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View Article OnlineView JournalNanoscaleAccepted ManuscriptThis article can be cited before page numbers have been issued, to do this please use: H. Aldewachi, T.Chalati, M. N. Woodroofe, N. Bricklebank, B. Sharrack and P. H. Gardiner, Nanoscale, 2017, DOI:10.1039/C7NR06367A.Volume 8 Number 1 7 January 2016 Pages 1–660Nanoscalewww.rsc.org/nanoscaleThis is an Accepted Manuscript, which has been through theRoyal Society of Chemistry peer review process and has beenaccepted for publication.Accepted Manuscripts are published online shortly afteracceptance, before technical editing, formatting and proof reading.Using this free service, authors can make their results availableto the community, in citable form, before we publish the editedarticle. We will replace this Accepted Manuscript with the editedand formatted Advance Article as soon as it is available.You can find more information about Accepted Manuscripts in theauthor guidelines.ISSN 2040-3364PAPERQian Wang et al.TiC2: a new two-dimensional sheet beyond MXenesPlease note that technical editing may introduce minor changesto the text and/or graphics, which may alter content. The journal’sstandard Terms & Conditions and the ethical guidelines, outlinedin our author and reviewer resource centre, still apply. In noevent shall the Royal Society of Chemistry be held responsiblefor any errors or omissions in this Accepted Manuscript or anyconsequences arising from the use of any information it contains.rsc.li/nanoscale
Page 1 of 16Please doNanoscalenot adjust marginsView Article OnlineDOI: 10.1039/C7NR06367ANanoscaleGold Nanoparticle-Based Colorimetric Biosensorsaa,baacaH. Aldewachi, † T. Chalati, † M.N. Woodroofe, N. Bricklebank, B. Sharrack, P. GardinerReceived 00th January 20xx,Accepted 00th January 20xxDOI : 10.1039/x0xx00000xwww.rsc.org/Gold nanoparticles (AuNPs) provide excellent platforms for the development of colorimetric biosensors as they can beeasily functionalised, displaying different colours depending on their size, shape and state of aggregation. In the lastdecade, a variety of biosensors have been developed to exploit the extent of colour changes as nano-particles (NPs) eitheraggregate or disperse, in the presence of analytes. Of critical importance to the design of these methods is that thebehaviour of the systems has to be reproducible and predictable. Much has been accomplished in understanding theinteractions between a variety of substrates and AuNPs, and how these interactions can be harnessed as colorimetricreporters in biosensors. However, despite these developments, only a few biosensors have been used in practice for thedetection of analytes in biological samples. The transition from proof of concept to market biosensors requires extensivelong-term reliability and shelf life testing, and modification of protocols and design features to make them safe and easy touse by the population at large. Developments in the next decade will see the adoption of user friendly biosensors forpoint-of-care and medical diagnosis as innovations are brought to improve the analytical performances and usability of thecurrent designs. This review discusses the mechanisms, strategies, recent advances and perspectives for the use of AuNPsas colorimetric biosensors.Keywords: biosensors, colloids, gold nanoparticles, nanotechnology, surface plasmon resonance, enzymes, quantification.IntroductionGold nanoparticles (AuNPs) (derived from the Greek wordnanus, meaning dwarf) are currently used in a variety ofbiomedical applications, due to their size-dependent chemical,electronic and optical properties. The pertinent physicalproperties include a high surface-to-volume ratio,biocompatibility, in addition, the dimensions of the metal NPsare comparable to those of biomolecules such as proteins(enzymes, antibodies) or DNA, whose dimensions are in therange of 2-20 nm thus imparting a structural compatibility of1,2these two classes of material. Moreover, the multitude ofavailable shapes of AuNPs allow easy surface functionalisationwith probes and other compounds of interest, thus makingthem amenable to a variety of detection modalities and3–5techniques as shown in (Fig. 1).Modern scientific evaluation of colloidal Au began withMichael Faraday’s work in the 1850s, which recognised that6the colour observed was due to the size of the Au particles.Faraday’s rationale in investigating colloidal phenomenafollowed his interests in the interaction between light andmatter. Technological advances in the development ofmolecular beam techniques have made it possible to study anddetermine the morphological, physical and chemicalproperties of AuNPs.7,8The chronology of the historical events that led to thedevelopment of nanotechnology is listed in (Table 1).Colloidal Au has been used since the last century for the studyof cerebrospinal fluid by using the Lange reaction in whichcolloidal gold reaction was used to detect infection of thecentral nervous system for the early diagnosis and prognosis ofobscure neurological conditions. Briefly, a series of spinal fluidsamples diluted in aqueous saline solution were treated with acolloidal gold solution and the reaction was allowed to standfor 24 hours to get a final reading (Fig. 2). Depending on thepathological conditions investigated, a certain pattern ofcolour change of the colloidal auric solution occurs. Thisapplication may have been the first recorded practicalapplication of extremely small gold particles for biosensing.9The use of AuNPs for colorimetric sensing exploits the interparticledistance dependent localised surface plasmon resonance (LSPR)10–12property.Biological processes and biomolecular-interactionscan be monitored because they can be used to control thedispersion and aggregation of the NPs. Depending on the size of theAuNPs, controlled aggregation of the particles can result in colour13–15changes,from pink to violet to pale blue. This phenomenon hasbeen used in home pregnancy tests and in analyses for specific gene16,17sequencesand for colorimetric detection of a variety of18–20analytes.It is the anticipated colour changes during aggregation(or dispersion of aggregates) that provide a platform for21,22colorimetric detection using AuNPs as signal transducers.Theaggregated AuNPs not only give different colours from dispersedAuNPs but also different surface enhancement abilities of Raman23scattering.J. Name., 2013, 00, 1-3 1This journal is The Royal Society of Chemistry 20xxPlease do not adjust marginsNanoscale Accepted ManuscriptPublished on 28 November 2017. Downloaded by UNIVERSITY OF LINCOLN on 28/11/2017 11:17:07.ARTICLE
Please doNanoscalenot adjust marginsPage 2 of 16View Article OnlineDOI: 10.1039/C7NR06367AARTICLEJournal asmonresonanceLuminescenceTarget analyteDispersed AuNPsAggregated AuNPsFigure 1 Physical and chemical properties of AuNPs and schematic illustration of AuNPs (aggregation/dispersion) colorimetric baseddetection systems. The unique properties of AuNPs, such as their high absorption coefficient, scattering flux, luminescence andconductivity, as well as their ability to enhance electromagnetic fields, quench (or enhance) fluorescence and catalyse reactions, providenumerous possibilities to exploit these particles for sensing and quantification purposes.10,186,187Typically, NPs biosensors consist of immobilised ligand or abiological substrate which undergo transformation in the presence24of an analyte. The analyte induces a modification in the substratecomposition or conformation, thus imparting a change to theenvironment of the NPs, resulting in changes in the aggregationstatus of NPs leading to detectable colour changes.25–27 In order todevelop efficient and reliable sensors, it is essential to improve boththe recognition and transduction processes through thedevelopment of novel materials. Nanomaterials can be fabricatedto produce platforms with improved signal to noise (S/N) ratios by28miniaturisation of the sensor elements.Traditionally, analyte detection and quantification involverecording the absorbance or fluorescence emitted fromsubstrates modified with chromogenic or fluorogenic reportermolecules. Fluorescence resonance energy transfer (FRET)substrates or indirect sensor systems depend on sensing thereactions of unmodified substrates to produce a detectablespectroscopic signal. Although these approaches, in general,are adequate for many applications (commercial assays kitsare available), there is a need to improve sensitivity for a29–33variety of other applications.NPs-based assays have now made it possible to measure minute34changes in enzyme activity with high accuracy and precision. Avariety of NPs-based sensing systems have been developed withvarying degrees of success and reliability. These sensing systems arevaluable tools for the measurement of enzyme activity in real timeand can be used for high-throughput screening of enzyme activity35and in drug discovery. This review includes a brief introduction tothe physical phenomenon (i.e., colours) associated with AuNPs andtheir aggregation, discussion of the inter-particle forces of AuNPsand factors controlling AuNPs colloidal stability and aggregation,along with general strategies for the stabilisation or aggregation ofthe colloidal particles. The focus is on the mechanisms andstrategies of biosensing assays, the common challenges, currenttrends in the field, real sample analysis, and exploitation of the36–38anisotropic properties of AuNPs as colorimetric probes.1. Localised surface plasmon resonance (LSPR) ofAuNPsThe fundamental concept underpinning light absorption by metalNPs is the coherent oscillation of the conduction band electrons26induced by the interacting electromagnetic field. In the case ofAuNPs, the oscillations involve the 6s electrons in the conductionband. The boundary and surface effects become more dominantwhen the particle dimensions become less than 100 nm. The opticalproperties of small metal NPs are dominated by the collective39oscillation of the conduction electrons. When the incident photonfrequency is resonant with the collective oscillation of theconduction band electrons, the radiation is absorbed to give anabsorption band. This phenomenon is known as localized surfaceplasmon resonance (LSPR).Unique LSPR properties and the colours associated with theaggregation and dispersion of the colloidal particles make AuNPs2 J. Name., 2012, 00, 1-3This journal is The Royal Society of Chemistry 20xxPlease do not adjust marginsNanoscale Accepted ManuscriptPublished on 28 November 2017. Downloaded by UNIVERSITY OF LINCOLN on 28/11/2017 11:17:07.Surfacefunctionalisation
Page 3 of 16Please doNanoscalenot adjust marginsView Article OnlineDOI: 10.1039/C7NR06367AJournal NameARTICLE21,52Published on 28 November 2017. Downloaded by UNIVERSITY OF LINCOLN on 28/11/2017 11:17:07.Table 1 Chronological order of events leading to the different uses of AuNPs.Periodth4 Century A.Dth17 CenturyInventorsRomansAchievementLycurgus 51-1973FrensTurkevichFeynman"Purple of Cassius" for glassstainingScientific evaluation ofAuNPs colour changeInvention of ultramicroscopeMie theory – Fundamentalunderstanding of the NPsinteractions withelectromagnetic radiationSynthesis of AuNPpreparationsMention of NPs in a famouslecture in which hepropounded that "There'splenty of room at thebottom" meaning at thenanoscale.First biomedical use inimmunochemical staining19601971Faulk andTaylorRef40416424344,45determined by the material composition and particle size.Larger NPs offer higher sensitivity as their surface plasmons havehigher molar extinction coefficients. It has been found that themolar extinction coefficients triple in magnitude when the AuNPs53–55size increases from 4 to 35 nm.The ratio of maximumabsorbance at the longer and original wavelength (e.g., A600/A520 forAuNPs) is often used to quantify the extent of aggregation and it is56,57known as an aggregation parameter.2. Colloidal AuNPs stabilizationA major consideration in the use of AuNPs in a variety of biomedicalapplications is that the stability of colloidal solutions and changes inaggregation should be controllable and predictable. Stability of thegold solutions can be achieved by the introduction of moleculesthat interact with AuNPs through bonding and/or electrostaticinteractions.58,59For this purpose, various biological probes have been used for thestabilization and/or functionalisation of colloidal AuNPs; theseinclude nucleic acids, enzymes, receptors, lectins, antibodies andsuperantigens.60–644647It has been found that the electromagnetic coupling of NPsbecomes effective when the inter-particle distances are less than48,492.5 times their individual diameters.Aggregation can induce thecoupling of the AuNPs plasmon modes, producing a red shift andbroadening of the SPR band, associated with the longitudinal8resonance in the optical spectrum. As a result, aggregation usuallychanges the original red colour of the AuNPs dispersion into purple50or blue. The strong enhancement of the localized electric fieldwithin the interparticle spacing, broadens and red shifts the SPRspectra. Interparticle plasmon coupling is rather complex anddependent on a number of factors such as aggregate morphology19and NPs density.Aggregation or dispersion of NPs can be initiated by changes in theexternal environment. These stimuli can cause the AuNPs to eitheraggregate or disperse, accompanied by a shift in the absorptionspectrum of the AuNPs, and consequently the colour of thecolloidal solution changes. The extent of aggregation/re-dispersionis proportional to the absorption peak shift, and thus the extent ofsignal change is quantifiable offering a direct measure of the effectof the inducing agent e.g., an active enzyme.51 For AuNPs in the sizerange of 13-300 nm, progressively increased aggregation ischaracterized by a gradual decrease of the plasmon peak at 520 nmand the appearance of a new peak between 600-700 nm withcolour change of the resultant solution ranging from red to purpleor blue depending on the degree of aggregation (Fig. 3A) whereasthe band at 520 nm is the SPR of the spherical AuNPs, however withaggregation the new band appear 600 – 700 nm appears (see Fig.3B). In some cases, the LSPR spectrum may be featureless and thesolution could turn colourless, showing extreme aggregation, whenthe plasmon band shifts into the infra-red (IR) region where mostvisible light is scattered.The sensitivity of a colorimetric assay is dependent on the molarextinction coefficients of the NPs plasmon bands, which are in turnFigure 2. The reaction of Lange gold chloride test on the cerebrospinal fluidin congenital syphilis. This Figure has been reproduced from Ref 9.2.1 DLVO and non-DLVO forcesThe stabilisation phenomenon of Au particles in a well-defined andcontrolled assembly has been generally explained by the Derjaguin65,66Landau-Verwey-Overbeck (DLVO) theory,usually expressed inJ. Name., 2013, 00, 1-3 3This journal is The Royal Society of Chemistry 20xxPlease do not adjust marginsNanoscale Accepted Manuscriptideal colorimetric reporters for biological analysis.
Please doNanoscalenot adjust marginsPage 4 of 16View Article OnlineDOI: 10.1039/C7NR06367AJournal Nameabcdefjh(A)(B)AbsorbancePublished on 28 November 2017. Downloaded by UNIVERSITY OF LINCOLN on 28/11/2017 11:17:07.terms of the balance between attractive Van der Waals forces andthe repulsive electrostatic interactions, to describe the colloidalstability of aqueous dispersions.66 The DLVO theory accounts for thepotential energy variations that occur when two particles approacheach other with the resultant net attraction and repulsion forces asa function of interparticle distance.65–672.2 Stabilization strategiesStabilization of colloidal Au is achieved either electrostatically orsterically by the use of various surface ligands or by a combinationof both electrostatic and steric repulsion forces (Fig. 4 A-C) 58,69–71.In aqueous solutions, zero charged bare AuNPs tend to aggregatebecause of Van der Waals attractive forces. The fundamentalimportance in the design of AuNPs-based colorimetric sensingplatforms is to achieve colloidal stabilization by introducingrepulsive forces between the particles in order to prevent colloidalaggregation in the absence of the target analyte. AuNPsstabilization or aggregation depends on the net potential betweeninterparticle attractive and repulsive forces.58,69–73Further control of AuNPs stability is usually achieved through theintroduction of colloidal stabilizers by using chemical couplingmethods (e.g., Au–thiol, Au–amine), electrostatic and physicaladsorption, etc. Common colloidal stabilizers include charged smallmolecules, polymers and polyelectrolytes. In the case ofelectrostatic stabilization (Fig. 4A), each particle carries a "similar"electrical charge, and together with the counter ions in themedium, they form a repulsive electric double layer that stabilizes74the colloid against Van der Waals attractive forces. Since thethickness of the electrical double layer is governed by the bulk ionicstrength of the liquid medium, electrostatic stabilization is highlysensitive to salt concentration.72,73With steric stabilization (Fig. 4B), ligands adsorbed or bound to theparticle surfaces form a physical barrier that prevents the particlesfrom crowding. The strength of this stabilization effect is notsensitive to change in ionic strength but determined by molecularsize and capping density. Both electrostatic and steric stabilizationare known as the electrosteric effect (Fig. 4C). Biomolecules, forexample, drugs, peptides, nucleic acids, and proteins that are highlycharged and have polymeric properties can be effective stabilizers.69–71Wavelength nmFigure 3. A) The gradual colour change as functionalised AuNPs are exposedto increasing enzyme activity resulting in increased aggregation, B) Spectralchanges of AuNPs solutions after incubation with increasing enzyme activity(incubation of peptide capped AuNPs with the target enzyme for 10 minutesat 37 C). This figure has been adapted from Ref 100 with permission fromElsevier.According to this theory, the net interaction potential G betweentwo AuNPs is determined by the Van der Waals attraction (G vdW)and electrostatic repulsion (G elec) values,ΔG ΔG Van der Waals Δ G electrostatic (1)Although there is considerable body of research information insupport of the DLVO model, it has long been understood that theclassical DLVO theory does not completely explain the results acrossdifferent experimental settings. For example, the prediction of themodel is contradicted when two particles or surfaces approach68closer than a few nanometres. In this instance, non-DLVO forcessuch as different hydrophobic, steric and solvation forces come intoplay. As a result, the traditional DLVO theory has thus beenextended to include the latter as described in the followingequation:ΔG ΔG Van der Waals attraction ΔG electrostatic repulsion ΔGnon-DLVO forces . (2)The common approach for the use of AuNPs in colorimetric assaysinvolves the preparation of a stable colloidal solution, whosestability is disrupted upon the addition of the analyte with resultant75colour change . The mechanisms involved in interactions betweenthe colloidal particles leading to aggregation or dispersion of theparticles are given below:(i) formation of interparticle bond crosslinking (CL), (ii) removal ofcolloidal stabilisation leading to non-crosslinking (NCL) aggregation,(iii) There is also another colorimetric sensing strategy that does notrely on changes in NPs stability, but on morphology changesinduced by a chemical reaction on the surface of the metal NP(AuNPs based plasmonic ELISA sensors).3. Interparticle crosslinking (CL) aggregationInterparticle CL aggregation is a mechanism in which A
as colorimetric biosensors. Keywords: biosensors, colloids, gold nanoparticles, nanotechnology, surface plasmon resonance, enzymes, quantification. Introduction Gold nanoparticles (AuNPs) (derived from the Greek word nanus, meaning dwarf) are currently used in a variety of biomedical applications, due to their size-dependent chemical,
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Materials Science and Engineering, Massachusetts Institute of :liju@mit.edu cCollege of Physics and Electronic Engineering, Jiangsu Normal University, Xuzhou 221116, China This journal is ª The Royal Society of Chemistry 2012 Nanoscale, 2012, 4, 4883-4899 4883 Nanoscale Dynamic Article LinksC
Accounts of Lincoln’s interest in colonization include Eric Foner, “Lincoln and Colo-nization,” in Our Lincoln: New Perspectives on Lincoln and His World, ed. Eric Foner (New . 118 civil war history Despite the considerable attention to Lincoln and the black abolitionist
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