Molecular Self-Assembly: Smart Design of Surface and Interface via

Invited Feature Article pubs.acs.org/Langmuir

Molecular Self-Assembly: Smart Design of Surface and Interface via Secondary Molecular Interactions Ilsoon Lee* Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, Michigan 48824-1226, United States ABSTRACT: The molecular self-assembly of macromolecular species such as polymers, colloids, nano/microparticles, proteins, and cells when they interface with a solid/substrate surface has been studied for many years, especially in terms of molecular interactions, adsorption, and adhesion. Such fundamental knowledge is practically important in designing smart micro- and nanodevices and sensors, including biologically implantable ones. This review gives a brief sketch of molecular self-assembly and nanostructured multifunctional thin films that utilize secondary molecular interactions at surfaces and interfaces. films and sensors. Even though the LB technique has been extensively used by many researchers, it has some limitations because of the difficulty of firmly trapping molecules at the air− water interfaces. This limits the use of a variety of complicated large molecules for the LB-deposited functional nanostructured films. However, Kim and Swager overcome the difficulty of obtaining precise conformational and spatial arrangements of conjugated polymers to study the intrinsic spectroscopic properties for applications in electronic, sensor, and display technologies.4 They designed and synthesized four poly(pphenylene-ethylene) compounds (PPEs) using four surfactant building blocks that display preferential orientations at the air− water interface, as shown in Figure 1. Unique combinations of those building blocks allowed them to control an isolated polymer chain’s conformation and interpolymer interactions. Another classic but still widely used thin organic film deposition technique involves the self-assembled monolayers that are formed spontaneously by the immersion of an appropriate substrate such as gold, silver, copper, platinum, aluminum oxide, or silicon oxide and glass slides into a solution of active amphiphilic molecules such as surfactants.5 Strong molecular−surface interactions that form SAMs on a surface include alkyltrichlorosilanes on hydroxylated surfaces (Si−O, covalent bond), alkanethiols on gold (Au−S, covalent but slightly polar), and carboxylic acids on AgO/Ag (−CO2−Ag+, ionic bond). In such interactions, molecules try to occupy any possible surface binding site, and thus surface-bound molecules are pushed together to form a tightly bound SAMs on a surface. The alkyl chains of the surface-bound surfactant molecules interact via van der Waals interactions. Van der Waals interactions are the main interactions in the case of simple

1. INTRODUCTION Surfaces and interfaces capable of repelling, attracting, and selectively detecting molecules have attracted attention for their important application in catalysts, coatings, sensors, and devices, including biologically implantable ones. Designing and engineering surfaces and interfaces of multifunctional films on the molecular level are even more important because oftentimes subtle changes in structure and composition can result in dramatic performance enhancement. The surface functionality and physicochemical topography affect the conformation and connectivity of the adsorbed macro/ biomolecular species and particles as well as the adsorption/ adhesion dynamics, where molecular interactions at the surfaces or interfaces are the main controlling factor. Chemistry, physics, biology, and nanotechnology are rapidly approaching maturity on the small length scale. This allows us to design new materials properties via the development of new multifunctional nano/biocomposite particles and films where the interfacial interactions on the molecular level become the key to success and such new properties do not appear directly from each individual component.1 A polymer that can be functionalized to enhance the adhesion/adsorption of the polymer to the solid surfaces has been extensively studied for its important applications in industrial processes, such as composite manufacturing and durability, coatings and packaging for bio/microelectronics components, and biologically implantable devices. In the study of a molecular-level nanostructured film, the Langmuir− Blodgett (LB) technique used to be a dominant technique in nanostructured film studies before other new techniques such as self-assembled monolayers (SAMs) and layer-by-layer (LbL) assembly started to become more popular.2,3 The LB technique uses the formation of monolayers on a water surface and then transfers the formed monolayers onto a solid surface for a variety of fundamental and applied applications such as optical © XXXX American Chemical Society

Received: October 17, 2012 Revised: January 10, 2013

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dx.doi.org/10.1021/la304123b | Langmuir XXXX, XXX, XXX−XXX

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Invited Feature Article

Figure 1. Conformations and spatial arrangements of polymers 1−4 at the air−water interface and their reversible conversions among face-on, zipper, and edge-on structures. Polymer 1: number-average molecular mass Mn = 23 000, polydispersity index, PDI = 2.4. Polymer 2: Mn = 293 000, PDI = 1.7. Polymer 3: Mn = 115 000, PDI = 2.2. Polymer 4: Mn = 96 000, PDI = 2.8. Monomers A−D are represented by green, orange, yellow, and gray boxes, respectively. Reproduced with permission from ref 4.

such as proteins, small molecules, nanoparticles, micelles, cells, viruses, clay nanosheets, carbon nanotubes, graphenes, and polymers.1,13,14 The LbL deposition technique has been applied to virtually all kinds and shapes of surfaces including colloids, paper, fruit, textiles, biomolecules DNA and RNA, and living cells. The modern popularity of this LbL deposition technique over the LB deposition technique was initiated by Decher and Hong in the beginning of 1990.7,8 However, historically, the first report on the LbL deposition technique was made by Iler of Du Pont de Nemours & Co. in 1966.15 He reported the fabrication of colloidal multilayer films by the alternating deposition of positively and negatively charged particles. The simplicity and unique features of the LbL deposition technique compared to the complicated LB deposition technique make it possible that the use of a variety of secondary molecular interactions to form complicated multifunctional nanostructured molecular films on any surface. The secondary molecular interactions used in building such multifunctional LbL nanostructured films include ionic and

alkyl chains to be closely packed and ordered on surfaces. When a polar bulky group replaces the alkyl chain, another secondary interactionelectrostatic interactionbecomes more important energetically than the van der Waals attraction. As a smart surface design approach, Lahann et al. reported reversibly switching surfaces that exhibit dynamic changes in interfacial properties of hydrophilicity and hydrophobicity by an electronic switch, as illustrated in Figure 2.6 They used a smart design of loosely packed (16-mercapto)hexadecanoic acid (MHA) SAMs on a gold surface by using a globular bulky terminal group of MHA. Such loosely packed MHA SAMs on a gold surface showed reversible conformational transitions that were confirmed by many analytical tools including sumfrequency generation spectroscopy and contact angle measurements. A more recent and currently popular approach to fabricate multifunctional nanostructured films is the layer-by-layer (LbL) assembly technique.7−12 The LbL deposition technique has allowed people to choose a variety of different components B


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Figure 2. Idealized representation of the transition between straight (hydrophilic) and bent (hydrophobic) molecular conformations (ions and solvent molecules not shown). The precursor molecule MHAE, characterized by a bulky end group and a thiol headgroup, was synthesized from MHA by introducing the (2-chlorophenyl)diphenylmethyl ester group. Reproduced with permission from ref 6.

3. DIRECTED SELF-ASSEMBLY OF MULTILAYER FILMS AND DIRECT PATTERNING The different types of secondary interactions including adhesion promoting, resisting, and neutral (e.g., positive charge, negative charge, and neutral, respectively) can allow us to build a variety of assembled 2-D and 3-D nanostructured multifunctional composite films. The smart design and selection of the secondary interactions, often followed by postchemical treatment of the surfaces and interfaces, will lead to the fabrication of novel devices, sensors, and important parts of future complicated materials. Lee et al. challenged the combination of SAM deposition, LbL deposition, and microcontact printing (μCP) to control the colloidal clusters in patterned LbL deposited films via the directed assembly of colloidal particles on confined surfaces.20 As shown in Figure 4, patterned and controlled LbL-deposited multifunctional and nanostructured thin films on a surface can serve as an excellent molecular template for many hightechnolgy applications in biosensor arrays, drug screening devices, and optoelectronic display materials. μCP has been used in physics, chemistry, materials science, and biology to form patterned thin multifunctional and nanostructured films on surfaces.21,22 μCP has advantages over conventional photolithographic techniques because of its simplicity and nondiffraction limitation. They presented how to obtain 2-D single-particle arrays and groups of particles on the LbLdeposited and μCP-patterned polymer films formed on the thiol 16-mercaptohexadecanoic acid (COOH−, adhesionpromoting) and oligoethylene glycol-terminated (EG−, adhesion-resisting) patterned SAMs on a gold surface (Figure 4). Without starting from SAMs on a gold surface, we have also challenged new patterning approaches on any surface including glass, metal, and plastics for the last several years. For the first time, we demonstrated SAM patterning on LbL-deposited polymer films, as opposed to that on gold or silicon substrates.23 In this work, the process of creating chemically patterned and physically structured surfaces was realized by stamping polyethylene acid molecules on LbL-deposited coated polymer surfaces, as shown in Figure 5. The activated carboxylate functional group electrostatically binds to the

hydrogen bonds and van der Waals, hydrophobic, and coordination interactions.14 Even though the LbL deposition technique has been developed on the basis of a variety of secondary interactions, the major driving force used for the fabrication of multifunctional nanostructured films is electrostatic interactions. However, such molecular films formed by secondary interactions often need postchemical processing to make more robust films.14 To impart robustness to the films, the latter are often made to undergo chemical treatment following LbL deposition. For example, electrostatically formed LbL films are not stable enough to be used under extreme conditions such as high or low pH and high salt concentration. To convert such loosely bonded films into more robust films, Zhang et al. proposed a combined method of LbL deposition and postphotochemical reaction.16 They used diazoresin (DAR, a reactive, water-soluble polycation) as one of the building blocks along with sulfonated polystyrene (SPS), forming SPS/ DAR multilayered films. UV irradiation converts DAR to its phenyl cationic form, and then this was followed by an SN1 attack by sulfonate to form a cross-linked multilayer film. This combined approach changed the ionic secondary interacting film into a stronger covalent multilayered film, which enhanced the robustness of the formed polymer films.

2. INTERFACIAL INTERACTIONS OF POLYMERS ON SOLID SURFACES As observed by Lee and Wool, the interfacial structure and strength are closely related to each other, and both can be controlled by various modification methods.17−19 Wool’s research group examined the role of sticker groups X on the polymer and receptor groups Y on the solid substrate, as illustrated in Figure 3. They found that a precise number of sticker groups (ca. 3 mol %) and receptor groups (ca. 30% coverage of a solid) were required to optimize the adhesion strength of the interface. The optimal design of the coupling molecules requires it to stick to at least two points on the surface while making an excursion into the matrix molecules by at least the radius of gyration of the entanglement network. C


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Figure 3. (a) Schematic representation of the X−Y problem at a polymer−solid interface. X represents specific polymer sticker groups, and Y represents specific substrate receptor groups. φ is the mole percent or the mole fraction of the groups. (b) Schematic representation of the polymer− metal interfaces. (c) Fracture energy of the cPBD−AlS interfaces as a function of the substrate receptor group density, φY(NH2). (d) Schematic representation of interfacial chain restructuring with bond formations (a) at a high-energy surface (case I, φY = 1) and (b) at a low-energy surface (case II, φY = 0.3). Reproduced or adapted with permission from ref 18.

surface design. For robust, strong functional films, postchemical treatment can be used to make the interaction permanent. On the contrary, our group has exploited the concept of electrostatic interaction instability under a high salt, high pH, or low pH condition to form removable functional patterns. On the basis of these novel patterned and functional SAM systems on polymer (PEM) surfaces by secondary molecular interactions, we further developed novel salt-tunable resistive PEG SAMs on polymer surfaces that can provide a tunable template for designing a variety of sorted surfaces, as demonstrated in Figure 6.24 The formed PEG patterns were tuned under various conditions to elucidate active regions that can be used to create multicomponent and nanostructured systems. This study extended the tunable PEG surfaces formed

topmost positive surface of the polyelectrolyte multilayer (PEM) surfaces, and the other end (PEG units) resists the deposition of subsequent polymer (polyelectrolyte) layers. To deposit thin uniform PEG SAMs on PEMs, electrostatic interaction was used. The μCP-deposited PEG patterns acted like resistive templates that resist the nonspecific adsorption of polyelectrolytes, charged particles, and biomolecules and cells. The exposed active polymer regions (positively charged or negatively charged) served as active surfaces attracting a variety of functional species, such as polymers, dyes, particles, proteins, cells, metal nanoparticles, and graphene, by secondary molecular interactions. The use of secondary molecular interactions can impart some versatility to smart functional D


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Figure 4. (a) Schematic diagram illustrating the concept of controlling the position and number of colloidal particles in confined surface regions of patterned polyelectrolyte multilayers to make 2-D colloidal arrays. D and d are the diameters of the multilayer circular feature and the colloidal particle, respectively. (b) Overall schematic of the sample fabrication process. Right optical images are examples from Lee et al.20,60 Reproduced with permission from refs 20 and 60.

by secondary interactions at the interface to engineer multicomponent systems of macromolecules with similar physical and chemical properties. Such smart, tunable (resistive and removable PEG) patterns on PEMs facilitated the directed deposition of various macromolecules such as dyes, polymers, proteins, colloidal particles, liposomes, and cells. We compared the directed μCP deposition technique and directed self-assembly to form similar patterned and nanostructured multifunctional films. The latter uses secondary molecular interactions at the surfaces. Often there is no clear understanding of the underlying driving force when a target molecule has multiple routes for deposition on surfaces via different secondary interactions. Molecules with complex multifunctional groups lead to complexity in the directed selfassembly process. Directed self-assembly of functional species onto LbL-deposited and -patterned films can be hindered by a lack of chemical contrast between features and the background,

making it difficult to form additional layers from the features or just the background. This problem can be particularly challenging when a layer of amphiphilic or multifunctional macromolecules or biological species adsorbs to hydrophilic and hydrophobic surfaces. To overcome these complicated deposition issues, we developed a new multilayer patterning approach, intact pattern transfer (IPT), especially to establish well-defined, 3-D, layered bionanocomposite nanostructured films containing alternating layers of polyelectrolytes, dendrimers, and amphiphilic proteins.25,26 Hammond’s group at MIT also developed a similar multilayer pattern-transfer technique that has been used to build multilayered and patterned PEM and particle-embedded PEM films.27,28 Unlike the directed self-assembly approach, this direct deposition technique allows high-quality, 3-D-patterned, LbLdeposited films on substrates whose surface properties are incompatible with existing self-assembly methods. Using this E


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Figure 5. Illustration of patterned PEG SAMs on PEM (top) and AFM images and topography of complex nano and microstructures with different numbers of bilayers of PDAC/SPS built atop the PEG patterns on PEMs: (a) 10 bilayers, (b) 20 bilayers, and (c) 40 bilayers. Reproduced with permission from ref 70.

spin-inking. The well-known influences of spin speed, concentration, and solvent on the thickness of spin-coated films were confirmed in the work. Methods used to fabricate arrays of bilayer lipid membranes (BLMs) and liposomes on PEMs were also presented by us.31 Arrays of BLMs were created by exposing poly(diallyldimethylammonium chloride) (PDAC) patterns, poly(ethylene glycol) (m-dPEG acid) patterns, and PAH patterns on PEMs to liposomes of various compositions. Also, the formation of a novel biomimetic interface consisting of a gold film overlaid with a tethered bilayer lipid membrane (tBLM) was demonstrated by us.32 A method to control 2-D polyelectrolyte aggregates created by μCP was developed by us.33 A key feature of this work is the thin-film morphology study of μCP-printed polyelectrolyte aggregates. The polyelectrolyte inking and stamping processes were designed for the formation of treelike ramified structures, as demonstrated in Figure 8. It was also reported that the coarsening of the ramified structures of polyelectrolyte was accomplished by confining the stamp’s contact area to a size in which the pattern is smaller than that of the ramified structures. Finally, it was introduced that the ramified structures can be directed by directional stamping without conformal contact at the interface.

new approach, we demonstrated a simple method of creating patterned conductive multilayered polymer/graphene films on a nonconductive substrate, as shown in Figure 7.29 First, multilayered graphite was exfoliated, followed by milling to create size-controlled graphenes. The graphenes were then coated with a negatively charged polymer to form a stable aqueous solution. The solution was used for electrostatic LBL assembly, with a positively charged polyelectrolyte as the counterion, onto the surface of an uncharged hydrophobic elastomeric stamp. Once the film was formed, it was placed in direct contact with a substrate of the opposite charge to transfer the patterned conductive composite film directly. Before LBL deposition, the elastomeric stamp is coated with a layer of polyelectrolyte using relatively weak hydrophobic secondary interactions between the stamp and film. When the stamp is removed from the substrate, the strong electrostatic secondary interactions between the oppositely charged films on the stamp and substrate hold the multilayer film on the substrate surface. The first application of μCP deposition of the amphiphilic and cross-linkable poly(amidoamine organosilicon-dimethoxymethylsilyl) dendrimers and poly(amidoamine) (PAMAM) dendrimers30 on glass slides, silicon wafers, and PEMs was reported by us. The pattern average thickness was controlled by F


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Figure 6. (A) Diagram illustrating the formation of salt-tunable m-dPEG acid SAMs on a PDAC/SPS multilayer platform. (i) PEMs (PDAC/ SPS)10.5 built on top of the substrates. (ii) Patterned PEG SAMs on PEMs. (iii) Directed assembly of molecules due to the presence of resistive PEG SAMs. (iv) PEG SAMs are removed by treatment with salt, giving rise to new active regions. (v) The new active regions are filled with a new set of molecules. Chemical structure of the m-dPEG acid molecule. (B−D) Optical microscope images of the directed deposition of macromolecules on PEG patterns: (B) 0.5 μm colloid particles (brown lines), scale bar = 25 μm. (C) Alexa Fluoro-tagged sADH, scale bar = 25 μm. (D) FITC-tagged nucleic acid, scale bar = 50 μm. The dark lines represent the m-dPEG acid regions. Reproduced with permission from ref 24.

during such interactions. Elucidating these interactions and how they can be controlled is important to understanding how to manipulate and design better biological systems and medical devices. The physical and chemical properties of a substrate affect the attachment and growth of cells. With respect to these points, PEMs have become excellent candidates for biomaterial applications because of (1) their biocompatibility and bioinertness, (2) their ability to incorporate biological molecules such as proteins, and (3) the high degree of molecular control of the film structure and thickness, providing a much simpler approach to constructing complex 3D surfaces as compared to photolithography. We described the successful attachment and spreading of primary hepatocytes on polyelectrolyte multilayer (PEM) films without the use of adhesive proteins such as collagen or fibronectin.23 We demonstrated for the first time that primary hepatocytes when attached and spread on a synthetic PEM surface terminating in poly(4-styrenesulfonic acid) (SPS) as the topmost layer can be helpful in albumin and urea production. The aim of the study was to characterize the attachment, spreading, and function of primary rat hepatocytes cultured on PEM surfaces in which PEMs were used to produce defined cell-resistant and cell-adhesive properties, depending on the topmost surface and the type of cells used. This was extended to describe the formation of patterned cell cocultures using the LbL deposition technique for synthetic ionic polymers without the aid of adhesive proteins/ligands such as collagen and fibronectin.37 To create patterned cocultures on PEMs, we capitalized on the preferential attachment and

Recently, we reported an interesting dynamic self-assembly concept in the transitional behavior of droplet formation during the emulsification process from nanoscale emulsion droplets to microscale droplet aggregates, as depicted in Figure 9.34 In the inertial turbulent flow regime, the eddy diameter is less than the stable droplet diameter, and larger droplets are located outside the smaller eddies whereas in the viscous turbulent regime the smaller droplets are located inside the larger eddies. We speculate that as the viscosity is increased there is a shift in the mixing regime from inertial to viscous turbulent fluid flow and that the nanodroplets are caught inside the larger eddies, leading to the dynamic self-assembly of droplets in the viscous turbulent fluid flow regime, resulting in the formation of hollow microparticles of polymers instead of polymer nanospheres.

4. MOLECULAR INTERACTIONS OF THE BIOLOGICAL SYSTEMS 4.1. Cell−Substrate Interactions. Recently, Rubner et al. reported that they could attach multifunctional PEM “backpacks” to a small fraction of the membrane surface area of living immune system cells.35,36 This technique allowed the cell to perform its native functions because the polymer backpack does not completely occlude the cellular surface. This work presented a new way to design phagocytosis-resistant materials that may be useful in advanced vaccine therapies. Cell−substrate interactions at the interface are important to many biological phenomena. One of the major challenges is discerning the relative role of the chemical functional groups G


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Figure 7. Optical microscope and SEM images of PAH/(xGnP-SPS/PDAC)4 films transferred to a PEM-coated substrate via IPT. Illustration of the process used to form xGnP, subsequent film formation on PDMS, and transfer to a PEM-coated substrate. Reproduced with permission from ref 29.

proliferation of three types of mammalian cells: transformed 3T3 fibroblasts (3T3s), HeLa (transformed epithelial) cells, and primary hepatocytes.39 Postcell seeding and differences in cell attachment and spreading were observed, depending on the grooves and patterns on the PDMS surfaces. Using imaging techniques, we reported that changes in the surface topographical features alter the attachment and spreading of cells, suggesting a physical means of controlling the interaction between the cell and its environment. In addition, we reported that increasing the number of bilayers (deposition cycles) of PDAC/SPS films from 10 to 20, corresponding to a film thickness of 37.6 nm (40 nm) to 95.9 nm (100 nm), respectively, switches the films from a cytophilic to a cytophobic surface, as demonstrated in Figure 11.40 We demonstrated this effect with bone marrow mesenchymal stem cells (MSCs) and NIH3T3 fibroblasts. The thickness increases linearly as the number of bilayers increases, causing a shift to cytophobic behavior with a concomitant decrease in cell spreading and adhesion. A finite element analysis was implemented to help elucidate the observed trends in cell spreading. Cells can maintain a constant level of energy

spreading of primary hepatocytes on SPS as opposed to PDAC surfaces. In contrast, fibroblasts readily attached to both PDAC and SPS surfaces, and as a result, they were able to obtain patterned cocultures of fibroblast and primary hepatocytes on synthetic PEM surfaces. As a further development of our multilayer composite filmtransfer technique, in noncontact mode, we demonstrated that PEM films can be transferred from a stamp to the base substrate under aqueous conditions, as for the two surfaces in Figure 10.38 This new noncontact film-transfer mode approach allowed us to show an alternative method for creating a sandwiched 3-D cell coculture by transferring PEMs onto a charged “base” substrate under aqueous conditions. In this noncontact transfer mode, the base substrate and the stamp do not come into contact with each other during the multilayer transfer. Noncontact multilayer transfer can be useful for creating a 3-D cellular coculture with a permeable polymer layer sandwiched between two monolayers of cells. Regarding such specific cell−surface interactions at the interface, we found that PEM-coated PDMS surfaces with different topographies affect the attachment, spreading, and H


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Figure 8. Optical micrographs of polycation (PDAC) fractal growth and aggregations created by μCP on surfaces. (a) Dark-field image of PDAC ramified structures on a SPS surface. (b) Bright-field image of overdeveloped ramified structures on a glass surface. (c) Dark-field image of directed (to the right) fractal growth by directed polymer stamping. (d) Isolated fractal growth of polymer thin film aggregation. Reproduced with permission from ref 33.

hyaluronic acid/poly(L-lysine) (PA/PLL) films as a means of controlling the mechanical properties of thin LbL films and thus optimized cell adhesion.41 More related recent work on the design of PEM films for applications in biomaterials and tissue engineering and for fundamental biophysical studies has been reviewed by Gribova et al.42 4.2. Protein−Substrate Interactions. The fabrication of high-sensitivity, fast-response biosensors critically depends on the preserved activity of proteins transferred onto a substrate such as a bioelectronic interface. In biosensor work, we presented the first continuous electrochemical biosensor for the real-time rapid measurement of neuropathy target esterase (NTE or NEST) activity.25 The biosensor was fabricated by coimmobilizing NEST and tyrosinase on an electrode using the LbL deposition approach. Potential applications of the biosensor include detecting the presence of neuropathic agents that target NTE, screening industrial and agricultural OP compounds for NTE inhibition, studying the fundamental reaction kinetics of NTE, and investigating the effects of NTE mutations on its enzymatic properties. On the basis of the experimental observation, we developed a theoretical model for analyzing the bienzyme electrode containing NEST and tyrosinase.43 We also demonstrated a novel method based on LbL self-assembly to fabricate a renewable bioelectronic

Figure 9. Schematic illustration of the transitional behavior of droplet formation, single polymeric emulsion droplets in the inertial turbulent regime (top) where droplet size > eddy size, and multiple emulsion droplets in the viscous turbulent regime (bottom) where droplet size < eddy size. Smaller eddies break up larger polymer-containing droplets under dynamic conditions. When mixing is stopped, droplets are stabilized. Smaller emulsion droplets are caught in a larger eddy, dynamically self-assembling or coalescing inside the eddy and forming a multiple emulsion such as a droplet (W/O/W) when mixing stops. Reproduced with permission from ref 34.

consumption (energy homeostasis) during active probing and thus respond to increases in the film stiffness by adjusting their morphology, and the number of focal adhesions utilized and thus their mode of attachment to a substrate change. Recently, Schmidt et al. studied the incorporation of nanoparticles into I


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Figure 10. Fluorescent (confocal and conventional microscopy) images and DIC/phase contrast images of primary hepatocytes and fibroblast cultured in 3-D using the NAM multilayer transfer process. DIC/phase contrast images show both primary hepatocytes and fibroblasts, and the corresponding fluorescent images (above the DIC/phase contrast images) show only the stained primary hepatocytes. Fibroblasts can be seen on the bottom layer below the primary hepatocytes, as indicated by the arrows in the DIC/phase contrast images. Successful staining of the top layer of cells (i.e., primary hepatocytes) and no staining of the bottom layer of cells (i.e., fibroblasts) suggests that the (PDAC/SPS)80.5 multilayers were transferred during the NAM transfer process. Thick (PDAC/SPS)80.5 films prevented the diffusion of the staining dyes from reaching the fibroblast layer. Six different images corresponding to six different samples/replicates are shown, illustrating the NAM transfer. Reproduced with permission from ref 38.

Figure 11. Diagram showing multilayers composed of linearly growing strong polyelectrolytes. Linearly growing ultrathin polyelectrolyte multilayer (PEM) films of strong polyelectrolytes, poly(diallyldimethylammonium chloride) (PDAC), and sulfonated polystyrene, sodium salt (SPS) exhibit a gradual shift from cytophilic to cytophobic behavior, with increasing thickness for films of less than 100 nm The simulation results suggest that cells maintain a constant level of energy consumption (energy homeostasis) during active probing and thus respond to changes in the film stiffness as the film thickness increases by adjusting their morphology and the number of focal adhesions recruited and thereby their attachment to a substrate. Reproduced with permission from ref 40.

interface in which the enzyme and cofactor can be removed and replaced.44 Polycation poly(ethylenimine) (PEI) was used to couple the electron mediator, cofactor, and enzyme to a carboxylic acid-modified gold electrode in such a way that mediated electron transfer was achieved. Decreasing the pH of the solution led to the protonation of surface-bound carboxylate ions, thus disrupting the ionic bonds and releasing both the enzyme and the cofactor. Following the neutralization

step, fresh enzyme and cofactor could be bound, allowing the interface to be reconstituted. Novel nonoxidized conductive graphene decorated with precious metal nanoparticles along with polymer assembler has been tested for the first time in a glucose biosensor.45 In this work, nafion was used to solubilize metal-decorated graphite nanoplatelets, and a simple cast method using a large quantity of organic solvent was used to prepare the biosensors. The addition of precious metal J


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Figure 12. Fluorescent images demonstrating patterned siRNA delivery to HeLa cells with multilayer-mediated forward transfection (MFT) using (PAA/PEG)6.5 multilayer assembly, fluorescent dsRNA oligomers (100 pmol), and Lipofectamine 2000 (LF2k, 5 μg). Nanoparticles and HeLa cell patterns were transfected with (a) Alexa Fluor 555-labeled oligomers and (b) Fluorescein and Alexa Fluor 555-labeled oligomers (overlaid images). (Top) CLSM images of LF2k-fluorescent oligomer nanoparticles arrayed on the multilayer. (Middle and bottom) HeLa cell patterns transfected with fluorescent oligomers and their corresponding phase-contrast images acquired using CLSM (middle) and conventional fluorescence microscopy (bottom). The scale bar represents 500 μm. Reproduced with permission from ref 54.

surface-mediated release of DNA.51 They discovered that the LbL film growth proceeded in a stepwise and linear manner so that control over the loading of DNA in the LbL-deposited polymer film was possible. Degradable multilayer assemblies based on the sequential embedding of drugs during fabrication can incorporate any drug independently of the molecular weight of the drug. The fabrication of hydrogen bond (H bond)-based LbL multilayer films was initially reported by Rubner and co-workers.46 We presented a simple approach to the controlled delivery of proteins52 and also arabinofuranosylcytosine (Ara-C)53 from agarose gels, where the proteins are incorporated within the degradable LbL multilayer coatings formed over agarose. Carboxylic acid (−COOH)-based weak polyelectrolytes form H-bond interactions at low pH (e.g., pH

Molecular Self-Assembly: Smart Design of Surface and Interface via

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