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biosensors Article

Computational Study of Sensitivity Enhancement in Surface Plasmon Resonance (SPR) Biosensors by Using the Inclusion of the Core-Shell for Biomaterial Sample Detection Widayanti 1 1 2

*

ID

, Kamsul Abraha 2, * and Agung Bambang Setio Utomo 2

Department of Physics, Universitas Islam Negeri (UIN) Sunan Kalijaga, Yogyakarta 55281, Indonesia; [email protected] Department of Physics, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia; [email protected] Correspondence: [email protected]

Received: 24 May 2018; Accepted: 1 August 2018; Published: 7 August 2018







Abstract: A theoretical analysis and computational study of biomaterial sample detection with surface plasmon resonance (SPR) phenomenon spectroscopy are presented in this work with the objective of achieving more sensitive detection. In this paper, a Fe3 O4 @Au core-shell, a nanocomposite spherical nanoparticle consisting of a spherical Fe3 O4 core covered by an Au shell, was used as an active material for biomaterial sample detection, such as for blood plasma, haemoglobin (Hb) cytoplasm and lecithin, with a wavelength of 632.8 nm. We present the detection amplification technique through an attenuated total reflection (ATR) spectrum in the Kretschmann configuration. The system consists of a four-layer material, i.e., prism/Ag/Fe3 O4 @Au + biomaterial sample/air. The effective permittivity determination of the core-shell nanoparticle (Fe3 O4 @Au) and the composite (Fe3 O4 @Au + biomaterial sample) was done by applying the effective medium theory approximation, and the calculation of the reflectivity was carried out by varying the size of the core-shell, volume fraction and biomaterial sample. In this model, the refractive index (RI) of the BK7 prism is 1.51; the RI of the Ag thin film is 0.13455 + 3.98651i with a thickness of 40 nm; and the RI of the composite is varied depending on the size of the nanoparticle core-shell and the RI of the biomaterial samples. Our results show that by varying the sizes of the core-shell, volume fraction and the RIs of the biomaterial samples, the dip in the reflectivity (ATR) spectrum is shifted to the larger angle of incident light, and the addition of a core-shell in the conventional SPR-based biosensor leads to the enhancement of the SPR biosensor sensitivity. For a core-shell with a radius a = 2.5 nm, the sensitivity increased by 10% for blood plasma detection, 47.72% for Hb cytoplasm detection and by 22.08% for lecithin detection compared to the sensitivity of the conventional SPR-based biosensor without core-shell addition. Keywords: biomaterial detection; SPR-based biosensors; computational study; Fe3 O4 @Au core-shell

1. Introduction Currently, there is increasing interest in the development of magnetic and plasmonic nanoparticles as active materials for biomolecule detection [1]. A new nanoparticle that combines multiple functions or properties has attracted considerable attention because of its revolutionary technology which enables the sensitivity enhancement of surface plasmon resonance (SPR)-based biosensors. The optical sensor based on SPR is one of the most sensitive methods for detecting biomolecules and works by detecting the changes of the material refractive index, having a fast response and real-time, bio-specific interaction analysis as well as being a label-free technique [2]. SPR is a physical process that occurs Biosensors 2018, 8, 75; doi:10.3390/bios8030075

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when the wave vector of the evanescent wave (EW) matches the wave vector of the surface plasmon (SP) under the total internal reflection condition. This resonance condition is expressed as ω0 ω0 n p sin θSPR = c c

ε m n2d ε m + n2d

!1/2 (1)

The variable on left hand side is the propagation constant of a light beam incident at a resonance angle θSPR through the light coupling device (prism) of a refractive index, n p , while the right-hand is the propagation constant with ε m as real part of the metal permittivity and nd as the refractive index of a dielectric material or sensing medium. ω0 and c are the light frequency and the speed of the light in a vacuum, respectively. The evanescent wave occurs at the metal–dielectric interface when a p-polarized wave passes a prism through a metallic layer into a dielectric media. The wave vector of the evanescent wave is a function of refractive indices of the dielectric, metal and analyte, i.e., the sensing medium. Therefore, if there is a local change in the refractive index of the sensing medium near the metal surface, this will in turn lead to a change in the propagation constant of SP and in the angle of incidence of light in order to satisfy the resonance. When applying an SPR biosensor, the Kretschmann geometry [3] of attenuated total reflection (ATR) has been found to be very suitable for this sensing and has become the most widely used geometry in SPR biosensors. Mostly, the metallic layer that is used in SPR biosensor measurement consists of either gold or silver. The first demonstration of SPR-based sensors for bio-sensing was reported in 1983 by Liedberg et al. [4]. Several methods to enhance the sensitivity of SPR biosensors for detecting biomolecules have been explored for the detection of DNA hybridization [5], acetylcholinesterase [6], membrane protein [7] and human blood-group [8]. SPR can also be a potential candidate for bio-sensing other biological properties such as haemoglobin concentration. Some research has indicated that the conventional SPR-based biosensor was not capable of sensing a small amount of biomolecules such as DNA, virus or bacteria [9] due to the poor attachment of biomolecules onto the metal surface, and the fact that the low concentrations involved are difficult to detect directly [10]. In addition, the changes in the refractive index of the medium [11] under a thin metal layer are very small. Therefore, the enhancement of sensitivity for detecting small biomolecules can be developed by several approaches, such as by adding a nanoparticle core-shell as the active material in the conventional SPR-based biosensor. Comparing with a nanoparticle with a spherical shape, the inclusion of a core-shell aims to avoid polar resonance [12] and to obtain the plasmonic wavelength by varying the radius of the core and the thickness of the shell. A core-shell was said to be a unique material since it is a combination of magnetic and plasmonic materials which have different optical properties to the core and the shell. Some studies have observed, either experimentally or theoretically, the optical properties of the core-shell when included in SPR-based biosensors. It is observed that the optical response or resonance spectrum of the core-shell depends on the size of the core and the thickness of the shell. Hence, the core-shell can be used to tune the plasmonic wavelength [13], e.g., for AgSiO2 [12], TiO2 @Au, TiO2 @Ag [14] and Fe3 O4 @Au [15]. The study of the optical response of an Fe3 O4 @Au core-shell was performed by varying the radius of Fe3 O4 and the thickness of Au. There was a shift in the resonance spectrum due to the changes in the size of the core and the shell. The core Fe3 O4 can make the biomolecule attachment easier with its magnetic properties, while the shell Au exhibits nontoxicity and compatible properties. Furthermore, the performance of the SPR-based biosensor can be enhanced by using the nanoparticle core-shell Fe3 O4 @Au rather than using only Fe3 O4 or only Au. The presence of Fe3 O4 @Au is also capable of enhancing the immobilization of biomolecules such as haemoglobin [16], as well as detecting antibody IgG [17] and detecting the DNA of chum salmon [18]. The inclusion of Fe3 O4 @Au in the SPR-based biosensor was performed for the enhancement of the detection of thrombin [19] and the protein concentration of interleukin IL17 [20]. Detection of haemoglobin concentration has been explored by SPR-based biosensors for three

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wavelengths (401.5 nm, 589.3 nm and 706.5 nm) with haemoglobin concentrations varying between 0 Biosensors 3 of 14 and 140 g/L 2018, [21].8, x FOR PEER REVIEW Due to the coating of the Au shell for the magnetic core, which protected it from oxidation and concentration has been explored by SPR-based biosensors for three wavelengths (401.5 nm, 589.3 nm aggregation, the stabilization of the core-shell (Fe3 O4 @Au) was obviously enhanced. In addition, and 706.5 nm) with haemoglobin concentrations varying between 0 and 140 g/L [21]. the current SPR technology has a number of advantages; i.e., a high processing sensitivity and Due to the coating of the Au shell for the magnetic core, which protected it from oxidation and selectivity, being the non-destructive, a large tunability into the infrared (IR) spectrum aggregation, stabilization of the core-shell (Fe3O4from @Au) the was visible obviously enhanced. In addition, the region, label-free analysis and being capable of real-time monitoring. SPR is a kind of electromagnetic current SPR technology has a number of advantages; i.e., a high processing sensitivity and resonance that exists when there is an interface between thevisible metalinto andthe dielectric. This system has selectivity, being non-destructive, a large tunability from the infrared (IR) spectrum analysis and being[22,23]. capable of method real-time monitoring. is ashape kind and of the been region, used to label-free sense various biomolecules This is very sensitiveSPR to size, electromagnetic resonance that exists when that therekeeps is an interface between dielectric. refractive index of the surrounding medium contact with the the thinmetal metaland layer. When the This system has into beencontact used to with sense the various biomolecules [22,23]. This method sensitive biomolecule comes metal thin film, it is adsorbed onto isitsvery surface and to hence size, shape and the refractive index of the surrounding medium that keeps contact with the increases the refractive index at the interface, resulting in a change of their resonance angle. thin metal layer. When the biomolecule comes into contact with the metal thin film, it is adsorbed onto its In this paper, we have been investigating the ATR spectrum of four-multilayer biosensors surface and hence increases the refractive index at the interface, resulting in a change of their based on an SPR system with Fe3 O4 @Au core-shell addition to detect biology samples that play resonance angle. roles in the of light tissue of the as blood plasma, haemoglobin In interaction this paper, we have and beenthe investigating thebody, ATR such spectrum of four-multilayer biosensors (Hb) cytoplasm andanlecithin. Thewith magnetic properties ofaddition Fe3 O4 @Au are not utilized in this because based on SPR system Fe3O4@Au core-shell to detect biology samples that work play roles we were notinteraction applied the concern Fe3plasma, O4 @Auhaemoglobin properties such in the of external light andmagnetic the tissuefield. of theWe body, such at as the blood (Hb)as its cytoplasm and to lecithin. The magnetic Fe3biocompatible. O4@Au are not utilized in this work because dispersivity, easily its fabrication and properties synthesis of and The refractive indices of those we were not applied the external magnetic field. We concern at the Fe 3 O 4 @Au properties such as its biomaterial samples have been measured by total internal reflection [24]. The blood plasma delivers dispersivity, easily to its fabrication and synthesis and biocompatible. The refractive indices of those oxygen and nutrients to the cells of the organs of the body and also transports waste products to be biomaterial samples have been measured by total internal reflection [24]. The blood plasma delivers excreted. Hb cytoplasm is the functional molecule in the erythrocytes, increasing oxygen carrying oxygen and nutrients to the cells of the organs of the body and also transports waste products to be capacity. Lecithin is the fundamental component of the membrane lipid of cells. The different effective excreted. Hb cytoplasm is the functional molecule in the erythrocytes, increasing oxygen carrying permittivity of Fe3 O4 @Au + biomaterial composites leads to a change in the SPR resonance angle. capacity. Lecithin is the fundamental component of the membrane lipid of cells. The different This study was focused on effects of the size of the core radius and shell thickness on the effective effective permittivity of the Fe3O 4@Au + biomaterial composites leads to a change in the SPR resonance permittivity of Fe O @Au by computational approximation. Also, studied the effects of the volume 3 4 angle. This study was focused on the effects of the size of the corewe radius and shell thickness on the fraction and the size of the core-shell on the composite effective permittivity and on the reflectivity effective permittivity of Fe3O4@Au by computational approximation. Also, we studied the effects of of the volumebiosensor fraction and size of thesample core-shell on the composite permittivity and on the of the SPR-based for the biomaterial detection. Then, theeffective enhancement of the sensitivity reflectivity of the biosensor for biomaterial sample detection. Then, the enhancement of SPR configuration wasSPR-based estimated. the sensitivity of SPR configuration was estimated.

2. Materials and Methods 2. Materials and Methods

2.1. Kretschmann Configuration with Four Layers 2.1. Kretschmann Configuration with Four Layers

Here, we apply the analytical and computational approximation to calculate reflectivity in the Here, we apply the analytical and computational approximation to calculate reflectivity in the attenuated total reflection (ATR) method and determined the effective permittivity of the composite attenuated total reflection (ATR) method and determined the effective permittivity of the composite (the mixture of Fe O @Au and biomaterial embedded in water). In this study, we used the Kretschmann (the mixture3 of4 Fe3O4@Au and biomaterial embedded in water). In this study, we used the configuration [3] with four layers. I.e., four prism/Ag/composite/air, shown in Figure 1. Figure The angle θi and Kretschmann configuration [3] with layers. I.e., prism/Ag/composite/air, shown in 1. The θr areangle the incident and the reflection angle, respectively, k is the wave vector component along x-axis, x respectively, is the wave vector θ i and θr are the incident and the reflection angle, and dcomponent is the thickness of eachand layer. along x-axis, d is the thickness of each layer.

Figure 1. Kretschmann configuration forfor a surface plasmon with the Figure 1. Kretschmann configuration a surface plasmonresonance resonance(SPR)-based (SPR)-based biosensor biosensor with 3 O 4 @Au core-shell. the inclusion of Fe inclusion of Fe3 O4 @Au core-shell.

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Figure Figure 22 shows shows the the model model of of the the composite compositelayer layercontaining containingthe theinclusion inclusionmaterial material(Fe (Fe33O O44@Au + biomaterial samples) and the host material (water). The inclusion material consists of the scattered material (water). scattered grain material (Fe @Au) and and the the interfacial interfacial shell shell material material (biomaterial (biomaterial sample). sample). (Fe33O44@Au)

Figure 2. The composite model contains the complex particle (inclusion material) and the host material. Figure 2. The composite model contains the complex particle (inclusion material) and the host material.

In this SPR configuration, the refractive index of the BK7 glass prism is 1.510, the wavelength of In this SPR configuration, the refractive index ofrefractive the BK7 glass is 1.510, the +wavelength of the electromagnetic wave is 632.8 nm, the complex indexprism of silver 0.13455 3.98651i [25], the electromagnetic wave is 632.8 nm, the complex refractive index of silver 0.13455 + 3.98651i [25], and the refractive index of biomaterial sample is varied. The refractive index of water and air is 1.33 and index of biomaterial sample varied. refractive of water was and dair is 1.33 and the 1.0, refractive respectively [9]. The thickness of the Agisfilm was The d = 40 nm, andindex the composite = 20 nm. and 1.0, respectively [9]. The thickness of the Ag film was d = 40 nm, and the composite was d = 20 nm. The ATR reflectivity R is given by the Fresnel equation [26]. The ATR reflectivity R is given by the Fresnel equation [26].

with with

2 ik j z d j

2

2 ri j + rj k e j z dj R = ri j k2 = ri j + r j k e2ik 2 ik j z d j R = ri j k = 1 + ri j rj k e 2ik d 1 + ri j r j k e j z j

(2) (2)

ki ε j − k j ε i r i j = ki ε j − k j ε i ri j = ki ε j + k j ε i

(3) (3)

2

ki ε j + k j ε i

where rij is the surface reflectivity coefficient between medium i and medium j. k ij is the wave vector where isperpendicular the surface reflectivity coefficient between i and medium j. kito is wave component to the surface, k x is the wavemedium vector component parallel thethe surface, j whereas d and ε are, respectively, the j-th layer thickness and the i-th medium dielectric constant. j i perpendicular to the surface, vector component is the wave vector component parallel to the surface,

whereas and are, respectively, the j-th layer thickness and the i-th medium dielectric constant. 2.2. The Effective Permittivity of the Spherical Core-Shell 2.2. The Permittivity of 3the Core-Shell OurEffective simulation of the Fe O4Spherical @Au core-shell is performed on the model as shown in Figure 3. The magnetic nanoparticle core-shell consists of an Fe3 O4 coreonofthe radius b coated by ainmetallic AuThe of Our simulation of the Fe3O4@Au core-shell is performed model as shown Figure 3. thickness a − b . The dielectric constants of the magnetic nanoparticle and the metallic Au are ε ( ) c, magnetic nanoparticle core-shell consists of an Fe3O4 core of radius b coated by a metallic Au of and ε s , respectively. Thedielectric dielectricconstants constantsof ofthe the magnetic materials nanoparticle are dependent on the their refractive thickness ( − ). The and metallic Auindices. are , and

, respectively. The dielectric constants of the materials are dependent on their refractive indices.

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Figure @Au core-shell. core-shell. Figure 3. 3. The The model model of of the the nanoparticle nanoparticle Fe Fe33O4@Au

is adopted adopted from from Schlegel Schlegel [27] [27] through through reflectivity reflectivity measurement and The value of complex ε c is the Kramers-Kronig relation, and can be quoted from the work by Johnson and and Christy [25]. [25]. The Kramers-Kronig relation, and ε s can be quoted from the work by Johnson Christy effective permittivity thethe FeFe 3O4O core-shell is isderived (ε eff(ε) effof) of The effective permittivity core-shell derivedfrom fromthe theinternal internal homogenization homogenization 3 @Au 4 @Au for plasmonic and dielectric constituent materials [28], namely namely εsε )s) aa33 ((εεcc++2ε 2εs )s )++2b23b(3ε(cε−c −

ε ε eff==ε ε s eff

s

aa 3 ((εεc c++2ε2εs )s − ) −bb(3ε(cε−c −ε sε) s ) 3

3

(4) (4)

2.3. The Effective Permittivity of the Composite

2.3. The Permittivity of the TheEffective effective permittivity ofComposite the composite (ε effc ) is calculated by neglecting the correlation between inclusion materialof(complex material(ε or) Fe sample) and host 4 @Au + biomaterial The the effective permittivity the composite is3 O calculated by neglecting the correlation effc material (water) using the Maxwell Garnett formula [29]: between the inclusion material (complex material or Fe3O4@Au + biomaterial sample) and host   material (water) using the Maxwell Garnett [29]: ε effc −formula εm ε effc − ε n (1 − F ) +F =0 (5) 2ε effc + ε m ε effc + ε n with

with

(1 − F )

 ε −ε  ε effc − ε m + F  effc n  = 0 2ε effc + ε m + εn  εε − 2ε + ε + 2α effc ε

εn = ε1

( 1 ( 2 2) 1) (2ε 1 + ε 2 ) − α(ε 2 − ε 1 )

(5) (6)


3 where α = Ra , a is the radius of Fe3 O4 @Au, radius + 2α ( 2ε1 +Rεis2 )the (ε 2 −ofε1the ) complex particle (Fe3 O4 @Au + ε n =fraction ε1 biomaterial sample), F is the volume of the inclusion material to the host material, ε n is(6) the − α (ε 2 − ε1 ) ( 2ε + ε 2 )the dielectric constant of the complex particle and1 ε m is dielectric constant of the host material. ε 1 is 3 the biomaterial sample dielectric constant as the interfacial shell, while ε is the dielectric constant of where α =  a  , a is the radius of Fe3O4@Au, R is the radius of the 2complex particle (Fe3O4@Au R the scattered grain (Fe O 3 4 @Au core-shell). In this condition ε 2 = ε eff in the Equation (4).  

+ biomaterial sample), F is the volume fraction of the inclusion material to the host material, εn is 2.4. Sensitivity from ATR Spectrum the dielectric constant of the complex particle and ε m is the dielectric constant of the host material. The calculation of the sensitivity of the SPR-based biosensor is written as [30] ε1 is the biomaterial sample dielectric constant as the interfacial shell, while ε 2 is the dielectric ∆θSPR constant of the scattered grain (Fe3O4@Au core-shell). In this condition ε 2 = ε eff in the Equation 4. (7) S= ∆n where ∆θSPR isfrom the difference in the SPR angle and ∆n is the change in refractive index. Whereas the 2.4. Sensitivity ATR Spectrum sensitivity enhancement can be obtained from the relation The calculation of the sensitivity of the SPR-based biosensor is written as [30] S − S core−shell θSPR ∆S = core−shell Δno × 100% (8) Sno = −shell S core (7)

Δn

where Score−shell is the sensitivity of the conventional system (prism/Ag/biomaterial sample/air), ΔθSPRis the is the difference in the SPR angle and Δ is the change in refractive index. Whereas where Sno core−shell sensitivity of the proposed system (prism/Ag/Fe 3 O4 @Au + biomaterial sample/air). the sensitivity enhancement can be obtained from the relation

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3. Results and Discussion The changes of the radius of the Fe3 O4 core and the thickness of the Au shell lead to changes in the effective permittivity of the Fe3 O4 @Au core-shell, while the change of the inclusion material to the host material leads to a change in the effective permittivity of the composite. Therefore, if the complex particle is applied to the SPR-based biosensor system, this change leads to the enhancement of the sensitivity of this biosensor. We can show from the reflectivity spectrum that the resonant angle shifts to the right. Table 1 shows the effective permittivity of the core-shell (Equation (4)) for variations in the shell thickness. Table 2 shows the effective permittivity of the core-shell for variations in the core radius, and Table 3 shows the effective permittivity of the core-shell for f = (b/a)3 variation. The data in Tables 1–3 are presented in Figures 4–6, respectively. Table 1. The effective permittivity of an Fe3 O4 @Au core-shell for variations of shell thickness. Imag: imaginary. b (nm)

a (nm)

Shell Thickness (nm)

f = (b/a)3

εeff (Real, Imag)

10 10 10 10 10 10 10 10

11 13 15 17 20 30 40 100

1 3 5 7 10 20 30 90

0.75 0.46 0.30 0.20 0.13 0.03 0.02 0.001

1.0092, 3.2011 −2.5021, 3.0123 −4.8721, 2.6948 −6.4556, 2.3952 −7.9297, 2.0516 −9.7428, 1.5407 −10.212, 1.3921 −10.539, 1.2845

Table 2. The effective permittivity of an Fe3 O4 @Au core-shell for variations of core radius. b (nm)

a (nm)

f = (b/a)3

εeff (Real, Imag)

10 12 14 16 18 20 100

11 13 15 17 19 21 101

0.75 0.78 0.81 0.83 0.85 0.86 0.97

1.0092, 3.2011 1.3637, 3.2017 1.6230, 3.2000 1.8209, 3.1975 1.9768, 3.1947 2.1028, 3.1921 3.0427, 3.1587

Table 3. The effective permittivity of an Fe3 O4 @Au core-shell for variations of f = (b/a)3 . b (nm)

a (nm)

f = (b/a)3

εeff (Real, Imag)

9.5 9.0 8.5 8.0 7.5 7.0 6.5

10 10 10 10 10 10 10

0.85 0.73 0.61 0.51 0.42 0.34 0.27

2.04008, 3.19339 0.77837, 3.19889 −0.49070, 3.16118 −1.74550, 3.08115 −2.96636, 2.96227 −4.13333, 2.81043 −5.22780, 2.63368

Figure 4 shows that the increasing shell thickness for a fixed core radius (10 nm) leads to the decreasing of the real and imaginary part of the core-shell’s effective permittivity. However, the real part tends to be constant at the shell thickness above 30 nm.

7.5 8.0 7.0 7.5 6.5 7.0

10 10 10 10 10 10

0.42 0.51 0.34 0.42 0.27 0.34

−2.96636,3.08115 2.96227 −1.74550, −4.13333,2.96227 2.81043 −2.96636, −5.22780,2.81043 2.63368 −4.13333,

6.5 10 0.27 −5.22780, 2.63368 Figure 4 shows that the increasing shell thickness for a fixed core radius (10 nm) leads to the the real andthe imaginary part of the core-shell’s permittivity. real Biosensorsdecreasing 2018, 8, 75 4ofshows Figure that increasing shell thickness for aeffective fixed core radius (10 However, nm) leadsthe to the part tends of to the be constant the shell part thickness 30 nm.effective permittivity. However, the real decreasing real and at imaginary of theabove core-shell’s

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part tends to be constant at the shell thickness above 30 nm.

( ⁄f )=. (b/a)3 . 4. The effective permittivity core-shell for of shell thickness and = Figure 4.Figure The effective permittivity ofofa acore-shell forvariations variations of shell thickness and Figure 4. The effective permittivity of a core-shell for variations of shell thickness and

=( ⁄ ) .

Figure 5 shows that increasing the core radius for a fixed shell thickness (1 nm) leads to an increase Figure 5real shows that increasing the corepermittivity radius for a fixed shell thickness (1 nm) leads to an increase in the of thethat core-shell’s effective imaginary tends to beto constant. Figurepart 5 shows increasing the core radius for awhile fixedthe shell thicknesspart (1 nm) leads an increase

in the real part the core-shell’s permittivity while the imaginary part to be constant. in the real of part of the core-shell’seffective effective permittivity while the imaginary part tends to betends constant.

Figure 5. The effective permittivity of a core-shell for variations of the radius of the core and ( ⁄5. )The . effective permittivity of a core-shell for variations of radius the radius of core the core Figure Figure 5. = The effective permittivity of a core-shell for variations of the of the andand f = (b/a)3 . =( ⁄ ) .

If the core-shell’s permittivity is viewed only from the = ( ⁄ ) variation, it shows that the If the core-shell’s viewed only from it shows )3 variation, ⁄ )permittivity increase = (permittivity leads toisis an increase in from the real imaginary partsit of the effective ⁄ ()b/a If the of core-shell’s viewed only thetheand =f (= variation, shows that the that the 3 PEER REVIEW Biosensors 2018, 8, x FOR 8 of 14 ⁄ ) leads an increase theand realimaginary and imaginary the effective increaseincrease of f = of(b/a=) ( leads to an to increase in theinreal partsparts of theofeffective permittivity

(Figure 6). Different radii of core-shell (a = 5 nm) with the same f = (b/a)3 variation shows the same permittivity (Figure 6). Different radii of core-shell (a = 5 nm) with the same = ( ⁄ ) variation effective permittivity value. Then, the effective permittivity of the composite can be obtained from shows the same effective permittivity value. Then, the effective permittivity of the composite can be Equation (5). from Equation (5). obtained

Figure 6. The effective permittivity of a core-shell for variations of f = (b/a)3 . Figure 6. The effective permittivity of a core-shell for variations of

=( ⁄ ) .

The thicknesses of the metalininthis thisSPR SPR system system isisthe thatthat must be carefully The thicknesses of the AgAg metal theother otherparameter parameter must be carefully controlled in order to obtain optimum performance for surface plasmon excitation. Therefore, the controlled in order to obtain optimum performance for surface plasmon excitation. Therefore, choice of the metal thickness is of utmost importance. In the configuration of SPR biosensor is prism/Ag/Fe3O4@Au + biomaterial sample/air, by varying the Ag thickness, the ATR spectrum shows where the Ag metal film thickness yields the most desirable resonance peak. As the Ag thickness increases (50–60 nm), the depth of the resonance peak decreases. This indicates a reduced coupling efficiency of light into the SP mode on the film. This is due to the fact that the metal begins to act as a reflectance plane when its thickness increases to a point where light cannot couple into the surface

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8 of 14 Figure 6. The effective permittivity of a core-shell for variations of

=( ⁄ ) .

the choice ofThe thethicknesses metal thickness of utmost importance. theparameter configuration biosensor of the Ag is metal in this SPR system is the In other that mustofbeSPR carefully is prism/Ag/Fe O @Au + biomaterial sample/air, by varying the Ag thickness, the ATR controlled3 in4 order to obtain optimum performance for surface plasmon excitation. Therefore, spectrum the shows where thickness most desirable resonance peak. Asbiosensor the Ag thickness choicethe of Ag themetal metal film thickness is of yields utmost the importance. In the configuration of SPR is 3O4the @Audepth + biomaterial varying the Ag thickness, the ATR spectrum shows increasesprism/Ag/Fe (50–60 nm), of the sample/air, resonancebypeak decreases. This indicates a reduced coupling the Ag filmmode thickness the most resonance Ag thickness efficiencywhere of light intometal the SP on yields the film. Thisdesirable is due to the factpeak. that As thethe metal begins to act increases (50–60 nm), the depth of the resonance peak decreases. This indicates a reduced coupling as a reflectance plane when its thickness increases to a point where light cannot couple into the efficiency of light into the SP mode on the film. This is due to the fact that the metal begins to act as a surface charge oscillations that upincreases the plasmon mode; whereas if thecouple Ag thin is very thin reflectance plane when its make thickness to a point where light cannot into film the surface (20–30 nm), this results that in more coupling intomode; the SP mode, but of (20–30 the evanescent charge oscillations make up the plasmon whereas if the Ag the thin amplitude film is very thin nm), this results in more coupling materials into the SPon mode, but thelayer amplitude of thethan evanescent wave that of the wave that penetrated to dielectric the metal is higher the amplitude penetrated to generated dielectric materials on thethe metal layer is was higher than the Obviously, amplitude offrom the surface surface plasmon that from metal, sensitivity reduced. these effects, plasmon that generated from metal, the sensitivity was reduced. Obviously, from these effects, a a compromise must be reached to obtain a satisfactory SPR system. Figure 7 was shows the optimal compromise must be reached to obtain a satisfactory SPR system. Figure 7 was shows the optimal thicknessthickness to support an SPR system determined to lie at 40 nm. From other literature, we get the to support an SPR system determined to lie at 40 nm. From other literature, we get the standardstandard of the thickness of theofmetal is in the nm. of the thickness the metal is in therange range 40–50 40–50 nm.

Figure 7.Figure The attenuated total reflection (ATR) spectra metalthicknesses thicknesses varying 7. The attenuated total reflection (ATR) spectrafor for Ag Ag metal varying from from 20 nm20 nm 60 nm SPR biosensor configuration prism/Ag/Fe33O biomaterial sample/air at to 60 nmtowith thewith SPRthe biosensor configuration prism/Ag/Fe O44@Au @Au+ + biomaterial sample/air at a =the 2.5 nm, the biomaterial sample is Hb cytoplasmwith withRI RI 1.3800 1.3800 and a = 2.5 nm, biomaterial sample is Hb cytoplasm andF =F 0.1. = 0.1. Biosensors 2018, 8, x FOR PEER REVIEW

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Based on the above results, we can choose the values of the core radii, the shell thickness and on the results, weradii can choose of the core the shell thicknesspermittivity and the ratio of Based the core to above the core-shell f = (the b/avalues theradii, desirable effective )3 to obtain ( ⁄ ) the ratio of the core to the core-shell radii = to obtain the desirable effective permittivity of of the Fe3 O4 @Au core-shell. Figure 8 shows that the desirable effective permittivity is obtained at the Fe3O4@Au core-shell. Figure 8 shows that the desirable effective permittivity is obtained at f = 0.85 and f = 0.73. For the presented model, we chose the moderate value of f = 0.73 for reflectivity f = 0.85 and f = 0.73. For the presented model, we chose the moderate value of f = 0.73 for reflectivity calculation because the shell is very thin for calculation because the shell is very thin forf f== 0.85. 0.85.

3 Figure 8. The8.ATR spectra with variations = ( (/b/a with biosensor configuration ) )with Figure The ATR spectra with variationsofof f = thethe SPRSPR biosensor configuration prism/Ag/Fe 3O4@Au/air (a = 2.5 nm) prism/Ag/Fe O @Au/air (a = 2.5 nm). 3 4

Figures 9 and 10 shows the effective permittivity of the composite (inclusion material) with volume fraction (F) variation given by the size variation of the core-shell a from 2.5 nm to 10 nm for the chosen fixed = ( / ) = 0.73. Here, F is the ratio between the amount of the inclusion material to the host material.

Figure 8. The ATR spectra with variations of

= ( / ) with the SPR biosensor configuration

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Figures 9 and 10 shows the effective permittivity of the composite (inclusion material) with volume Figures 9 and 10 shows the effective permittivity of the composite (inclusion material) with fraction (F) variation given by the size variation of the core-shell a from 2.5 nm to 10 nm for the chosen volume fraction (F) variation given by the size variation of the core-shell a from 2.5 nm to 10 nm for fixed = ( / ) = 0.73. Here, F is the ratio between the amount of the inclusion material to the the chosen fixed f = (b/a)3 = 0.73. Here, F is the ratio between the amount of the inclusion material host material. to the host material.

(a)

(b)

Figure 9. The composite effective permittivity with variations in the volume fraction (F) of the Figure 9. The composite effective permittivity with variations in the volume fraction (F) of the composite for the fixed size of the core-shell of (a) 2.5 nm and (b) 5.0 nm. composite for the fixed size of the core-shell of (a) 2.5 nm and (b) 5.0 nm.

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(b)

Figure 10. The composite effective permittivity with variations in the volume fraction (F) of the Figure 10. The composite effective permittivity with variations in the volume fraction (F) of the compositefor forthe thefixed fixedsize sizeofofthe thecore-shell core-shellofof(a) (a)7.5 7.5nm nmand and(b) (b)10 10nm. nm. composite

The reflectivity from the SPR-based biosensor consisting of a nanoparticle core-shell is shown in The reflectivity from the SPR-based biosensor consisting of a nanoparticle core-shell is shown Figures 11 and 12. If the layers only consist of prism/Ag/Hb cytoplasm/air (conventional SPR), the in Figures 11 and 12. If the layers only consist of prism/Ag/Hb cytoplasm/air (conventional SPR), dip of the ATR curve occurs at the incident angle 45.44° (black line). After the composite had been the dip of the ATR curve occurs at the incident angle 45.44◦ (black line). After the composite had been deposited on to the surface of the Ag thin film, the dip of the reflectivity curve was shifted to a larger deposited on to the surface of the Ag thin film, the dip of the reflectivity curve was shifted to a larger angle. Referring to Figure 11 for the volume fraction (F) = 0.1 and the Fe3O4@Au radii (a) varying angle. Referring to Figure 11 for the volume fraction (F) = 0.1 and the Fe3 O4 @Au radii (a) varying from from 2.5 nm to 10 nm, the SPR angle was shifted to a larger angle. By increasing the radii of 2.5 to 10the nm,angle the SPR angle wasincreases shifted toasa well. largerItangle. increasing the11radii Feminimum 3 O4 @Au, Fe3nm O4@Au, of resonance can beBy seen in Figure that of the the angle of resonance increases as well. It can be seen in Figure 11 that the minimum reflectivity are reflectivity are seen at 45.86° for core-shell radii 2.5 nm, while from Figure 12, for the volume fraction ◦ for core-shell radii 2.5 nm, while from Figure 12, for the volume fraction (F) = 0.8 and seen at 45.86 (F) = 0.8 and the Fe3O4@Au radii varying from 2.5 nm to 10 nm, the SPR angle is shifted to a larger the Fe3as O4well. @Au The radiifigure varying fromthat 2.5 the nm minimum to 10 nm, the SPR angle is shifted to a larger angle as well. angle shows reflectivity occurred at 47.40° for core-shell radii ◦ for core-shell radii of 5 nm and at The figure shows that the minimum reflectivity occurred at 47.40 of 5 nm and at 47.55° for radii of 7.5 nm. 47.55◦ for radii of 7.5 nm.

from 2.5 nm to 10 nm, the SPR angle was shifted to a larger angle. By increasing the radii of Fe3O4@Au, the angle of resonance increases as well. It can be seen in Figure 11 that the minimum reflectivity are seen at 45.86° for core-shell radii 2.5 nm, while from Figure 12, for the volume fraction (F) = 0.8 and the Fe3O4@Au radii varying from 2.5 nm to 10 nm, the SPR angle is shifted to a larger angle as2018, well.8, The Biosensors 75 figure shows that the minimum reflectivity occurred at 47.40° for core-shell10radii of 14 of 5 nm and at 47.55° for radii of 7.5 nm.

Figure 11. 11. The TheATR ATRspectra spectra volume fraction the composite = 0.1. radii of the forfor the the volume fraction of theofcomposite F = 0.1.FThe radiiThe of the core-shell 3 = 0.73 (biomaterial sample is Hb cytoplasm 3 core-shell varied from 2.5 nm to 10 nm with a fixed ( / ) varied from 2.5 nm to 10 nm with a fixed (b/a) = 0.73 (biomaterial sample is Hb cytoplasm with with a refractive of 1.3871 the concentration a refractive of 1.3871 or theorconcentration 12.93 12.93 mmolmmol L−1 ). L−1). Biosensors 2018, 8, xindex FOR index PEER REVIEW 11 of 14

Figure 12. 12.The TheATR ATR spectra the volume fraction the composite = 0.8. The of the Figure spectra for for the volume fraction of theof composite F = 0.8. FThe radius of radius the core-shell 3 3 (biomaterial sample iswith Hb core-shell to a10 nm(b/a) with =a 0.73 fixed(biomaterial ( / ) = 0.73 varied fromvaried 2.5 nmfrom to 102.5 nmnm with fixed sample is Hb cytoplasma with aofrefractive of 1.3871 or the concentration acytoplasma refractive index 1.3871 orindex the concentration 12.93 mmol L−1 ). 12.93 mmol L−1). In this presented model, biomaterial samples are blood plasma, Hb cytoplasm and lecithin with RIs of In this presented model, biomaterial samples are blood plasma, Hb cytoplasm and lecithin with 1.3479, 1.3800 and 1.4838, respectively. Figure 13, Figure 14 and Figure 15 show the comparison of the angular RIs of 1.3479, 1.3800 and 1.4838, respectively. Figures 13–15 show the comparison of the angular shift shift of the SPR angle for three different configuration respectively.

of the SPR angle for three different configuration respectively.

Figure 12. The ATR spectra for the volume fraction of the composite F = 0.8. The radius of the core-shell varied from 2.5 nm to 10 nm with a fixed ( / )3 = 0.73 (biomaterial sample is Hb cytoplasma with a refractive index of 1.3871 or the concentration 12.93 mmol L−1). In this presented model, biomaterial samples are blood plasma, Hb cytoplasm and lecithin with RIs of 1.3479, 1.3800 and 1.4838, respectively. Figure 13, Figure 14 and Figure 15 show the comparison of the angular shift of the SPR angle for three different configuration respectively.

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Figure 13. The ATR spectra fordifferent different configuration with the volume fraction Fof the composite Figure 13. The ATR spectra for configuration with the volume fraction of the composite = 0.1, F = 0.1,the thesize size of core-shell the core-shell a =and 2.5 =nm and f = 0.73.Prism/Ag/water/air, (conventional:noPrism/Ag/water/air, of the a = 2.5 nm 0.73. (conventional: core-shell: 3O4@Au+blood plasma + water/air). Prism/Ag/blood plasma + water/air, with + core-shell: Prism/Ag/Fe no core-shell: Prism/Ag/blood plasma water/air, with core-shell: Prism/Ag/Fe 3 O4 @Au+blood plasma + water/air). Biosensors 2018, 8, x FOR PEER REVIEW

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Figure 14.Figure The14. ATR spectra for different configuration with the volume fraction of the composite The ATR spectra for different configuration with the volume fraction of the composite F = 0.1, F = 0.1, the the core-shell = 2.5 and(conventional: f = 0.73. Prism/Ag/water/air, (conventional: Prism/Ag/water/air, the size size ofofthe core-shell a = 2.5a nm and nm = 0.73. no core-shell: Figure 14. TheCytoplasm ATR spectra for different configuration with the volume fraction cytoplasm of the composite F = 0.1, Prism/Ag/Hb + Cytoplasm water/air, with Prism/Ag/Fe O4@Au+Hb + water/air). no core-shell: Prism/Ag/Hb +core-shell: water/air, with 3core-shell: Prism/Ag/Fe 3 O4 @Au+Hb the size of the core-shell a = 2.5 nm and = 0.73. (conventional: Prism/Ag/water/air, no core-shell: cytoplasmPrism/Ag/Hb + water/air). Cytoplasm + water/air, with core-shell: Prism/Ag/Fe3O4@Au+Hb cytoplasm + water/air).

Figure 15. The ATR spectra for different configuration with the volume fraction of the composite F = 0.1, the size of the core-shell a = 2.5 nm and = 0.73. (conventional: Prism/Ag/water/air, no core-shell:

Figure 15.Figure The ATR spectra for different configuration with the volume fraction of the composite F = 0.1, 15. The ATR+spectra for different configuration with the volume fraction of the composite F = 0.1, Prism/Ag/Lecithin water/air, with core-shell: Prism/Ag/Fe 3O4@Au + Lecithin + water/air). the size ofthe thesize core-shell a = 2.5a =nm f = = 0.73. Prism/Ag/water/air, no core-shell: of the core-shell 2.5 and nm and 0.73.(conventional: (conventional: Prism/Ag/water/air, no core-shell: Prism/Ag/Lecithin water/air, with core-shell: Prism/Ag/Fe 3Owhere 4@Au O + Lecithin + water/air). is the angular shift between no The angular shift of+ SPR angle havecore-shell: been showed at Table 4, Prism/Ag/Lecithin + water/air, with Prism/Ag/Fe @Au + Lecithin + water/air). 3 Δ4θ 1 core-shell configuration with the conventional configuration, whereas Δθ2 is the angular shift between with The angular shift of SPR angle have been showed at Table 4, where Δ θ1 is the angular shift between no core-shell configuration and no core-shell configuration. core-shell configuration with the conventional configuration, whereas Δθ2 is the angular shift between with core-shell configuration no core-shell configuration. Table 4.and Angular shit of SPR angle for different biomaterial sample detection.

Δθ1for differentΔbiomaterial θ2 Δθ = θdetection. Table 4. Angular shit of SPR angle sample 2 − θ1 Biomaterial Sample (degree) (degree) (degree)

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The angular shift of SPR angle have been showed at Table 4, where ∆θ1 is the angular shift between no core-shell configuration with the conventional configuration, whereas ∆θ2 is the angular shift between with core-shell configuration and no core-shell configuration. Table 4. Angular shit of SPR angle for different biomaterial sample detection. Biomaterial Sample

∆θ1 (degree)

∆θ2 (degree)

∆θ = θ2 − θ1 (degree)

Blood Plasma Hb Cytoplasm Lecithin

0.05 0.21 0.71

0.50 0.44 0.77

0.55 0.65 0.94

We can see that the angular shift for with core-shell configuration is higher than the angular shift for no core-shell configuration. Therefore, we can say that the involvement of Fe3O4@Au core-shell enhance the sensitivity of biomaterial detection. Therefore, the sensitivity and the sensitivity enhancement can be obtained from Equations (7) and (8) respectively that, the sensitivity enhancement is 10% for blood plasma, 47.72% for Hb cytoplasm and 22.08% for lecithin. The selectivity of the SPR sensor is shown in Figures 13–15, in which each biomaterial sample RI value has a unique SPR angle. An increase in RI leads to an increase of the SPR angle. According to these results, the SPR phenomenon sensor with the core-shell addition can be used to selectively and sensitively detect biomaterial samples. 4. Conclusions In summary, we have presented a theoretical analysis and computational study of the effect of the inclusion of a Fe3 O4 @Au core-shell to enhance the sensitivity of an SPR-based biosensor through ATR spectra investigation (the magnetic properties of Fe3 O4 @Au are not utilized in this work). Our calculations confirm that the property combination of the magnetic and plasmonic materials leads to the enhancement of the SPR-based biosensor sensitivity, which is applied to detect the existence of biomaterial samples such as blood plasma, Hb cytoplasm and lecithin as analytes. By varying the radii of the core (Fe3 O4 ) and the shell (Au), the refractive index and the permittivity of the core-shell changes and leads to changes in the composite’s (core-shell + biomaterial + water) permittivity. The SPR dip shifted to the right in the reflectivity spectra when the core-shell was added to the composite as the active material. This shift suggests the potential of the core-shell’s inclusion to enhance the sensitivity of SPR biosensors, in this case for sensing biomaterial samples. Author Contributions: Widayanti conceived the idea for the study, conceptualization, data curation, funding acquisition, methodology, software, visualization and writing original draft of the manuscript. Kamsul Abraha contributed to investigated, validated, writing-review & editing draft of the manuscript and Agung Bambang Setio Utomo contribute to helped for supervision and validation. Kamsul Abraha as the corresponding author for this manuscript. All author contributed significant effort to the manuscript preparation. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest.

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