REVIEW SUMMARY◥

MULTILAYER ASSEMBLY

Technology-driven layer-by-layerassembly of nanofilmsJoseph J. Richardson, Mattias Björnmalm, Frank Caruso*

BACKGROUND: Over the past few decades,layer-by-layer (LbL) assembly of thin filmshas been of considerable interest because ofits ability to exert nanometer control overfilm thickness and its extensive choice of

usable materials for coat-ing planar and particulatesubstrates. The choice ofmaterials allows for re-sponsive and functionalthin films to be engineeredfor various applications,

including catalysis, optics, energy, membranes,and biomedicine. Furthermore, there is now agrowing realization that the assembly tech-nologies substantially affect the physicochem-ical properties and, ultimately, the performanceof the thin films.

ADVANCES: Recent advances in LbL as-sembly technologies have explored differ-ent driving forces for the assembly processwhen compared with the diffusion-drivenkinetics of classical LbL assembly, where asubstrate is immersed in a polymer solution.Examples of different assembly technologiesthat are now available include: dipping, de-wetting, roll-to-roll, centrifugation, cream-ing, calculated-saturation, immobilization,spinning, high gravity, spraying, atomization,electrodeposition, magnetic assembly, electro-coupling, filtration, microfluidics, and fluidizedbeds. These technologies can be condensedinto five broad categories to which automa-tion or robotics can also be applied—namely,(i) immersive, (ii) spin, (iii) spray, (iv) electro-magnetic, and (v) fluidic assembly. Many of

these technologies are still new and are ac-tively being explored, with research sheddinglight on how the deposition technologies andthe underlying driving forces affect the for-mation, properties, and performance of thefilms, as well as the ease, yield, and scale ofthe processing.

OUTLOOK: Layer-by-layer assembly hasproven markedly powerful over the past twodecades and has had a profound interdis-ciplinary effect on scientific research. Scal-ing up the process is crucial for furtheringreal-world applications, and moving forward,an understanding of how to carefully selectassembly methods to harness the specificstrengths of different technologies has thepotential to be transformative. Comprehen-sive comparisons between the technologiesstill need to be conducted, especially in re-gard to coating particulate substrates, wherecomparisons are limited but crucial for ad-vancing fundamental research and practicalapplications.▪

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Australian Research Council (ARC) Centre of Excellence inConvergent Bio-Nano Science and Technology, and theDepartment of Chemical and Biomolecular Engineering, TheUniversity of Melbourne, Parkville, Victoria 3010, Australia.*Corresponding author. E-mail: fcaruso@unimelb.edu.auCite this article as J. J. Richardson et al., Science 348,aaa2491 (2015). DOI: 10.1126/science.aaa2491

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REVIEW◥

MULTILAYER ASSEMBLY

Technology-driven layer-by-layerassembly of nanofilmsJoseph J. Richardson, Mattias Björnmalm, Frank Caruso*

Multilayer thin films have garnered intense scientific interest due to their potentialapplication in diverse fields such as catalysis, optics, energy, membranes, and biomedicine.Here we review the current technologies for multilayer thin-film deposition usinglayer-by-layer assembly, and we discuss the different properties and applications arisingfrom the technologies. We highlight five distinct routes of assembly—immersive, spin,spray, electromagnetic, and fluidic assembly—each of which offers material and processingadvantages for assembling layer-by-layer films. Each technology encompasses numerousinnovations for automating and improving layering, which is important for research andindustrial applications. Furthermore, we discuss how judicious choice of the assemblytechnology enables the engineering of thin films with tailor-made physicochemical properties,such as distinct-layer stratification, controlled roughness, and highly ordered packing.

The performance of functional materials isgoverned by their ability to interact withsurrounding environments in a well-definedand controlled manner. Whether harness-ing photons or electrons, separating out gas

molecules or solutes, or responding to biomol-ecules or organisms, the environment-materialinterface is essential in determining the perform-ance of the materials in various applications.Coating technologies provide the means to con-trol the surface of a material, thus creating com-posite materials where the interface and the bulkof the material can, to a large extent, be engineeredand controlled independently.Layer-by-layer (LbL) assembly is a prevalent

method for coating substrates with functionalthin films. Following early studies that reportedmultilayer assembly (1, 2), it is only in the pasttwo decades that the field has witnessed con-siderable growth (3). Generally, LbL assembly isa cyclical process in which a charged materialis adsorbed onto a substrate, and after washing,an oppositely charged material is adsorbed ontop of the first layer. This constitutes a single bi-layer with a thickness generally on the orderof nanometers, and the deposition process canthen be repeated until a multilayer film of desiredthickness has been assembled (3). For certainapplications the substrate can then be removed,yielding freestanding macroscopic films, such asmembranes (4), or freestanding micro- or nano-scopic films, such as hollow capsules (5, 6). Al-though electrostatic interactions remain widelyused in facilitating formation of the films, othermolecular interactions (e.g., covalent, hydrogen-bonding, host-guest) are now well established

for LbL assembly, with diverse materials (e.g.,polymers, proteins, lipids, nucleic acids, nanopar-ticles, suprastructures) used as film constituents(7). The simplicity, versatility, and nanoscale con-trol that LbL assembly provides make it one ofthe most widely used technologies for coatingboth planar and particulate substrates in a di-verse range of fields, including optics, energy,catalysis, separations, and biomedicine (Fig. 1A).The widespread use of LbL assembly in fields

with different standard tools and procedures—as well as the different processing requirementsassociated with substrates such as porous mem-branes, particles, and biological matter—has ledto the development of a number of LbL assem-bly technologies. Examples include dipping (2),dewetting (8), roll-to-roll (9), centrifugation (10),creaming (11), calculated saturation (12), immo-bilization (13), spinning (14), high gravity (15),spraying (16), atomization (17), electrodeposition(18), magnetic assembly (19), electrocoupling (20),filtration (21), fluidics (22), and fluidized beds(23). These different methods have often beentreated as “black boxes,” where the main focushas been on what materials are used (the input)for assembling the thin films (the output), withlittle focus placed on the actual assembly meth-od. However, there is now a growing realizationthat the assembly method not only determinesthe process properties (such as the time, scalabil-ity, and manual intervention) but also directlyaffects the physicochemical properties of the films(such as the thickness, homogeneity, and inter-and intralayer film organization), with both setsof properties linked to application-specific per-formance (Fig. 1B).

Unpacking the “black box”

The basis of LbL assembly is the sequential ex-posure of a substrate to the materials that willcompose the multilayer films. The assembly tech-

nologies used to assemble such films form fivedistinct categories, namely: (i) immersive, (ii) spin,(iii) spray, (iv) electromagnetic, and (v) fluidicassembly (Fig. 2). These assembly technologiesaffect both the process properties and the re-sultant material properties (Table 1), and there-fore careful choice of the assembly method canbe crucial for successful application of the assem-bled films. Furthermore, two main themes can beidentified for current developments in assemblytechnologies: The first is the move away fromrandom diffusion-driven kinetics for layer deposi-tion, and the second is the advancement frommanual assembly toward automated systems.

Immersive assembly

Immersive LbL assembly, sometimes referred toas “dip assembly,” is the most widely used meth-od and the standard that newer technologies areoften compared against. Immersive assembly istypically performed by manually immersing aplanar substrate into a solution of the desiredmaterial (2, 24, 25), followed by three washingsteps to remove unbound material (26). Partic-ulate substrates can also be layered using immer-sion; however, the washing and deposition stepsare generally broken up by centrifugation to pelletthe particles (5, 6, 10). Early studies on using par-ticles for depositing planar multilayers notedthat, theoretically, any material capable of havinga surface charge (such as metals, nonmetals, or-ganics, and inorganics) could be applied for grow-ing multilayers if suitable conditions are used(2, 24, 27). Further, it was also reported that thethickness of each layer corresponds to the thick-ness of the particles being adsorbed (24, 28). Im-mersive assembly allows for more homogenousfilms [when using either particle (27) or polymermultilayers (3)] in comparison with non-LbL as-sembly technologies such as gas deposition andnucleation deposition, making LbL assemblywidely used for thin-film formation.Improvements in immersive assembly include

speeding up the process by shifting the deposi-tion kinetics away from random diffusion towardfaster kinetics, such as those arising from dewetting(8), and by automating labor-intensive steps withrobotic immersion machines (24, 26, 29, 30). Thecolloids used for planar assembly in early studiesrequired only 1 min of immersion for each ad-sorption step (31); however, for immersive as-sembly using polymers, the substrate is ideallyimmersed for ~15 min for sufficient layer depo-sition (25, 26). To reduce the assembly time forpolymers and to allow for the deposition of low–surface charge and/or small–contact area mate-rials, solutions doped with organic solvents (e.g.,dimethylformamide) can be used to eliminatethe need for rinsing and drying steps throughthe process of dewetting (8). Dewetting leads toa ~30-fold reduction in assembly time becausethe adsorption process is no longer governedby diffusion but by evaporation and dewetting.Another interesting move away from randomdiffusion utilizes polymer solutions that are con-stantly stirred by magnetic stirrer bars, whichallows for robust layers to be deposited within

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Australian Research Council (ARC) Centre of Excellence inConvergent Bio-Nano Science and Technology, and theDepartment of Chemical and Biomolecular Engineering, TheUniversity of Melbourne, Parkville, Victoria 3010, Australia.*Corresponding author. E-mail: fcaruso@unimelb.edu.au

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tens of seconds after immersion (32). Instead ofspeeding up the adsorption process by usingdifferent adsorption kinetics, handling timescan be decreased by automating the process(9, 24, 26, 27, 29, 30, 33). One approach to auto-mation uses a quartz crystal microbalance (QCM)as a substrate, allowing for layering to be con-trolled with a computer-monitored feedbackloop (30). QCM enables the layering process tobe based on a fixed mass of adsorbed materialrather than fixed immersion times. Further-more, the feedback loop allows for precise andreproducible control over the film growth andallows for linear film growth to be engineeredfrom polymer combinations that give nonlinearfilm growth using fixed times (30). For fixed-time immersive assembly, computer-programmedautomated slide stainers can be retrofitted forautomated multilayer assembly, allowing foragitation and solution exchange during washingsteps (24, 29). A similar, although custom-built,computer-programmed machine can deposit~1000 layers of charged colloids onto particulatesubstrates (substrates ~100 mm in diameter) (27).Although automation decreases manual in-

volvement, it does not substantially reduce theoverall assembly time, which is why some effortshave focused on combining faster depositionkinetics with automated systems. For example,one commercially available robot uses a rotatingslide holder to speed up the assembly process(26). This rotation allows for a 3- to 10-fold re-duction in adsorption times and allows for thickerfilms to be prepared using higher rotation speeds.Roll-to-roll assembly also allows for layering tobe performed faster (by 5- to 10-fold), throughthe use of flexible substrates (9). The immersiontime and speed of the rolling process play a largerole in determining the film properties, and thedrying conditions, wettability, and substrate move-ment speed require optimization to produce filmswith similar properties to standard immersiveassembly (9). A further improvement to roll-to-roll assembly uses a nip-roll technique to pre-vent excess solution from cross-contaminatingthe system, resulting in more homogenous coat-ings than immersive assembly (34).Immersive assembly can be performed on par-

ticulate substrates that are too small to sedimentquickly or physically move between solutions,such as micro- and nanoparticles. The most com-mon technology for immersive assembly on par-ticulate substrates is performed by adding polymersolution to dispersed dense particulate substrates,pelleting the particles with centrifugation, remov-ing the supernatant, washing multiple times witha similar pelleting process, and then repeatingthe steps for multilayer growth (5, 6, 10). Thisis generally time-consuming and labor-intensivedue to the centrifugation steps, and particlesdense and large enough to be pelleted arerequired. However, by using particulate sub-strates lighter than water (e.g., emulsions),creaming and skimming cycles can be appliedfor washing steps (11), although centrifugationcan also be used to speed up the flotation andcreaming process (35), with lighter emulsions

capable of creaming in a matter of minutesrather than hours (36). The use of emulsionsas templates results in thicker films comparedwith using solid templates, probably due to

the surfactants used for emulsion stabilization(36).The major driving force behind the develop-

ment of immersive assembly technologies for

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Fig. 1. Versatility of layer-by-layer assembly. (A) Schematic overview of LbL assembly and (B) anoverview showing that the assembly technology influences film and process properties, as well asapplication areas. [Illustration credit: Alison E. Burke and Cassio Lynm]

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particulate substrates is the attempt to avoidcentrifugation, as it can lead to aggregation, islabor intensive, and is generally difficult to auto-mate. A simple way to avoid centrifugation is toremove the need for washing steps. This can beachieved by adding exact amounts of polymer

calculated to saturate the surface of the partic-ulate substrates (12, 37), rather than the highconcentrations of excess polymer solution gen-erally used (5, 6, 10). Initially, only two to threelayers could be deposited before the particlesstart to aggregate (12), but more layers can be

deposited by incrementally measuring the zetapotential during assembly (37). Additionally,the use of constant mixing for soft particulatesubstrates such as emulsions (38) or sonica-tion during layer deposition for hard particu-late substrates like drug crystals (39) reducesaggregation. By optimizing the protocol, thesaturation method gives a similar shell thick-ness to centrifugation-based assembly but isabout three times faster (37, 39). This technol-ogy requires constant monitoring and surfacearea calculations to avoid adding excess polymerand therefore does not reduce manual involve-ment. A technology that focuses on decreasingmanual involvement and reducing the need forcentrifugation uses particulate substrates immo-bilized in agarose to convert collections of par-ticulate substrates into a macroscopic substrate(33). This macroscopic collection of immobilizedparticles can be treated like a planar substrateand immersed in polymer solutions using a ro-botic dipping machine, allowing for full auto-mation during the layering process. Althoughthis technology generates films roughly halfthe thickness of those prepared by conventionalcentrifugation-based assembly, probably due tothe impeded diffusion of polymers through theagarose hydrogel, ~80% of the particles can berecovered, which is an improvement over the~90% loss that has been reported for centrif-ugation-based assembly at high layer numbers(21, 33).Due to the ease of use and versatility of mate-

rial and template choice, immersive assemblyhas been applied for numerous applications. Forexample, light-emitting diodes (LEDs) can beprepared from immersive assembly on planarsubstrates, with the polymer choice and multi-layer thickness giving control over luminanceand the turn-on voltage (29). Automated roll-to-roll immersive assembly can be used for deposit-ing conductive and flame-retardant coatings (34).Planar substrates coated with particle multi-layers can be used for the detection of small par-ticles invisible to the naked eye through colorshifts in the multilayer films (2). Glass slides canalso be coated with particle multilayers for thepreparation of antireflective, antifogging, andself-cleaning surfaces (24). Fusion microreactorscoated with particles are more conducive towardreaction (27). Certain particulate substrates easilyallow for the removal of the template particle,leaving behind hollow multilayer capsules. Sim-ilarly, drugs themselves can be used as the par-ticulate templates, with both types suitable fordrug delivery, (5, 6, 33, 38–40).In summary, immersive assembly is the most

commonly used LbL assembly technology andthe de facto standard against which other tech-nologies are compared. The simplicity of immers-ing substrates of almost any shape or size intocontainers with layering solution makes thistechnology easily accessible. The films producedhave an interpenetrated structure and form“fuzzy” nanoassemblies that are almost synon-ymous with LbL assembly (3). Much recent workhas been focused around shorter assembly times

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Fig. 2. Layer-by-layer assembly technologies. (A to E) Schematics of the five major technologycategories for LbL assembly. [Illustration credit: Alison E. Burke and Cassio Lynm]

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and automated systems with less manual inter-vention. For coating particulate substrates, therehas also been considerable interest in technol-ogies applicable to coating smaller, low-densityparticles (such as silica nanoparticles), whichcan be difficult to handle with the conventionalcentrifugation-based assembly. As immersive as-sembly typically requires more material thanother technologies, especially to submerge largesubstrates on industrial scales, waste can be an

issue, although solutions can be reused as long ascross-contamination remains low. Immersive as-sembly has been the workhorse of LbL assemblyand will undoubtedly continue to play an integralpart in the development of new and improvedthin films.

Spin assembly

Layer-by-layer assembly using spin coating (i.e.,“spin assembly”) utilizes the common coating

technology of spinning a substrate to facilitatethe deposition of materials (14). Although dryinga substrate after immersive LbL assembly canbe achieved through spinning (41), the majorityof spin assembly is performed by either castingthe solution onto a spinning substrate (42) orcasting the solution onto a stationary substratethat is then spun (43). Spinning quickens theassembly process considerably, allowing for lay-ers to be deposited in ~30 s due to the various

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Table 1. Selected LbL assembly technologies and properties arising from using each technology.The table is intended to provide a general overview andis not exhaustive. NR indicates not reported in selected references. [Illustration credit: Alison E. Burke and Cassio Lynm]

*Typical order of magnitude substrate sizes are indicated. Larger or smaller substrate sizes are possible. †Typical thicknesses per layer for linearly growingfilms are indicated. Per-layer thicknesses for exponentially growing films vary widely, given the nonlinear growth profile. ‡Time with or without agitation,respectively. §Dewetting can make use of materials that are usually difficult to layer (e.g., materials with low charge or with low surfacecontact). ‖Centrifugation processing time is highly variable due to manual pipetting and resuspension steps. ¶Thickness is dependent on time. **Fragilesubstrates, such as mammalian cells, can be layered using fluidic filtration.

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forces governing the process (43). Furthermore,spin assembly allows for automation and the coat-ing of substrates up to 10 cm in diameter usingcommercially available spin coaters (44, 45). How-ever, standard spin coaters are generally designedfor flat surfaces and are not amenable to the com-plex shapes accessible to immersive assembly.Spin assembly typically results in more homoge-

nous films compared with immersive assembly.This is because assembly is driven by a collectionof forces including electrostatic interactions, whichcause the adsorption and rearrangement of poly-mers, and centrifugal, air shear, and viscous forces,which cause desorption of weakly bound poly-mers and dehydration of the films (43). Theseforces are also the reason why spin assemblycan be orders of magnitude faster than immersiveassembly. The salt concentration of the polymersolution has a larger effect at higher spin speeds,meaning that electrostatic forces play a greaterrole at low ionic strength, and shear forces domi-nate at high ionic strength (46). These shear

forces produce thinner, highly ordered films withspecific layer interfaces when compared with im-mersive assembly, which produces thicker inter-penetrated films (47). Specifically, the thicknessfor spin-assembled polymer films is generallylinked to the spin speed, with higher speeds lead-ing to thinner films (42). When depositing col-loids, the forces experienced during spinninglead to a monolayer of colloids, whereas standardimmersive assembly often leads to a pseudo-monolayer in which the substrate is not fullycoated (43, 48). A comparison study of the dif-ferences between automated immersive assem-bly and automated spin assembly found thatimmersive-assembly prepared thicker, rougherfilms, whereas spinning resulted in thinner,smoother films (44). The films differed visu-ally, as the spin-assembled films were transpar-ent because of their distinct-layer stratification,and the immersive-assembled films were opaquedue to their inhomogeneous, interpenetrated lay-ers (Fig. 3). The contact angle and the relative

concentration of polymers were consistent acrossall bilayers for spin-assembled films, whereasimmersive-assembled films became rougher withtime, giving varying contact angle and relativeconcentration ratios between the two constitu-ent layers (44). Another study, which comparedspin assembly and immersive assembly, showedthat clay nanocomposites in spin-assembled filmshave a higher degree of orientation (45). How-ever, one issue that can result from spin assem-bly, which is not a concern for other assemblytechnologies, is that at higher ionic strengths ofpolymer solution, and also at lower spin speeds,the films can be thicker where the solution wascast when compared with the edges of the sub-strate (42, 46).In a special case of spin assembly, the sub-

strate can be placed in a closed container with apolymer solution or a colloidal dispersion paral-lel to the axis of rotation (rather than perpendicu-lar). Upon spinning, centrifugal force pushes thelayer material directly onto the substrate ratherthan across the substrate, hence the name “high-gravity assembly” (15). This allows for improvedfilm deposition and uniformity, especially at lowpolymer concentrations, because the rotationand increased turbulence lower the thicknessesof both the laminar layer and the diffusing layeraround the substrate. The adsorption equilibriumcan be reached at least five times faster than im-mersive assembly and is controllable by the spinspeed. Furthermore, polymer combinations thatgrow exponentially using immersive assembly alsogrow linearly using this technology. Similarly,the roughness is much lower (~2- to 10-fold) forLbL films assembled in this way (49).Spin assembly typically produces substantially

more organized films and multilayers than im-mersive assembly, which has made it a usefultool in preparing optical coatings with controlla-ble and homogenous color (14) and for preparingtransparent films (44). Similarly, spin assembly isuseful for preparing LEDs with higher luminancethan immersive assembly (41). A primary limita-tion for spin assembly in terms of application isthat it is limited to coating small planar sub-strates, as increasing the substrate size requireshigher spin speeds. Furthermore, spin coatingof nonplanar surfaces is complicated.In summary, spin assembly uses rotating sub-

strates to deposit layers and remove excess coat-ing material. Spin assembly typically producesthinner, more organized, and more stratifiedmultilayers than does immersive assembly, andthe process can be much faster. The spin coaterneeded for assembly is commonly accessible inmany research environments and even some in-dustrial settings, such as with the robotic waferprocessing common in the semiconductor indus-try, which could facilitate translation from thelaboratory to real-world applications. Further-more, depositing multilayer films on nonflatsurfaces, or even flat but rough surfaces, can bechallenging due to the shear forces involved withfilm assembly. Nevertheless, the film and processproperties arising from spin assembly, includ-ing smooth films assembled in a relatively short

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Fig. 3. Comparison between immersive and spin assembly. (A) Schematic comparison with layersof different materials. (B) Comparison between an immersive-assembled film (left) and a spin-assembled film (right). Films are made of hydrophobically modified poly(ethylene oxide) and poly(acrylicacid). [Adapted with permission from (44). Copyright 2008 American Chemical Society.] [Illustrationcredit: Alison E. Burke and Cassio Lynm]

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time, continue to make this method an attract-ive choice.

Spray assembly

Spray LbL assembly is another assembly cat-egory, where films are assembled by aerosoliz-ing polymer solutions and sequentially sprayingthem onto substrates (16). Although spraying airhas been used to dry films during LbL assemblyto reduce contamination (and align carbon nano-tubes) (50), here we discuss spray assembly solelyin the context of layer deposition. Standard sprayassembly is much faster (as quick as ~6 s per layer)than immersive assembly (51) and approachesan industrial level far surpassing that of spinassembly (52, 53). Vacuum can also be used tofurther speed up the process by minimizing thelag time between spraying and washing, andvice versa, and to facilitate the spray coatingof three-dimensional (3D) objects like mem-branes (54).In spray assembly, the film properties—such

as the morphology, uniformity, chemical compo-sition, and selective membrane properties—canbe tailored to be similar to those prepared by im-mersive assembly, with the film thickness influ-enced by suspension concentration, spray flowrate, spray duration, resting duration, whetheror not the substrate is washed and for how long,and whether the solution is sprayed vertically orhorizontally (16, 51, 55–57). This control arisesfrom the two main forces governing the sprayassembly process, namely, bulk movement in theactual spray and randommovement in the liquidfilm (56). The random movement in the liquidfilm allows for polymer rearrangement and gen-erates much higher convection close to the sub-strate, allowing for improved deposition. This isbecause of the submicron thickness of the liquidfilm at the substrate interface and because of thespeed at which the spray contacts the substrate(16, 56). Washing the substrate generally producesthicker films than leaving the substrate unwashed,due to polymer rearrangements during washing(51). Like spin assembly, the films resulting fromspray assembly have more distinct layers in com-parison to immersive assembly (16, 53).Spray assembly has also been combined with

other technologies to leverage technology-specificadvantages and automate the assembly process.For example, a disadvantage of spray LbL assem-bly is that the obtained films may not be homo-geneous due to the effects of gravity draining,causing increased deposition in the vicinity of thesolution drips, and because of irregular patternscaused by the spray nozzles at certain distances(51, 57). To address this problem, rotating thesubstrate during spray assembly allows for thepreparation of more homogeneous films andsubsecond spray times for each layer (56, 58, 59).By spraying rotating substrates, a majority ofthe polymer added to the substrate is adsorbed.In comparison, the vast majority of polymer re-mains in the coating solutions after immersiveassembly. Therefore, applicable concentrationsroughly 10 to 50 times less than those requiredfor immersive assembly can be used for spray

assembly on rotating substrates (55, 59). Larger3D substrates, such as tubular membranes, canalso be coated by rotating the substrate duringspraying (60). A further improvement has beenthe computer-aided automation of spray assem-bly to reduce manual processing (58, 60). Similarto the use of automated immersive assembly onQCM chips, the use of QCM chips for automatedspray assembly enables feedback loop controland tracking of real-time film growth (61). Auto-mated spray assembly has also been combinedwith roll-to-roll processing for coating industrial-size substrates (i.e., substrates that are tens ofmeters long) (62). Roll-to-roll spray assembly canalso be used to coat particulate substrates withmultilayer films by performing spray assemblyon particulate substrates immobilized on top ofa dissolvable surface (63).A stand-alone spray assembly technology for

coating particulate substrates uses surface acous-tic waves of 1 to 10 nm in amplitude to atomizepolymers and cargo (17). As the atomized dropletsmove through the air, the solvent evaporates andthe polymer condenses into particle form, result-ing in the first atomized solution becoming thetemplate for subsequent coatings, with ~1000 car-riers produced from each microliter of solution.The particles are dialyzed to remove excess poly-mer, added to a solution of oppositely chargedpolymer, and then re-atomized to coat the par-ticles. This process can be repeated for multi-layer assembly; however, the dialysis processincreases the processing time of this technologyto ~24 hours for each layer.Spray assembly has found use for a wide vari-

ety of applications because it can be used to coatindustrial-scale substrates with relative ease (62)and is not limited to planar substrates (54, 60, 63).Spray assembly has been used to prepare flame-retardant films over cotton cloth, where it wasshown that spraying on vertically oriented sub-strates produced superior flame-retardant filmscompared with both spraying on horizontallyoriented substrates or dipping (57). Clothing ma-terial was also coated with spray assembly tocontrol air flux and provide chemical protec-tion, potentially for use with military uniforms(54). Like other assembly technologies, spray as-sembly has been used to prepare antireflectivecoatings (61), and similarly, car tinting with struc-tured coloring to reduce heating from infraredlight (62). Membrane tubes could also be coatedto improve the separation of organic dyes fromwater (60). Because the structure of the films canbe controlled at the nanometer-level by the spraytime, spray assembly can be used to control con-ductance in thin films in ways that are not avail-able to other assembly technologies (59). Sprayassembly has been used to prepare particles toexamine cellular uptake of different coatingsand aspect ratios of particles (63) and for genedelivery in vitro (17). Spray assembly has founduse in diverse applications and industry becauseit offers rapid assembly times and is amenableto both automation and scale-up.In summary, spray assembly produces multi-

layer films by aerosolizing coating solutions and

spraying them onto the substrate. The resultingfilms are typically well organized with distinctlayers. Spray assembly is a quick and easy meth-od to coat large or nonplanar substrates, althoughimmersive assembly remains the method of choicefor coating complex 3D substrates. Spray assem-bly is one of the most highly relevant technol-ogies for industrial applications, as it is alreadywidely used in industry.

Electromagnetic assembly

Electromagnetic assembly is based on the use ofan applied electric or magnetic field to effect lay-ering, such as by coating electrodes in polymersolutions or by moving magnetic particulate sub-strates in and out of coating solutions (18, 19). Theformer, commonly referred to as electrodeposi-tion, is a well-established technology for coatingmaterials using an applied voltage in electrolyticcells. In the standard electrodeposition setup,two electrodes are immersed in polymer solution,then an electric current is applied. The electrodesare then washed and placed into solution of anoppositely charged polymer; the polarities of theelectrodes are reversed, and the process is re-peated (64). Electrodeposition can be used torapidly assemble ions, polymers, and colloids inmuch less time than in immersive assembly (18).For example, bimetallic mesoporous LbL filmscan be prepared by electrodeposition, with theelectrodeposition time determining the layerthickness at ~1.5 nm/s (65). In another setup, thesubstrate can be placed between the two elec-trodes, allowing for planar substrates to be coated(66), or even immobilized particles (13). This tech-nology results in films roughly twice the thicknessof those resulting from centrifugation-based as-sembly. Electrodeposition can also use highervoltages, upwards of 30 V (13, 66); however, theassembly process for immobilized particles cantake as long as 15 min per layer (13).The thicknesses of the electrodeposited films

are directly related to the voltage used duringassembly, with the optimum voltage for achiev-ing the thickest films dependent on the pH ofthe polymer solution (67). Higher voltages cancause desorption of the film as the electrode(i.e., the substrate) begins to repel the previouslydeposited layer. Generally, pH values lower thanthe pKa (where Ka is the acid dissociation con-stant) of the polymers need lower voltages toreach peak thickness, and that peak thickness isalso larger than the peak thickness at higher pH,closer to or above the pKa of the polymers. How-ever, if the voltage is raised high enough, a sec-ondary peak thickness can be reached, allowingfor the assembly of films at pH values otherwisedifficult to grow using other technologies (67).The reason for this “valley” in thickness is thatat high voltages, the electrolysis of water at theelectrode plays a bigger role in hindering poly-mer adsorption; however, at even higher volt-ages (>3 V) the electrostatic interaction betweenthe polymer and electrode exceeds any hin-drance due to electrolysis (67). For example,polymer-enzyme films are roughly twice asthick when assembled at an optimal voltage of

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1.2 V, compared with using lower or higher vol-tages (below 3 V) (68). These studies show thatelectrodeposition is similar to other LbL assemb-ly technologies in the sense that the pH of thepolymer solution, and therefore the configura-tion of the polymer itself, is crucial in controllingfilm thickness.At higher voltages, electromagnetically as-

sembled films are more interpenetrated thanimmersive-assembled films, which is in contrastto the highly stratified films prepared at lowervoltages (66). When forming polymer-polymerfilms, the refractive index does not change sub-stantially during film growth in a flow cell underan electric current, suggesting a more homoge-nous deposition than in immersive assembly(69). Similarly, polymer-colloid films show highorganization, as the refractive index decreasesand transmittance increases when assemblingfilms under higher voltages (70). Correspond-ingly, electrodeposited enzyme-polymer films aremore uniform than immersive-assembled films,with 90% coverage of the substrate versus ~50%coverage, respectively (68). Because of this stratifi-cation and high surface coverage, electrodeposi-tion allows for control over the spacing betweenlayers (68).Electrodeposition can also be achieved by

using local effects at the electrodes, such as in-ducing redox reactions or changes in pH. ThepH of the solution near the anode and cathodechanges markedly from bulk solution to lowerand higher pH values, respectively (71). The lowpH near the anode can induce polymer deposition.However, this pH-induced electrodeposition isfairly limited, as only a few bilayers can be de-posited (using materials such as alginate andchitosan) because the layers become too thick(tens of micrometers) for the electric current topenetrate, resulting in no pH change and there-fore no deposition. Using a similar principle,covalently stabilized films can be prepared bygenerating copper(I) from copper(II) in situat the electrode (i.e., the substrate) for cross-linking azide- and alkyne-containing polymerswith copper-catalyzed “click” reactions (20).Polymers containing electrically sensitive clickgroups can also be electrocoupled, allowing for500-nm-thick transparent, and therefore strati-fied and homogenous, films to be prepared in~30 min (72). One-pot synthesis can be per-formed using the same basic principles byswitching between oxidative and reductive reac-tions by alternating the voltage, allowing for wash-free assembly using electropolymerization (73).Magnets, rather than electric currents, can be

used to assemble LbL films on sensitive partic-ulate templates, such as emulsions (74), or smalltemplates difficult to pellet through centrifuga-tion, such as sub–10-nm iron oxide nanoparticles(19). Template particles containing magnetic nano-particles can be separated from the polymersolution using a magnet, which, similar to thefiltration method, allows for nearly 100% ofthe particles to be recovered in a centrifugation-free LbL assembly process (75). Magnets or anexternal field can also be used to orient layered

magnetic nanoparticles on a planar substrate sothat a subsequent layer of nanoparticles can de-posit more rapidly and in an oriented fashion(76). This technology uses standard immersiveassembly for the deposition of positively andnegatively charged magnetic nanoparticles withapplication of a magnetic field between depo-sition steps. Therefore, the thickness does notincrease in relation to standard immersive as-sembly; however, the absorbance of the film in-creases with application of the magnet, suggestingincreased packing (76).Electromagnetic assembly has found use in

several different applications, as it can be used toform LbL films with compositions that are notreadily assembled using other technologies. Bi-metallic films of Pt and Pd layers have Brunauer-Emmett-Teller surface areas of ~40 m2 g−1 andtherefore exhibit enhanced electrochemical activ-ity in the methanol oxidation reaction, comparedwith single-layer films (65). Antireflective coat-ings can be prepared by adjusting the refrac-tive index of the films by assembling the films atdifferent voltages (70). Biological applications havealso been explored, as biocompatible coatingscan be formed using electromagnetic assembly,with in vitro tests confirming negligible cyto-toxicity (71). Bienzyme films with bioelectric cata-lytic properties have higher surface coverage, andtherefore activity, when compared with tradi-tionally prepared films (68). The stratification ofthe assembled films is also conducive towardhigh-performance photoelectric devices (72) andseparation membranes (66). Hollow polymercapsules (from micrometers to sub–100 nm indiameter) can also be prepared using electro-deposition on immobilized particles (13).In summary, electromagnetic assembly uses

electric or magnetic fields, typically in the formof electrodes in polymer solutions or magneticparticulate substrates, to deposit films. Electro-magnetic assembly can exploit current-inducedchanges in pH or redox-reactions to effect filmassembly, thus using a driving force substantiallydifferent from that of the other main assemblycategories. Generally, electromagnetic-assembledfilms are thicker and more densely packed thanfilms prepared using other LbL assembly meth-ods (13, 68). Electromagnetic assembly is still notas common as some of the other technologies,and even though it requires special equipmentand expertise, it does offer a different approach tomultilayer film assembly (e.g., through magnetichandling of substrates and materials or throughelectrically induced assembly), thereby providingalternative opportunities for assembling films.

Fluidic assembly

Fluidic assembly can be used to deposit multi-layers with fluidic channels, both by coating thechannel walls and by coating a substrate placedor immobilized in a fluidic channel (77). The gen-eral method involves using pressure or vacuumto sequentially move polymer and washing solu-tions through the channels, which can be fluidiccomponents, such as tubing or capillaries, ordesigned microfluidic networks (78, 79). Flow-

chamber–based QCM is a common fluidic assem-bly technology used for investigating thin-filmproperties and multilayer growth by providingcrucial real-time information (22). Higher con-centrations of polymer solution typically yieldthicker films (79), with the contact time ratherthan the flow rate as the crucial factor deter-mining the amount of adsorbed polymer underflow (80).Fluidic assembly is typically implemented using

a pump, capillary forces, or spinning to trans-port the liquid through the channels, althoughpipetting and static incubation can also be used.However, fluidic assembly strongly resemblesimmersive assembly when polymer solutionsare allowed to remain in static contact with thesubstrate for more than 10 min (81, 82). Polymerand washing solutions loaded into channels witha pump or vacuum can deposit ~1.5-nm-thicklayers in 5 to 10 min (83). Capillary forces canalso be used to pull polymer solutions throughmicrofluidic channels by placing droplets ofsolution at fluidic inlets, followed by spinningthe substrate to remove the solution, allowing for~1.2-nm-thick layers to be deposited in less than2 min (84). Fluidic layering based on capillaryforces is easy to implement, as capillary actiondoes not require external active components,but it is not suitable for larger volumes or whendynamic control over the flow rate is needed.Fluidic devices and perfusion chambers can

also be used to achieve region-specific fluidic as-sembly or to perform fluidic assembly on morecomplicated 3D structures. For example, complexautomated microfluidic devices can be used to as-semble hundreds of layers in parallel using cap-illary flow and vacuum to fill and empty multiplechannels (85). This enables the high-throughputscreening of film libraries using small quantitiesof materials, as only a droplet is needed to fill asingle microchannel. Region-specific films canbe coated on substrates by affixing a geometricchamber over the substrate and then flowingthe solution through the chamber and over thesubstrate (80). Perfusion chambers can be usedfor fluidic layering on complex 3D substrates suchas sensitive biological substrates (like arteries),which must remain constantly hydrated duringlayering (86). Similarly, perfusion chambers canbe used to hold agarose that contains immobilizedparticles for fluidic assembly (87). This technologynot only allows for the deposition of polymers butalso for the deposition of larger cargo, such asgold nanoparticles or liposomes, and producesfilms with nearly identical thickness to those pre-pared by standard centrifugation-based assem-bly (87).Vacuum is typically used with other assembly

technologies, such as spray assembly, or to re-move the solution from channels in fluidic as-sembly, but it can also be used to formmultilayersin a macrofluidic-type assembly, especially on un-usual substrates like aerogels. Aerogels can befunctionalized using vacuum assembly by pour-ing solutions of conducting polymers, biomole-cules, or carbon nanotubes from the top andapplying vacuum to pull these solutions down

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through the aerogel (88). Vacuum assemblycan also be used to deposit materials, such asreduced-graphene oxide, that would otherwisepose a challenge to the creation of uniformmulti-layers (89). For particulate substrates, vacuum as-sembly can be performed using separating filters,down to 200 nm in pore size, for centrifugation-free layering (21, 90). Vacuum is not applicablefor all sensitive templates; however, for templateparticles including emulsions (91), cell islets (92),or calcium carbonate nanowires (93), a slightvacuum (~100 mbar) can facilitate the layeringprocess (21). Less than 3% of the particles are lostduring assembly using an optimized procedure,far less than with the calculated saturation-based method, where ~50% can be lost, or thecentrifugation-based method, where more than80% can be lost at high layer numbers (21). Thiscombined filter-and-vacuum assembly technol-ogy yields a layer thickness of ~1.3 nm and asurface roughness of ~5 to 10 nm, which are bothsimilar to those prepared via centrifugation-basedassembly (94). A filtration setup has also beenautomated for coating cell islets, using a feed-back loop for evacuating the fluid from the re-action chamber, thereby reducing the manualhandling time by ~60% (95).Like vacuum assembly, fluidic assembly is not

restricted to planar substrates and is a viablealternative for centrifugation-free assembly onparticulate substrates (96–98). Many fluidic as-sembly approaches coat emulsions or liquid crys-tals, as these materials are well studied in thefluidics field. Generally, the coating and washingsolutions are deflected past the flow of particlesby using physical gaps smaller than the particlesso that the flow can enter perpendicular (96)or parallel to the particle flow stream (97). Forfluidic assembly in parallel flow systems, largertemplate particles (~50 mm in diameter) are nec-essary, as they can be deflected in a zig-zag pat-tern using solid pillars at a ~45° angle to threeparallel laminar flow streams: solution A, wash-ing, and solution B. This gives a layer thicknessof ~2 to 3 nm (97). A similar technology can beused to coat 15-mm beads with avidin and biotin,where higher deflection angles have a high cor-relation to failure rates, with angles of 1° optimalfor a failure rate of virtually zero (99). Instead ofpillars, specific geometries can be used to catchemulsions for the fluidic assembly of lipid layers(98). For coating lipid particles with polymers,tangential flow filtration can be used as a typeof expedited dialysis for removing excess poly-mer solution (100). To coat sufficiently largeand/or dense particles, a setup based on fluid-ized beds can be used. This allows for assem-bly that is ~eight times faster when comparedwith centrifugation-based assembly and producesfilms twice as thick (23). In this instance, theforce of the washing or polymer solution liftingthe particles is balanced against the force ofgravity sedimenting the particles, resulting in afluidized bed where washing and polymer solu-tions can be pushed past the particles. A similarsetup can be used to coat larger (>100-mm) par-ticles in packed columns, although these beds do

not need to be fluidized due to the large particlesize, and gravity rather than a vacuum or pump-driven fluidics can be used to pull the coating andwashing solutions through the column (1).Numerous applications have been introduced

during the process of developing technologiesfor fluidic assembly. Many applications, suchas improved capillary electrophoresis, are real-ized inside capillaries (81). Fluidic assembly canalso be used to engineer complex flow patterns,such as having flow in opposite directions in thesame capillary, simply by changing the outercoating of the capillary walls and generatingflow with an electric current (82). Fluidic assem-bly is not limited to planar substrates: For ex-ample, multilayer coatings can be prepared onaerogels, resulting in improved compressivestrength, wet-state super elasticity, fluorescence,and mechano responsive resistance, while alsocreating high charge-storage capacity (88). Dam-aged aortic porcine arteries can be repaired exvivo with fluidic assembly, to protect the arteryagainst unwanted blood coagulation, as well asto facilitate healing (86). Similarly, catheter tubingcan be coated with antifungal multilayers to re-duce fouling (78). Chromatography beads coatedwith multilayers of particles increase the surfacearea of the beads, thereby improving chromatog-raphy (1). Although fluidic assembly is typicallyperformed on larger particles (tens or hundredsof micrometers in diameter), smaller particles(below ~5 mm in diameter) can be coated andloaded with functional cargo for potential drugdelivery applications by combining microflu-idics with immobilization (87). Fragile particu-late substrates like emulsions can also be coatedwith lipids, using fluidic assembly for the gen-eration of synthetic cells (98). Neuronal cells canbe patterned with fluidic assembly (83), and cellislets can be coated to improve robustness, allow-ing for in vivo transplantation (92, 95). Fluidicassembly functions as a valuable tool for coatingsensitive particulate substrates, like mammaliancells, that may be damaged using other technol-ogies, such as during handling in centrifugation-based assembly.In summary, fluidic assembly provides the

means to assemble multilayers on surfaces noteasily accessible to other methods (e.g., inside cap-illaries), provides new ways for region-specificpatterning (e.g., by masking a surface with afluidic channel), and increases the industrialcapacity of multilayer assemblies (e.g., throughparallelization of film assembly and decreaseof reagent consumption). Although the special-ized equipment and expertise required to set up(micro)fluidic systems can complicate the use offluidic assembly, these advantages make it at-tractive for many applications.

Challenges both big and small

Over the past two decades, LbL assembly has un-dergone an explosive growth in usable materialsand substrates. When taken together with all ofthe different assembly technologies available, itbecomes obvious why LbL assembly is prevalentacross a broad spectrum of disciplines. Despite

this extensive toolbox, relatively few multilayerfilms have had widespread impact outside ofresearch environments. One focus for industrialapplications is the identification of reliable, sca-lable, and resource-effective assembly processes,although this may require different approachesfor macroscopic substrates and for microscopicparticulate substrates.For macroscopic substrates, improved high-

throughput assembly methods for conformalcoatings will play a key role. Immersive and sprayroll-to-roll assembly are industrially relevant butonly readily applicable to flexible planar substrates;therefore, innovation is needed in systems thatcan be easily scaled for coating large or numerous3D macroscopic substrates. Similarly, reducingmaterial waste during the coating process re-mains important, especially for valuable coatingmaterials like biomolecules and custom polymers.Another challenge for films intended for in vivobiomedical application, such as drug delivery andtissue engineering, is ensuring sterility of theproduct. This is typically achieved through steri-lization (heat, ultraviolet light, chemical treat-ment, etc.) just before use, which can affect filmproperties and performance. Finally, increasingthe reliability and reproducibility of the films—for example, by increasing automation and reduc-ing manual intervention—is crucial for extendingknowledge about film properties and assemblytechnologies and also for applying the multi-layer films in real-life applications.Similar challenges exist for particulate sub-

strates. One crucial difference is that severalparticulate assembly methods depend on cen-trifugation, which remains difficult to scale or com-bine with minimal-intervention high-throughputassembly. Furthermore, yield and size rangesneed to be specified for the various technolo-gies, as these details are often not determined.Detailed film properties (such as layer interpen-etration, layer density, film stability or respon-siveness, and permeability) that have primarilybeen studied on planar substrates also need tobe investigated so that further comparisons be-tween planar and particulate substrates canbe drawn. Altogether, these challenges are nottrivial and require focused efforts to overcome;they are also not unique to the field of LbL as-sembly. One way to address these challenges isto continue to be open and look for solutions innew and sometimes unexpected areas, both inneighboring and more distant fields; this hasunderpinned much of the technological innova-tion in LbL assembly.

Opportunities: Thinking outside the box

Layer-by-layer assembly is a firmly establishedtechnology and shows great promise in multi-ple, diverse fields. Much of the development upuntil now has focused on using new moleculardriving forces for film assembly, thus enabling theuse of a suite of substrates and layer materials.However, this enormous potential still remainslargely limited to small-scale research settingsand requires technological and methodologicalinnovation. Despite a surge of new technologies,

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many being recent developments, unmet chal-lenges still remain, both for harnessing thespecific strengths of different technologies forparticular applications and also for develop-ing new and improved technologies.Although much work has been undertaken on

establishing new assembly technologies, only afew studies have chosen a specific assembly tech-nology for the material properties generated (e.g.,stratification, density, roughness) rather thanthe processing properties used (e.g., ease-of-use,material and time savings, lowered involvement,larger batches). For example, for applicationswhere electrical conductivity is important (suchas fuel cells and batteries), the conductivity ofan immersive-assembled film can be superiorto that of spray-assembled films, which can beexplained by differences in the interlayer orga-nization of the constituent conductive layer ma-terials (interpenetration versus stratification) (59).Conversely, for applications where optical clar-ity and/or wetting behavior is important, spin-assembly can allow for an optically transparentfilm with well-controlled water-contact anglesto be assembled due to the smooth, stratifiedlayers formed, whereas an immersive-assembledfilm can be translucent and with a contact anglethat drastically changes depending on the num-ber of layers deposited due to the rough, inter-penetrated layers formed (Fig. 3) (44). However,layer structure is only one of the critical filmproperties to be taken into account when design-ing films for specific applications. For example,the higher surface coverage and layer densityassociated with electromagnetic assembly canallow for electrodeposited enzyme films to havehigher enzymatic activity than comparableimmersive-assembled films (68). Of course, thelayer structure and density are not relevant ifthe desired film components cannot be layered,which can be an issue, for example, when usingmaterials with low charge density (e.g., reduced-graphene oxide) or with a low surface area ofcontact (e.g., branched nanowires). In suchcases, technologies such as dewetting andvacuum assembly enable film formation usingconstituents that cannot be easily layered usingother technologies (8, 89). These examples dem-onstrate how the judicious choice of assemblytechnology can enable the assembly of new andimproved thin films. As our understanding of thedifferent technologies and how they compare toeach other increases, so does the opportunity tolet this insight help guide the development of thenext generation of LbL assembled thin films.It is noteworthy that the assembly technologies

discussed herein were not originally developedfor LbL assembly, and crossover technologiesfrom other fields will continue to play an im-portant part for new, and perhaps even revolu-tionary, developments. One interesting exampleinvolving industrial-scale layering was performedusing a modified car wash for spray assembly ona full-sized car (101). Technologies long used inthe pharmaceutical industry, such as methodsused to treat, purify, and concentrate pharma-ceuticals, may prove transformative for biomed-

ical applications. Similarly, using everyday objectslike spray-paint cans could revolutionize assem-bly methods by essentially combining dewettingand spray assembly for rapid region-specific as-sembly with little to no material waste and nowashing steps. Other combinations between ex-isting assembly technologies should also help toexpedite and automate the assembly process.Along these lines, technologies for assembly onparticulate substrates are expected to continueto integrate immobilization methods, as they al-low collections of particles to be treated like pla-nar substrates, making accessible many of theplanar assembly technologies discussed herein.Another promising approach for particulate sub-strates could be to use a type of “sponge” to ad-sorb excess polymer from solution, thus removingthe need to pellet the particles. In terms of futuredevelopments for applications, it will be im-portant to understand the interaction betweenmultilayer films and complex and natural en-vironments, such as those found in the humanbody (40), outdoors, or in seawater. An impor-tant aspect of this could be the use of functionalsubstrates capable of compounding the benefitsof different multilayers in a synergistic fashion.Overall, the future of LbL assembly is bright,and as the black box of assembly technologies isslowly illuminated, great potential for innova-tion and application will be found.

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ACKNOWLEDGMENTS

This work was supported by the ARC under the Australian LaureateFellowship (FL120100030 to F.C.) and the Australian governmentthrough an Australian Postgraduate Award (to M.B.). This workwas also supported by the ARC Centre of Excellence in ConvergentBio-Nano Science and Technology (project number CE140100036).

10.1126/science.aaa2491

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Technology-driven layer-by-layer assembly of nanofilmsJoseph J. Richardson, Mattias Björnmalm and Frank Caruso

DOI: 10.1126/science.aaa2491 (6233), aaa2491.348Science 

, this issue 10.1126/science.aaa2491Sciencebroadening the use of these techniques.because there is tremendous scope for fine-tuning the structure and properties of the multilayers, there is interest in can be deposited, the techniques remain mostly confined to the lab because of challenges in industrial scaling. Butcoating, spraying, and electrochemical deposition. Despite the versatility of the methods and the range of materials that

review some of the techniques and materials that are used to make thin films, including sequential dipet al.Richardson Layer-by-layer processes involve the sequential deposition of two or more materials that physically bond together.

The deposition of thin films from multiple materials is essential to a range of materials fabrication processes.Thin-film fabrication

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