listed addressing resolution or morphological variability, interface design additionally requires the development of site-selective chemistry within such materials. In that regard, the selective addressing of individual domains in block copolymer nanostructures by crosslinking, side-chain modification, or selective swelling or complexation is a vibrant area of research and still contains ample room for improvementsboth concerning selectivity, reversibility, and spatial encoding with nanometer precision.51 Interface adaptivity, on the other hand, requires the incorporation of suitable functionality (or combinations) that respond to internal or external triggers in terms of polarity, structure and feature size, or chain dynamics. While stimuli-responsive polymeric surfaces have been explored widely during the past decades,52 fewer examples are found for adaptive block copolymer films. One very recent example demonstrated the pH-mediated ordering in poly(oligoethylene glycol methacrylate)-block-poly(2-vinylpyridine) (POEGMA-b-P2VP) films.53 Depending on the concentration of acid, the protonation of P2VP led to an in situ transition from disordered to microphase-segregated films featuring a lamellar or cylindrical morphology. This process is also dependent on the type and amount of salt being present. A further aspect which in our opinion is of interest to interface design is the incorporation of reversibly cross-linkable segments into block copolymer materials, as e.g. recently shown for thiolterminated block copolymer ligands on Au nanoparticles54 or PEO-block-poly(furfuryl glycidyl ether) (PEO-b-PFGE) block copolymer films.55 Both these approaches require external

chemistry or solubility of the desired monomer combination prevents access using one single polymerization technique. Here, macromolecular ligation techniques10,15 have evolved as powerful tools where orthogonally functionalized building blocks are joined to block copolymers, ideally rapid, under mild conditions, and with quantitative yields.40 Important for interface design using block copolymer selfassembly, the intrinsic immiscibility of unlike polymeric segments usually leads to microphase separation. With that, the formation of nanostructured materials with domain sizes of 10−100 nmboth in the bulk and in thin filmscan be achieved with a broad variety of morphologies. Thereby, the most important parameters are block sequence, overall molecular weight, and the respective weight fractionsalthough in the case of thin films also the respective surface energy of the constituting building blocks may affect structure formation.41,42 Especially in the latter case, long-range order in block copolymer nanostructures still is a pressing issue, in particular when aiming at lithographic applications or processes where rapid pattern formation is desirable.43 Quite recently, it has also been shown that the compositional range of certain periodic or bicontinuous morphologies can be broadened if the dispersity of one block is systematically increased. For example, polystyrene-block-polybutadiene-block-polystyrene (PS-b-PB-b-PS) triblock copolymers with narrowly dispersed PS blocks and a middle PB segment with dispersities up to 2 showed unprecedented stability of periodic microphases in the bulk.44 Nevertheless, block copolymer self-assembly allows encoding of different functional groups, material properties such as hardness or stiffness, and wettability to surfaces with resolutions down to 10 nm in bottom-up processes. Clearly, one limitation is that for microphase separation to occur, certain molecular weights of the underlying block copolymers are required; hence, feature sizes of less than 10 nm usually are challenging and identified (see below) as a key issue. One possibility to circumvent the molecular weight aspect is the use of systems with a strong tendency to segregate (high χ systems)45 such as polystyreneD


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Figure 3. (A) Multicompartment micelles formed by PB-b-PMAA-b-PDMAEMA triblock terpolymers in aqueous media at different pH. Reproduced with permission from ref 60. (B) Transfection efficiency for human leukemia cells in comparison to PEI and PDMAEMA. Reproduced with permission from ref 60. (C) Patchy nanocapsules with a PVFc-b-PMMA shell. Reproduced with permission from ref 61. (D) SEM as well as SFM images before (left) and after oxidation (right). Reproduced with permission from ref 61.

small, the im-IPEC shell splits into several patches; we regard this as an elegant approach to control homogeneity, charge/ charge density, and surface polarity of these nanostructured interfaces. As this takes place within a relatively narrow pH regime (pH 5−7), these materials were employed in a proof-ofprinciple study as nonviral gene delivery vehicles.60 Notably, the transfection of both adherent and suspension cells was superior to both linear poly(ethylene imine) (PEI) and PDMAEMA at considerably lower cytotoxicity (Figure 3B). In our view, one key aspect is that the patchy and discontinuous im-IPEC shell is able to translate into patchy polyplexes, which lead to facilitated cellular uptake. As another example, Crespy, Gallei, and coworkers61 reported nanocapsules where the shell is formed by a poly(vinylferrocene)-block-poly(methyl methacrylate) (PVFc-bPMMA) block copolymer. Microphase separation within the shell led to the formation of PVFc patches of approximately 25 nm size, and these could be selectively oxidized using H2O2 or KMnO4. After oxidation, the drastically increased hydrophilicity of poly(vinylferrocenium) resulted in a considerable swelling of these patches, thereby generating pores within the capsule wall and facilitating release of encapsulated cargo, which in the reported case was a pyrene model system (Figure 3C,D). These examples, along with aforementioned strategies in thin films, showcase that block copolymers represent a unique toolbox for creating, manipulating, and addressing (polymer) interfaces. Besides the possibility to further decrease feature sizes (see above) or segment dispersity and, with that, the size distribution of solution nanostructures, one immensely important aspect in (solution) self-assembly is the process itself.62 Morphological variety and shape of (solution) nanostructures crucially depend on our ability to control assembly parameters and to purposefully access or trap nonequilibrium morphologies.

temperature input and thus still feature limited adaptivity. The incorporation of sequence defined macromolecules as segments in block copolymers is an alternative strategy to decrease feature size: Theoretically, the positioning of chemical functionality with sub-nanometer resolution (on the monomer level) can be envisioned within domains of 10−100 nm size (block copolymer microphase segregation). Besides thin films, solution self-assembly of block copolymers is a way to generate polymer interfaces with spatially encoded chemical information, e.g., through the formation of multicompartment micelles featuring an inhomogeneous shell or corona. Early examples have been demonstrated by Hillmyer and Lodge57 or Laschewsky58 and co-workers via incorporating both fluorinated and non-fluorinated hydrophobic segments in ternary systems. For an overview, the reader is directed to an excellent recent review.59 With regard to the scope of the current Perspective, we selected two recent examples where spherical nanostructures in solution (i) feature a chemically patterned surface and (ii) are capable of adapting to changes in environmental conditions in terms of morphology, charge, or degree of swelling (Figure 3). Schacher and coworkers recently reported the formation of multicompartment micelles from linear polybutadiene-blockpoly(methacrylic acid)-block-poly(N,N-dimethylaminoethyl methacrylate) (PB-b-PMAA-b-PDMAEMA) ABC triblock terpolymers.60 In aqueous media, these materials undergo selfassembly into core−shell−corona micelles where the shell is formed by an intramicellar interpolyelectrolyte complex (imIPEC) between PMAA and PDMAEMA (Figure 3A). Thereby, the overall im-IPEC volume depends on the degree of neutralization and thus on the pH, and the interface between im-IPEC and the PB core is highly unfavorable. Under conditions where the volume of the IPEC layer is relatively E


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Figure 4. Structured polymer interface design on PDA and cellulose substrates using a photochemical top-down approach. (A): (a) synthetic scheme for photopatterned p(MeOEGMA) brushes from PDA surfaces, (b) ToF-SIMS overlay image constructed from spatially grafted PEG fragments, (c) cell pattern following the interface design after 7 h culture, fixation, and staining. (B): (a−d) high resolution FT-IR microscopy images of single fibers of initiator (e) and zwitterionic polymer (f) functionalized cellulose strands in the cellulose fingerprint region (a, c) and single fiber imaging in the carbonyl region before (b) and after grafting (d). Reproduced with permission from refs 71 and 72. Copyright 2013 and 2014 Wiley-VCH.

nanoscale. As one example, microcontact printing63−65 is a widely employed method for structuring surfaces with polymer strands. Even patterning with a submicron resolution has been achieved,65−67 yet such high resolution microcontact printing remains scarce due to the operational principle of the process. With the exception of one example for tip-guided nanolocal chemistry using atomic force microscopy (see below), we focus on light driven protocols as they allow for a wide length scale of structure to be covered, including approaches that do not require any masks. Here, lithographic processes as well as direct laser writing (DLW) approaches are dominant and show the largest potential for increasing encoding resolution as well as precision. Encoding chemical information onto interfaces in the form of polymers by DLW and lithographic techniques requires mild, fast, and efficient reactions, specifically with regard to the interaction with sensitive biomolecules. Notably, low-energy activated reactions induced in the visible light regime while concomitantly featuring high quantum yields resulting in quantitative conversions under equimolar reaction conditions

The interaction between a functional polymer surface and its environment triggered by one or more signals provoking a response of the surface or property change is key for the design of structured interfaces. While the above examples were focused on self-assembly processes (bottom-up) of complex macromolecular building blocks such as block copolymers, we now switch the point of view and address the modification of macroscopic surfaces (top-down) to transform them into responsive interfaces. Here, we highlight examples of recent studies where the interface directs the position of (bio)macromolecules orimportantlycells by providing precisely structured two- or three-dimensional spaces. In addition, we will highlight the latest advances regarding the role of polymer chemistry in the design of three-dimensional functional interfaces. Top-down approaches are commonly employed to achieve (micro- and macroscopic) structure formation on surfaces. Among others, applying mechanical force to (macro)molecules bound to a surface via an AFM tip can lead to structures on the F


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translated to the development of novel bioactive papers and micropads (μPADs). Both approaches (summarized in Figure 4) serve to highlight the power and versatility of light driven chemistries enabling top-down strategies for spatially resolved interface design. Needless to say, other light driven approaches are equally capable of providing macroscopically structured polymer interfaces.73−75 The above examples employ photochemical approaches to macroscopically (feature size millimeters) structured surfaces, turning them into spatially resolved functional interfaces. Beyond these examples, the specific attraction of light driven interface designbeyond the capabilities of e.g. microcontact printing76is the possibility to shape arbitrarily formed threedimensional objects and concomitantly write feature sizes which have no theoretical resolution limit (see below) in 2 and 3 dimensions. Most prominent in this area is the already noted top-down technique of DLWsignificantly pioneered by the team of Wegener77where during a two-photon process a laser voxel is moved through a photoresist consisting of (typically) a multifunctional vinyl monomer and a photoinitiator to create a three-dimensional construct consisting of crosslinked macromolecules. In principle, the spatial resolution of DLW is limitedjust like any photochemical lithographic processby diffraction criteria (typically λ/2), which can however be overcomeat least theoreticallyby employing concepts such as stimulated emission depletion (STED)78 to polymerizable photoresists. Access to such diffraction unlimited constructs down to a few nanometersbe it in two or three dimensionswould arguably revolutionize structured interface design by top-down methodologies. We will explore the potential of diffraction unlimited STED for functional interface generation in the last section of this Perspective, which addresses long-term visions. Access to precision designed three-dimensional polymer scaffolds with a defined elasticity and chemical functionality at specific scaffold positions is key for designing interfaces, which can interact with complex biological entities such as single cells in a highly defined and precise fashion. By fine-tuning threedimensional polymer interface chemistry and providing spatially resolved functionalization, specific cues can be provided to the environment. Such an approach is mandatory for understanding cell interactions with their environment, as cells have the ability to sense and react to various external triggers.79 For example, cells respond to both physical and chemical signals such as ligand spacing,80 material stiffness,81 protein availability,82 geometrical cues,83 and topographical characteristics of the substrate.81 These factors can affect the way cells adhere, spread, migrate, and decide their fate.74 Standard 2D cell cultures are however not ideal mimics of the natural cellular environment, as they can suffer from abnormally high level of growth factor solutions, high oxygen tension, low organization of cell−cell interactions, and the absence of 3D cues.84 Thus, there is an urgent need to generate polymer interfaces with the ability to provide cues in 3D environments. Evidence regarding the fundamental difference in cell behavior between 2D and 3D environments was first collated by Harrison a century ago showing the different shape of embryonic frog cells on flat glass surface (polygonic) or in 3D spider webs (elongated with spindle shape).85 Currently, 3D cell behavior studies are typically achieved by using fibrous collagen or Matrigel matrices.86 However, these materials feature an inherent random porosity, ill-defined architectures, and chemical functionality. Therefore, a critical need for a better 3D scaffold

are considered ideal. Nanometer thick polymer layers consisting of single polymer chains on surfaces are often sufficient to induce a strong property change and a responsive nature of the resulting material. Whether the chains prepared via RDRP methods (or small molecules) are tethered using grafting-to or grafting-from reactions has great impact on the grafting density. Each of the two approaches has specific advantages and disadvantages, which have been covered in great detail in the literature and will thus not be reiterated here.68−70 To achieve interface structuring by lithographic techniques, a multitude of photochemical processessome of which adhere to the above ideal reaction criteriahave been developed. Herein, we will not focus on the details of the chemistries of the transformation, but rather on the structured polymer interface function itself. For a recent overview of the currently employed advanced photochemical patterning methods, the reader is referred to a recent review by our team.73 In the context of polymer-based interface design, nitrile−imine tetrazole−ene cycloadditions (NITEC) are often employed, as the reaction is self-reporting generating a fluorescent cycloadduct, which allows to trace the ligation process. In a recent study from our laboratories, the NITEC reaction protocol was fused with a biomimetic approach on structured polydopamine (PDA) interfaces as a typical example how effective light driven lithography can effect precision interface design (Figure 4A). PDA-coated silicon wafers were globally functionalized with a methoxydiaryltetrazole species and subsequently patterned with a RDRP (ATRP) initiator to grow in a second step polymer brushes of oligoethylene glycol methyl ether methacrylate (p(MeOEGMA)).71 We demonstrated that when the structured interface is incubated with rat embryonic fibroblast cells, these are exclusively found in the nonirradiated zones and not in the functionalized p(MeOEGMA) areas with extremely high precision (Figure 4A,c). The spatially distributed cells were fixed and stained for cell nuclei identification and to detect focal contacts in those cells not expressing vasodilator-stimulated phosphoproteins. NITEC driven polymer interface designas general example for light driven lithographycan be readily extended to biosubstrate surfaces by grafting of preformed macromolecules onto paper to protect it from biological impact with applications in paper based sensor design (Figure 4B).72 To be able to work in the UVA region, a requirement for more sensitive biological systems such as proteins, we used a tetrazole derivative with a methoxy substituent in the para position of the N-phenyl ring. Paper exclusively consisting of cellulose was esterified with the tetrazole species to provide a photoreactive biosubstrate and subsequently modified with an ATRP initiator in a photolithographic process using a photomask. In the irradiated areas where the ATRP initiator was photochemically attached, a coppercatalyzed reversible-deactivation radical polymerization of carboxybetaine acrylamides was initiated to achieve site-selective cellulose modification. The effect of the spatially resolved functionalization is the protection of the paper against biological impact in specific regions, evidenced by challenging it with fetal calf serum (FCS), a high fouling complex biological fluid. As a result, the cellulose can be protected with poly(carboxybetaine acrylamides) in specific regions as assessed via X-ray photoelectron spectroscopy (XPS) and time of flight−secondary ion mass spectrometry (ToF-SIMS), indicating the nonfouling character of the carboxybetaine acrylamide brushes. The spatially resolved protection approach of biosubstrate interfaces against biological fluids such as fetal calf serum can possibly be G


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Figure 5. Top: (A) Strategy to dual photochemically encoded DLW written polymer scaffolds resting on two photochemistries for spatially resolved 3D interface design. The basic interface consisting of two orthogonally photoreactive regions can be orthogonally encoded upon a light pulse activating two disparate chemical species in a one pot process. Bottom: Imaging the successful light responsive nature of the (B) TOF-SIMS (view from the top) and (C) confocal fluorescence spectroscopy. Halogen and dye-tagged markers were employed for coding. Reproduced with permission from ref 96. Copyright 2016 Wiley-VCH.

precision 3D interface design with orthogonally functionalized biomarkers for e.g. targeted cell attachment. Current approaches in the field are aimed at further increasing the number of orthogonally written resists to allow for an even higher order orthogonal encoding of three-dimensional polymer interfaces with specific small molecule markers. Alternative design routes99not resting on orthogonal photochemical encoding as aboveto spatially resolved 3D interfaces for cell interaction studies include those with a protein attractive as well as a protein repellent nature spatially separated from each other.100 The protein attractive surface areas are typically fabricated by hybrid organic (acrylic based)/inorganic (Si−O− Si) polymeric mixtures such as Ormocer (ORganically MOdified CERamics). Protein repellent regimes can be achieved by employing hydrophilic poly(ethylene glycol) diacrylate (PEGDA) grafts on the interface surface. The combination of these two resists into one spatially resolved interface allows for targeted cell attachment within the protein attractive regimes (Figure 6).

fabrication exists with the following requirements: (i) control of the 3D topology and architecture, (ii) fine control of the chemical surface properties, and (iii) control over mechanical properties of the scaffolds.87 DLW is an ideal process to provide such highly specific three-dimensional polymer interfaces. From a polymer chemist’s perspective, generating these environments requires the design of highly defined photoresists.88−95 Currently, multifunctional photoresists are being developed, which, on the one hand, can be written with DLW while they can, on the other, be functionalized by a secondary light impact in predefined places. Figure 5 shows a recent example, a scaffold written from two different photoresists, each expressing a different secondary photochemistry.96 The approach is realized by copolymerizing two photoreactive monomers within the respective resists: one resting on phenacyl sulfide functionalities (which release thioaldehydes after irradiation)97 and one resting on so-called photoenols, i.e., photocaged dienes.98 The strategy, depicted in Figure 5, allows to encode one DLW written scaffold with two functionalities in a one-pot photochemical irradiation step, paving the way for H


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Figure 6. Encoding cell adhering and cell repulsive polymer regimes into one three-dimensional scaffold to direct cell−interface interaction via DLW. Clearly visible is the preferential attachment of the cells to the protein adhering areas. Top: basic interface structure (A) with protein attractive patches (B, C). Bottom: evidence of cell attachment to specific interface areas. Reproduced with permission from ref 100. Copyright 2011 Wiley-VCH.

Although the experimental approach is conceptually valuable, the resulting materials cannot reach very steep gradients (e.g., needed for cell migration), cannot be erased or reprogrammed, and are nonadaptive. In the field of linear gradient interfaces, Diederich and colleagues reported the crosslinking of gradient hydrogels using acrylamide and N,N′-methylenebis(acrylamide) (Figure 7). Hard and soft domains were obtained depending on the crosslinking density, which delivered different environments

The encoding of chemical information on 2- and 3dimensional interfaces in highly defined places is of key importance for not only guiding cell adhesion but also regarding surface wettability, site-selective catalysis, or possibly data storage. On the other hand, chemical informationwhich can significantly affect the material properties of the interface such as stiffnesscan also be encoded as gradients in polymeric materials. On a longer perspective, spatial encoding in combination with material gradients might yet add another level of complexity in material design, as will be discussed in our last section. Gradient materials are ubiquitous in Nature, such as in the attachment of ligaments to bones or in the squid beak.101 They serve stress delocalization and optimize mechanical properties with regard to toughness, stiffness, and abrasion resistance.102 Sandwich type (layered) gradients can be realized with classical engineering approaches using the stacking and fusing of mechanically different materials or using sequential photo-crosslinking of subsequently deposited layers.103−105 Although such strategies are rather established, recent examples demonstrate their significance for delocalizing strain through layers of continuously increasing stiffness or for actuation of bilayer stripes using hydrogel layers with polymers of different swelling response.105 In contrast to sandwich gradients, approaches toward lateral gradients are much more scarce and mostly use irreversible crosslinking reactions to change the crosslinking density and thereby the mechanical stiffness of the interface. Most of the approaches toward lateral patterning focus on linear gradients.103 For instance, Claussen et al. reported gradients using di- or trifunctional acrylates (as crosslinkers) and thiosiloxane (as prepolymer) via the controlled mixing and lateral deposition using two syringes filled with prepolymer and crosslinker and by changing their mixing ratios during extrusion.106 The approach was extended to prepare gradient biopolymer gels and films via a combination of fibroin and gelatin.107 Typically, mechanical properties were replicated for selected positions of the gradient ex situ by measuring tailored mixtures reminiscent of the composition of the gradient.

Figure 7. Gradient interface design for directing cell attachment. (A) Possible geometries of compositional gradient materials.103 (B) Difference between a cross-sectional and thickness gradient.103 (C) Images of fibroblast morphology on polyacrylamide hydrogels with a gradient in mechanical compliance at different times.108 Scale bars are equal for all pictures. Reproduced with permission from refs 103 and 108. Copyright 2012 and 2013 Wiley-VCH. I


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reactions (see below). In addition, photoresponsive entities require clear differences in activation and deactivation wavelength to access their different property states. Red Shifting of Light Triggered Reactions: To date, very few photochemical ligation procedures exist that can be excited in the visible light regime in the absence of any catalyst (be it metal or otherwise) and under ambient conditions (i.e., in the presence of oxygen and water). In addition, these reactions need to be pericyclic in nature to fulfill strict chemical orthogonality criteria. Having such processes at hand would allow advancing λorthogonal chemistry as noted above, particularly on surfaces and to exploit the earlier mentioned approaches to spatially encode chemical functionality within soft matter at different length scales. Although first results addressing this challenge have been made,116,117 there is substantial room for improvement. Recently developed red-shifted systems based on azirines116 and tetrazoles117 are operating close to 420 nm, and also entirely new photoswitches such as acylhydrazones118 are being explored. Nevertheless, catalyst-free photoinduced ligation reactions activated above 500 nm are as highly sought as they are scarce (or nonexistent). Access to such reactions would not only advance our abilities to orthogonally address interfaces but also critically aid in interface construction via direct laser writing. In that way also 3D interfaces with different, e.g., mechanical properties, depending on the actual wavelength used for DLW, can be envisaged if new photoresists are developed that can be activated using disparate activation wavelengths. Sequence Defined Macromolecules: In our opinion, the strongly emerging area of sequence defined polymers20−26 is key for further increasing precision in interface design, for both bottom-up and top-down approaches. As already briefly outlined above, equipping interfaces with monodisperse chains of controlled sequence will lead to previously unreachable proximity of ideally orthogonal reactivity (both chemically and photochemically). Further, the use of perfectly defined segments and thus monodisperse blocks in block copolymers allows to accurately locate functionalities in predefined places. This could lift the field of self-assembly as well as block copolymer lithography to new levels in terms of resolution or the formation of hierarchical structures. The key requirement herefor both uniform chains and block copolymersis that high(er) molecular weights can be reached, going far beyond oligomers (20 units at most) available today. First examples are already found in the literature; e.g., a very recent report by Cheng and co-workers where polyhedral monodisperse silsesquioxane building blocks of varying sequence and architecture have been attached to a PS block and a variety of (hierarchical) microphase-segregared nanostructures has been found in the bulk.119 It can be foreseen that combinations of state-of-the-art block copolymer chemistry, sequence-defined building blocks, and principles guiding structure formation such as control over the assembly pathway62,120 or increasing compositional stability of desired phases (see above)44 will further increase the variety and applicability of bottom-up nanostructured materials in the near future. Finally, beyond 2D interfaces, monodisperse polymers of a defined sequence applied as photoresists can lead to ultraregular networks with characteristics and feature densities unknown today. Gradient materials are inspiring for future synthetic materials in both structural and functional applications. In terms of chemistry, the main challenge here is to combine the respective functionality or activation step with polymer processing technology necessary for encoding gradients into macroscopic

for cells. The kinetics of cell spreading was shown to be influenced by the material stiffness, whereby fibroblasts transformed rapidly from a rounded to a spread adherent morphology on hard hydrogel areas, while they retained rounded morphologies on soft parts (Figure 7).108 The above example highlights the importance of encoding gradients for biomaterial applications and for studying and controlling the interface between materials and tissues. As noted at the start of the current section, AFM-based technology can lead to even better resolution in structuring surfaces as light driven lithographic processes. One recent exampleoutside the polymer realmof site-selective chemistry with nanometer resolution was presented by Deckert and co-workers. These authors used silver-coated AFM tips of approximately 10 nm radius in tip-enhanced Raman scattering (TERS) experiments for the protonation of 4-mercaptopyridine monolayers on gold surfaces upon irradiation with laser light. Although these experiments depend upon a rather sophisticated setup and the structuring of larger areas will require substantial amounts of time, such an approach could still serve as model experiment for site-selective chemistry with nanometer precision using immobilized catalysts.109 Later, other groups monitored the photoisomerization of azobenzylthiols on Au surfaces 110 using a combination of scanning tunneling microscopy and TERS or combined TERS with electrochemistry to study the nanolocal redox behavior of nile blue.111 Nevertheless, we submit that the translation of such AFM-based methodologies for the functionalization of individual polymer strands for structuring interfaces based on appropriate chemical transformations is a long-term target in polymer interface design.

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ENVISAGED ADVANCES In the following we will identify required developments within the realm of synthetic polymer chemistry and material integration that arein our viewnecessary to advance the design of polymer interfaces in terms of spatial control, adaptivity, and functionality. In our opinion, this will affect both bottom-up and top-down approaches. Chemically, we identify the following areas: Orthogonality of Reactivity: Structured interfaces critically depend on avenues to address different areas of the interface’s surface independently.112 Such site specific addressability can be achieved by structuring orthogonal reactivity onto a surface (as in the example depicted in Figure 5 or, alternatively, by inducing orthogonality by light, so-called λ-orthogonality.113 In the realm of chemical orthogonality,114 it remains to be established how many different orthogonal ligation points can be integrated on one interface without showing any cross-reactivity. Despite the large amount of reactions claimed to fall under the click definition,115 closer inspection reveals that a significant number of reactions are not orthogonal. We submit that present ligation technology does not allow to execute five or six reactions at the same time from one reaction mixture. It thus appears mandatory to explore and then expand the limits of orthogonality, initially in solution and subsequently on interfaces. Similarly, light driven modular orthogonality is a key concept yet to be established on variable interfaces, as it would allow addressing different parts of an interface by simply changing the activation wavelength. The question of establishing truly λ-orthogonal reaction systems, which are not sequence dependent (i.e., independent in the order in which the different wavelength are applied), is critically connected with the question of red shifting light activated J


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Figure 8. Current state-of-the-art examples of STED-type routes to diffraction unlimited direct laser writing. (A) STED-DLW principle: calculated isointensity surfaces of the foci of the femtosecond excitation beam (red) and the continuous-wave depletion beam (green). This combination reduces the effective exposure volume (blue), in both axial (z) and lateral (xy) direction. Reproduced with permission from ref 121. Copyright 2011 OSA Publishing. (B) Electron micrographs of direct-laser written line gratings prepared via regular DLW (a, c) and STED-DLW (b, d). Reproduced with permission from ref 121. Copyright 2011 OSA Publishing. (C) SEM image of a line fabricated at a fixed scanning speed of (a) 3 μm at a constant laser power of 200 nW. Power levels of the inhibiting laser: (b) 0, (c) 1.0, (d) 1.5, and (e) 2.0 μW (scanning speed 3 μm/s, irradiation of initiating laser: 200 nW; scale bars: 200 nm). Reproduced with permission from ref 122. Copyright 2011 OSA Publishing. (D) Left: spectra of the photoinitiator 7diethylamino-3-thenoylcoumarin in pentaerythritol triacrylate. Right: SEM images of the written lines (a) with conventional two-photon DLW and (b) STED-DLW. Reproduced with permission from ref 123. Copyright 2013 OSA Publishing. (E) STED lithography experiments on cluster-doped photoresists. (a) Minimum lateral feature size of a written line is 72 nm (excitation power 3.2 mW (at 780 nm); depletion power 7.8 mW (at 532 nm)). (b) AFM: Multiphoton and STED lithographically fabricated lines using a photoresist doped with 1 wt % the mercaptopropionate ligand ZrSH1. Reproduced with permission from ref 124.

are mandatory to address complex lateral patterning with highest spatial resolution. Moreover, they are the only reaction schemes that can be used to potentially even pattern in 3D using direct laser writing (DLW) in confocal volumes or crossed laser beams. This would give rise to a new generation of complex, intrinsically structured materials useful for advanced mechanical performance, complex morphing procedures in structured, responsive hydrogels, and for instructing cellular migration and colonization with spatiotemporal control.

materials. For solid materials it is for instance desirable to provide more durable synthetic connectors between regions of high elasticity and those of high stiffness. In hydrogels, the crosslinking density and therewith the mechanical properties provide instructive cues for cell proliferation, cell migration, and stem cell differentiation. Encoding gradients into such hydrogels would allow to program cell colonies and directional tissue formation. If they were reprogrammable, more complex operations could be performed on-demand. Although there have been approaches for encoding lateral and predominantly linear gradients, advances toward next-generation reprogrammable or rewritable gradient materials (including in 3D) or even dynamically switching and adaptive gradients are virtually nonexistent. Furthermore, sophisticated in situ testing methods, which are especially required to characterize complex patterns and steep gradients, are scarce and need to be developed to clearly visualize and quantify more complex 2D and 3D patterns with steep gradients. Judging from these challenges, it becomes obvious that well-tailored molecular photochemical reactions

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LONG-TERM VISIONS The final section of our Perspective will seek to summarize some long-term visions that willin our viewput structured interface design on a new level, be it for the emulation of functional naturally occurring interfaces, where the control exerted today over interface design is insufficient, or precision scaffolds. In the following, we will discuss examples that are to a significant degree science fiction yet have the future potential to become science fact. As noted, the resolution level at which K


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chemistry provides some tools for the design and self-assembly of macromolecules, and with the envisioned advances in synthetic technology it is not out of the realm of possibility that the design of an artificial cell that carries the characteristics of life is possible. The idea of synthetic cellularity is under debate since about a decade,128 and there has been considerable progress concerning the role of macromolecular chemistry, e.g., by directing fatty acid membrane assembly using preformed oppositely charged coacervates,129 polymersomes, or compartmentalized colloidosomes. While the aim to create systems capable of undergoing evolutionary developments may still seem to be far off, the intrinsic programming of polymer interfaces is definitely within technological reach. Impressive examples of programmed macromolecular solution chemistry have emerged,130−132 and these concepts wait to be adapted and translated to more complex programmed self-assemblies to generate interfaces or surfaces that feature autonomous time programmed functions. Even more, we begin to understand how and when we have to intervene in self-assembly processes to direct structure formation and eventually access nonequilibrium morphologies. Given the above, it is not unrealistic to exploit diffusion processes, nonlinear reaction kinetics, or the exchange of reactants across or even on a polymeric interface by using determinants such as charge, size, or the presence/absence of a specific functionality.

macromolecules can be tethered to interfaces is classically either defined by the wavelength of the light that is employed to trigger the chemical ligation processes (diffraction limit) or limited by the ability of block copolymer self-assembly in the solid and liquid state, which is controlled by the physical parameters of the used materials. A true molecular encoding strategy forat bestsingle macromolecules does not exist. At the same time, block copolymer lithography is facing limits in terms of resolution or feature shape. Surface Encoding and Scaffold Generation on a SubDiffraction Length Scale. As alluded to in the State-of-the-Art section of our Perspective, one possible avenue to circumvent the limits of diffraction in either 2D line encoding or 3D writing is STED processes. In the past decade, STED-inspired direct laser writing has led to several advances in three-dimensional lithography (refer to the extensive reviews77,99). After first efforts by Li et al.125 and Scott et al.,126 the to-date smallest achievable line widths or feature sizes are in the 60 nm regime.122,123 The minimal distance between two lines was shown to be 120 nm in the lateral direction,123 while Wegener and colleagues fabricated functional nanostructures with high axial resolution.121 Some recent examples of STED DLW approaches alongside its working principle are depicted in Figure 8. Taking inspiration from STED technology, excitation and de-excitation of molecules with molecular precision would represent a major breakthrough in surface chemistry and be an invaluable asset in advancing nanotechnology on anisotropic interfaces. In that way, researchers would be able to “write” with molecular precision on surfaces, construct interfaces in 3D with molecular precision, and thus generate molecularly tailored (polymer) interfaces; to achieve this, suitable STED “switches” have to be implemented into and onto polymeric materials (= immobilized) and directly addressed using suitable irradiation setups. The particular challenges facing subdiffraction surface encoding are twofold. First, a suitable chemical system capable of being depleted needs to be available. Several such system some resting on intermediates generated in photochemical ligation approachescan be envisioned and some have already been followed as noted above. Here, STED-DLW critically depends on our ability to derive a much deeper understanding of energy distribution mechanisms within photoresponsive reaction systems. Second, the preparation of molecularly encoded interfaces requires suitable analytical technology to evidence the success of the encoding. While AFM-based approaches are certainly key for imaging on the nanometer or even subnanometer scale, Fö r ster resonance energy transfer (FRET)127 can also play a key role in probing encoded information on a molecular level. The visions spelled out for molecular encoding and writing will not only enable the constructions of interfaces that are able to interact and interrogate complex natural systems such as cells with to-date unknown precision but may also enable the encoding of information on interfaces formed by bottom-up approaches, opening the exciting prospect of fusing top-down with bottomup technology on a molecular level. Programming Interfaces with Time-Dependent Properties and Self-Executing Assemblies. If one takes Nature as a guide for polymer interface design, it is evident that interfaces areas already noted in the introductionthe basis of life itself. A cell can be viewed as an intricate macromolecular machine whose main functions are based on the highly specific interactions in between and the transport through macromolecular interfaces. As we have seen, today’s synthetic polymer

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AUTHOR INFORMATION

Corresponding Authors

*E-mail [email protected], christopher. [email protected] (C.B.-K.). *E-mail [email protected] (F.H.S.). Notes

The authors declare no competing financial interest. Biographies

Christopher Barner-Kowollik received a PhD in Physical Chemistry in 1999 (Göttingen University). After postdoctoral research with Prof. Tom Davis and academic positions at the Centre for Advanced Macromolecular Design at the University of New South Wales in Sydney, he was appointed Full Professor of Polymer Chemistry in 2006 at the same institution. Since 2008 he holds the chair for Macromolecular Chemistry at the Karlsruhe Institute of Technology (KIT) and is a Professor of Materials Science at the Queensland University of Technology (QUT). His research interests include macromolecular precision design in solution and on surfaces via rapid light-induced methodologies, the design of hybrid and adaptive polymer materials at the interface of polymer chemistry and materials science, advanced macromolecular characterization via high resolution L


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providing some of the images as well as helpful advice and discussions regarding subdiffraction limited direct laser writing. In addition, the authors are indebted to Prof. Martin Bastmeyer (KIT) for providing images illustrating targeted cell attachment. The authors also thank Dr. Andreas Walther (DWI at the RWTH Aachen) for helpful discussions regarding gradient materials.

hyphenated mass spectrometric techniques, and mechanistic investigations into polymerization processes.

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REFERENCES

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Anja S. Goldmann graduated from the University of Bayreuth (Polymer- and Colloid Chemistry) and completed her PhD in 2010 under the supervision of Prof. Axel H. E. Müller (University of Bayreuth, Germany). Since 2010, she is the research manager in the Barner-Kowollik team at the Karlsruhe Institute of Technology (KIT). Her research interests include novel efficient (light-triggered) ligation techniques, synthetic approaches to complex macromolecular designs, functional polymers, synthetic biomimetic molecules, and the application of those to (bio)surface modification, particle modification, and materials science.

Felix H. Schacher studied chemistry at the Universities of Bayreuth (Germany) and Lund (Sweden) and obtained his diploma in 2006. After his PhD under the supervision of Axel H. E. Müller in 2009, he joined the group of Ian Manners at the University of Bristol as DAAD postdoctoral fellow. In 2010 he was appointed Juniorprofessor at the Friedrich-Schiller-Universität Jena and became Full Professor at this institution in 2015. He has been awarded the Dr.-Hermann-SchnellFellowship of the GDCh in 2013. His scientific interests include controlled/living polymerization techniques, block copolymers, polyelectrolytes, and polyampholytesall in the context of using (directed) self-assembly processes for material design in the fields of membranes, hybrid materials, and biomedicine.

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ACKNOWLEDGMENTS C.B.-K. acknowledges the SFB 1176 (specifically projects A1, A2, A3, B4 and C4) funded by the German Research Council (DFG) for support as well as continued support by the Karlsruhe Institute of Technology (KIT) via the Helmholtz BIFTM and STN programs, and the Queensland University of Technology (QUT). The authors are grateful to Prof. Martin Wegener, Patrick Müller, and Dr. Benjamin Richter (all KIT) for M


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