Chinese Chemical Letters  2017, Vol. 28 Issue (4): 675-690   PDF    
Patterned surfaces for biological applications: A new platform using two dimensional structures as biomaterials
Wen-Dong Liu, Bai Yang     
State Key Laboratory of Supramolecular Structure and Materials, International Joint Research Laboratory of Nano-Micro Architecture Chemistry, College of Chemistry, Jilin University, Changchun 130012, China
Abstract: With the highly interdisciplinary of research and great development of microfabrication techniques, patterned surfaces have attracted great attention of researchers since they possess specific regularity and orderness of structures.In recent years, series of two dimensional patterned structures have been successfully fabricated, and widely used in anti-reflection, anti-fogging, self-cleaning, and sensing, etc.In the meantime, patterned structures have been gradually used in biologically relative fields such as biomaterials, aiming to deepen the perception of organism and understand the vital movements of human body.In this review, we provide a brief introduction on current status of techniques for two dimensional patterns fabrication, the applications of patterned surfaces in biologically related fields, and give out a prospective on the development of these patterned surfaces in the future.
Key words: Pattern     Microfabrication     Sensing     Adhesion     Biomolecule     Biomedical    
1. Introduction

With the repaid development of nanotechnology and deepening understanding of nature, many ordered two dimensional structures existing in nature have been discovered and various intriguing surface properties have been widely evaluated [1, 2]. Series of artificial patterned surfaces inspired from lotus leaves [3], gecko feet [4], insect compound eyes [5], spider silks [6-8], etc. have been successfully fabricated and used for self-cleaning, antifogging, anti-reflection, water-oil separation, and so on [9-14]. Highly ordered hierarchical structures from micro to nanoscale makes the artificial patterned surfaces well inherited and integrated unique functionalities of the natural biological surfaces, such as controllable suprawetting, anisotropic wetting, oriented adhesion, and other optical properties [15, 16]. And much work has been done to fabricate patterned surfaces which were constructed by micro-or nanoscale structure arrays with multiple functions under the help of new insights and fabrication rules provided by the patterned surface existing in natural [17-26]. Based on this background, researchers turned their attention to using the patterned surfaces as biomaterials for biological applications, such as biosensing, controllable bioadhesion and biopatterning, and tissue engineering in vitro, since the patterned surfaces can provide more reaction sites, assured anchor points and oriented directions, feature structures for adhesion than that of the nonpatterned surfaces [27-30]. Herein, we provide a review on basic fabrication strategies, biological applications of patterned surfaces, and give a prospective of the development of which in the future.

2. Microfabrication strategies to achieve patterned bio-surfaces

Up to date, there are two predominant methods to obtain patterned bio-functional surfaces. One is post modification of the patterned surfaces which were fabricated by microfabrication techniques (photolithography, colloidal lithography, nanoimprinting lithography, and electron-beam lithography), the other one is using biomolecules or bio-functional materials as inks to prepare the patterned surfaces directly via printing (micro-contact printing) or using atomic force microscopy tips (dip-pen nanolithography) [17, 29]. In this part, we present a brief description of microfabrication techniques related to the two predominant strategies for preparing patterned bio-functional surfaces.

2.1. Photolithography and colloidal lithography

Photolithography is still the most popular method to prepare patterns in microscale since decades ago [31-37]. Falconner et al. developed a facile approach which combined photolithographic and molecular-assembly to achieve functional micropatterns for applications in biosciences [38]. During this process, the photoresist pattern was transferred into objective biochemical patterns, and biological relevant matters adsorption proceeded with the photoresist lift-off spontaneously. The space between reactive patches were then rendered into non-fouling via post modification. The density of biotin molecules on the functional patterns can be quantitatively tailored and cells perform selective growth on the bio-functional patterns.Fig. 1a shows the basic process of fabricating the functional patterns. Firstly, the patterns on a photolithography mask were transferred into photoresist patterns via UV illumination. Secondly, PLL-g-PEG/PEG-X which possesses a portion of PEG side chains modified with bioligand was anchored onto the substrate randomly. Then the photoresist was washed off with no influence on the PLL-g-PEG/PEG-X anchoring onto the photoresist-unprotected areas. Finally the oxide background area were modified with non-functionalized PLL-g-PEG to make it resistance to the non-specific adsorption of protein, obtaining the functional patterned surfaces.Fig. 1b-f presents the confocal images of the obtained patterns with different biotin ligand surface densities, which could be easily varied by regulating the ratio of biotin-functionalized and non-functionalized PLL-gPEG at stage Ⅱ. The images demonstrate that the biotin surface density performs continuous decrease with the ratio of biotin functionalized PEG reducing (Fig. 1g). These results clearly proved that the functionalized patterns were successfully obtained while the grafting density finely regulated. Zhang et al. prepared nanoscale patterns on inorganic substrates using photolithography, the patterns were functionalized with hydroxyl group which provide binding sites to bind the DNA structures that obtained by the DNA origami method [39]. Wang et al. developed the photolithography method using phase transited lysozyme as the resist, these kind of materials can react with proteins via the functional group it possess to form protein patterns directly [40]. These new materials being used as resist further accelerate the development and practical applications of photolithography.

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Figure 1. Molecular-assembly patterning of protein with the help of photolithography. (a) The basic fabrication processs of the photolithography assisted molecular-assembly patterning; (b-f) confocal images of MAPL patterns with controlled biotin ligand surface densities ((b) 26.6; (c) 13.3; (d) 5.3; (e) 2.7; and (f) 0 pmol cm-2); (g) a linear correlation between the fluorescence intensity of streptavidin and the absolute biotin surface density. Adapted with permission from Ref. [38]. © 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Colloidal lithography is a relatively novel and favored way to obtain patterns in nanoscale, since the feature structure parameter of which can be easily modulated by varying the parameters of the colloidal crystal mask while the two dimensional hexagonal close packed structure of the mask provide a new kind of pattern [20, 21, 41, 42]. There are two pathways to prepare bio-functional surfaces via colloidal lithography: one is using the colloidal crystal as template to deposit molecules onto the colloid nanospheres non-protected area, then the patterns are obtained after removing the nanospheres. Singh et al. used binary colloidal crystals which consist small and large spheres as masks to prepare aminomodified chemical patterns with the help of plasma polymerization [43, 44]. During this process, the small spheres play an important role in allowing the diffusion of plasma to the substrate, and resulting in the formation of plasma-polymer film under the small spheres while the substrate directly contacting large spheres is still uncoated. Moreover, patterns with various feature heights can be obtained with the sample areas of which reach several cm2 by modulating the morphology of the binary colloidal crystal mask and the deposition time of plasma-polymer. Another one is using colloidal crystal as mask to etch the substrate through reactive ion etching. The patterns fabricated in this approach were on the substrate directly, avoiding the adhesion between the substrate and the post deposition matters effectively. Recently, our group developed an approach to prepare bio-functional polymer brush patterns based on colloidal lithography [45], the basic process of which is shown in Fig. 2a. Firstly, the atom-transfer radical polymerization (ATRP) initiator immobilized on the substrate were patterned by colloidal lithography, and then polymer brushes patterns were obtained via polymerizing the monomers through 'grafting from' method. Then bio-functional substrate can be easily obtained by grafting immune protein or extracellular proteins onto the polymer patterns (via covalently coupling reaction). Fig. 2b demonstrates the uniformly distribution of IgG with the signal intensity across the entire area was almost the same, and every protein dot could be seen clearly. These results prove that no denaturation of the biomolecules happen during the anchoring process. The obtained bio-functional surfaces pave a way to prepare biosensor for antibody-antigen interactions detection with high sensitivity and signal-to-noise ratio. Besides, other kind of patterns such as rings, and elliptical rings also obtained by colloidal lithography derived methods (Fig. 2c-f) [46]. Though colloidal lithography can provide an ease approach to prepare patterns in nanoscale, it has its own drawbacks. The pivotal issue in this technique is colloidal spheres, which greatly limit the symmetry of patterns, and the defects forming during the assembling process also cannot be avoided. In general, colloidal lithography has emerged as new force in nanofabrication techniques and provided a new train of thought for preparation of bio-functional patterns.

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Figure 2. Fabrication of functional patterns by colloidal lithography. (a) Schematic procedures of colloidal lithography; (b) fluorescent photograph of the IgG patterns after bonding FITC-anti-IgG, the scale bar is 2 μm. Adapted with permission from Ref. [45]. © 2012, Royal Society of Chemistry. (c-f) Nanoring patterns with different aspect ratio ((c) 1; (d) 1.5; (e) 2; (f) 2.5) prepared by colloidal lithography derived approaches. Adapted with permission from Ref. [46]. © 2013, American Chemical Society.

In order to meet the increasing demands of hierarchical patterns, researchers have tried much to combine photolithography and colloidal lithography together for hierarchical patterns preparation, since photolithography can provide a geometric pattern over a large area with micrometer scale in each unit, and the colloidal lithography can produce nanoscaled arrays in each unit of the photolithography patterns [45, 47, 48]. Hierarchical patterns can be achieved on the same substrate with structures both in micro and nanoscale. Based on this strategy, our group fabricated some hierarchical patterned surfaces possessing biological functions. Fig. 3a presents the basic process of this integrated technique. In brief, polymer brush film grafted on the substrate was firstly etched into nanocone arrays by colloidal lithography, using polystyrene or silica spheres as the mask. After then, a layer of photoresist was spin-coated on the surface and a photolithography mask were compressed onto the photoresist film. Experiencing the UV irradiation and development process, photoresist patterns were obtained on the surface of substrate with some polymer brush arrays immersing in photoresist while others exposing to air. Finally the hierarchical polymer brush patterns were achieved after a secondary etching process to erase the exposing one and washing off the photoresist. Such hierarchical polymer brush patterns can be further used as biological adhesion substrate or biosensors after specific modification. Fig. 2b-e shows the hierarchical protein and ssDNA patterns we obtained after reacting with fluorescent dye modified target protein and ssDNA. The fluorescent images clearly show that the microscale patterns (prepared by photolithography) are constructed by nanoarrays (fabricated through colloidal lithography), which finely inherited the specific patterns of photolithography mask and the orderness of colloidal crystals. Taking advantages of both photolithography and colloidal lithography (such as ease fabrication, diversity of the masks and cost-efficiency), the combined techniques will continue to play an important role in fabrication of bio-functional patterning surfaces.

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Figure 3. Hierarchical biomolecule patterns prepared based on the combination of photolithography and colloidal lithography. (a) Schematic fabrication procedures combined colloidal lithography and photolithography. Adapted with permission from Ref. [47] © 2015, American Chemical Society. (b-c) Fluorescent photograph of the multiscale IgG patterns after covalently bonding FITC-anti-IgG. Adapted with permission from Ref. [48] © 2013, American Chemical Society. (e-f) Fluorescence images of the hierarchical DNA patterns after binding FITC-conjugate complementary oligonucleotide. Adapted with permission from Ref. [47] © 2015, American Chemical Society.

2.2. Nanoimprinting lithography

With the further expansion of research, nanoimprinting lithography has become another method for preparing biofunctional patterning surfaces [49-51]. This microfabrication approach attracts great attention of researchers since it possesses its own advantages such as high throughput, cost efficiency, rapid fabricating process, and so on [52, 53]. Nanoimprinting lithography also needs a stamp, which is similar to photolithography and colloidal lithography, to transfer physical features onto specific substrate. In this case, the stamp is usually prepared on inorganic substrates (such as silicon and silica substrates) by traditional lithography approaches. The briefly process is illustrated in Fig. 4a, the rigid inorganic stamp were compressed onto the surface of flexible substrate (usually polymer film) and then heated till above the glass transition temperature of the polymer. The softened polymer will dewetting the stamp and form physical structures which are opposed to the stamp. Guo et al. prepared PMMA based nanofluidic channels by utilizing a mold with nanoscale protrusion to imprint the PMMA covered glass substrate [54]. The dimension of the nanochannel was finely modulated by varying the initial layer thickness of PMMA and the pattern configuration of the mold. Fig. 4b-d presents SEM images of the PMMA nanochannels with different dimensions, further proving the effectiveness of this method. After the PMMA nanochannels achieved, they were successfully used for DNA stretching. Yim et al. fabricated nanopatterned gratins on PDMS and PMMA covered substrate by nanoimprinting lithography method, and used these patterned polymer structures to culture bovine pulmonary artery smooth muscle cells [55]. The cells performed obvious elongation and alignment, both in cytoskeleton and nuclei. Compared with cells on non-patterned substrates, the one on the nanopatterned substrates performed a microtubule organizing centers polarization along with the direction of cells alignment in in vitro wound healing assay.

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Figure 4. Nanoimprinting lithography based preparation of patterned surfaces. (a)Schematics of the typical processing of nanoimprinting lithography; (b-d) SEM images of the obtained nanofluidic channels with various cross sections ((b) 300(width) × 500nm (height) channels; (c) 300 ×140 nm channels; (d) 75 ×120 nm channels). Adapted with permission from Ref. [54] © 2004, American Chemical Society.

Nanoimprinting lithography is an efficient method to prepare patterned substrates for sensing and bio-adhesion applications. In order to realize the pattern's fidelityespecially for subtle structures in large area, there are still some drawbacks need to be solved (e.g., size limit of patterns, target structure damage caused by demolding process, and fouling of the mold). Besides, with the introduction of microfluidic ideology, micro and nanofluidic devices can be successfully prepared for the fabrication of labon-a-chips by manipulating biomolecules.

2.3. Electron-beam lithography

Electron beam (e-beam) lithography, as a kind of maskless patterning strategy, has been used to fabricate patterns with high resolution (feature size 5-10 nm) by utilizing electron beam to scan all over the surface, and now widely applied in patterning biomolecules [56, 57]. It is also possible to fabricate patterns with nanoscale inter feature spacing by using this e-beam lithography method for heterogeneous patterns construction, since it can precisely control the spaces and locations of the patterns and obtain arbitrary protein nanopatterns with different shapes, sizes and curvatures [58].

Taking advantages of the E-beam-lithography, Maynard et al. have prepared some patterned biomolecule surfaces [59, 60]. Fig. 5a-e presents the typical process of preparing proteinpatterns. Firstly, functionalized the eight-arm poly-(ethylene glycol) (PEG) (with the reactive moieties for protein conjugation) were transferred onto the substrate. Then the PEG film was etched into patterns by e-beam, which could also induce the functionalized PEG cross-linking to the silicon substrate, and the unirradiated regions were further washed off. Then protein patterns with specific composition were easily achieved through the specific reaction between protein and the functional moieties as shown in Fig. 5f. Besides, with the help of programmable property of this method, different patterns with specific structure and feature parameters can be easily obtained (Fig. 5g).

In addition, e-beam lithography can also be used to construct structures with three-dimensional multiple biomolecule distribution for sophisticated applications. The first multicomponent and multilayer protein patterns fabricated by e-beam lithography were achieved by Maynard et al., the size of which could be finely regulated from nanometer to micrometer. Schlapak et al. prepared high-resolution protein patterns which can react with different targeting molecules by using e-beam lithography [61]. And they successfully achieved a miniaturized gray-scale image of "The Mona Lisa" by using this patterned substrate to react with different ligands. Moreover, Maynard et al. develop a trehalose glycopolymer based new resist which can protect proteins during e-beam exposure and direct-writing of multiple proteins processes. The pendant trehalose units in the polymer can effectively anchor to surfaces as negative resists, meanwhile providing stabilization to proteins during the vacuum and e-beam irradiation processes. Using this new kind resist, they successfully obtained arbitrary patterns of proteins such as enzymes, growth factors and immunoglobulins [62]. In addition, Omenetto et al. developed an all-water-based e-beam lithography using silk as a resist. The doping of silk solution enables a wide array of functional, biobased resists and the water based approach eliminates the need to use and dispose of noxious chemicals, which makes it an eco-friendly nanofabrication method with a chance to achieving a green cleanroom processing workflow [63]. Like the mask needed fabrication method, e-beam also has its own drawbacks, such as needing complicated equipment, small sample area, time-consuming, etc. But these can never stop its development, since the patterns obtained by this method have excellent ordering and the size of the structure can be easily modulated, suggesting that ebeam lithography will still be a mainstream microfabrication method in a long time.

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Figure 5. Electron-beam cross-linking of end-functionalized eight-arm PEG polymers for protein patterning. (a) The eight-arm PEGs on Si wafers were partially cross-linked to the substrate using e-beam lithography to achieve specific patterns. (b) Alexa Fluor 568 SAv was anchored to biotin-PEG patterns using biotin-SAv interaction. (c) BSA was grafted to maleimide-PEG patterns with the help of the free cysteine in the BSA. (d) Pyridoxal-5-phosphate modified myoglobin was linked to aminooxy-PEG patterns through a specific covalent binding. (e) Histidine-tagged calmodulin was immobilized to Ni2+-NTA-PEG patterns based on the nickel-histidine affinity interaction. (f) Fluorescence images demonstrating the obtained microscale patterns of two proteins (scale bar = 10 μm). Adapted with permission from Ref. [59] © 2009, American Chemical Society. (g) Different patterns (square, triangle, concentric square, and circle) fabricated with the help of e-beam lithography. Adapted with permission from Ref. [60] © 2008, American Chemical Society

2.4. Micro-contact printing

In order to meet the development of stamp microfabrication techniques, and the demands for cost reduction, preparing patterned surfaces using indirect pattern transfer techniques has become an alternative choice since they possess a relative high cost-efficiency and facile conduct process [64-66]. Micro-contact printing has become a popular technique and been widely used for functional patterned surfaces fabrication. The feature structure of patterns can reach submicrometer and nanometer scale due to the highly development of stamp fabrication techniques [67, 68].Fig. 6a shows the typical process of micro-contact printing. Firstly, stamps were prepared by colloidal lithography, e-beam lithography or transfer the patterns to a flexible substrate (for example PDMS) from a rigid one. Secondly, the stamps (or post modified stamps) were immersed into the ink (including the chemical matters for patterning), and then being compressed onto the substrate for a certain time. Finally, the patterned surfaces were obtained by removing the stamp with the ink materials anchoring onto the purpose substrate. Nam et al. prepared separated patterns with 2 μm lines width and ca. 400 μm of the space between lines. Based on such patterns, extracellular matrix protein patterns were successfully achieved which maintained the biological activities of the proteins, and were used as functional substrates for cell culture and pH sensitive surfaces [69]. Bernard et al. also prepared multiple protein patterns possessing two (Fig. 6b) and sixteen (Fig. 6c) kinds of specific proteins via printing the same substrate for several times with different stamps, different patterns and/or various inks [70].

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Figure 6. Patterned surfaces achieved by microcontact printed molecules onto a substrate. (a) The procedure of m-CP. Adapted with permission from Ref. [69] © 2012, The Korean BioChip Society and Springer-Verlag Berlin Heidelberg. (b) Fluorescence image of two different proteins have been subsequently printed onto the same glass substrate using different PDMS stamps. (c) Fluorescence photograph of 16 different proteins were patterned onto the polystyrene surface of a cell culture dish using a stamp inked by means of a microfluidic network. Adapted with permission from Ref. [70] © 2000 WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany.

As a facile, cost-efficiency method, micro-contact printing can realize the preparation of patterns with large area by utilizing the flexibility of stamps. Though this technique has many advantages, external forces in the fabrication process have great influence on the behavior of ink molecules which will further affect the surface properties of the obtained samples. Thus, it is still a challenge for researchers to eliminate the external influences and maintain the activities of the inks during the preparation of patterned biofunctional surfaces.

2.5. Dip-pen nanolithography (DPN)

As a popular patterning technology, DPN has been reported by Mirkin's group in 1999, and widely adopted today [71-74]. The main principle of DPN is as follows: since the tip is covered by 'ink', a liquid bridge will form between tip and substrate when two of which is getting closer. The molecule in the 'ink' will move to the substrate automatically caused by the physical/chemical absorption between the molecules and the substrate. Then the preparation of patterns with different structures can be realized by computer program [75-78]. Fig. 7a presents part of the two dimensional arrays with 55, 000 pen which is highly ordered for precisely patterning. Fig. 7b shows the patterns of rhodaminelabeled 1, 2-dioleoyl-sn-glycero-3-phosphocholine obtained by writing inks onto specific substrate, and the obtained pattern finely inherited the ordering of the pen arrays. By taking advantage of DPN, gold nanoparticles hybridized to DNA patterns (Fig. 7c), and protein patterned surfaces (Fig. 7d) were also achieved. As for the patterns prepared by specific molecules, the resolution of which can be controlled by scanning speed, chemical properties of the surface, temperature and humidity [79, 80]. Different materials can be used to fabricate patterned structures by using this DPN technology, such as conductive polymers, biomacromolecules, bacteria and so on [81-84].

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Figure 7. Dip-pen nanolithography approach for the preparation of functional patterns. (a) SEM image of part of a 55, 000-pen 2D array. (b) Fluorescence microscopy of 1 mol% rhodamine-labeled 1, 2-dioleoyl-sn-glycero-3-phosphocholine. (c) Dark-field light-scattering image of gold nanoparticles hybridized to immobilized DNA patterns created by passive 26-pen arrays. (d) Fluorescence images of protein patterns generated by DPN. Adapted with permission from Ref. [76] © 2007, American Chemical Society.

In summary, DPN, as a versatile direct-writing nanopatterning technique, can be used for not only protein patterns fabrication but also chemical templates for further study of bio-recognition processes. It can also be applied to fabricate patterns with the size of single biomolecule and multi-dimension, showing its potential in studying the interaction between single protein and cell. In spite of this, the practical application of DPN is severely limited since it is based on the absorption of protein solution on the tip, causing the precision of the pattern greatly influenced by many factors, such as the tip's width, relative humidity of the environment and intrinsic properties of the protein solution and so on.

3. Patterned surfaces for biological applications 3.1. Biosensing

Patterned surfaces which possess ordered structures have been introduced into the field of sensing, since their ordered two dimensional structures, which can provide more reactive sites, enhanced sensitivity and obvious visualization. Avariety of sensing platforms based on two dimensional patterned surfaces have been fabricated for protein, DNA, cell and bacteria sensing. In this part we will present a brief introduction of the research progress focused on the patterned surfaces based sensing.

3.1.1. Protein sensing

As an important component of organism, protein has played a specific role in maintaining daily activities [85-97]. Protein can perform incredible stereostructures since it does not have a predictable sequence and always perform multimerization and post-modification after the translation process. The structures of protein are also diverse and have great effect on the organism functions in daily lives. Thus, it is important to build a facile and sensitive platform for detection of the proteins that act as feature markers for specific functions [98-109]. Taking advantages of patterned surfaces, Zhang et al. fabricated sensitive protein sensors based on elevated silver nanohole arrays by reactive ion etching and vapor deposition [110]. The normal process is as follows: two dimensional colloidal crystals (PS microspheres) were firstly assembled onto the glass substrate, and the hexagonal-closepacked PS microsphere arrays were etched into a non-closepacked (ncp) state under the reactive ion etching treatment. Then, the ncp PS arrays were used as the masks for further thermal vapor deposition of silver. Finally the elevated silver nanohole arrays were achieved after removing the masks by adhesive tape and being treated with 1% HF (Fig. 8a). This elevated silver structure presents an enhanced sensitivity to refractive index due to the decrease in spatial overlap between the substrate and evanescent field (excited on the Ag nanohole film). And such noble metal based surfaces were further covalently grafted with human-IgG and reacted with with BSA, anti-rabbit IgG, and anti-human IgG for biosensing. The specific recognition between human IgG and antihuman IgG can cause a ca. 10 nm red shift of the transmission peak while the spectra shift of BSA and anti-rabbit IgG adsorption can be omitted. In addition, such sensing platform presents a linear response within the regulating concentration range and the detection sensitivity can reach 1 nm mL mg-1 (Fig. 8b). Besides, Ye et al. also prepared silver nanowell arrays through further deposition silver onto Ag nanohole arrays (Fig. 8c), and finely regulating the lattice constant could achieve the highest FH/FWHM value of 45.3 × 10-3 nm-1 and the highest FOM value of 55.2 RIU-1 [111]. The same as the Ag nanohole arrays, this Ag based nanowell can also be used for protein sensing with the detection resolution can reach 0.1 nm L nmol-1.

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Figure 8. Noble metal arraysbased biosensing platforms. (a) Crosssection SEM images and AFM measurements of Ag NAs; (b) linear calibration curves for the EANAs. The slope indicates the sensitivity. Adapted with permission from Ref. [110] © 2012, Royal Society of Chemistry. (c) Typical SEM image of Ag nanowell crystal. The inset is the corresponding cross-sectional image and the scale represent 200nm; (d) linear calibration curve for immunoassay. Adapted with permission from Ref. [111] © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Besides the work mentioned above, Lau et al. fabricated a multiplex immunoassay system by using e-beam lithography and direct writing antibodies on substrate [112]. The protein patterns constructed by anti-interleukin 6 and antitumor necrosis factor alpha in micro-and nanoscale were precisely modulated and successfully used for the detection of cytokines secreted from stimulated RAW 264.7 macrophages. Hu et al. prepared a poly [oligo(ethylene glycol)methacrylate-co-glycidyl methacrylate] (POEGMA-co-GMA) brush based supporting matrix for surface plasmon resonance imaging [113]. This platform can effectively load probe proteins in a high capacity (1.8 protein monolayers) with neglible non-specific protein adsorption, and it can be used for simultaneously multiplex sensing of β-fetoprotein, carcinoembryonic antigen, and hepatitis B surface antigen in human serum samples using one chip, while the detection limits can reach 50, 20, and 100ngmL-1. And Gaster et al. reported an autoassembly protein array for analyzing antibody cross-reactivity [109]. This protein array based sensor can conduct a rapid and high-density screening of antibody cross-reactivity with a high sensitivity to 50fmolL-1.

3.1.2. DNA detection

Besides the protein mentioned above, DNA is another kind of important macromolecules that exists in organisms. It has a long history which can trace back to the birth of life, carrying genetic information, and acting as the foundational materials for biological heredity. Life will present unexpected phenotype or subject to different diseases due to the mutation at specific sites of its backbone structure. Therefore it has become a very important problem for rapid DNA detection to evaluate the health status of life before the phenotypes emerging. Taking advantages of the feature double helix structure, DNA chains can exist various secondary structures, which endowed the DNA chains strong ability to recognize DNA, RNA, protein, and other molecules. And this provides opportunities for researchers to prepare DNA sensors based on patterned surfaces with a low detection limit, simplified approaches, less input and conduct in a rapid manner with high performance [114, 115].

Liu et al. reported a facile and cost-efficiency method to fabricate single-strand DNA (ssDNA) nanoncone arrays and hierarchical ssDNA patterns, which perform great potential in specific DNA sensing [47]. In this work, poly(2-hydroxyethyl methacrylate) (PHEMA) brushes were grafted onto the silicon substrate by using SI-ATRP method. The polymer brush film was further etched into patterns using reactive ion etching method and traditional photolithography. After covalently grafting ssDNA, ssDNA nanocone arrays (Fig. 9a) and hierarchical DNA patterns (Fig. 9c) were successfully obtained with the reactivity of ssDNA maintained. It is worth mentioning that these polymer brush mediated ssDNA patterns possess specific quasi-3D structure which is different with other flat systems. This structure can greatly enhance the specific surface area and raise the recognition efficiency of target DNA, which possesses a detection limit reaching 1.6 nmolL-1 to hybrid with complementary target DNA. Moreover, with the introduction of microfluidic ideology, they can achieve hierarchical-multiplex DNA patterns (Fig. 9b) which are promising platforms for rapid, visible, and multiplex DNA sensing.

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Figure 9. Polymer brush patterns mediated DNA sensing system. (a) Fluorescence image of the DNA nanocone arrays with the period of 620nm after binding the FITC-conjugate complementary oligonucleotide; (b) fluorescence image of hierarchical DNA patterns after binding FITC-conjugate complementary oligonucleotide. (c) The enlarged fluorescence photograph of the DNA pattern in image (b). [148_TD$DIF]Adapted with permission from Ref. [47] © 2015, American Chemical Society.

Besides, Zhao et al. fabricated a multiplex label-free DNA detection system which is based on the quantum-dot-tagged bioresponsive hydrogel suspension arrays [116]. DNA-responsive hydrogel microspheres which incorporated with quantum dots (QDs) were used as high quality encoded microcarriers. This system possessed high selectivity and sensitivity for label-free DNA detection with a relatively lower detection limit of 1 nmolL-1 than other platforms based on expensive approaches. And this work realized the detection of genetic variation and sequencing genes in a low cost, miniaturized, simple and real-time manner, which greatly accelerates the development of advanced sensors.

3.1.3. Cell isolating and sensing

Another important sensing application of patterned surfaces is specific cell detection [117-119]. Cells, as the building block for the organisms, have great effect on the functions and behaviors of organisms, and there possess various kinds of cells with specific functions to support their daily lives. Just as each corn has two sides, there also exist some bad cells which will cause detrimental diseases. For example, circulating tumor cells, a kind of cancer cells which break away from tumor or metastatic sites, circulating in peripheral systems as the original metastasis and providing facile assessment to all disease sites [120, 121]. Thus, it is of great importance to detect and analyze such kind of bad cells and provide helpful information for disease status evaluation. Based on this, series of efficient platforms for specific cells in patients' blood samples identification have been successfully fabricated with common efforts in chemistry, material science and bioengineering [122-128]. And patterned surfaces have become an alternative system to sense different cells in a facile, real-time, and visible manner.

Hsiao et al. prepared PEDOT (poly(3, 4-ethylenedioxythio-phene)) derivatives based rod arrays for the capture of circulating tumor cells with the rod sizes ranging from micrometer to nanometer [129]. In this work, the PEDOT derivative rod arrays were fabricated with the help of mask replica method which used silicon rod arrays as the initial templates. The obtained PEDOT derivative rod arrays were shown in Fig. 10a, the structure of which were highly repeated with excellent mechanical properties and arranged in square arrays that inherited the ordering of the mask. Taking advantages of the specific biochemical and topographic interactions between cells and substrates, this PEDOT based rod arrays perform a specific capture of MCF7 cells, meanwhile presenting a lower nonspecific adhesion to HeLa cells that used as negative controls (Fig. 10b). Moreover, this platform can perform a greater than 70% capture of MCF7 cells from healthy blood with the density various from 10 cell mL-1 to 1000 cellmL-1 which is efficient for clinical samples, laying the foundation for its practical applications.

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Figure 10. Specific cell sensing on patterned structures. (a) SEM images of PEDOT-based micro/nanorod array films; (b) cell-capture efficiencies from suspensions of breast(MCF), lung (A549, HCC827), cervical (HeLa), prostate (PC3), and brain (U87) cell lines; inset: two-color fluorescence image based on DiO membrane (green) and DAPI nuclear staining. Adapted with permission from Ref. [129] © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

In addition, Custódio et al. fabricated biomolecule based patterned surfaces by introducing light responsive o-nitrobenzyl caged biotin [130]. After the light activation, specific biotinylated antibodies were anchored onto the substrate, forming patterned biointerface. Specific cell phoenotypes were then successfully addressed onto the patterned surfaces by certain interaction between antibodies and cells, realizing the specific cells detection. Meng et al. prepared nanosisal-like self-cleaning TiO2 arrays which can efficiently detect circulating tumor cells from artificial whole blood samples with high viability by using the synergistic effect of specific molecular recognition and topological interaction [131]. All these reported works indicate the feasibility for the practical sensing application of patterned surfaces, and it is still crucial to further develop patterned surfaces based sensing platforms with high efficiency for practical trace agent detection.

3.2. Cell adhesion and patterning mediated by patterned surfaces

As is known to all, organisms are constructed by structure units which are orderly assembled from nanoscale to macroscale. And as a kind of component of lives, cells playa crucial role in realizing the specific functions of different organisms with the help of interaction between cells and the different structures they adhere to. Based on this background, more and more work has been done to study the adhesion behavior of cells incubated on substrates. And patterned surfaces with tunable feature structures and regularity have become alternative platforms for evaluating the interaction between cell and substrates [132-134]. The patterned surfaces provide clear structure properties (such as morphology, structure parameter, chemical and physical characters), and in vivo biological microenvironment can be easily mimicked in vitro via elaborating design of specific structures [135-140]. In this part, we will provide a brief introduction of the applications of patterned surfaces in cell adhesion, cell patterning and effecting cell fates.

3.2.1. Cell adhesion on patterns

In organisms, cells have many interactions with the microenvironment to maintain their activities and provide their functions. The two primary interactions are cell-cell and cell-substrate interactions. Unlike the cell-cell interaction, the interaction between cells and substrates are mainly affected by the physical and chemical properties that the substrate possesses [141, 142]. Due to the difference between the assemblies in organisms, cells will perform different adhesion behaviors, which will further express their relevant functions during the embryonic development, angiogenesis, and metabolism processes. Thus, utilizing patterned surfaces as the substrates for cell adhesion in vitro will help us better understand the biological behavior and the state of cells in vivo. Meanwhile, it will also provide a biological guidance for damage repair and transplantation materials design.

Li et al. developed the patterned extracellular protein surfaces by covalently grafting protein onto the polymer brush patterns and incubated with cells to study the adhesion behavior in vitro [45]. In this work, the polymer brush film grafted on the substrate was firstly etched into nanocone arrays by colloidal lithography, using the assembled colloidal microspheres as mask. Then microscale stripe polymer patterns constructed by nanocone arrays were obtained via further etching the substrate using the photoresist pattern as mask (Fig. 11a-b). After modified with reactive groups on the side chains of polymer brush, extracellular protein (fibronectin) were grafted onto the polymer chains to form patterns. Using this protein patterns as the substrates for MC3T3-E1 osteoblast cell incubation, the cells performed a specific adhesion to the protein regions (Fig. 11c-e). In addition, cells adhere to the stripe patterns present a directional elongation spreading along the fibronectin patterns and exhibit spindle profiles. The filopodia and lamellipodia formed on the living cells are preferentially settled on the fibronectin nanocones, proving that the feature structures play an important role in promoting the cell adhesion and spread by providing more anchor site. Cell adhesion and cellular organization have also been studied as a function of micrometer-scale patterns. Liu et al. fabricated elliptical polymer brush ring arrays to mediate protein patterning with the aim of studying the adhesion behavior of cells cultured on asymmetric structures [46]. The polymer brush patterns were prepared by polymerizing the monomer on the patterned initiator fabricated by colloidal assisted de-wetting and reactive ion etching. The aspect ratio of the ring arrays was well modulated from 1 to 2.5 via regulating the micromolding process. Then fibronectin was anchored onto the polymer brush patterns to study the cell adhesion behaviors on holomorphic and unholomorphic symmetry substrates. It can be seen that cells adhere well on the protein patterns and maintain good biological activity, while the adhesion behaviors are different. On the ring arrays, the cells have disclike morphology with disordered spread and the actin cytockeleton of which presents a flexible state with clew-like morphology (Fig. 11f). But on the elliptical structured substrate, the cells are elongated with the cytoskeleton showing a rigid state and distributing in a polarized orientation (Fig. 11g), suggesting, the structures of the substrate can greatly influence the cell adhesion behavior. Since the ring arrays cannot provide the polarized induction, while the elliptical structures possessing different amounts of protein anchor sites, resulting in a polarized spread of cell and promoting the orientation of skeleton. These further proved that different patterns of the extracellular matrix protein can regulate cell adhesion behavior and organization of cytoskeleton in vitro.

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Figure 11. Patterned surfaces induced cell adhesion. (a) The photograph of the stripes of the polymer brush patterns, the scale bar is 100 μm. (b) 3D AFM images of the polymer brush patterns, z scale is 100 nm and sizes are 10 μm × 10 μm. (c) The MC3T3-E1 osteoblasts adhere on the complex fibronectin patterns, the scale bar is 100 μm. (d-e) The SEM images of the cells on the fibronectin patterns, the scale bars are 10 μm and 1 μm respectively. Adapted with permission from Ref. [45] © 2012, Royal Society of Chemistry. (f-g) Confocal fluorescent microscopy images of the cell cultured on the ring (f) and elliptical ring (g) patterns: blue, nucleus; red, actin cytoskeleton; green, vinculin. Adapted with permission from Ref. [46] © 2013, American Chemical Society.

Besides, Meng et al. incubated cells on planar substrates with patterned ligands, which perform greatly effects on the spatial organization of cells and the directional outgrowth of neurons interacting with the surfaces of astrocyte cell later [143]. Bae et al. prepared multiscale hierarchical structures to control the cell structure and function, single and multicellular morphology and orientation, and they found out that the structures and orientations of fibroblast cells were greatly influenced by nanotopography rather than microtopography [144]. Subramani et al. used gold nanoparticle based patterns for cell culture to study the cell growth and adhesion on charged and uncharged surfaces [145]. They found that protein resistance patterns demonstrate an effective communication between the surface and the cells. Other work was also done to control the focal adhesion [146, 147], single cell adhesion [148], polarization [149], orientation [150], cell migration [151-153], and cell-substrate interaction [154] based on patterned surfaces, providing significant results for people to understand the relationship between cell and substrates in vitro.

3.2.2. Cell patterning induced by feature patterns

Since tissue function is greatly dependent on the proper distribution of different types of cells, it is of great importance to build platforms with finely controlled structures for cell distributions regulation in vitro. In recent years, much efficient work has been done to pattern and align different types of cells with the highly development of microfabrication techniques, and patterned surfaces have played an important role in finely controlling the cellular activities for tissue regeneration [155-159].

Li et al. prepared cell patterns using multiscale patterned surfaces [48]. The cell adhesion and patterning behavior were mediated by the extracellular protein pattern, which is prepared by covalently grafting protein onto the multiscale polymer brush patterns. Fig. 12a-d presents the mouse MC3T3-E1 osteoblast cell patterns they obtained, indicating that the multiscale patterns were ideal substrates to promote cell adhesion and patterning. With the help of the microstripe patterns, cell's adhesion and elongation can be controlled simultaneously (Fig. 12a-b). Cells maintained their biological activities and the actin of which performed an organized fashion in the region of FN. Besides, single cell pattern can be obtained by regulating the diameter of the disc patterns near to 20 μm (Fig. 12c-d). Seo et al. immobilized protein onto the chemical patterns (fabricated by micro-contact printing) to get protein patterns, and incubated with cell on which, forming cell patterns [160]. Patterns with specific type of cells can be easily achieved by specific aptamer-cell interaction, providing an alternative platform for simultaneously cell sensing. Li et al. exploited cell patterns by using UV-crosslinkable chitosan gel as base material to encapsulate live cells and then being patterned by photolithography method [161]. The obtained cell pattern perfectly replicated the structure of photomask and the cells in the chitosan gel maintained high cell viability of 96% (Fig. 12e-f). Such gel encapsulated cell patterns provide a new strategy to prepare multiple-types of cell in gel with defined size and dimensions, which can be used as building blocks for co-culture cell arrays and regenerative tissue units with specific physiological functions construction.

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Figure 12. Patterned surface mediated cell patterning. (a-d) Cell adhesion on the FN patterns. (a, c) Optical images of mouse MC3T3-E1 osteblasts after 3 h culture, (b, d) fluorescent mages presenting F-actin in the cytoskeleton. Adapted with permission from Ref. [48] © 2013, American Chemical Society. (e-f) Fluorescence images of patterned NIH/3T3 cells in the N-MAC microgels with concentric rings. Adapted with permission from Ref. [161] © 2015 Published by Elsevier Ltd. All rights reserved.

In addition, patterned biomaterials have been widely used in gene, drug delivery and tissue engineering, since they can provide us the opportunity to control the arrangement and location of chemical and biological matters which can further modulate activities and behaviors of cells. Finely controlled cell patterns show great promise in fundamental biological study and practical application as commercial product in the future.

3.2.3. Regulating cell fate

Another kind of application for patterned surfaces on cell level is to determine the fate of cells in vitro [132, 162]. Cells in vivo are not only affected by chemical factors but also the physical factors of the assemblies existing in the microenvironment from nanoscale to microscale. Patterned surfaces possess near-perfect artificial structures that are similar to the assemblies in vivo, and the feature parameter of which can be finely modulated to mimic the physical factors acting on the cells. Thus, patterned surfaces have been widely used in regulating cell fate, introducing neuronal growth and osteogenesis [163-169].

Gong et al. fabricated dynamically tunable polymer micro-well arrays, and successfully directed the differentiation of mesenchymal stem cells into osteogenesis [170]. In this work, the authors prepared various micro-well arrays with tringle-, square-, hexagon-and round shapes via thermal lithography (Fig. 13a-d), and the polymer they used is six-arm poly (ethylene glycol)-poly(ε-caprolactone), which has excellent thermal activated shape memory function. The morphology and the mechanical force caused by these thermal activated polymer patterns show significant performance in modulating the formation of cytoskeleton and the tension of cells, comparing to the static substrates in vitro (Fig. 13e). Cellular and molecular analyses proved that the cells present disparately differentiation along adipogensis and osteogensis under the control of the patterned surfaces. Moreover, these patterned substrates can also promote the differentiation of mesenchymal stem cells into osteoblast to repair bone defect by being implanted in vivo. Zhao et al. prepared ordered quadrate convex patterns which greatly stimulated cell adhesion, spreading and proliferation, and inducing the osteogenic differentiation of bMSCs [171]. Tien et al. developed patterned silk film scaffolds which can induce the formation of aligned lamellar bone tissue by culturing with MSCs [172]. Kim et al. prepared nanopillar arrays with different density via capillary force lithography, and found that nanotopographical density have a great influence on modulating the behaviors of human osteoblast-like cells, and such kind of structure can exhibit higher bone mineralization than the plat substrate [173].

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Figure 13. Polymer micro-well arrays directed the differentiation of mesenchymal stem cell into osteogenesis. (a-d) SEM images of different topographic microwells ((a) tringle; (b) square; (c) hexagon; (d) round); (e) confocal laser scanning microscope images of immunostained cellular components (merged) of the rBMSCs, in which rhodaminephalloidin labeled F-actin (red) and DAPI stained nuclei (blue) (scale bar: 20 μm).Adapted with permission from Ref. [170] © 2015, Royal Society of Chemistry.

In addition to inducing the osteogenesis, improving the differentiation and growth of neuronal structure is another important application of patterned surfaces. Marino et al. fabricated aligned submicrometric ridges and successfully improved the neuronal outgrowth by using such kind of structures as substrate [174]. Polymer based ridges with feature structure parameters were prepared by direct laser writing. And then collagen was covered on the polymer structures to increase cell adhesion. Finally, PC12 cell line derived from rat adrenal pheochromocytoma and SH-SY5Y human neuroblastoma derived cell line were used as model for neuronal outgrowth and differentiation toward neurons in vitro, respectively. The authors found that the rat PC12 neuron-like cell and human SH-SY5Y derived neurons perform significant differentiation on the patterned surfaces with the feature parameter shown in Fig. 14a-d. The cells adhere onto the ridges possess strongly aligned and significantly longer neurites than the one incubated on flat substrate, and the neurites showed good living condition with the axon exerting forces which is strong enough to bend the ridges. Limongi et al. successfully triggered the development of three dimensional neuronal networks using patterned micropillar arrays (with nanoscale patterns on the sidewall) that fabricated by lithographic and etching techniques [175]. Using the pillar arrays for neurites incubation, the neurites presented fat adhesion onto the patterned pillar sidewalls and subsequently showed a suspended growth and adhesion between pillars, forming three dimensional networks which is greatly different with the neurons growing on the bottom surface of smooth pillar arrays (Fig. 14e-j). Moreover, the neurons perform an enhanced survival rate and the networks possess physiological excitability compared to the standard cultures. This work solves a big problem in neuroscience for generation of three dimensional networks of primary neurons in a certain extent, and also indicates the importance of using nanostructured surfaces for direct three dimensional neuronal growth and design of biomaterials for neuronal regeneration.

Besides the works mentioned above, patterned surfaces have also been used as the cell culture substrates to control the division, differentiation, proliferation, function, responses, and carbohydrate expression of cells [176-182]. And all of these cell behaviors are greatly related to the cell-substrate interaction, which is deeply dependent on the morphologies and the feature structure parameters of the patterns. Thus, patterned surfaces can be further applied in controlling cell fates for further study how external factors affect the cell behavior, and provide theoretical guidance for researcher to understand specific cell behaviors in vivo.

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Figure 14. Patterned structures improved the growth of neuronal structure. (a-d) SEM images and 3D rendering of a z-stack confocal acquisition of PC12 (a-b) and SH-SY5Y cells(c-d). Adapted with permission from Ref. [174] © 2013, American Chemical Society. (e-j) SEM images of 3 DIV hippocampal neurons drop-plated on superhydrophobic nanostructured (e-g) and smooth (h-j) pillared substrates. Scale bars: 10 μm (e, h), 5 μm (f, g, i), and 3 μm (j). Adapted with permission from Ref. [175] © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

3.3. Biomedical applications

Besides sensing, bio-adhesion and tissue engineering applications, patterned surfaces with two dimensional structures have also been used in biomedical fields such as drug delivery, biomedical engineering and so on [183-185].

Chen et al. reported a simple technique for drying immune therapeutics with targeting delivery of vaccines to skin through dip-coating immune agents onto densely packed, two dimensional short microprojection arrays [186]. In their system, the strong capillary was mitigated and the coating length on the projections could be finely controlled by increasing the viscosity of the coating solution. The coating on the microprojection arrays is robust, with the intactness remained during the insertion process. Meanwhile, this drug delivery platform shows a rapid release process within the desired skin strata with approximately 80% of the immune agent delivered to the target position within 2 min. Moreover, this two dimensional projection arrays mediated drug delivery is efficient for various molecules, such as OVA protein vaccine, DNA, and fluorescent dyes, endowing it great potential for practical applications in large vaccination campaigns. Chen et al. used diamond nanoneedle arrays as media for fast and powerful intracellular delivery [187]. The nanoneedle also can deliver probe and anticancer drug molecules to various cells, especially for direct nucleus delivery of luminescent probe molecules. Besides, DeMuth et al. successfully fabricated silk/PAA composite microneedles for programmable vaccine release and enhanced immunogenicity in transcutaneous immunization [188]. When the microneedle patches to skin, PAA dissolved and released the protein subunit vaccine bolus, meanwhile, forming persistent cutaneous silk implants to mediate the sustained low-level delivery of vaccine over time. The release kinetics of this microneedle mediated system is exceeded 10 folds of increasing in specific immune responses than that of traditional parenteral needle. Rasekh et al. successfully prepared two dimensional polycaprolactone and its composites based topographic structures with the help of electrohydrodynamic print-patterning and solvent evaporation techniques [189]. The feature structure of patterns (such as porosity) can be easily modulated by computer, and bioactive structures can be finely regulated via the deposition of bioactive molecules which offers great promise in biomedical engineering.

3.4. Other biological applications

With the deepening research of disciplinary, patterned surfaces have also been applied in other aspects. Liu et al. fabricated a bioinspired polyethylene terephthalate nanocone arrays with high aspect ratio (Fig. 15a) [190]. This polymer-based nanocone arrays possess anti-bioadhesion property, the cells cultured on which perform an inhibited adhesion behavior. Cells cultured on the nanocone arrays are mostly circle-like or short rod-like shape but not highly spread morphology on the flat substrate. And the cytoskeleton performs a disordered aggregating state, which directly reflects the suppression of cell adhesion (Fig. 15b-c). This kind of patterned surface has great potential to be used as antibioadhesion surfaces. Luz et al. achieved the spatial control of biomineralization by using patterned surfaces to incubate cells, and providing an alternative method for preparing patterned medical membranes with distinct properties and bioactive pattern for tissue regeneration [191]. You et al. prepared microwell patterned surfaces which can be used for primary hepatocytes cultivation [192]. The heparin hydrogel and other polymer based microwell patterns were fabricated with the help of micromolding and microcontact printing techniques, and then the floor of the microwell was modified with collagen I to promote cell adhesion. After incubating cells on the microwell arrays with different compositions, all-heparin gel microwells perform the most conducive to hepatic phenotype maintenance with the stronger E-cadherin expressed and localized at cell-cell junction in hepatocytes (Fig. 15d-f). Besides, fibroblasts could also be cultured with hepatocytes to form co-cultures system, which can cause about 3.5 folds of enhancement in producing albumin than monocultures. This kind of pattern based cell culture platform will effectively improve the microenvironment niche for hepatocyte maintenance and liver-specific differentiation of stem cells. Sakimoto et al. took silicon nanowire arrays for bacteria culture, realizing the self-assembly of bacteria by regulating the ion concentration and pressure, and investigating the physical interaction between bacteria and nanostructures [193]. Taking advantages of the predictive power obtained from the silicon nanowire induced bacteria assembly, researchers are able to analysis and modulate the subtle interplay of thermodynamic and driving forces to modulate colloidal interaction. As mentioned above, the biological application fields of patterned surfaces can be further broadened and play an important role in daily life.

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Figure 15. Anti-bioadhesion and cell co-culture under the help of patterned surfaces. (a) Tilt view SEM image of the PET nanocone arrays with an AR of 6; (b-c) confocal fluorescent microscopy images of the cell cultured on the PET nanocone arrays: blue—the nucleus; red—the actin cytoskeleton. Adapted with permission from Ref. [190] © 2014, Royal Society of Chemistry. (d) Primary rat hepatocytes cultured on Heparin gel microwells on the glass surface for 5 days; (e-f) intracellular albumin and expression of E-cadherin in hepatocytes cultured on heparin gel microwell on pure glass. Green fluorescence was intracellular albumin and blue fluorescence was DAPI staining of nuclei. Scale bar = 50 μm. Adapted with permission from Ref. [192] © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

4. Conclusions and perspectives

In this review, we provide a brief introduction of basic techniques for patterned surfaces fabrication, and applications of two-dimensional patterns in bio-sensing, bio-adhesion, biomedical and so on. The platforms based on such patterned surfaces have provided a new train of thought for exploring the feature properties and questions faced in ordered structures for practical applications. Although various techniques have been developed to prepare patterned surfaces and some of which have already been used in practical applications. There still exists some challenges for researchers to overcome in the near future, which mainly concentrate in two aspects: techniques and practical applications. Firstly, a simple, fast and cost-efficiency fabrication process is still needed to prepare patterns which are constructed by ordered nanoscale structures with high resolution in large area. The existing techniques always need high equipment consumption, and complex fabrication process. Meanwhile, exploring real three dimensional fabrication technique is in urgent need, since mimicking the microenvironment of cells by real three dimensional struture will help us understand the relationship between physical signals and the behaviors of cells (differentiation, proliferation or apoptosis), providing useful theoretical guidance for practical clinical research. Secondly, the biological applications of patterned surfaces need to be deeply investigated and expanded. Much more specific structures are required to enhance the detection sensitivity and specificity of pattern based biosensors, aiming at providing more accurate information in early diagnosis of diseases. Furthermore, finely designed artificial structures which mimick the assembly structures in organisms are still needed for in-depth study on cell-substrate interactions. And chemical, physical, mechanical factors should be integrated with the patterned structures to perfectly mimic the in vivo environment, and provide data supporting for better understanding of the life activities in nature. In general, patterned surfaces have shown a great important role for biological applications, since they can make certain of the relationship between humans and their compositions. New patterned structures will be constantly developed by cooperating researchers in chemistry, physics, biology, engineering and clinical.

Acknowledgments

This work was financially supported by the National Basic Research Program of China (973 program, No.2012CB933800), and the National Natural Science Foundation of China (NSFC, No.91123031).

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