Simple SERS substrates: powerful, portable, and full of potential.

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PERSPECTIVE

Cite this: Phys. Chem. Chem. Phys., 2014, 16, 2224

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Simple SERS substrates: powerful, portable, and full of potential Jordan F. Betz,ab Wei W. Yu,ab Yi Cheng,bc Ian M. Whiteab and Gary W. Rubloff*bc Surface enhanced Raman spectroscopy (SERS) is a powerful spectroscopic technique capable of detecting trace amounts of chemicals and identifying them based on their unique vibrational characteristics. While there are many complex methods for fabricating SERS substrates, there has been a recent shift towards the development of simple, low cost fabrication methods that can be performed in most labs or even in the field. The potential of SERS for widespread use will likely be realized only with development of cheaper, simpler methods. In this Perspective article we briefly review several of the more popular

Received 21st August 2013, Accepted 9th December 2013

methods for SERS substrate fabrication, discuss the characteristics of simple SERS substrates, and examine

DOI: 10.1039/c3cp53560f

directions for simple SERS substrates, focusing on highly SERS active three-dimensional nanostructures

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fabricated by inkjet and screen printing and galvanic displacement for portable SERS analysis – an area that we believe has exciting potential for future research and commercialization.

several methods for producing simple SERS substrates. We highlight potential applications and future

Introduction The successful detection of an analyte by surface enhanced Raman spectroscopy (SERS) is influenced by many factors.

a

Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA b Institute for Systems Research, University of Maryland, College Park, MD, USA. E-mail: rubloff@umd.edu; Fax: +1 301-314-9920; Tel: +1 301-405-3011 c Department of Materials Science and Engineering, University of Maryland, College Park, MD, USA

Jordan F. Betz is a Robert W. Deutsch Graduate Research Fellow and PhD candidate in the Fischell Department of Bioengineering and the Institute for Systems Research at the University of Maryland. His dissertation research in Dr Gary Rubloff’s Nano-Bio Systems Laboratory is centered on labelfree methods to detect intercellular signaling phenomena using microand nanofabricated systems. Prior to graduate school, he worked for a Jordan F. Betz medical biotechnology company, developing non-invasive molecular diagnostic tests. In addition to label-free detection of biomolecules, Jordan’s research interests include biofabrication, protein engineering, and metabolic engineering.

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Arguably the most important of these factors is the SERS substrate, a metal surface that has nanoscale features. The type of metal and the nanoscale features of the substrate largely determine the overall enhancement of Raman scattering. For a newcomer to the SERS field, or to a researcher looking to harness the power of this label-free vibrational spectroscopic technique, the number of SERS substrate fabrication methods can be overwhelming. Many of these substrates are air sensitive (especially those made from Ag) or otherwise have a limited shelf life, need highly specialized fabrication equipment, or require expertise in nanoparticle synthesis and handling that

Wei W. Yu

Wei W. Yu is a postdoctoral research associate in the Fischell Department of Bioengineering at the University of Maryland, College Park. His research areas of interest are in paper analytical devices, surface enhanced Raman spectroscopy, synthesis of nanoparticles and their applications in bioengineering. Wei holds a MS from the University of Southern Mississippi and a BS from the University of the South Pacific.

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may put SERS beyond the reach of all but research labs. These barriers to adoption of SERS for otherwise routine chemical analyses create the opportunity for a new group of substrate fabrication methods that are simple and accessible to most scientists and technicians. Another driving force behind the push towards simple SERS substrates is the movement towards portable analytical instruments and point-of-sampling analysis. Handheld and portable Raman spectrometers have been improving in quality and decreasing in cost thanks to advances in microfabrication and optics. The ability to perform SERS in the field for applications such as forensics, food safety, environmental protection, standoff detection and defense could help reduce the cost and time delays associated with a central lab model common to regulatory and accreditation agencies, as well as open new avenues for analysis of labile samples that would

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decompose or otherwise change between the point of sampling and the laboratory in which they are analyzed. Thus there is not only a need for simple methods to fabricate SERS substrates, but also an opportunity to develop new methods that would expand the community of researchers and scientists who use SERS. In this article, we first review the more popular methods of SERS substrate fabrication with an eye towards simplicity and portability. We then outline criteria we have identified that make for simple SERS substrates. Finally we focus on inkjet and screen printing and galvanic displacement as SERS substrate fabrication methods that have potential individually and synergistically as simple, inexpensive methods that are readily integrated with portable SERS analysis methods. A brief SERS primer

Yi Cheng received his BS in Applied Physics from Anhui University (China) in 2002. He received his PhD in Physics from Florida State University under the supervision of Prof. Peng Xiong in 2009. He is currently a Robert W. Deutsch Postdoctoral Fellow at the Institute for Systems Research at University of Maryland. His research interests include biosensing with low-dimensional nanomaterials, biofabrication with stimuliYi Cheng responsive biopolymers, biomolecule detection with surface-enhanced Raman spectroscopy, and building bioMEMS devices for bacterial signaling studies.

The SERS phenomenon was first observed in 1974 by Fleischmann et al.,1 who reported that the Raman signal of pyridine was greatly enhanced at the surface of an electrochemically roughened silver electrode. Three years later, Jeanmaire and Van Duyne2 and Albrecht and Creighton3 were the first groups to propose that the electrochemically roughened surfaces contributed to an increase in the Raman cross-section of the molecule, rather than simply an increase in the amount of surface area for the pyridine to adsorb. Moskovits4 attributed the increase in Raman cross-section to the excitation of surface plasmons on the roughened electrode surface. For a more detailed and comprehensive review of the SERS phenomenon, we direct the reader to excellent reviews by Moskovits,5 Otto et al.,6 and Stiles et al.7 Another major milestone in the SERS field was reports of single-molecule detection by Kneipp et al.8 and Nie and Emory9 in 1997. The high level of enhancement and the possibility of single-molecule sensitivity of many analytes, as well as the possibility of multiplexed analysis10,11 brought renewed interest to the

Ian M. White received his PhD in electrical engineering from Stanford University in 2002, where his research was conducted under the umbrella of the Next Generation Internet Initiative. He then worked as a Member of Technical Staff at Sprint’s Advanced Technology Laboratories. In 2005, Dr White shifted his research to biosensors upon receiving an appointment as a Life Sciences Postdoctoral Ian M. White Fellow at the University of Missouri. In 2008, Dr White received an appointment as an Assistant Professor in the Fischell Department of Bioengineering at the University of Maryland. Currently, his research group investigates the integration of optical sensing technologies into analytical systems.

Gary W. Rubloff received his PhD in physics from the University of Chicago in 1971. After a postdoc in physics at Brown University, he joined IBM Research in Yorktown Heights in 1973 where he did fundamental surface science, electronic materials and processing science, silicon technology and manufacturing research, as both researcher and manager. He has been Professor in Materials Science and Engineering and the Gary W. Rubloff Institute for Systems Research (ISR) at the University of Maryland since 1996, serving previously as ISR Director, and currently as founding Director of the Maryland NanoCenter, Minta Martin Professor of Engineering, and Director of Nanostructures for Electrical Energy Storage, a DOE Energy Frontier Research Center.


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SERS field. For the most part, single-molecule level SERS has been limited to resonant detection of fluorescent dyes such as crystal violet8 and Rhodamine-6G,9 although there are reports of single-molecule level detection of biologically relevant compounds such as adenine,12 short peptides,13 and alkaline phosphatase.14 For more about single-molecule SERS, we refer the reader to articles by Le Ru et al.,15 Kneipp et al.,16 Otto,17 and Qian and Nie.18 More recently, SERS research has greatly increased in diversity of applications, branching out into explosives detection,19–24 food safety and security,25–34 and live cell imaging and bioanalysis,27,35–37 just to name a few of the many exciting areas of research. SERS is being combined with other advanced techniques such as in vivo imaging38–42 and microfluidics29,43–50 to provide researchers with more flexible and powerful analytical tools. Advances in portable spectrometers, diode lasers, and even collection optics51 are making portable, on-site Raman detection and analysis a reality, which will certainly open up a wide variety of new avenues for research. However, a major factor in the successful employment of SERS detection is the SERS substrate, the nanoscopic structures that greatly enhance Raman scattering.

SERS substrates The current understanding of the SERS phenomenon holds that the laser light used in the detection, when properly matched to the nanoscale geometry and material that define the SERS substrate, excites localized surface plasmons on the metal.5 This creates a strong, localized electromagnetic field, which greatly enhances Raman scattering of molecules within a few nm of the substrate surface.52,53 There are additional reports of a chemical charge transfer mechanism6,54 that contribute to the overall SERS effect. An in-depth review of the SERS mechanism is beyond the scope of this Perspective, and can be found elsewhere.6,55 Since the SERS substrate material and geometry56–58 play such key roles in the surface enhancement phenomenon, a great deal of research effort has been devoted to the development and characterization of SERS substrates.59,60 We will now briefly review the major categories of SERS substrates and their associated manufacturing methods. This is not intended to be an exhaustive and comprehensive list, but instead a brief overview of the more popular and successful methods of substrate fabrication. Electrochemically roughened electrodes Since the first description of the SERS phenomenon on an electrochemically roughened electrode, many papers have employed this method to fabricate SERS substrates. This method has fallen out of favor due to the simplicity and better performance of other SERS substrates. Making an electrochemically roughened electrode is relatively straightforward, and requires only an electrode, a power source, a signal generator to control the power source, and a solution in which to roughen the electrode. Each of the components contributes to the overall nanoscale roughness and features of the electrodes, and


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several methods for electrochemically roughening an Au or Ag surface to use as a SERS substrate exist in the literature.64,65 An electrode, once electrochemically roughened, is easy to use as a SERS substrate—one simply deposits the solution to be analyzed on the electrode or immerses the electrode in the solution for a given amount of time, and then allows the electrode to dry. Since SERS is such a highly distance-dependent phenomenon, this has the effect of concentrating the analyte molecules at the nanostructured surface of the electrode, resulting in a higher overall SERS signal than performing the analysis through a volume of liquid on the electrode surface. The surface roughness and subsequent SERS enhancement depend on the oxidation– reduction cycle rate and number.64 Depending on the roughening procedure used, electrodes can have highly variable surface roughness which results in non-uniform enhancement across the surface of the electrode.66 Colloidal nanoparticles Arguably the most popular substrate fabrication method, colloidal nanoparticles have been in use as SERS substrates for several decades.67 Fig. 1 shows representative scanning electron micrographs of colloidal nanoparticles. Formed primarily by the reduction of Au or Ag salt solutions, nanoparticles can be made relatively easily in the laboratory. Furthermore, a number of chemistries exist for controlling the shape of the seed crystals,68 allowing researchers to tailor the nanoparticles to their needs. Control of nanoparticle properties Both nanoparticle size and geometry can be controlled by altering experimental conditions. Controlling the geometry of the nanoparticles is more complex than size; the reaction conditions must be adjusted such that growth in a desired crystal plane is favored energetically.69 One of the most popular methods for controlling nanoparticle morphology stems from the polyol synthesis of silver nanocubes by Sun and Xia.70 Etchants and surfactants can be added to the reaction to aid in altering the thermodynamic landscape of the reaction, directing growth along a desired crystal face.63,71 Some of the most striking demonstrations of controlled nanoparticle geometry are shown in Fig. 1b–f and come from the laboratories of Xia and Yang. In addition to the nanocubes,70 these groups have produced octahedra and cuboctahedra,72 octapods,63 and complex concave variants of these structures.69 Additional work from the labs of El-Sayed73–75 and Murphy76–78 has contributed to the control of particle morphology, yielding a variety of interesting and useful structures. Since the size, shape, and material of the particles govern the resulting plasmonic resonance characteristics, significant effort has been exerted in the control of plasmon resonance via core–shell and alloyed particles, to which the Halas group has contributed greatly.79–81 Once synthesized, performing SERS analysis is straight forward; the sample is mixed with the colloid solution and analyzed for SERS activity in a cuvette. In certain situations, drying the mixture helps to promote the adsorption of the analyte to the nanoparticle surface which can lead to a higher


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support to form substrates. SERS substrates have been fabricated by employing various approaches of depositing nanoparticles onto different surfaces. These simple deposition approaches include micropipetting,88 soaking,89 screenprinting,90 filtration,91 and inkjet printing.92 However, a major concern with these simple deposition processes is that the hotspots are generated and distributed randomly over the substrate. We will discuss techniques to address this issue in detail in a later section. In order to obtain more consistent hotspots from nanoparticles, researchers have explored both self-assembly88 and directed assembly techniques, such as the Langmuir–Blodgett techniques,95 to create regular arrays of nanoparticles. However, these techniques also introduce more complexity to the fabrication process as compared to the simple deposition mentioned previously. In addition to assembly of nanoparticles into regular arrays, the tools and techniques of micro- and nanofabrication developed by the semiconductor industry have been adapted to create SERS substrates having nanoscale features as well.

Non-lithographic microfabricated substrates There are several SERS substrate fabrication techniques that make use of the microfabrication processes and procedures developed by the semiconductor industry. Fig. 2 shows SERS substrates formed by using several of these microfabrication techniques.

Fig. 1 Representative scanning electron micrographs of nanoparticles with different morphology: (a) nanoparticles produced by reduction of Ag ions, (b) Ag nanocubes, (c) Ag nanocubes etched by HAuCl4, (d) Ag octahedra, (e) Ag octahedra etched by HAuCl4, (f) Ag octapods etched from Ag by HAuCl4 octahedra. (a) Adapted with permission,61 copyright 2006, John Wiley and Sons. (b and c) Adapted with permission,62 copyright 2004, American Chemical Society. (d–f) Adapted with permission,63 copyright 2010, American Chemical Society.

SERS intensity. While individual nanoparticles provide some measure of SERS enhancement, especially for nanostructures with sharp edges, the enhancement is much greater at so-called ‘‘hotspots’’:82 areas where two nanoparticles approach one another within approximately a 2 nm distance.83 These hotspots create a very high SERS enhancement, enabling the detection of trace analytes. For colloidal solutions, nanoparticle aggregation can be induced by the addition of aggregating agents such as chlorides, bromides, nitrates and other ionic species to alter the zeta potential. However, the extent of aggregation can be difficult to control using this approach. Over-aggregation can lead to nanoparticles falling out of solution due to the formation of large clusters which have reduced or no plasmonic activity.84–87 Moreover, not all analytes of interest are soluble to an appreciable degree in water; consequently the use of colloid solutions for general SERS analysis can be limited. An alternative to obtain more stable hotspots is to cast nanostructures onto a solid


Fig. 2 Scanning electron micrographs of some microfabricated SERS substrates. (a) Metal film deposited over a layer of nanoparticles, (b) Metal islands deposited through a nanosphere mask, (c) Regular array of metal structures patterned by electron beam lithography, and (d) Array of plasmonic nanoholes created using lithography, atomic layer deposition (ALD), metal deposition, and anisotropic etching. (a and d) Adapted with permission,93 copyright 2010, American Chemical Society. (b) Adapted with permission,52 copyright 2005, American Chemical Society. (c) Adapted with permission,94 copyright 2008, American Chemical Society.


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One such popular technique, pioneered by Van Duyne’s group,96 involves the assembly of polystyrene nanospheres into a regular array, using this as a mask to create periodic nanostructures, sometimes called ‘‘metal island films’’, by the evaporation of Ag or Au through the gaps created by the packing of the nanospheres, followed by removal of the nanospheres. A variation on this method, called ‘‘metal film over nanospheres’’, is to evaporate a metal film directly onto the nanosphere template, using closely-packed nanospheres to pattern the substrate surface itself.97 A related method involves using polystyrene nanospheres to create voids within an electrodeposited layer of Au.65,98–100 Evaporation and sputtering of metal is another popular choice for depositing SERS-active metals on surfaces.101–105 Polystyrene spheres can be used to create nanobowls106 and nanocrescents107 using metal evaporation techniques. Oblique angle deposition is a method pioneered by the laboratories of Zhao and Dluhy108 that produces arrays of aligned silver nanorods that make excellent SERS substrates. They have used these substrates to demonstrate applications such as virus detection,109–111 micro RNA detection,112 and coupling the substrates to fiber optic probes.113 Lithography-based microfabricated substrates Etching and lithography processes are well known and characterized for silicon, offering control over structure size, shape, and spacing of micro- and nanostructures. Micro- and nanofabrication techniques such as electron beam lithography and deep reactive ion etching, followed by evaporation of Au or Ag onto the structures, have been used to create highly uniform and reproducible SERS substrates.93,94,114–117 These techniques, while excellent at making SERS substrates with defined characteristics, are hampered by the slow, serial nature and high cost of the processes used in their fabrication. Limitations of SERS While a comprehensive review of the SERS phenomenon is well beyond the scope of this Perspective article, we believe it is important to underscore some of the physical limitations of Raman spectroscopy that currently limit a more broad application of the technique. In order for the Raman scattering of the analyte to be enhanced by the SERS phenomenon, it must be in very close proximity to the SERS substrate.52,53 If the analyte cannot adsorb onto or remain in close proximity to the substrate, SERS will not occur. This remains a major limitation, as many analytes will not bind to the SERS substrate; others will do so under certain conditions. Furthermore, the orientation of the molecule with respect to the substrate determines which vibrational modes are enhanced.118,119 Another major limitation of SERS has been reproducibility of the enhancement of SERS substrates. A number of factors can contribute to this variability, and they have been reviewed elsewhere.43 Taken together, these limitations have reduced the broad adoption of SERS, but also represent areas of future growth and development in the field.


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Simple SERS substrates We identified four characteristics of SERS substrates that are conducive to simple substrate fabrication. These are not the only criteria for simple SERS substrates, but rather serve as guidelines for identifying and developing simple fabrication methods. 1. Fabricated using equipment and reagents commonly found in chemistry laboratories The first, most important aspect of a simple fabrication method is ensuring that the equipment and reagents used are readily available to most researchers. Common equipment like pipettes, filters, syringes, centrifuges, heaters, and magnetic stirrers are ubiquitous in the modern laboratory. This characteristic precludes the methods reviewed earlier that require ultrahigh vacuum or micro/nanofabrication technology requiring a cleanroom for the substrate fabrication. In addition, the reagents used for the synthesis should be readily available and ideally nontoxic. 2. Minimal training or experience required for fabrication All fabrication methods have a learning curve; one key aspect conducive to rapid and widespread adoption of a technique is a shallow learning curve. In addition to requiring specialized equipment, the ultrahigh vacuum and microfabrication techniques require additional training in sample preparation and handling, as well as how to use the equipment. The popularity of borohydride and citrate reduced nanoparticles is a testament to the ease of fabrication of these substrates. 3. Easily transported to or fabricated at the point of sampling This characteristic is more of an ideal based on our view that the field of SERS is progressing more towards portable systems enabling point of sampling SERS analysis. This is somewhat more difficult to achieve with nanoparticles given that the most popular methods pioneered by Lee and Meisel67 often make use of a heat source and/or constant stirring. Preparing the nanoparticles beforehand is an option, but depending on the synthesis approach, colloidal solutions subjected to prolonged storage and fluctuating environmental conditions from transportation can result in uncontrolled aggregation, which poses a problem for on-site analysis. Capping nanoparticles is a possibility, but then the capping agent must be selected carefully such that it does not interfere with the interaction between the analyte and the substrate or the SERS spectrum of the analyte present in the sample. This places more emphasis on the rapid and reliable fabrication of the substrate, which includes a minimization of the number of steps necessary to fabricate the substrate. On-demand fabrication, where the SERS nanofeatures are generated fresh and used immediately, would be ideal. Alternatively, the substrates should have an acceptable shelf life. 4. Easily integrated into analytical systems In addition to being easy to fabricate and transport, the resulting substrates must be readily integrable into simple analytical


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systems and procedures. Using simple SERS substrates but requiring complicated, multi-step preparatory or analytical protocols would be superfluous. Below we describe in some detail inkjet printing on paper120–122 and screen printing of nanoparticles,90 as well as galvanic displacement26,123 approaches, which meet all four of these requirements for simple SERS substrates.

Inkjet and screen printing as a simple SERS substrate fabrication method Inkjet and screen printing of nanoparticles are two very simple and promising methods for SERS substrate fabrication. Inkjet printing of paper-based SERS substrates using a commercial inkjet printer is illustrated in Fig. 3 and has been demonstrated to be suitable for simple and inexpensive SERS substrate fabrication.91,92,124–126 Screen printing of nanoparticles for SERS substrates is less prevalent,90 as the technique is better known for its use in making screen printed electrodes, which can subsequently be modified to be SERS substrates.127,128 Since more papers have been published on inkjet-printed SERS substrates than screen-printed SERS substrates, much of our discussion will center on inkjet printing, although many of these aspects could potentially be generalized to screen-printed substrates as well. Both techniques meet the simple SERS substrate criteria identified earlier: Both processes use simple nanoparticles and common lab reagents, as well as equipment common to almost all laboratories and offices (inkjet printers) or slightly more specialized equipment (screen printers). Designing and creating SERS substrates involves little more than designing a substrate pattern and printing it. Substrates can be printed on-site with portable printers. Selection and preparation of the proper support surface (e.g., paper) can supersede the need for upstream purification and concentration, simplifying the integration of the substrates into portable and laboratory-based analytical systems. Substrate fabrication by printing nanoparticles Inkjet-printed and screen-printed substrates share several commonalities. Both printing techniques require the formulation of a nanoparticle ink in an appropriate liquid carrier for proper viscosity and surface tension. A pattern is required for both processes, although the method of developing the pattern is different. Finally, a solid support matrix is necessary for depositing the nanoparticle ink. We will now consider each of these factors in turn. Nanoparticle inks The Lee and Meisel method is popular for the production of silver nanoparticle colloids, and the resulting colloid is suspended in water. A water-based ink does not necessarily offer the ideal viscosity and surface tension properties for printing of the nanoparticles on paper or polymer supports, and so the colloids must first be concentrated (usually by centrifugation)90,92 and then dispersed in a medium with the desired properties.


Fig. 3 Inkjet-printed SERS substrates. (a) Printing of paper SERS substrates using a commercial ink-jet printer. With up to four different colors available (black, cyan, magenta, and yellow), this setup allows for flexibility in the design and implementation of substrates. (b) Printed paper SERS substrate with applied sample. Paper can be treated to be hydrophobic on areas where nanoparticles are not printed, effectively concentrating the sample over the nanoparticles. (c) Scanning electron micrograph of nanoparticles on the paper. Nanoparticle ink must be properly formulated to allow for adequate nanoparticle aggregation and hotspot formation.

Commercial nanoparticle inks are also available from several chemical and specialty suppliers. With dispensed volumes as small as a picoliter, inkjet printing can offer better control over the nanoparticle aggregation and distribution compared with traditional methods such as micropipetting, thus yielding more reproducible SERS substrates. The small volumes used also reduce ink waste relative to screen printing, as the nanoparticles can be delivered very precisely in a predefined region.


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Substrate pattern design With inkjet-printing, substrate fabrication can be as rapid and simple as printing out a document. Inkjet printing is precisely computer controlled, thus avoiding complicated handling procedures, and complex geometries can be designed very easily – often, this can be as simple as drawing a pattern using drawing software available on most computers. Since inkjet printers are designed to print several different colors, it is conceivable that SERS-active nanoparticles can be created in situ by printing the precursor reagents rather than the nanoparticles themselves.129–132 Other alternatives could be the printing of functionalizing reagents for the substrate, or for the nanoparticles using the additional ink cartridges. In another variation, the nanoparticles can be dispensed from the printer directly onto the surface to be analyzed in a one-step process. The screen printing substrate design process is inherently different than the inkjet process. In this case, a master or stencil containing the pattern must be created first. The voids in the master define the pattern of ink on the underlying support matrix, thus defining where nanoparticles are placed. Since a master must first be created, the screen printing process does not allow for on-the-fly reconfiguration of substrate geometries. Solid support matrix While both inkjet and screen printing are extremely useful techniques for inexpensive substrate fabrication, astute selection of the surface onto which the nanoparticles are deposited can impart an additional functionality to the substrate. Surfaces such as glass, silicon and polymers have been used for more traditional SERS substrate fabrication because they do not retain liquid from the sample, helping to ensure that most of the analyte adheres to the nanoparticles, but these substrates tend to be brittle and can break easily, which make them less useful as a printed SERS substrate support matrix. Here we consider the advantages and disadvantages of using several solid support matrices more commonly used in printed SERS substrates. Silicon. Silicon substrates have a relatively low background within the Raman fingerprint region, aside from the characteristic peaks associated with the silicon crystal vibrations. Since they are brittle and can break easily, they must be handled with care. This also adds the requirement that the inkjet printer used to fabricate the substrate can print on flat substrates,125,126,133 as opposed to the style of inkjet printers commonly found attached to personal computers. The brittleness of silicon wafers precludes them from being easily transported to the point of use, unless the wafers are diced and immobilized on another support, such as a glass slide. The printers used for silicon substrates have similar form factors and power requirements to standard desktop inkjet printers, and thus have approximately the same requirements for on-site substrate fabrication. Glass and quartz. Various forms of glass are also used in printed SERS substrates. Qu et al.90 evaluated both glass and glass fiber solid supports in their use of screen printed substrates, ultimately selecting glass fiber plates because solid


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glass is fragile and potentially too rigid. Fierro-Mercado et al.126 used quartz plates to support their printed nanoparticle substrates. Fused silica and quartz have very low SERS background and are readily integrated into other analytical systems, as well as being less expensive than silicon substrates. Paper. Paper is extremely useful as a vehicle for supporting nanostructures for SERS applications and has several advantages over other widely used supporting materials. Most importantly, paper possesses natural hydrophilicity, which can be leveraged for analyte collection, separation and concentration. The wicking ability of cellulose can be utilized to drive the flow of samples without relying on any mechanical components. The hydrophilicity of cellulose proved to be a problem for Qu et al.90 when evaluating filter paper for their screen printed substrates because the sample spreads out over a large area, but paper can be modified very easily to have varying degrees of hydrophobicity, strength and other physical properties by coating or impregnating with other materials. In fact, modified cellulose products have been demonstrated for the fabrication of devices with capabilities similar to microfluidic devices.120–122 Paper is also widely available, relatively inexpensive and made from renewable resources. Cellulose fibers are intrinsically compatible with biomolecules, making paper useful for biosensing applications. For these reasons, paper is increasingly being explored for a variety of sensing applications.134–156 However, many of the current sensors rely on simple colorimetric changes or electrochemical techniques for detection. The coupling of highly sensitive SERS to paper-based sensors has the potential to improve the sensitivity of these sensors dramatically. With these considerations in mind, paper-based SERS has the potential to become a simple yet highly sensitive detection platform that can rival traditional trace analysis techniques such as HPLC-MS and compete with recent advancements such as lab-on-a-chip devices. Paper based SERS substrates have been developed to take advantage of the special properties of paper, as demonstrated by spot-on assays,92 wipes and swabs,89,157 simple dipsticks, and lateral flow assays.124,158,159 In a spot-on assay, a microliter drop of analyte is placed onto the substrate and then dried. Since the paper is pretreated to be hydrophobic, the analyte is not absorbed into the cellulose. Instead, it dries onto the nanoparticles, effectively concentrating the analyte onto a small spot. This spot-on assay is useful in cases where the sample volume is small. As wipes or swabs, the flexible paper SERS substrate can be wiped over a surface to collect the analyte, unlike more rigid solid supports such as silicon and glass. Other advantages of flexible SERS substrates are well-covered elsewhere.160 Additionally, the surfaces do not have to be simple and smooth—surfaces with complex features, such as fruit and vegetable produce, fingertips, and luggage zippers, as well as large surface areas such as countertops or benches can be easily examined using a wipe or swab. As dipsticks, the paper SERS substrates can be applied directly to a liquid sample, where the dipstick is simply dipped into the sample as shown in Fig. 4. Furthermore, relatively large sample volumes (tens of mL) can be loaded onto the paper by dipping it in the sample, whereas glass


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for a host of applications, ranging from trace chemical detection to environmental and food monitoring to biomedical applications in disease monitoring. Spot-on assays can be used for analyzing multiple samples in a parallel, array-like format. Wipes and swabs can be used for field-based applications such as detection of pathogens or toxins at medical facilities, explosives at ports of entry, illicit drugs by law enforcement agencies, and food contamination. Dipstick SERS substrates can be used for detection of contamination of drinking water or fuel. Chromatographic separation of analytes from complex samples has been demonstrated using paper SERS devices with minimal sample preparation.161 The potential impact of printed SERS sensors is immense and holds promise for sample separation, analyte concentration and multiplexed detection of several analytes simultaneously. Coupled with miniature portable SERS detection systems and computer software for automated detection and quantification of analytes, untrained users will be able to perform complex assays with ease. The life span of paper substrates have been shown to range from days to weeks, although the simplicity of the fabrication process means the shelf life of the nanostructures is essentially a non-issue since they can be created on demand. These simple SERS substrates have been shown to have a fairly large average enhancement factor of 105–108. While this is still far from the theoretical 1015 enhancement that allows for single molecule detection,8,9 with better control of the fabrication process (e.g., improved control over the dispersion of the nanoparticles, utilizing solvent evaporation/coffee ring effects, etc.), it should be possible to achieve even higher enhancement factors. With the development of large-scale fabrication techniques, mass production of inexpensive, reliable SERS substrates becomes a real possibility.

Galvanic displacement as a simple SERS substrate fabrication method Fig. 4 Example of a printed SERS substrate taking the form of a swab or dipstick. (a) Nanoparticles can be printed onto filter paper in any desired geometry, including that of a swab or dipstick. (b) When the printed SERS substrate is inserted into a sample, the natural hydrophilicity of the paper wicks the sample upward, concentrating it at the upper tip of the dipstick, enabling sample separation and concentration in a single step.

and silicon supported substrates would have to be soaked for long periods of time (Z1 hour). Dipsticks and lateral flow assays have the added advantage of being able to separate and concentrate analytes where the particles are printed, without the need for upstream preparation and separation processes.161,162 Applications and potential impact of printed SERS analytical devices The vision of simple, printed SERS substrates is that by virtue of their simplicity and low cost, they will become widely adopted


Galvanic displacement, also called galvanic replacement or galvanic exchange, has been receiving increased attention recently from the SERS community for its simplicity and ability to produce highly enhancing substrates.163 It is a spontaneous electrochemical reaction in which a metal ion in solution displaces atoms from a solid metal or semiconductor surface. This reaction is driven by the free energy change resulting from the difference in reduction potential between the two species. This process is shown schematically in Fig. 5. In the case of galvanic displacement of Al by Ag, Ag+ ions diffuse to defects present in the native oxide of Al, and directly oxidize the Al atoms to form Al+ ions. In terms of stoichiometry, three Ag+ ions would be required to produce one Al3+ ion; whether all of the oxidation–reduction occurs at the surface or can occur in solution once a monovalent ion is created is currently an open question. Recent evidence suggests that the reaction takes place by means of a hydride transfer.164 Thus, aluminum hydride surface groups are able to be displaced by Ag+ ions while aluminum hydroxide surfaces are not. These newly reduced Ag0 atoms are


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reaction results in the production of many sharp angles and branch points that are believed to contribute to the large SERS enhancement exhibited by substrates formed using galvanic displacement. A downside to this reaction is that the random, uncontrolled nature of the reaction results in substrates that have a high degree of variability in terms of SERS enhancement from point to point and between different substrates of the same material. The galvanic displacement reaction can readily be combined with other nanoparticle or microfabricated SERS substrates to create new substrates with a specific set of properties. This is best exemplified by the creation of gold ‘‘nanocages’’ in the laboratory of Xia.62 Xia’s group has developed methods to fabricate these nanocages by first making use of the galvanic displacement of Ag from cubic nanoparticles by using an Au salt solution. Then, the particles undergo a dealloying step to remove remaining Ag, leaving gold nanocages similar to the particles shown in Fig. 1c. These gold nanocages have interesting catalytic properties in addition to their use as SERS substrates. SERS substrates made by galvanic displacement meet the criteria for simple SERS substrates as follows: Galvanic displacement forms substrates using common metal salts and solid metal or semiconductor surfaces. Substrate fabrication involves dispensing a metal salt solution onto the surface or immersing the solid in the metal salt solution. Substrates can be made on site using small pieces of the solid metal or semiconductor and a pre-dispensed volume of metal salt. Since the substrate is formed by the addition of a single metal salt solution, the substrates can be formed and used on demand, allowing integration with other preparatory and analytical procedures. Substrate fabrication by galvanic displacement

Fig. 5 Schematic overview of the galvanic displacement mechanism. (a) A metal salt solution is placed onto a solid metal or semiconductor surface, where the reaction takes place. (b) At the interface highlighted in the box in part a, metal ions (blue circles) diffuse to defects in the metal oxide layer (red circles). (c) The metal ion is reduced to a zero valent state by an oxidation–reduction reaction directly with the bulk metal (brown circles), presumably through a hydride transfer.164 (d) The zero valent metal acts as a nucleation point for crystal growth at the defect site through additional rounds of oxidation–reduction of other metal ions from solution.

believed to serve as nucleation points for the growth of Ag crystals that extend outward from the Al surface. Galvanic displacement reactions tend to be diffusionlimited,165,166 and the crystalline features that result are often fractal, dendritic, or polygonal.163,167 This diffusion-limited


Galvanic displacement has many attractive characteristics as a fabrication method for simple SERS substrates. The gold and silver salts used to displace ions from metal or semiconductor surfaces are commonly available from chemical suppliers. Several different types of metal and semiconductor have been used in the galvanic displacement reaction, including silicon wafers,168–172 metal foils and tapes,26,165,173–176 thin metal films,177,178 and even the surfaces of coins.26,123 Metal foils and silicon wafers are readily available from specialty suppliers. In our experience, even aluminum foil purchased from the grocery store is able to produce SERS substrates with excellent enhancement characteristics. Fabrication of SERS substrates by galvanic displacement is straightforward as well. Since the reaction is entirely based on solution chemistry with no need for an external voltage source, the process is often as simple as pipetting the metal salt solution onto the solid metal or semiconductor surface, or alternately, immersing the solid metal or semiconductor into a bath of the metal salt solution. Several groups use HF169–171,174 or other acids123,177 to remove any oxide layer present on the surface of the material to be displaced, although this is not


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absolutely necessary to form SERS substrates by galvanic displacement.26 Crystals formed by galvanic displacement often are easily dislodged from the surface, and Maboudian’s group took advantage of this to obtain dendrites via filtration.173 Furthermore, the cost of creating a substrate by galvanic displacement is low relative to micro- and nanofabricated substrates as well, depending on the choice of solid surface to be displaced. Coins, metal foils, and silicon wafers are all relatively inexpensive compared to thin films, which would probably be on par with some of the microsphere lithographic methods in terms of cost per unit area, due to the expense of thin film deposition. The solution-based nature of these substrates makes them highly amenable to portable analytical systems. In the simplest case, e.g. a solution of AgNO3 or HAuCl4 on a solid metal such as Al or Cu, the reaction can be performed at the point of analysis, enabling portable SERS sensing. Furthermore, the substrates are formed in seconds to minutes under some circumstances, allowing the substrates to be created on demand. Since the SERS substrates form on a solid surface, they can easily interface with other portable analytical instruments, such as a handheld desorption electrospray ionization mass spectrometer.179,180 Large-scale production of SERS substrates by galvanic displacement The fundamental processing steps needed to produce galvanic SERS substrates are well developed for manufacturing, relying mainly on solution processing. Furthermore, the substrates can be premade, then chemically activated on demand for use where and when they are needed. Advances in roll-to-roll thin film processing technology, driven by commercial interest in thin film solar cells and flexible electronics, and atmospheric pressure atomic layer deposition,181 may be adapted to the production of these substrates on a large scale and reduced cost. Since the substrates can be formed on-site and on demand, shelf life becomes a non-issue. The metal salt solution, along with any other additives required to achieve the desired substrate morphology, could be pre-packaged in sealed containers, and dispensed on site by a moistened sponge, a marker, or even a moist towelette similar to those given out by some restaurants and airlines. We demonstrate the use of a marker to dispense AgNO3 solution onto a glass slide coated with aluminum in Fig. 6, as well as the resulting particle morphology and a representative SERS spectrum of Rhodamine-6G. Coupling these mass-produced and engineered substrates with commercially available handheld portable Raman spectrometers could move SERS analysis of samples from the laboratory to the field or production line in the near future. Inkjet printing of galvanic displacement SERS substrates Combining the simplicity and flexibility of the inkjet-printed substrates described earlier with the galvanic displacement reaction may also provide another way to create highly effective SERS substrates on demand and in sufficient quantities to keep overall fabrication costs to a minimum. This has recently been


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Fig. 6 Fabrication of SERS substrates using a marker and an aluminum slide. (a) A refillable marker is loaded with Ag+ solution and applied to an Al covered slide. (b) The Ag+ solution reacts with the aluminum, forming a SERS-active surface. (c) Scanning electron micrograph of the SERS substrate shown in (b). (d) Representative SERS spectrum of 1 mM Rhodamine 6G from the same SERS substrate.

demonstrated on silicon.133 The ability to dispense a controlled volume of solution from any of four fluid reservoirs (previously used to hold cyan, yellow, magenta, and black ink in conventional ink-jet printers) offers a great degree of control over reaction conditions, and could easily be used to optimize reaction conditions by means of combinatorial experiments. Coupled with a motorized x–y stage, one could optimize reaction conditions for a desired analyte in the laboratory before filling a marker or sponge with a solution containing the optimized reagents for field use with a handheld portable Raman spectrometer. Alternatively, one or more of the fluid reservoirs can be filled with affinity molecules such as antibodies or aptamers capable of binding the desired analyte, which would then be directly printed onto the substrates to improve the signal to noise ratio when separating analytes out of complex biological samples.

Future challenges in simple SERS substrates Substrate morphology control with galvanic displacement Given that the Raman scattering enhancement is governed by the nanoscale geometry of the substrate, controlling the morphology and distribution of the resulting nanoscale features is essential for creating highly enhancing and reproducible substrates. While there are currently no reports of quantitative substrates formed by galvanic displacement, there are galvanic displacement substrates that offer reproducibility within 10–15%. These methods require the use of HF169–171,174 and long reaction times,169 excluding them from consideration as simple SERS substrates amenable to portable analysis based on the characteristics of simple SERS substrates listed previously. Brejna and Griffiths used microsphere lithography to demonstrate a method


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to control substrate morphology and nanostructure spacing, but the extensive amount of processing necessary to fabricate these substrates precludes them from consideration as simple SERS substrates.171 A general method for creating simple, portable, quantitative, and reproducible substrates by galvanic displacement has not yet been put forth. We believe that by controlling the surface chemistry and characteristics of the metal or semiconductor to be displaced and the composition of the displacing solution, the problem of substrate reproducibility, which is directly related to crystal morphology and distribution, can be greatly reduced while still maintaining the excellent enhancement characteristics and simple preparation methods of galvanic displacement substrates. Many of the previous reports of SERS substrates formed by galvanic displacement168–174 relied on the use of HF to remove the native oxide layer present on metal and semiconductor surfaces, since the native oxide layer inhibits galvanic displacement177 and defects in the oxide are believed to act as nucleation points for crystal growth. In the simplest cases, this harsh treatment is unnecessary with many metals including Al164 and Cu.26,166 Since many metal oxides are amphoteric, acidification of the displacing solution, especially using a metal with a common anion (e.g. HNO3 for AgNO3 solutions), can help to remove the native oxide layer and facilitate galvanic displacement without requiring the use of concentrated acids or HF to form the substrate. Amphoteric metal oxides can also be dissolved using a basic solution, expanding the parameter space for the galvanic displacement reaction. The anions of these basic solutions can complex Ag+ and Au3+, which alters the effective reduction potential of the ions,182 changing the free energy of the reaction. Furthermore, there is evidence that the anion plays an important role in determining the morphology of the structures that form due to standard reduction methods of nanoparticle synthesis182 as well as galvanic displacement with Ag.166 One could conceivably adjust the composition, pH, and free energy of the galvanic displacement solution to allow for the creation of more structures with a given morphology that produce highly enhancing SERS substrates for a given application. Another approach to controlling the galvanic displacement reaction would be to directly engineer the metal oxide layer itself. One example of such a method is shown schematically in Fig. 7. While the most common method to control the oxide is to remove it entirely using acid, this need not be the only approach. Several of the techniques necessary to do this very precisely and in a controlled fashion are currently prohibitively expensive and highly specialized, and thus research in this area would primarily serve to answer the question as to whether engineering the metal oxide layer itself could control the galvanic displacement reaction. Atomic layer deposition (ALD) is a technique used extensively in the semiconductor and other industries to produce thin films with unprecedented uniformity at the atomic scale, achieved by means of an alternating, self-limiting surface reaction of metal precursors and oxidizers in ultrahigh vacuum conditions. Recent reports have extended ALD to roll-to-roll processing under atmospheric pressure


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Fig. 7 Schematic overview of how to control the galvanic displacement reaction. (a) Aluminum is deposited onto a cleaned glass slide. (b) Aluminum oxide is grown conformally over the aluminum metal by atomic layer deposition. (c) Defects are introduced into the aluminum oxide layer by ion milling. (d) A more controlled defect distribution should yield improved control over the resulting SERS-active dendrite structure and size.

conditions, driven by the dramatic lowering of cost this will achieve.183 This can be used to tune the plasmonic properties resulting from controlled galvanic reaction with the underlying substrate.184 Given the uniformity and control over the thickness of the oxide layer, a highly uniform metal oxide film could be deposited, and defects could then be introduced using other techniques common in the semiconductor industry, such as ion implantation, ion milling, or focused ion beam ablation. By controlling the parameters of these techniques, one could achieve a desired density of defects in the oxide layer, such that the defects are all very similar (monodispersed). Uniform defect characteristics in the oxide could enable considerably more uniform SERS structures to be formed at those defects, as compared to galvanic reaction at random defects in a native oxide that has evolved without control. Additives such as polyvinylpyrrolidone (PVP), KI, and cetyl trimethylammonium bromide (CTAB) also have been shown to influence substrate morphology in galvanic displacement reactions.176 PVP is a common capping agent used in the synthesis of Ag nanocubes, and directs growth along the h111i direction by adsorbing selectively to the h100i facets.70 In the case of galvanic displacement of Zn by Ag, Lv et al. found that Ag tends to form spherical structures with nanorods extending radially, similar to the shape of a sea urchin.176 When they replaced PVP with KI, the structures formed a porous, irregular, interconnected mesh of Ag nanosheets. The addition of CTAB, a detergent commonly used in the formation of Au nanorods,185 results in the growth of rod-like aggregates. Furthermore, Lv et al. found that the presence of halide anions (I from KI and Br from CTAB) changed the nature of the reaction from a thermodynamically governed system to kinetic


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control which they say favors anisotropic growth of Ag particles. The order and timing of the addition of these compounds could also be adjusted to further control the morphology of the substrates. For example, since the additives mentioned result in Ag structures dominated by {111} facets, adding them to the reaction at a later time point may allow for the formation of new morphologies by allowing early isotropic growth of nanoparticles prior to Ostwald ripening and formation of rods or dendrites.186 Reducing substrate variability and expanding available analytes for simple SERS substrates With SERS substrate fabrication by the printing methods and galvanic displacement described above, the formation of SERS hotspots is a random process; as a result, these SERS substrates can have much higher point-to-point variability than specially designed, highly regular substrates such as those formed by lithographic processes. This variability stems from two main sources: nanoscale factors, including the size, shape, and distribution of the enhancing nanostructures, and macroscopic factors, such as process reproducibility. Macroscopic factors are usually addressed through process optimization and scaleup for commercial manufacturing. It is the nanoscale sources of variability that present the most challenges and the greatest opportunities to improve these simple methods for SERS substrate fabrication. In practice, the SERS signal variations from these substrates are not as large as expected, possibly because so many nanoscale hotspots exist within the region illuminated by the laser that the variations from hotspot to hotspot are averaged out. This would, of course, depend on the laser spot size on the sample. One key factor to improving the consistency of these simple SERS substrates lies in controlling the deposition process, or controlling the rate and composition of the reaction in galvanic displacement. Thus far, research indicates that simple SERS substrates fabricated by inkjet and screen printing methods can be fabricated fairly consistently, with low percentage variations within a substrate and from batch to batch.89–92,157 Substrates formed by galvanic displacement are prone to hotspot effects, but this is still highly dependent upon the reaction conditions.26,123,169,171 In addition to improvement in the fabrication processes used for simple SERS substrates, signal variability can be reduced by simple changes to acquisition procedures. For instance, the variability of the SERS signal can be reduced by constantly moving the laser spot or SERS substrate, a technique called rastering, which has been demonstrated to be effective.187–189 Wide area illumination is another approach where a large diameter laser beam is used to excite hotspots over a wider region. Finally, sampling and averaging from multiple regions on the substrate can also be employed. In essence, these techniques average the SERS signals over numerous hotspots, thus reducing the variability.190 Two major areas for future development of simple SERS substrates are in improving upon both the sources of variability inherent in the substrates themselves, as well as the acquisition techniques used both in the field and in the laboratory. Finally, it bears repeating that not every analyte can be detected via SERS, regardless of whether a simple or more


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complex substrate is used. The analyte must be in close proximity to the surface (within a few nanometers) or directly adsorbed onto the surface to take advantage of the plasmonic effects that give rise to the surface enhancement phenomenon. Given that the substrate, the analyte, and the environment in which the detection takes place all influence the resulting spectra, new methods and techniques are necessary to expand the repertoire of analytes that exhibit high Raman enhancement. We have previously mentioned traditional affinity molecules, such as aptamers and antibodies, as ways to separate out analytes. Through clever assay design, these affinity molecules can also be used to bring the analyte (or a SERS-active molecule such as Rhodamine-6G) in close proximity to the surface of the SERS substrate, resulting in improved detection of the analyte. Careful selection of capping agents can also mean a strong surface enhancement, as in the case of SERS detection of TNT.24 Recently, graphene oxide functionalized particles have been shown to improve the signal obtained from certain aromatic molecules.191–193 Furthermore, graphene oxide has already been combined with the galvanic displacement reaction.194 Perhaps graphene oxide could be combined with a galvanic displacement ink (or printed at a later point) to allow for improved detection of aromatic molecules. This aspect is one of the most challenging facing the field of SERS, and represents a key area for future developments in the field.

Conclusions Advances in manufacturing processes have made smaller, less expensive, and portable Raman spectrometers available commercially, opening the door to the possibility of portable SERS analysis. Accordingly, low cost SERS substrates that are easily transported to or created at the point of use and are readily integrated into analytical systems will be of increasing importance and utility in the realm of portable SERS analysis. In addition, these simple SERS substrates can be easily integrated with other analytical techniques, such as electrochemistry or mass spectrometry, further enhancing their performance. In this work, we have explored how these SERS substrates can be created by printing of nanoparticles onto solid support substrates and galvanic displacement of a metal or semiconductor by a metal salt solution, both meeting the four requirements for broad deployment of SERS analyses. Indeed, these substrate fabrication methods are simple and inexpensive enough that they could be incorporated into an undergraduate chemistry laboratory curriculum, introducing aspects of nanoscience, physical chemistry, and analytical chemistry to broader audience. This rapidly growing field offers many exciting opportunities for the development of new and innovative SERS substrate fabrication techniques.

Acknowledgements The work of J.F.B., Y.C., and G.W.R. was supported by a grant from the Robert W. Deutsch Foundation and in part by the NSF-EFRI


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grant NSFSC03524414. The work of W.W.Y. and I.M.W was supported by the National Institute for Biomedical Imaging and Bioengineering (5K25EB006011) and the Maryland Department of Business and Economic Development’s (DBED) Nanobiotechnology Initiative. We acknowledge the support of the Maryland NanoCenter, its FabLab, and its NispLab. The NispLab is supported in part by the NSF as a MRSEC Shared Experimental Facility.

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Review of SERS Substrates for Chemical Sensing.

Plasmonic "Nanowave" Substrates for SERS: Fabrication and Numerical Analysis.

Bioenabled SERS Substrates for Food Safety and Drinking Water Monitoring.

Fast electrically assisted regeneration of on-chip SERS substrates.

Au-ZnO hybrid nanoparticles exhibiting strong charge-transfer-induced SERS for recyclable SERS-active substrates.

Nanostructured plasmonic substrates for use as SERS sensors.

Rapid in situ identification of arsenic species using a portable Fe3O4@Ag SERS sensor.

Plasmonic-enhanced Raman scattering of graphene on growth substrates and its application in SERS.

Sensing of p53 and EGFR Biomarkers Using High Efficiency SERS Substrates.

Heparin assisted photochemical synthesis of gold nanoparticles and their performance as SERS substrates.

Self-assembly of Au nanoparticles on PMMA template as flexible, transparent, and highly active SERS substrates.

Hierarchical 3D SERS substrates fabricated by integrating photolithographic microstructures and self-assembly of silver nanoparticles.

Realizing nurses' full potential.

An in situ approach for facile fabrication of robust and scalable SERS substrates.

Simple device to measure patient position on portable chest radiographs.

A SERS and electrical sensor from gas-phase generated Ag nanoparticles self-assembled on planar substrates.

Ag Nanorods Coated with Ultrathin TiO2 Shells as Stable and Recyclable SERS Substrates.

Anemone-like nanostructures for non-lithographic, reproducible, large-area, and ultra-sensitive SERS substrates.

Flexible membranes of Ag-nanosheet-grafted polyamide-nanofibers as effective 3D SERS substrates.

Capillary force-induced glue-free printing of Ag nanoparticle arrays for highly sensitive SERS substrates.

The effect of silver thickness on the enhancement of polymer based SERS substrates.

Gold nanoisland films as reproducible SERS substrates for highly sensitive detection of fungicides.

Organic-free synthesis of ultrathin gold nanowires as effective SERS substrates.

Optimization of Nanoparticle-Based SERS Substrates through Large-Scale Realistic Simulations.