Design Considerations and Limitations for Miniature SPR Devices

12.1 Introduction Since the last three decades, surface plasmon resonance (SPR) has provided new horizons to the chemical/biomedical industry as an optical tool for the analysis of molecular interactions and sensing applications. In the current age of exponential growth of technologies, real-time and label-free detection of biomolecular interactions by optical means is unthinkable without SPR. The phenomenon basically refers to the electromagnetic oscillation of coherent collective-free electrons at a semi-infinite interface Chapter 12 Design Considerations and Limitations for Miniature SPR Devices Plasmonics-Based Optical Sensors and Detectors Edited by Banshi D. Gupta, Anuj K. Sharma, and Jin Li Copyright © 2023 Jenny Stanford Publishing Pte. Ltd. ISBN 000-000-0000-00-0 (Hardcover), 000-000-0000-00-0 (eBook) www.jennystanford.com Anand M. Shrivastav,a Marwan J. AbuLeil,a,b and Ibrahim Abdulhalima aDepartment of Electrooptic and Photonics Engineering, Ilse Katz Institute of Nanoscale Science and Technology, ECE School, Ben Gurion University of the Negev, Beer Sheva 84105, Israel bPhotonicsys Ltd., House 54, Wahat Alsalam-Neveh Shalom 9976100, Israel [email protected] 372 Design Considerations and Limitations for Miniature SPR Devices associated with a metallic-dielectric interface when the incident photon momentum along the interface, with polarization in the plane of incidence, matches that of the plasmon. Due to the confinement of the field normal to the interface local enhancement appears. This is expressed as an integrated exponentially decaying electromagnetic field distribution along and normal to the interface and the associated wave is termed surface plasmon wave (SPW) or surface plasmon polariton (SPP) or simply extended plasmon. The reflectivity at the SPW has a large dependency upon the refractive index (RI) of the metal and dielectric materials. Hence, one can easily monitor the RI variation of the dielectric layer near the metal surface. Based on this methodology, SPR-based sensors are conceptualized [1–3]. Going back in time to 1902, the SPR concept was first visualized by observing metal-supported diffraction grating with an uneven distribution of the reflected spectrum [4]. Afterward, this light distribution was termed “surface plasmons (SPs)” by Ritchie, where he reported the SPs existence at a thin metal surface [5]. However, the main milestone in this field was given by Kretschmann in 1968, when he proposed a simple prism-based configuration to achieve SPR, where a thin metallic film was deposited on the base of a high index prism and the resonance is obtained at the other side of a metal-dielectric interface, named as Kretschmann configuration [6]. However, in terms of sensing applications, the first SPR-based biosensor work was pioneered by Liedberg and co-workers in 1983, where the detection of halothane gas and IgG antibodies was demonstrated [7]. Since then, the technology based on SPR has shown incredible growth, especially in the field of chemical/ biosensing applications, due to the integration of nanotechnology, microfluidics, and biotechnology advancements. Seeking the quick, highly sensitive, and label-free detection of biological analytes, several commercial SPR-based devices are also available in the market. The first commercial SPR-based device was launched by Biacore Instruments in 1990, which was able to analyze biomolecular interactions with high sensitivity, and rapid response time in addition to accurate, reliable, and reproducible results [8]. After the first commercialized device and technological developments, SPR became one of the “gold standard” transducing mechanisms for real-time monitoring of biomolecular interactions. In continuation, IBIS technology launched the cuvette-based SPR system in 1995 373 Introduction and a modified version (IBIS II) along with two-channel SPR was launched in 1997 [9]. Since then, a number of companies launched their commercialized SPR systems ranging from high-cost, large with highly resolved devices to compact, low-cost with reasonable resolution. A comprehensive survey of several commercialized SPR products has been listed in Table 12.1. Table 12.1 A list of commercial SPR systems available in the market Model Manufacturer Website Resolution claimed Size (weight) BI-4500 BI-2500 SPRm 200 Biosensing Instruments (USA) www.biosensingusa. com <0.06 RU <0.06 RU <0.6 RU 11.5 kg 8 kg 21 kg Biacore T200 Biacore S200 Biacore X-100 Biacore 8K+ Biacore (USA) www.biacore.com <0.03 RU <0.015 RU <0.1 RU <0.02 RU 60 kg 60 kg - 141 kg BIOSUPLAR-6 Biosuplar (Germany) www.biosuplar.com <3 mdeg 2.5 kg Carterra LSA Carterra (USA) www.carterra-bio. com – – IBIS MS96 IBIS iSPR6 IBIS Technologies B.V. (Netherlands) www.ibis-spr.nl – – MP-SPR-Navi Bionavis (Finland) www.bionavis.com – – NanoSPR8 NanoSPR9 NanoSPR103 NanoSPR77 NanoSPR (USA) www.nanospr.com 2¥10–5 RIU 2¥10–5 RIU 0.005 RIU 5¥10–7 RIU 2.2 kg 2.2 kg 3 kg 3 kg Open-SPR Nicoya (USA) www.nicoyalife.com – 20 kg P4SPR Affinite Instruments (Canada) www. affiniteinstruments. com 1¥10–6 RIU 1.3 kg Pioneer FE SensiQ Technologies (USA) www.sensiqtech. com – – Plasmetrix CORGI Plasmetrix (Canada) www.plasmetrix. com 1¥10–6 RIU – (Continued) 374 Design Considerations and Limitations for Miniature SPR Devices Model Manufacturer Website Resolution claimed Size (weight) Reichert 4SPR Reichert 2SPR Reichert Technologies (USA) www.reichertspr. com 1¥10–8 RIU 1¥10–7 RIU – – Sierra SPR® Pro Bruker (USA) www.bruker.com < 0.02 RU 70 kg SPR H-5 SPR MH-5 (Magnetic nanoparticles enabled) Photonicsys (Israel) www.photonicsys. com 1¥10–5 RIU 1¥10–6 RIU 1 kg 1 kg White FOx system Fox Biosystems (Belgium) www.foxbiosystems. com –24 kg Xel-PlexTM SPRi-Arrayer OpenPlex Horiba Scientific (Japan) www.horiba.com – – Although there are several companies listed providing SPR systems, there are several challenges while developing a commercial SPR device. These challenges include accurate signal measurements, affecting the signal noise such as light source, integration with microfluidic channels, binding analysis, etc. This chapter covers the design considerations and instrumental optics of a typical SPR device along with the interrogation schemes, various analytical methods to find the suitable SPR dip position, several parameters affecting the signal noise, and other basic units of the SPR system covering the flow channels and their properties along with sensogram of a generic SPR sensor at different sensing stages. 12.2 SPR Instrumental Optics As mentioned in the introduction section, Kretschmann proposed the conventional prism-based configuration to realize SPR, also known as the Kretschmann configuration. The configuration consists of a high index prism coated with a few tens of nanometres thick plasmonic metals, followed by a dielectric layer over the other metallic Table 12.1 (Continued) 375 SPR Instrumental Optics interface, as shown in Fig. 12.1a. In this configuration, p-polarized is launched at the metal-prism interface facilitating total internal reflection (TIR). The evanescent wave generated due to TIR provides the photon momentum, necessary for the SPW to be generated at the metal-dielectric interface, and this coupling leads to a sharp dip in the reflectance spectra at the specific resonance parameters [10]. In addition to the worldwide broadly used prism-based configuration, optical fiber and grating-based SPR are the two other configurations, which are used to excite SPR as pictorially replicated in Fig. 12.1b,c, respectively. A more extensive understanding of these two SPR configurations can be found elsewhere [11–13]. Figure 12.1 Optical configurations to realize SPR. (a) Conventional prismbased configuration. (b) Optical fiber configuration. (c) Grating coupled SPR configuration. Reprinted with permission from Springer Nature [13]. In general, prism-based SPR devices are configured in three different categories based on interrogation schemes: (i) intensity interrogation, (ii) angular interrogation, and (iii) spectral interrogation. We will discuss each interrogation scheme and its respective advantages and challenges one by one. 12.2.1 Intensity Interrogation Scheme The intensity interrogation method corresponds to monitoring the intensity fluctuations in the reflectivity changes of SPR signal where SPR is excited at a fixed incident angle and wavelength of incident p-polarized light. The change in RI of the sensing layer, 376 Design Considerations and Limitations for Miniature SPR Devices over the metallic thin film results in variation in the reflected intensity of reflected light, which can be measured by a detector. A basic understanding of the measurement process and the dynamic sensogram response is pictorially represented in Fig. 12.2. Figure 12.2 Reflectivity response and corresponding dynamic sensor response (sensogram) for intensity interrogation scheme. In this case, monochromatic light is detected at a fixed angle of the photodetector one line. The SPR instruments based on intensity interrogation follow the change in the curve’s reflected intensity, which is obtained due to a shift in SPR dip as shown through vertical lines A to B in the above figure. These types of SPR devices have a robotic stepper motor facility to find the required angle of incidence that provides maximum reflectivity change. A similar mechanism is also used as the basic principle for sensing devices based on SPR imaging (SPRi). SPRi adopts the Kretschmann configuration keeping a fixed angle and wavelength of the incident light, while the reflected light is recorded by a charge-couple device (CCD) camera [14]. This setup allows the real-time visualization of the biochip and the sensor surface can be split into multiple sensing spots to achieve high throughput sensing. The first type of such sensor was reported by Rothenhausler and Knoll in 1988, and they call this innovative technique as SPR microscopy [15]. Jing et al. reported a combined protocol where SPR imaging and cell edge tracking were simultaneously used to analyze binding interactions. The first method provided the ligand mass binding kinetics with the surface, while the latter was used for small molecule binding detection capability [16]. The setup and corresponding results are represented in Fig. 12.3. 377 SPR Instrumental Optics Figure 12.3 (a) Schematic of the setup for simultaneous operation of SPR imaging and bright field imaging. (b) A comparison of bright-field and SPR images at the scale bar of 20 µm. (c) A zoom-in schematic of one cell to illustrate binding affinity and kinetics analysis simultaneously by the edge tracking method and the SPR method. Reproduced with permission form [16]. Due to the intensity interrogation, the SPRi-based sensors suffer about one order worse resolution than the conventional reflectivitybased SPR sensors [11, 17, 18]. The reflected light intensity basically depends upon the coupling of incident p-polarized light with the plasmonic oscillations at the M/D interface and hence, it can be related to the RI of the medium over the metallic interface. Fu et al. introduce an SPR-based imaging sensor to increase the stability and SPR image contrast using a white light source along with a band pass filter [19]. The sensor was working at 853 nm operating wavelength with Ri resolution of 3¥10–5 RIU and an upper limit of the spatial resolution with 50 µm. In addition, an SPRi configuration with increased resolution (~5¥10–6) using the polarization contrast and a custom-designed multilayer structure was reported by Piliarik et al. [20]. In the study, the prism-based SPR device was kept between two crossed polarizers where the output polarizer blocked all the reflected light obtained from the inactive sensing regime. It would be important to mention that in such sensors, the factors which strongly affect the signal noise are the sensor surface roughness, 378 Design Considerations and Limitations for Miniature SPR Devices fluctuations in light source intensity, wavelength deviations, photodiode resolution, CCD properties, etc. A brief discussion of these parameters will be done in the forthcoming sections of the chapter. 12.2.2 Angular Interrogation Scheme Figure 12.4 shows a sensogram of the SPR device, operating in the angular interrogation mode, where the position of the SPR dip is monitored as a function of time using a monochromatic light source and varying the angles of incident light and corresponding photodetector. The resonance angle of the SPR shifts from A to B in the SPR curve as the RI of the sensing layer changes from n to n+∆n (left side of the figure). Corresponding change with respect to time is tracked as a function of time as the dynamic behavior of the sensor in the sensogram as represented on the right side of Fig. 12.4. In such configuration, the SPR dip is fitted with a suitable analytical method corresponding to the resonance angle at minimum reflectance, to find the most reliable resonance angle. There are several methods are reported in the literature regarding the best ways to obtain suitable SPR dip quantitatively. These methods will be discussed in the next sections of the chapter. Figure 12.4 Sensorgram formation of angular interrogation-based SPR sensor by tracking the resonance angle with respect to time. The monitoring of SPR resonance angle change requires the angular movement of the photodiode with a range of angles at the 379 output end, which makes a little complex instrumentation compared to the intensity interrogation method. The complexity can be reduced by using an array-based photodiode to record the reflected diverging beam replacing the requirement of photodiode rotation (Fig. 12.5). Another option, which is a property of photonicsys, is inserting a screen at the output and capturing the signal by the camera, which causes a dark black line at resonance angle and can be tracked by suitable image processing algorithm (Fig. 12.6). Figure 12.5 Converging beam SPR setup with various detectors to avoid any moving part. The dark line in the screen can be divided into segments, which can later be used as the same amount of sensing channels. Several companies such as Biacore and Photonicsys use these configurations for simple and miniaturized device fabrication. This interrogation scheme was developed in the early 1990s with an impressive RI resolution of 2¥10–6 RIU [21–23] and Biocore advanced this method with better optical design in a series of commercial SPR devices offering high performance (resolution down to the 10–7 RIU) along with high throughput sensing. It may also be noted that the incident light can also have two different types of configurations, which include the converging light beam and as well as the diverging light beam (see Fig. 12.5 and Fig. 12.6, respectively). The converging beam SPR setup allows the focusing of the SPR line down to a tiny narrow line at the sensor surface. However, in the case of diverging beam setup (Fig. 12.6), the SPR resonance dip walks along the sensor chips as any biomolecular interaction happens. This leads to a spatially undefined SPR minimum location on the sensor surface [24]. SPR Instrumental Optics 386 Design Considerations and Limitations for Miniature SPR Devices 12.4 Factors Producing Noise in SPR Signal 12.4.1 Plasmonic Surface Roughness The surface roughness of plasmonic thin film is a very important factor that plays a crucial role in the sensor’s performance, which has been exhaustively investigated in several studies [35–37]. The SPR characteristics, resonance condition, propagation length, and hence the reflected and transmitted spectra are the important parameters, which are affected by the plasmonic thin film roughness [38, 39]. For example, in an experimental study reported by Yang et al., it has been demonstrated that the plasmonic resonance angle and depth are highly dependent on the surface smoothness, which is varied by using different annealing temperatures [40]. Similarly, studies showed that in general, the bulk sensitivity of the sensor degrades due to the thin film roughness [41], but in some cases, due to the high surface area for the chemical/biological sensing along with the LSPR effect, an enhanced sensitivity has been observed [42]. The general methods for thin film deposition methods are sputtering, thermal evaporation, and e-beam deposition. However, the advancement in nanotechnology has provided us with several methods to obtain highly smooth metallic thin films after some surface treatments such as the stripping method [43], the thermal annealing method [44], the chemical polishing method [45], etc. Treebupachatsakul et al. performed a rigorous coupled wave analysis along with the Monte Carlo method to observe the SPR reflectance spectra based on the several surface roughness profile, generated by the low-pass frequency filtering method [46]. With the help of a comprehensive literature survey, the root means square (RMS) roughness of various coating methods and surface treatments was obtained and utilized to calculate several RI sensing parameters such as sensitivity (S), full width half maximum (FWHM), intensity contrast (∆I), intensity at resonance angle (Isp), and figure of merit (FOM). The schematic of the sensor design and flow chart of the calculation process are represented in Fig. 12.11a and Fig. 12.11b, respectively, while Table 12.2 represents the calculated RI sensing parameters based on RMS values of different deposition and surface treatment methods, which claims that surface roughness plays a huge role in the performance of an SPR sensor. 387 Figure 12.11 (a) Schematic design and (b) model formulated for calculating various parameters of SPR sensors upon varying the surface roughness for plasmonic thin film. Reprinted with permission from Ref. [46]. 12.4.2 Light Source Based on the type of interrogation used for the SPR device, the light source is decided. In the case of intensity or angular interrogation scheme, monochromatic light sources, such as LED and laser, are used. However, in the case of the spectral interrogation method, a broadband light source like a white LED and a tungsten halogen lamp (THL) can be used. There are several possibilities for the noise in the signal as follows: Factors Producing Noise in SPR Signal 388 Design Considerations and Limitations for Miniature SPR Devices Table 12.2 Effect of plasmonic surface roughness on various RI sensing performance parameters. Reprinted from Ref. [46] Deposition method/ smoothing method RMS roughness (nm) Sensitivity of k-vector (rad/RIU. µm) θsp (deg.) FWHM in k-vector space (rad/µm) ∆IpIsp FOM (RIU–1) Ideal surface 0 7.46 71.40 0.039 0.64 0.007 139.16 Sputtering (without any modification) 1.2 7.55 71.51 0.040 0.60 0.024 90.09 Chemical polishing [45] 0.38 7.52 71.40 0.039 0.63 0.013 125.20 Mica substrate utilizing [43] 0.2 7.50 71.40 0.039 0.64 0.010 132.16 Chemically grown singlecrystalline gold [47] <1.0 >7.55 <71.51 <0.040 >0.61 <0.021 >98.77 Laser ablation [48] 0.17 7.50 71.40 0.039 0.64 0.010 132.77 Helium ion beam [49] 0.267 7.51 71.40 0.039 0.63 0.011 129.63 Thermal annealing [44] <1.0 >7.55 <71.51 <0.040 >0.61 <0.021 >98.77 12.4.2.1 Spectral width The angular interrogation method requires a light source with a single wavelength, but the light source used in the setup always has some spectral width, which causes some distorted SPR signal as for each wavelength of SPR light, there will be some different resonance angle. For example, considering the light source for 633 nm, the LED source with an FWHM value of 30 nm, and a laser source with a spectral width of 2 nm, the FWHM value of the corresponding SPR reflected beam is changed by a 0.05 degree along with a contrast degradation by 2% for the LED source. It can be simply observed in 389 Fig. 12.12, which corresponds to the SPR response for a conventional SPR chip designed by using SF11 glass as a substrate, 50 nm thick Au as plasmonic film, as the sensing medium with 1.33 RI. Figure 12.12 Effect in SPR reflectance curve for light sources with different spectral broadening ammeters. 12.4.2.2 Power fluctuations Power fluctuations are the most important sources of noise in resonance-based sensing devices. These fluctuations are generally originated from the unstable power supply, thermal drift affecting the heat produced in the material used, spatial vibrations, etc. Several studies have been done in the literature to find a relationship between the intensity noise of the light source and the corresponding noise in the SPR signal. Ma et al. made an effort to find the effects of several spectral powers and corresponding noise levels on the SPR signal through simulations and experiments [50]. The study claimed that the optimal SPR dip wavelength is changed, and the RI resolution can even be nearly twice when the spectral SNR is increased [50]. Figure 12.13a shows the different light sources used in the study and corresponding RI resolution with the addition of noise level and its double is shown in Fig. 12.13b,c respectively. Factors Producing Noise in SPR Signal 390 Design Considerations and Limitations for Miniature SPR Devices Figure 12.13 (a) Light source with different spectral power distribution (SPDs) and corresponding SPR RI resolution with the addition of (b) noise and (C) doubling the noise. Reprinted from Ref. [50]. Drayton et al. reported a study based on the various light sources (like Halogen, Fabry–Perot laser, and resonant cavity LED (RCLED) with wavelength filters and detectors (such as CCD and CMOS) to find the best combination based on low-cost sensing devices [51]. The study showed that the sensor based on lower Q-factors was more fault tolerant. The filtered RCLED is more advantageous to a laser source. The RCLED was preferred as compared to conventional LED, as it supports higher directionality and spectral density with the help of an additional filter. Although the filter added some extra cost, it helped to find a more defined central peak compared with that of the laser. The best-obtained resolution of the sensor was 1.7¥10–5 using RCLED as a light source and a complementary metal oxide semiconductor (CMOS) camera as the detection. Figure 12.14 represents the power fluctuations obtained for the unfiltered laser diode, LED, and RCLED. 391 Figure 12.14 Power fluctuations in (a) unfiltered laser diode, (b) LED, and (c) RCLED. 12.4.3 SPR Signal Detector There are several types of sources that are used as the detectors in SPR-based systems, these are mainly CCD and CMOS cameras, photodiodes, spectrometers, etc., based on the interrogation scheme used and obviously, the limitations of these detectors largely determine the resolution of the SPR system. The properties of these detectors, which affect the SPR signal, are the resolution, operating wavelength/ wavelength range, temperature stability, long-term working ability, etc. In the current era of smartphone devices, cameras are very simple and cost-effective solutions for the detector while working with intensity and angular-based interrogation schemes to avoid the use of mechanical equipment to cover a specific angle range. Broadly CCD and CMOS are the most used camera based on the technology’s maturity of low-cost devices [52]. In the case of CCD, it uses a shift register for charge carrier transport and a signal amplifier at each Factors Producing Noise in SPR Signal 392 Design Considerations and Limitations for Miniature SPR Devices row of a pixel. The repeatedly charge transportation during the signal readout produces temporal noise [53]. This noise cannot be easily noticed by the human eye, due to its time-dependent properties and the results based on this device impacts the sensor’s performance. Additionally, due to excess charge leakage through nearby pixels, sometimes CCDs also suffer from a smear. While, in the case of CMOS cameras, due to an individual amplifier per pixel, these sensors do not get any temporal and bleeding curves, but each pixel can get its own sensitivity and offset leading to a time-independent pattern and gain noise. These noises can be eliminated by specially designed driving circuits depending on the manufacturing company. Another parameter is the dynamic range, here CCD wins the race as compared with CMOS cameras. Similar stays in terms of fill-factor, the CCDs get nearly 100% but CMOS cannot, since the driving electronic reduces their SNR. Experimentally, the CMOS camera showed a better response for guided mode resonance-based sensing devices [51]. Similarly, in the case of spectral interrogation, the resolution and signal stability play a strong role in the precise detection of resonance wavelength. In general, the cost-effective spectrometers in the market are available with a resolution of 1–2 nm, which corresponds to 2.5¥10–4 RIU for an SPR sensor with a sensitivity of 4000 nm/RIU. To minimize the SPR resolution, the region of SPR curves is fitted with a suitable function to find the best dip, using one of the algorithms discussed in Section 3, and then the resolution of the sensor can be lowered down to the order of 10–7 RIU. 12.4.4 Ambient Temperature The temperature surrounding the SPR active region also plays a significant role to increase the noise level in the system. The substrate RI, plasmonic thin-film RI, and solution refractive change as the ambient temperature changes. According to the work done by Shengming Zhang, for an SPR configuration with BK-9 glass/ Au (50 nm)/ water (RI: 1.33), the resonance angle gets shifted by 0.05° as the ambient temperate changed by 100 °C or simply we can say the conventional SPR has the temperature sensitivity of 5¥10–4 deg/ RIU [54]. Hence, for a conventional sensor with an RI sensitivity of approximately 70 deg/RIU, the changes in an ambient temperature of 10 °C will increase a drift of 5¥10–5 RIU. This number does not 393 include the effects on the performance of the light source and camera while increasing the temperature, which also plays a significant role in the SPR device. Although 5¥10–5 RIU is a small number when considering highly sensitive SPR sensors but to design an SPR-based device with high resolution (approx. 10–6 to 10–7), it is very important to minimize the temperature drift or fluctuations in the devices. Hence, many devices used the temperature-controlled unit in their SPR systems, which led to minimum temperature drift in the signal. In addition to temperature-controlled units, a few works are reported to compensate for the noise level in the signal through some signal treatment. Filho et al. proposed a model for SPR-based biosensors, which includes roughly all possible disturbances and noise in the system. The possible variations in a monochromatic light source are the light source bias current, the temperature, and the exposure time. The temperature of the light source tunes the intensity and wavelength of the beam. The first affects the mean value of the signal providing an offset to the SPR curve, which can be minimized using a correction factor in the software with suitable feedback. The study reveals that the wavelength affected by temperature fluctuations has more pronounced effects. It varies the light beam aperture and materials used for SPR sensor design, along with photodetector sensitivity. Plasmonic thin film roughness, light source properties, detector configurations, and ambient temperature are broadly affecting parameters in the SPR signal along with beam uniformity, quality of optical components such as polarizers, lenses, and local vibrations. Hence, one needs to take care of all these factors while designing a stable and high-resolution SPR device. 12.5 A Commercial SPR Biosensor Figure 12.15 represents a schematic of three main units of an SPR device, which includes SPR optics as discussed earlier, specially designed SPR chips, additional liquid handling systems such as flow cells, and microfluidic channels to minimize the sample requirement and leakage in the system. SPR chip is the backbone of a sensing device, which is designed based on the type of target molecule to be detected. A Commercial SPR Biosensor 394 Design Considerations and Limitations for Miniature SPR Devices Figure 12.15 Main units of the optical head of a commercial SPR sensing instrument. SPR chip with approximate 50 nm thick gold coating is mostly used for biosensing applications, due to high stability, chemical internees, and biocompatibility. Although silver (Ag) shows better SPR performance than Au, rapid oxidization limits its applications. The coating of a thin film of oxides of silver layer causes unwanted ionic effects and hence, drifts in the SPR signal. It may be noted that the Au-coated SPR chip possesses a penetration depth of around 200 nm, which limits its applications for large biomolecule applications. In this case, the insulator-metal-insulator (IMI) chip is used to realize a long-range SPR (LRSPR) phenomenon, where the penetration depth of the SPR signal is covering a few microns [55]. In addition to the SPR chip and the optical setup, the liquid handling system is also a very important unit of the SPR instrument. This system decides the way based on which the analyte will interact with the sensor surface, which directly correlates with the mass transportation limits, binding constants, surface depletion, diffusion gradient, etc. Cuvettes and flow cells are two main types of liquid handling systems, which are used in many SPR devices. In the past, cuvettes were the widely used technique in SPR instruments but due to the technology developments, microfluidics-based flow cells are in use. Although, a few devices such as Octet (ForteBio, Pall) still use the same technique. 395 Cuvette systems are equipped with an open vessel, which can be filled automatically or manually using a specific liquid-handling robotic motor. The system is mounted over the SPR chip without any leakage or any other disturbance in the optical setup. The sensing interactions of the biological analytes take place over the sensor surface and at the bottom of the cuvette system. Cuvette systems should contain a suitable mixing system, as uncontrolled mixing will cause uncontrolled mass transport resulting in a deformed sensogram. Compared with the flow systems, these are more compatible with aqueous solutions containing solid particles such as cell cultures, blood plasma, fermented media, etc., except the sensor surface is not affected by them. However, the main disadvantage of the cuvette system is its open architecture, which allows the uncontrolled evaporation of solvents in aqueous solutions, leading to increased concentration and RI. Flow cells along with controlled microfluidics are currently used in many SPR-based sensing instruments, ranging from simple to highly automated cartridge systems. In this method, an aqueous solution is transported to the sensor surface for biomolecular interactions, through sample loops or pneumatic valves using syringes or flow pumps. The syringes or flow pumps are not providing sample transportation to the sensing surface but also, help control the hydrodynamic conditions of the fluid. These can mainly be fabricated using microfluid channels pressed with micromechanical devices. Biacore was the first who integrated the microfluidic channels for SPR technology using integrated microfluidic technology (IFC). This technology provides the analyte flow with a controlled and pulse-free flow with controlled constant analyte concentration and hydrodynamic conditions around the sensor surface. It has several other advantages such as minimal dispersion and dead volume, instantaneous sample transitions, and optimum thermo-stating of sample and surface chip [24]. 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