Advances in surface plasmon resonance–based biosensor technologies for Cancer Cell detection

Eﬀorts have been made to enhance the sensitivity of the conventional surface plasmon resonance biosensor. Two-dimensional heterostructure layer of titanium disilicide and black phosphorus has been deposited over the metal surface to improve the sensitivity. The titanium disilicide (TiSi 2 ) nanosheet is placed in between silver (Ag) and black phosphorus (BP) ﬁlms in the Kretschmann arrangement. This biosensor executes better over a wide range of refractive index variations, including biological cell distribution in individual blood. It may become a fast method of detecting cancerous cells and the several variants of corona and other viruses that turn into a pandemic. Using ﬁnite element method based simulation technique, sensitivity obtained as are 195.4 deg/RIU, 167.6 deg/RIU, 212.4 deg/RIU, 168.4 deg/RIU, 212.4 deg/RIU, 186.6 deg/RIU, 218.6 deg/RIU, 195.4 deg/RIU, 203.6 deg/RIU, 202.6 deg/RIU 203.6 deg/RIU and 202.6 for sensing Basal (Skin Cancer), Basal (Normal Cell), Hela (Cervical Cancer) MCF-7 (Breast cancer), Hela (Normal Cell), Jurkat (Blood Cancer), Jurkat (Normal Cell), PCI-2 (Adrenal Gland Cancer), PCI-2 (Normal Cell), MDA-MB-231 (Breast Cancer), MDA-MB-231 (Normal Cell), MCF-7 (Breast Cancer) and MCF-7 (Normal Cell) respectively, and other performance parameters such as detection accuracy, quality factor and full width and half maximum (FWHM) are also evaluated.


Introduction
Surface Plasmon Resonance (SPR) is the emerging optical technology to accurately measure the dimension of cell or viruses that cause the deadliest cancer [1,2]. The high sensitivity with the accurate and rapid analysis of the clinical diagnosis can be performed with the SPR biosensor [3]. SPR biosensor implemented using Otto and Kretschmann configuration. The Kretschmann configuration based on angular interrogation has been used in the present theoretical study, but conventional biosensor shows low sensitivity. The sensitivity is the key parameter to investigate the performance of the biosensor, and it should be high. The sensitivity of conventional biosensors can be enhanced by placing a layer of the 2-D material in the conventional sensor [4].
The metal is used as plasmonic material in the SPR sensor. The most common metals are gold (Au) and silver (Ag), which have been used for SPR sensors design [5]. The oxidation of the metals and surface corrosion weakens the plasmonic properties of the material. However, Au is costly though having better stability and superior optical performance. Au is considered a suitable material since it is corrosion-free; however, it gives a broad resonance peak that reduces the accuracy of analyte detection. Conversely, the SPR sensor based on Ag film shows the highest resolution. Using Ag in SPR sensors, better sensitivity can be achieved, but the chemical stability is poor as it creates brittle oxide with the liquid analyte [6,7].
When we introduced a layer of 2-D material, the performance of the biosensor improved. A layer of titanium disilicide is used in the proposed biosensor. The titanium disilicide (TiSi 2 ) is an orthorhombic transition metal having a heterostructure. However, it is a stable material that is easily oxidized when exposed to the aqueous solution. It has high absorption efficiency and provides a direct bandgap of 0.5 eV at room temperature. Therefore, it has low resistivity properties and is suitable to design biosensors [8].
Graphite is a carbon atom bonded with three neighboring atoms, while Black Phosphorus (BP) atoms are bounded in-plane to form 2-dimensional layers, and they interact through Vanderwall forces [9]. Further, the phosphorus atom has five valency shell electrons available for bonding (the valency shell configuration is 3p 2 3p 3 ). Each phosphorus atom has a lone pair of electrons, and they are highly reactive to air. Thus the property of BP enhances the sensitivity of the proposed structure [10,11]. Cancer is a disease in which somebody's cells grow uncontrollably and spread to other body parts. The human body is made up of trillions of cells; these cells grow and multiply, and this process is called cell division. When cells grow old, they die naturally [13]. The new cells take over. Breaking down the orderly process and abnormal cells grow and then multiply to form tumors, the lump of tissue. The tumors may be cancerous or may not but can travel to different parts of the body to form new tumors [14]. More than a hundred types of cancer are illustrated elsewhere and usually named for the host organ, such as lung cancer, brain cancer, etc [15].
There are specific types of cells; the first is Carcinomas; they are the common type of cancer. The second is Adeno Carcinomas, which form epithelial cells that produce fluids or mucus. Most cancers of the breast, colon, and prostate are Adeno Carcinoma. Basal cell carcinoma is cancer that begins in the base layer of the epidermis [16].
Among different types of cancer are Jurkat (Blood Cancer), Hela (Cervical Cancer), PCI-2 (Adrenal Gland Cancer), (MDA-MB-231 Breast Cancer type-1), MCF-7 (Breast Cancer type-2), and Basal (Skin Cancer) are the most dominating. The dimensions of these cells are in nanometer, which is not easily measurable. Therefore, the refractive index parameter is measured from the patient's blood sample. The refractive index values are given in Table-1 for select cancer types [12].
The proposed method can identify cancer cells in real-time, which is impossible with current techniques. Cancer screening: diagnosing cancer at its earliest stages often provides the best chance to cure. Studies show that screening tests can save lives by diagnosing cancer early. Other cancer screening tests are recommended why for people with increased risk [17].
A laboratory test, such as a urine and blood test, may identify abnormalities caused due to cancer [18]. The complete blood count may reveal an unusual number or type of white blood cells. There are several imaging tests such as; Computerized tomography (CT.) Scan, Magnetic Resonance Imaging (MRI) Scan, Position Emission Tomography (PET) Scan, Ultrasound and X-Ray, cancer sample test in a laboratory.
Normal cells look uniform, with similar sizes and orderly organization. Cancer cells look less orderly, with varying sizes and different organizations. An antibody test is another blood test preferred for a possible diagnostic tool. The immune system makes antibodies to help fight off foreign invaders like bacteria and viruses in the human body. The immune system also makes antibodies in response to cancer cells. The antibody test is not full proof and needs further improvement. Genetic blood tools: with a strong family history of cancer, a tumor marker test detects a higher protein in blood when cancer is present. The protein can be high in both ovarian and breast cancer. In conclusion, blood tests may eventually have a role in the early detection of cancer or its recurrences.
The manuscript is organized as: Section 2 elaborates the theoretical modeling of the proposed biosensor. Section 3 tells about the results and discussion of the theoretically investigated biosensor. Section 4 consists of the conclusion.
2 Theoretical modeling for the proposed sensor Figure 1 shows the layered structure in the modified Kretschmann arrangement. The monochromatic light (633nm) is incident on the one side of the BK7 prism, and refracted light is come out from the other side of the prism. Prism based biosensor is working on the principle of attenuated total reflection. The prism is covered with the thin layer of Ag of thickness D 1 =45nm, this Ag film is then covered by two-dimensional (2-D) TiSi 2 nanolayer's D 2 =P*2nm (where P is the number of TiSi 2 films), which in turn is covered with a BP thin film of thickness D 3 =B*0.5 nm (where B is the number of BP films). BP layer is sandwiched between TiSi 2 film and sensing medium. The role of the BP film is to enhance the bimolecular recognition element with the analyte. The BK7 prism is used as a coupling prism. The design parameters of the proposed sensor are given in Table 2. Table-2 indicates the design parameters like a layer of the material, refractive index (RI), coating thickness, and material used for the proposed work. The whole study has done with the help of the MAT-LAB simulation tool, and results are verified using COMSOL Multiphysics 5.6 version.
The sensing performance of the systems is evaluated by the transfer matrix method [9]. The formula estimates the reflectance r pm1d1m2d2 = r pm1 + r m1d1d2 e 2iK m 1x dm 1 1 + r pm1m2d1d2 e 2iK m 1x dm 1 (1) Fig. 1 The schematic diagram for the proposed sensor where, p, m, and d indicate the prism, metal, and dielectric, respectively. The dip in the resonance curve can be written as: n 0 is the RI of the sensing layer, ε s and ε m are dielectric constants of the analyte and metal, respectively, angle of resonance is θ SP R , and K sp the propagation constant. The reflectance is defined as R p = [r pm1d1m2d2 ] 2 where r pm1d1m2d2 is the reflection coefficient of the incident optical signal. The sensitivity is represented as S n = δθ SP R /δn s , where δθ SP R and δ s are the change in the resonance angle and the RI of the sensing layer, respectively.

Results and Discussions
The sensitivity and detection accuracy are the performance parameters of the biosensor, and the same is computed for the proposed biosensor. The sensitivity of the biosensor is represented as S = δθ SP R /δn, where δn is the change in the RI and δθ SP R is the change in resonance angle. The detection accuracy (DA) of the biosensor can be expressed as DA=1/FWHM, where FWHM is the width of the spectra of the SPR curve; at that point, the reflectivity is 50% of the maximum value. The high value of the sensitivity and DA is desirable [8]. The quality factor can be expressed as Q=S.DA=S/FWHM directly depends on the FWHM and sensitivity. The sensitivity characteristics of the modified Kretschmann structure are investigated here by adding TiSi 2 nanosheet and BP. To show the enhancement of the sensitivity performance, the variation in the reflectance of the biosensor as a function of the incident angle at the various refractive indices of the sensing layer is given in Fig. 2. In figure 2 (a), the number of layers in the structure is (TiSi 2 =0 and BP=0), which means TiSi 2 and BP layers are not present in the biosensor (conversational sensor). The sharp downfall in the reflectance curve is found at the range of specific angles due to the SPR excitation. This phenomenon shows that the sensor absorbs the incident light due to generated surface plasmons. However, the change in the RI of the sensing layer (contact layer) due to molecular interaction is very low. The resonance dip has a small excursion of about δθ=0.576°with minimum reflectance of 0.08454 and sensitivity obtained as 115.2°/RIU for the conventional sensor. In Fig. 2 (b), the biosensor has only a BP layer (TiSi 2 =0 and BP=1) inside it, and the remaining parameter is the same. The resonance offset dip increases and is found as δθ=0.591°with minimum reflectance 0.09036 and sensitivity obtained as 118.2°/RIU which is higher than the previous case when TiSi 2 and BP layers are not present in the biosensor. Now, the TiSi 2 sheet is taken into consideration and ignore the BP (TiSi2=1 and BP=0), the resonance angle is obtained as δθ=0.605°with minimum reflectance 0.25395 and sensitivity obtained as 121°/RIU (Fig. 2 (c)). TiSi 2 and BP layer (TiSi 2 =1 and BP=1) are added to the structure, and this modification greatly shifts the dip in the resonance curve. The resonance angle is obtained as δθ=0.631°w ith minimum reflectance 0.25363 and sensitivity obtained as 126.2°/RIU as shown in figure 2 (d). In the comparative study of the relevant data, it is found that the resonance angle offset is larger in the proposed biosensor in contrast with the conventional sensor due to the addition of TiSi 2 and BP layers. The proposed work shows a high improvement in the sensor's sensitivity by adding the TiSi 2 and BP layers.
To target the refractive index values of cancer types shown in Table-1. A four-layer combination has been optimized. Where BK7 prism has been placed over Ag with thickness 45nm and subsequent one layer of TiSi 2 with thickness 2nm and three layers of Black Phosphorus having thickness 0.5 nm each, with this the reflectance vs. angle of incident of the proposed biosensor for a different cancerous cell is depicted in Fig. 3. Fig.3 shows the performance parameters of The sensitivity and detection accuracy are the performance parameters of the biosensor, and the same is computed for the proposed biosensor. The sensitivity of the biosensor is represented as S=δθ SP R /δn, where δn is the change in the RI. The detection accuracy (DA) of the biosensor can be expressed as DA=1/FWHM, where FWHM is the width of the spectra of the SPR curve; at that point, the reflectivity is 50% of the maximum value. The high value of the sensitivity and DA is desirable [28]. The quality factor can be expressed as Q=S.DA=S/FWHM directly depends on the FWHM and sensitivity. Table-3 presents all these parameters while a layer of TiSi 2 =1 and BP=3 at 633nm wavelength.
In Fig.4 for the better explanation of proposed SPR Biosensor the electric field intensity plot with respect to distance from prism for Fig. 4(a) Ag and TiSi2 without B.P. layer and Fig.4(b) Ag, TiSi2 with B.P. layer, has been investigated. It is observed that, when the R.I. of analyte varies from 1.330 to 1.335 with B.P. layer the greater enhancement in the electric field. This shows strong surface Plasmon (SP) excitation. A slight change in R.I. of the sensing medium near the interface results in a large change in the surface wave characteristic which in turn causes the change in electric field.
At last, a comparative table (Table 4) shows the proposed biosensor's computed parameters with the previously reported works. 8 Article Title Fig. 3 Depicts reflectance vs. angle of incidence of targeted cancerous cells  performed on the human body and/or living organism/ animal. So, ethical approval from an ethical committee is not required. • Consent to participate: The author has given their consent to publish this work. • Consent for publication: I am willing to participate in the work presented in this manuscript. • Availability of data and materials: No data available. • Code availability: No data available.
• Authors' contributions BK formulated the problem statement, giving the theoretical background and mathematical modeling for the SPR biosensor. He also helped in drafting and finalizing the manuscript. AU provided the theoretical background to biosensing and the importance of Optical Biosensing. He also helped in finalizing the design of the proposed sensor.
AP worked towards the complete manuscript, formatting, and finalizing the manuscript.
VS provided statistical analysis for the results. He provided the theoretical background to SPR biosensors. He also helped in formatting the manuscript.