Draft:Enhancement of refractive index-based sensing Techniques

I. Overview
The refractive index is an intrinsic property of a medium which characterizes the light that passes through that medium. It's a dimensionless quantity which can be described by the ratio of speed of light in vacuum (c) to the speed of light in a given medium (v) and usually expressed by n (n = c/v). The refractive index depends on the wavelength of the light.. , concentration and temperature of the medium. The enhancement of refractive index sensing can lead to identifying the chemical species, controlling its purity and determine its composition in terms of molar fraction. Therefore, the sensitivity of refractive index sensing is crucial to improve monitoring and analyzing the changes in the refractive index of materials.

In advanced optical technologies, enhancement of refractive index sensing is a versatile approach which offers a precise and minute change in material characteristic in terms of refractive index. The enhancement of refractive index sensing significantly contributes to scientific research, healthcare sector, environmental monitoring, and industrial application by improving the analysis of material characteristics. There are numerous methods available to enhance the sensitivity of detecting the refractive index such as Surface Plasmon Resonance (SPR), Photonic Crystal Structure , Metamaterials , Whispering-Gallery Modes (WGMs) etc.

II. History and significance
The density of a glass that has increased in fused silica was first observed by Bruckner, 1970, when it was allowed to cool rapidly from higher temperature. This phenomenon has been confirmed later by Micro-Raman spectroscopy that, when the concentration of ring membered increases in the silica structure the density (refractive index) of the glass has also increased. However, change in concentration has been contributed to the change of refractive index by kramers-Koring mechanism was observed by. The enhancement of refractive index sensing contributes to advancing in several fields. This leads to improve the detection limit of low molecular weight molecules which can’t be detected and quantified in presence of the trace amount (picomoles and attomoles) are able to sense by surface plasmon resonance (SPR) sensors via increase the sensitivity of attenuated total reflection [9]. In 1983 Leidberg, Nylander and Lundström first incorporated the SPR-based sensor to monitor biomolecular interaction in terms of gas sensing. However, in 1920 the phenomenon was first observed by Wood when he shine light in the mirror and observed diffraction grating of dark and bright bands in the surface. In a material in which light required to confine at a small area to interact with material surface, the photonic crystal structure is the way of increase the interaction by enhancement of refractive index sensing, in which materials of different refractive index are ordered in different dimensional configurations to obtain a unique optical property by controlling the flow of photons. The periodicities of the unconventional materials enhance the response of photons with the surrounding medium.

In 1987, Eli Yablonovitch and Sajeev John first demonstrated the photonic crystal structure by ordering the materials in different dimensions. And they were able to show that, the materials can be oriented 1D, 2D and 3D configuration to enhance the refractive index sensing,. The materials that are not sensitive to the refractive index sensing can be artificially engineered to obtain different properties than the naturally occurring materials and those are called metamaterials. The customized design fabrication and engineered structure of the metamaterials exhibit optical properties which can control the light-matter interaction to enhance the sensing of refractive index. At the end of 19th century, Jagadish Chandra Bose first studied about the material structures in terms of light interaction. Later in 1940, the material possessed metamaterial characteristics has been developed by Winston E. Kock,.

To increase the sensitivity and specificity of biomarkers and rapid biosensing of diseases like ovarian cancer can be achieved by whispering gallery mode imaging technique. In whispering gallery modes (WGMs) the lights are internally reflected and concentrated in a concave surface which results in the generation of evanescent wave by attenuate total reflection of the light. The formation of evanescent waves thus changes the refractive index in the surrounding medium [16]. The whispering gallery mode was first demonstrated in terms of sound by Lord Rayleigh in 1878 which has been observed in St Paul’s Cathedral.

III. Enhancement Techniques
Several techniques have been employed to enhance the sensitivity of refractive index-based sensing. The development of new detection techniques, as well as the improvement of existing ones, is a current reality. Additionally, research and development of optical techniques that utilize light-matter interactions have shown great promise for detection. Indeed, excellent reviews related to those techniques are availlable, , , in the literature. This article, we will talk about some refractive index-based sensing techniques.

Generality
Surface plasmon resonance is an optical technique employed in the field of chemical and biological sensing. Under proper conditions, any optical changes in the medium surrounding a metal film are directly noticeable in the reflectivity of the metal,. SPR occurs because surface plasmons are highly sensitive probes of boundary conditions. This effect has potential in diverse areas, such as chemical sensing. In this article, we provide a description of how surface plasmon resonance can be used for the detection of molecules, as well as some relevant experimental results. Plasmon can be defined as quantum of rapid oscillations of electron density in conducting medias such as plasmas or metals.

The dispersion relation for such a plasmon is given by:  Ksp= ω*[(1/ε)+(1/εm)]-1/2 /C  and the wave vecteur Ks= ω(ε1/2 sinθ)/C, where ε, is the real part of the dielectric constant of the metal at a given frequency and εm is the dielectric constant for the dielectric medium outside the metal, C, the velocity of light, ω the frequency. SPR occurs when Ksp becomes equal to Ks. Then, by solving Ksp= Ks one can find the resonace angle θ and consequently the new (or the change in) refractive due to SPR phenomenon. These oscillations can be either localized or propagating, depending on the geometry and properties of the metal-dielectric interface.

Localized surface plasmon resonance (LSPR illustrated on the figure 1A) is an optical phenomenon resulting from a collective oscillation of free conduction band electrons, due to light absorption when the incident photons interact with the conduction band electrons of the noble nanoparticle. In propagating surface plasmon propagation (pSPR illustrated on the figure 1B), the plasmonic wave oscillates back and forth within the structure's boundaries. For the propagation to take place, the surface plasmons must exhibit at least one dimension that is comparable or larger than the wavelength of the incident light.

Figure 1. “Schematic illustration of the two types of plasmonic (nano)structures discussed in this article as excited by the electric field (E0) of incident light with wavevector (k).

In (A) the nanostructure is smaller than the wavelength of light and the free electrons can be displaced from the lattice of positive ions (consisting of nuclei and core electrons) and collectively oscillate in resonance with the light. This is known as a localized surface plasmon resonance (LSPR). In (B) the nanowire consists of one dimenssion which is much larger than the existing wavelenght variation. In this case, light coupled to the nanostructure will excite the free electrons to create a propagating surface plasmon (PSP) that can travel along the surface of the metal nanostructure.” taken from.

Here's a table summarizing the key differences:

How is SPR utilized for sensing applications?
Sensing chemical molecules in a low concentration condition is very important for medical diagnosis, contaminant detection and security monitoring, but is challenging. The working principle of SPR sensors is based on a unique and simple optical phenomenon. In a common SPR experiment, the first step is to immobilize the ligand on the sensor surface. The ligands play a key role in SPR; there most have good sensitivity, high specificity, stability, binding affinity and easy to immobilize to assure the efficiency of the detection process. After immobilization, the remaining binding sites are blocked and the surface is stabilized. Subsequently, the analyte to be detected is injected at a specific rate, concentration, and time (generally 2-5 minutes). The sensor chip is composed of a gold film that is coated onto a glass substrate, which has been chemically modified to assist in ligand immobilization onto the sensor surface. The optical system comprises a laser light source and a detector. The light source interacts with the gold film via a prism situated beneath the sensor chip, thus generating total internal reflection and the detector captures the unique optical spectrum created by the SPR phenomenon. Thus, the plasmonic wave generated on the surface of the gold produces an electric field that extends hundreds of nanometers above the sensor surface.

The reflected light experiences a significant reduction in intensity at a specific angle due to the surface plasmon wave. The detection of this phenomenon is carried out using a detector. When a molecule adheres to the sensor chip's surface, it leads to a shift in the angle of reflectance due to the change in refractive index, which the plasmonic wave travels through. The amount of bound material determines the shift's magnitude, which can be measured nearly instantaneously,. The SPR excitation is dependent upon metal film property. It leads to absorption of some this light by a set of electron (Plasmon) on sensor surface, accompanying by the modification in the Refractive index (RI) at that interface causing a measurable shift in the angle of minimum reflected intensity. Then, the surface become highly sensitive to any change in refractive index and consequently of resonance angle and wave length as illustrated on figure 1 bellow.

==== Figure 2 : Real-time label-free optical detection Improvement ==== Actually, Propagating SPR (PSPR) sensors which has better spectral tunabilities and Localized SPR (LSPR) sensors which with higher sensitivity both constitute the two types of SPR sensors,. However, both variants of SPR still require improvements because of their weakness in detecting molecules at very low concentrations (less than 1pM detection limit) and/or very small molecular weights (less than 8 kDa detection limit). Thus, numerous enhancement methods have been proposed and reported in the summarized diagram below (figure 2). Most of these approaches utilize metallic nanoparticles (such as Au and Ag nanoparticles), magnetic nanoparticles, carbon-based nanostructures (e.g., graphene), latex nanoparticles, and liposome nanoparticles, ,. '''Figure 3: Diverse types of nanomaterials for enhanced SPR sensing. Enhanced mechanisms: (a) electric field enhancement by coupling the LSPR excited on the surface of nanomaterials with the surface plasmon wave (SPW) excited on the sensing film; (b) large surface mass loading of the nanomaterials leading to large perturbations on the sensing surface; (c) charge transfer from the nanomaterial surface to the metallic sensing film surface that would induce larger evanescent field enhancement thereby magnifying the SPR signals; (d) enhanced adsorption efficiency due to pi-stacking force between target analyte and the nanomaterial surface; (e)''' catalytic activity of functionalized nanomaterials to further trigger secondary signal amplification – optional

2. Photonic Crystal Structures
Photonic crystals (PCs) are fascinating materials with unique optical properties. They are composed of periodic nanostructures, typically with a varying dielectric constant, that affect the propagation of light in a similar way that the atomic lattices of semiconductors affect the conductivity of electrons. This periodicity allows PCs to manipulate light in remarkable ways. Tailoring the geometry and structure of these structures can enhance their sensitivity to refractive index, rendering them valuable in sensing applications. PCs can assess an array of material properties through their unique optical response resulting from their ordered structure. The Bragg-Snell relationship described in Equation 1 enables the interpretation and prediction of wavelength shifts in the positions of diffracted light peaks from the material.

Sensing mechanism of Photonic Cristal
Optical sensors exploit the shift in the wavelength of the photonic bandgap (PBG) or stopband to identify and evaluate changes in the material or its surroundings by examining its optical response. The PBG is a range of wavelengths for which light cannot propagate through the Photonic Cristal (PhC). When an analyte is introduced into the vicinity of the PhC, it changes the effective refractive index of the surrounding medium or interplanar spacing (d), which can cause the PBG to shift. This shift in the PBG can be detected and used to measure the concentration of the analyte. Its dection limit is 10 fM for protein detection using a PhC nanobeam cavity. To estimate the effective refractive index neff in structures composed of alternating dielectric materials with refractive indices n1 and n2 occupying volume fractions φ1 and φ2, the following method is typically utilized: neff = n1 φ1 +n2 φ2 (1), ,.

'''Figure 4. Images of one, two and three-dimensional photonic band-gap structures .'''

3. Metamaterials
Metamaterials are a novel class of functional materials that are designed around unique micro- and nanoscale patterns or structures, which cause them to interact with light and other forms of energy in ways beyond what we see in nature. Unlike foams, metamaterials consist of "unit cells": geometrical building blocks arranged in a three-dimensional manner, ,. Metematerials typically consist of metal-insulator-metal triple layers, which are separated by thin dielectric spacers. Designing metamaterials to interact with light can significantly enhance refractive index sensitivity by manipulating the effective refractive index within the structure. “Most of the Metamaterial's enhanced near field is confined within the thin dielectric spacer between the antenna and the metal mirror layer” as illustrated in Figure 4. An antenna is a device that serves as the interface between radio waves moving through space and electrical currents moving in metal conductors and is used with a transmitter or receiver while metal mirrors are used as retroreflectors. Figure 5. (a) Schematic of a single unit of the metamaterial absorber (MA) with a nanogap. (b) Schematic cross-sectional view of a single unit of the MA with nanogap. (c) THz MM biosensor integrated with microfluidics. (d) RLCs equivalent circuit of the proposed SRRs with design parameters. Plasmonic hyperbolic metamaterial biosensor integrated with microfluidics. The assessment of sensitivity and lower limit of detection using lower-molecular-weight biomolecules. (e) 3D view of the plasmonic hyperbolic MM biosensor with a fluid flow channel. For detection, the sensitivity of plasmonic metamaterial biosensor is defined as S=Δλ/ΔC. Here Δλ is the change in peak reflection/transmission wavelength and ΔC is the change in virus concentration. It is repported in the litterature that, the detection limit with nanomaterials varies from 0.02524 µg/ml to 100pg/ml, while the operation frequency ranges from 1THz to 10GHz

How do metamaterials work?
Figure 6: Images from

According to the Snell’s law sinθ1/sinθ2= n2/n1= (μ1ε1/μ2ε2). The underlying secret of metamaterial is that both the dielectric function ε,´and the magnetic permeability, μ, happen to be negative. Since metamaterials refract light towards the left or at a negative theta angle, the refractive index n2 of the metamaterial medium is negative.

It should be highlighted that, in this case, only the negative value of the square root is considered for this refraction index value to better account for the left-refractive nature of the metamaterial, ,. This consideration is necessary to account for the left-handed refractory character of the metamaterial.

Metamaterials are engineered to exhibit unique characteristics that are absent in natural materials. This is accomplished through the assembly of atoms and/or molecules into nanoscale structural units with a well-defined size and crystal structure tailored to the desired properties. The properties of a metamaterial are influenced by the existence or lack of a hole or defect in its structure. The organization of nanoscale rationally designed units enables the manipulation of the refractive index of metamaterials, allowing it to range from negative to positive values. Their unique electromagnetic properties are dependent on the atoms arrangement in a certain geometry whose the manupulation leads to highly sensitive sensing applications.

4. Whispering Gallery Modes (WGMs)
Resonance phenomenon within cavities, whether acoustic, optical, mechanical, or otherwise, typically rely on precise geometric properties, including the size, shape, and composition of the supporting structure (molecules). Whispering gallery mode resonators have become a notable sensing method due to their exceptional sensitivity and efficiency in recent years. These resonators provide advantages such as high sensitivity, tiny form factor, and label-free sensing. As a result, their resonances are commonly referred to as morphologically dependent resonances (MDR), encompassing WGM in both the acoustic and optical domains. First explained by John William Strutt or rather Lord Rayleigh, , the acoustic waves involve a resonant electromagnetic wave that travel along the curved boundary of a dielectric microcavity such as a chemical structure. A visual example of WGMs can be found in figure 7. Figure 7: Mode-shift-based sensing. a) Transmission spectra showing the mode shift. b) Schematic of the basic WGM sensor setup. c) Resonance wavelengths shift in analyte binding process. Reproduced with permission.

Sensing Mechanism for Optical WGM Sensors
WGMs are present in microcavities with high-quality factors Q, allowing light to circulate within the cavity under the action of Total Internal Reflectance (TIR) giving birth to evanescent waves with exponential decay, ,. This phenomenon is a consequence of the light-matter interaction. This decay leads to the modifications in parameters of surrounding environment; optical path, refractive index near the cavity surface, causing a shift in the resonant frequencies and the decreasing in cavity liftime. This shift can be measured with high precision, allowing for the detection of various environmental changes. In fact, when specific molecules attach to the surface of the cavity, the frequency and refractive index change near the surface. This variation can then be utilized to identify the presence and concentration of those molecules. With these properties, WGM-based devices are quite effectives for sensing applications. The exploitation of the data from WGM-based devices involves, using the Fourier transform to get the Q factor which can be expressed as Q = ω/ δω = λ/Δδλ, where, λ the center wavelength of the resonant mode and δλ the full width at half maximum (FWHM) of the resonant mode.

IV. Applications of Enhanced Refractive Index-based Sensing
The enhanced refractive index sensitivity achieved through the aforementioned techniques finds applications in various areas of study. Surface plasmon resonance has been widely used for optical detection of various substances.

1. Biosensing
Enhanced refractive index sensitivity is crucial for the label-free detection of biomolecules, which aids in medical diagnostics and drug development. With the development of label-free biosensors, surface plasmon resonance and other techniques have been used in many biological applications. In 1998, Sota et. al. were first able to detect conformational changes in an immobilized protein using SPR. . They observed SPR was a good sensing technique for characterizing asymmetrical proteins such as immobilized proteins because of its real time sensing and ability to detect dielectric property changes. Whereas, previous methods proved more useful for characterizing proteins that are uniformly dispersed. The SPR sensor’s surface was covered with a carboxymethyldextran matrix layer that would connect with an immobilized protein that was genetically engineered from E. coli. When the protein bound to the sensor, pumps of different pH values were injected into the system. When the protein unfolded, a change in refractive index was able to be detected. This was able to be observed with a level of around 200 pg/mm^2 of surface protein

Later, in 2005, Endo et. al wrote about detecting PNA-DNA hybridization using localized surface plasmon resonance. Peptide nucleic acids (PNAs) were used as a biosensor since they have high affinity and selectivity for specific DNA sequences. The PNAs were placed on a gold-capped nanoparticle layer substrate to detect hybridization reactions when the target DNA sequences bind. The results were found with a detection limit of .667 pM of target DNA, and the sensor was able to discriminate between single-base mismatched pairs at a concentration of 1.0 uM. SPR has paved the way for highly specific and sensitive detection of DNA. A more recent application is identifying cancer-affected cells. Cells affected by cancer have a slightly higher refractive index than unaffected cells, meaning that they can be detected when compared to non-cancerous cells with techniques that utilize changes in refractive index. The cancer affected cells have a higher refractive index than the unaffected cells, because the cancer is detected by the level of certain cells in a sample. For example, a concentration of 30-70% of a cell known as Jurkat in blood cell liquid has a refractive index of 1.376 and is not indicative of blood cancer, while an 80% concentration of Jurkat has a refractive index of 1.39 and is indicative of blood cancer. Using a specialized surface plasmon resonance based photonic crystal fiber (SPR PCF) sensor, shown in the figure, the refractive index changes of such a small degree were able to be detected with a range of biomolecule sizes. These results were able to be achieved with a sensing performance of 10714.28 nm/RIU, transmittance variance of 5357.14 dB/RIU, amplitude sensitivity of −330 RIU-1, and a resolution level of 0.00933 RIU. Previous methods of cancer cell detection were only 7000 nm/RIU.

Additionally, with SPR, it is possible to detect trace amounts of glucose in urine. In diabetes patients, glucose in urine is often at a high level compared to non-diabetic patients. With increased concentration of glucose, there is an increase in the refractive index of urine, though slight. The refractive index of urine containing 0-15 mg/dL of glucose is 1.335, while the refractive index of urine containing .625 g/dL of glucose is1.336. With a specially made SPR sensor that uses silver, MXene, zinc oxide, and graphene, this slight increase of refractive index can be seen. Thus, a change in glucose level of only .6 g/dL is possible to detect using SPR methods. However, the typical glucose level for a diabetic patient is below this concentration, so room remains for increasing refractive index sensitivity even further. Enhancement of refractive index sensing has opened the door to optical sensing of glucose in urine. Besides SPR, whispering gallery modes also have potential in biosensing. Chen proposed a mechanism using a WGM cavity and an optical pump-probe system to measure the mass of a virus. . Other methods of measuring mass of a biomolecule, such as mass spectrometry, can potentially destroy or damage the biomolecule. With WGMs, an entirely optical sensing method, there is no potential to lose the species. Using a smallpox virus as a reference, it was calculated that such a sensor would be able to determine the mass of a single virus (at 9.5 fg) as well as other single or multiple biomolecules

2. Chemical and Environmental Sensing
Accurate measurement of refractive index changes is vital for identifying and quantifying chemical substances in diverse samples, including environmental pollutants and hazardous materials such as heavy metal ions, phenols, and pesticides. Monitoring environmental parameters such as pollution levels or changes in water quality often involves refractive index-based sensing, requiring enhanced sensitivity for precise measurements. SPR is often cheaper, easier to operate and analyze, or quicker than most other methods of environmental sensing, such as atomic absorption spectroscopy and inductively coupled plasma mass spectrometry. In 2020, Anas et. al. enhanced the sensitivity of SPR in detecting ferric iron ions (Fe3+) using quantum dots. . By depositing modified graphene quantum dots onto a gold film, such as is normally used for SPR, the detection of iron ions was increased. Ions in aqueous solution were able to be detected with a concentration as low as .001 ppm, or 6.165nM. For reference, other methods that used graphene quantum dots with different sensing techniques to detect ferric iron ions in solution found a limit of quantification of 1.622 to .0013 ppm, or 10,000 nM to 8nM

Chlorophene is an antimicrobial that is present in disinfectants and pollutes the environment, potentially leading to health risks and environmental damage. Until SPR, the detection of chlorophene was limited to chromatography only. However, using a biosensor and an SPR setup, shown in this figure, chlorophene can be detected with a limit of detection of 1.10 mg/L. This is because, when an analyte binds to the active site of the biosensor, a shift in the conformation and thus a change in the refractive index that is proportional to the concentration of the analyte is seen .Chlorophene and other halogenated phenols make up a significant majority of pollutants that come from personal care products. In theory, the same technique can be used for detection of other halogenated phenols. In this way, increasing refractive index sensing allows for closer monitoring of environmental pollutants.

Li et. al. detected carbendazim, a fungicide toxic to humans, using a Au/Fe3O4 nanocomposite using SPR techniques. Previous chromatographic methods of detection often require costly equipment and detailed analytical work, but SPR is relatively cheap and gives results in real time. With the nanocomposite enhancing the sensitivity of the SPR, carbendazim was able to be detected with a limit of detection of 0.44 ng/mL, compared to 2.81 ng/mL for the traditional SPR. With a low limit of detection and an acceptable accuracy, SPR with the correct enhancements can be used for effective carbendazim and pesticide detection.

In addition to heavy metal ions, phenols, and pesticides, SPR is well suited to monitoring of other environmental hazards. Microcystins, a group of substances produced by Microcystis and other freshwater cyanobacteria, are toxic to humans. They are also able to be effectively detected using SPR. . With a lower limit of 1 ug/mL detection of microcystins, the level that is allowed in drinking water, the method is able to be used to detect them effectively. Although the sensitivity was found to be lower than other methods, the SPR method was simpler, quicker, and more reusable

V. Conclusion
Increasing the sensitivity to changes in refractive index is a critical aspect of improving the accuracy and efficiency of optical sensing devices for many uses. Techniques such as surface plasmon resonance, photonic crystals, metamaterials, and whispering gallery modes offer promising approaches to achieving higher sensitivity. This higher sensitivity enables advancements in biosensing, sensing of various molecules, and environmental monitoring. The research and development in this field continues to grow, paving the way for innovative sensing technologies with broader applications.