Results in Optics 9 (2022) 100285 Contents lists available at ScienceDirect Results in Optics journal homepage: www.sciencedirect.com/journal/results-in-optics Integrated optical bimodal waveguide biosensors: Principles and applications Luis Torrijos-Morán a, c, *, Bárbara D. Lisboa b, Maria Soler b, Laura M. Lechuga b, Jaime García-Rupérez a, * a Nanophotonics Technology Center, Universitat Politècnica de València, 46022 Valencia, Spain b Nanobiosensors and Bioanalytical Applications Group (NanoB2A), Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC, BIST and CIBER-BBN, 08193 Bellaterra, Barcelona, Spain c Currently at Photonics Research Labs, iTEAM Research Institute, Universitat Politècnica de València, 46022 Valencia, Spain A R T I C L E I N F O A B S T R A C T Keywords: Integrated optical biosensors have become one of the most compelling technologies for the achievement of highly Optical biosensors sensitive, multianalyte, portable and easy to use point-of-care (POC) devices with tremendous impact in Integrated optics healthcare and environmental protection, among other application fields. In this context, bimodal waveguide Bimodal waveguides (BiMW) interferometers have emerged over the last years as a powerful biosensor technology providing the POC devices LOC systems benefits of extreme sensitivity under a label-free scheme, reliability and robustness within a highly compact footprint that can be integrated and multiplexed in lab-on-a-chip (LOC) platforms. In this review, we provide an overview of the state-of-the-art about integrated optical BiMW biosensors from the theoretical fundamentals to their practical implementation. Furthermore, we explore recent advances such as novel designs, integration in specific LOC systems and its application in real biosensing scenarios. Final remarks and perspectives on the potential impact of these biosensor interferometric structures are also provided, as well as some limitations that must be addressed in next steps. 1. Introduction Within this field, integrated optics (IO) play a prominent role in the development of LOC devices as they offer high potential for chip mini­ Optical biosensors are devices able to detect a certain amount of a aturization within tiny areas. They consist of compact light guiding specific analyte by means of its interaction with an optical signal structures capable of detecting the substance of interest via evanescent (McDonagh et al., 2008; Ligler, 2009). They provide several advantages wave mechanism (Lambeck, 1992; Lambeck, 2006), where part of the in terms of selectivity, sensitivity and real-time response, which ulti­ electromagnetic field is spread out outside the waveguide core, thus mately allows performing the detection without the need of target interacting with the surrounding volume. The most employed evanes­ labelling or amplification steps. These advantages make photonic bio­ cent field sensors over the years have been plasmonic ones due to their sensors suitable for point-of-care (POC) applications such as early simplicity and ability for detecting biological targets (Soler et al., 2019; diagnosis of diseases, environmental monitoring, or food quality con­ Lopez et al., 2017). However, in some cases, plasmonic label-free sen­ trol, among others (González-Guerrero et al., 2016). Moreover, they can sitivities are not high enough for real clinical and environmental ap­ be easily integrated in very small chips compatible with complementary plications, which can be at the pM-nM level for common biomarkers, but metal-oxidesemiconductor (CMOS) technology, which enables multi­ in the range of aM-fM concentrations for novel biomarkers or trace el­ plexed detection and low-cost mass production. To this end, the mini­ ements. Also, the integration of plasmonic biosensors in LOC systems is aturization of photonic biosensors that can be portable in lab-on-a-chip more complex than for IO sensors, especially due to the need of bulky (LOC) platforms is of great interest. These schemes include all kind of light coupling schemes (e.g., Kretschmann configuration), limited CMOS functionalities needed to perform an analysis, from microfluidics to compatibility of plasmonic metals like gold, or the sophisticated nano­ read-out systems, in order to provide results that can be easily inter­ fabrication methods required for nanoplasmonic sensor design. In preted by nonskilled personnel (Estevez et al., 2012; Duval et al., 2012). contrast, silicon-based integrated sensors provide extremely high * Corresponding authors. E-mail addresses: luistm@upv.es (L. Torrijos-Morán), jaigarru@upv.es, arru@ntc.upv.es (J. García-Rupérez). https://doi.org/10.1016/j.rio.2022.100285 Received 4 May 2022; Received in revised form 17 July 2022; Accepted 28 July 2022 Available online 1 August 2022 2666-9501/© 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). L. Torrijos-Morán et al. Results in Optics 9 (2022) 100285 sensitivities (up to pM-fM level) in compact devices that can be easily processes typically considered for other IO devices, thus preserving miniaturized and multiplexed (Fernández Gavela et al., 2016; Luan CMOS compatibility. Recently, the performance of BiMW has been et al., 2018). Different types of silicon-based optical sensors can be found enhanced by inserting periodic elements in the waveguide design, in the literature depending on its configuration and waveguide struc­ increasing the optical field interaction within the sensing area, which is ture. The most relevant examples are interferometers, grating couplers, translated into a higher sensitivity (García-Rupérez and Torrijos-Morán, ring resonators (RR), photonic crystals (PC), silicon wire, slot- 2021; Torrijos-Morán et al., 2020). Two different approaches involving waveguide based systems and subwavelength gratings (SWG). periodic BiMW have been reported depending on whether the Although they all operate via evanescent-wave mechanism, their wavelength-periodicity ratio operates at the SWG or the PC regime different waveguide structure provides different quantifiable properties (García-Ruperez et al., 2021). Including periodic configurations pro­ and performance such as the bulk and surface sensitivity or the detection vides not only higher light-matter interaction, but also additional limit. For instance, RR and PC structures have shown great potential due dispersive properties in the optical modes, which enhances the sensing to their highly compact footprint and high throughput analysis features compared to uniform BiMWs. (Ksendzov and Lin, 2005; Chow et al., 2004; Chrostowski et al., 2012). In this review, we present a comprehensive study of BiMW inter­ Besides, these sensors can be improved by combining them with slot- ferometric biosensors from an analytical to a practical point of view. A waveguides or SWG, thus increasing the waveguide sensitivity (Che­ description of the fundamentals is provided, focusing on the operation of ben et al., 2018; Wangüemert-Pérez et al., 2019; Barrios et al., 2008). the evanescent wave principle in this type of structures, and how Nonetheless, interferometric configurations are probably the most inserting periodic elements in the BiMW design benefits the sensing attractive for biosensing as they provide higher sensitivity values and response. Later, an overview of the surface functionalization methods lower detection limits, typically around 10-8 RIU, more than one order of and the sensor integration in LOC platforms is reported, as well as recent magnitude better than the aforementioned schemes. Among other con­ advances in biosensor experiments for real applications. Finally, in the figurations, Mach-Zehnder (MZI) and Young (YI) interferometers are the last part, we discuss the trends, perspectives, and next steps of BiMWs in most used for biosensing purposes (Heideman and Lambeck, 1999; the near future as one of the most promising IO-based structures for Ymeti et al., 2003). In an interferometric configuration, light is split into biosensor devices. two different optical paths or arms and recombined afterwards in the case of the MZI. A general approach is to design one of the arms isolated 2. Fundamentals and design as a reference and the other interacting with the substance of interest. Since the evanescent field of the guided light slightly extends into the 2.1. Evanescent field sensing principle surrounding medium, any change of the refractive index (RI) of the medium will directly affect the light phase of the sensing arm, causing a With the rapid growth of integrated optics, photonic chips based on phase difference between the paths at the recombined output. In this thin film technology emerged for all kinds of waveguide-based appli­ way, the binding of target molecules to the sensor surface will cause a cations, as in the case of biosensors (Tien, 1977; Soref, 2006). Light variation of the RI directly proportional to the analyte concentration, propagates through integrated waveguides via total internal reflection which can be monitored and quantified through the phase shift inter­ due to the high-index-contrast of the materials used. The most employed rogation. Planar MZI schemes were first demonstrated as an immuno­ platform is silicon-on-insulator (SOI) where optical modes are highly sensor in the early 1990s (Heideman et al., 1991) and some years later confined within the silicon core (Paniccia, 2010). A competitive alter­ they were fully integrated in a silicon platform (Schipper et al., 1997). native is silicon nitride, which provides a moderate-index-contrast Since then, the high number of publications with diverse MZI configu­ (around 0.5 compared to 1.5 in the case of SOI) and transparency for rations indicate the impact within the field of integrated optical bio­ visible wavelengths, which is very interesting for biosensing purposes, sensors (Sepúlveda et al., 2006; Gao et al., 2011; Liu et al., 2013). since most biomolecules (proteins, lipids, and nucleic acids) present Over the last years, another paradigm of interferometric scheme structural absorption peaks in the mid-IR region (Muñoz et al., 2017). using bimodal waveguides (BiMW) were first introduced theoretically in Common to all these platforms, the effective index is an important Levy and Ruschin (2009), where a single-channel waveguide structure parameter that characterizes a certain propagating mode and its sur­ supporting two orthogonal modes of the same polarization and with rounding medium. It relates the field distribution of a given mode and their own propagation constants is designed. By properly placing a polarization with the refractive index of the materials employed in the single-mode waveguide at the output, the power of both propagating core and the cladding. It is similar to thinking of a mode propagating modes is transferred to the fundamental one at that output waveguide, straight in an artificial waveguide with an equivalent refractive index leading to an interferometric response dependent on the differential neff . phase shift between those two modes, as it happens for other interfer­ In a BiMW as the one shown in Fig. 1, two modes of the same po­ ometric configurations. Later, this approach was experimentally larization and with propagation constants β1 and β2 , propagate through demonstrated in (Zinoviev et al., 2011), where instead of placing an the same optical waveguide with their own effective indices. As the output single-mode waveguide to combine both modes, a photodetector optical field penetrates in the upper cladding, where the sensing area is array was placed at the output to measure the free-space interference located, a variation of the effective indices of the modes is produced pattern produced between them, similarly to what happens for Young (Herranz et al., 2017). This part of the optical signal that interacts with interferometers. Since the evanescent field of both modes does not the target analytes is known as evanescent field as it decays exponen­ equally interact with the sample, a phase shift is produced at the output, tially with the distance to the waveguide core (typically 0.1–1 µm). As it as in the case of an MZI. However, in order to achieve low limits of is depicted in Fig. 1, the evanescent field is different for each mode in the detection, both modes must be equally excited by a single-mode wave­ BiMW, the fundamental mode (β1 ) is more confined within the wave­ guide, which is aligned out-of-axis respect to the bimodal waveguide. guide core than the higher order mode (β2 ) which extends throughout This is a non-trivial process and a proper design of the interface between the cladding region, resulting in a change of the effective index differ­ the bimodal and the single-mode part must be addressed to overcome ence between the modes when the sensing occurs. Interferometric con­ possible limitations in the overall performance. POC devices can benefit figurations including BiMW biosensors are shown in Fig. 2, which from BiMW as they present more compact designs than MZIs (the foot­ consist of a single-mode waveguide as input and output ports, and a print is reduced at least by a factor two due to the single-channel bimodal structure placed in between, where the sensing area is designed. configuration of the former), which is desirable for the integration of The bimodal part design must be larger than the single-mode wave­ multiple biosensors in a single chip. Additionally, since these BiMW are guides either by increasing its width or height, see Fig. 2b and c purely dielectric structures, they can be fabricated using the same 2 L. Torrijos-Morán et al. Results in Optics 9 (2022) 100285 Fig. 1. Scheme of the optical field propagation throughout a BiMW. A typical biosensing scenario in the upper cladding is represented, which is measured via evanescent wave mechanism. Fig. 2. Schemes of different interferometric sensor types: (a) conventional MZI, (b) uniform bimodal waveguide with increased height and (c) periodic bimodal waveguide with increased width. respectively, in order to support two electromagnetic modes. In next in terms of the effective index as sections, we explore two different types of BiMW configurations: uni­ 2π form and periodic in its propagation direction, Fig. 2b and c respec­ Δφ = (L1 neff 1 − L2 neff 2 ) (2) λ tively, and compare both with conventional MZI schemes, Fig. 2a. where λ is the operating wavelength, L1,2 are the physical lengths of the optical paths and neff 1,2 are the effective indices of the fundamental and 2.2. Uniform configurations higher order modes, respectively. Note that L1 and L2 are the same in the BiMW since both modes propagate through the same optical waveguide, Let us start with the simplest configuration: the uniform BiMW whereas neff1 = neff 2 in a MZI when the waveguide dimensions of the shown in Fig. 2b. Internally, it behaves like a MZI: an input optical beam arms are equally designed. This is the reason why MZI are typically is splitted into two and recombined afterwards to create an interference conceived with a large difference between the length of the arms in pattern at the output. In the uniform BiMW case, a single-mode wave­ order to enhance the phase shift accumulated at the output. Likewise, in guide supporting the fundamental mode of a given polarization excites a BiMW, since both modes propagate through the same optical path, the the first two lower order modes (even and odd parity) of the same po­ phase shift is produced as a result of the effective indices difference. larization in the bimodal region. Similarly, these two modes contribute Therefore, in a biosensing application, a change in the cladding refrac­ to the excitation of the fundamental one at the single-mode output tive index produces a variation in the effective index of the propagating waveguide. Due to the wave nature of light, the intensity at the BiMW modes. Specifically, the sensitivity of a BiMW sensor can be mathe­ output can be defined as a sinusoidal function depending on the phase matically defined as shift accumulated in the bimodal part, as follows ( ) √̅̅̅̅̅̅̅ Δφd 2πL ∂neff 2 ∂neff 1 Iout = I1 + I2 + 2 I1 I2 cosΔφ (1) S= = − (3) Δnc λ ∂nc ∂nc where I1,2 are the intensities of the fundamental and higher order modes where Δφd is the phase shift difference when the sensing takes place, and in the BiMW, respectively, and Δφ is the phase shift between these two Δnc is the change of the cladding refractive index. In a conventional MZI modes for a given wavelength. In turn, the phase shift can be expressed 3 L. Torrijos-Morán et al. Results in Optics 9 (2022) 100285 scheme, one of the arms is designed isolated to act as a reference, so that part so that they can be properly compared. the phase shift will solely depend on the change of the effective index in First modal configurations were introduced as interferometric de­ the sensing arm. In contrast, in a BiMW since both modes interact with vices to realize a magneto-optic isolator using a wide strip waveguide the sensing area, they are designed to maximize the effective index etched into two layers (Lohmeyer et al., 2001). Here, the width and difference, specifically to produce a large variation in the higher order thickness of the modal waveguide was studied for optimum performance mode compared to the fundamental one (typically around a factor of 6). and fabrication tolerances operating at the near infrared region. Similar This is because the higher order mode is less confined within the modal devices were later presented as temperature sensors by using fully waveguide core and thus more sensitive to cladding refractive index etched silicon waveguides with horizontal modal splitters and optimized variations than the fundamental one, which in turns acts as reference dimensions to maximize the sensitivity (Irace et al., 2003). More mode although it is not completely isolated. Note also that both the MZI recently, single-channel structures based on BiMWs were theoretically and BiMW sensitivity directly scales with the device length, which is described for refractive index sensing using vertical symmetry junctions common to all interferometric-based sensors measuring phase shifts and to excite both modes in the sensing area (Gao et al., 2011) and later explains the large footprints typically employed. Because of this fact, the experimentally demonstrated as biosensors for the first time on a silicon sensitivity is usually normalized to a 1 cm length of the bimodal sensing nitride platform, Fig. 3a (Zinoviev et al., 2011). The latter design Fig. 3. Types of uniform BiMW sensors: (a) Silicon nitride configuration based on vertical modal splitter and differential detection. Adapted with permission from (Zinoviev et al., 2011) © IEEE 2022. (b) Spiral silicon scheme with horizontal modal splitter. Adapted with permission from (Liu et al., 2014) © The Optical Society 2022. (c) Trimodal low-cost polymer-based waveguide with horizontal modal splitter. Adapted from Ramirez et al., 2019 4 L. Torrijos-Morán et al. Results in Optics 9 (2022) 100285 presents a thickness of 150 nm and 350 nm in the single-mode and mode waveguide, see Fig. 3c. Since this mode is highly sensitive for bimodal parts, respectively, for obtaining a response of more than 70 % cladding variations, high-performance, low-cost SU-8 polymer plat­ modulation. They were fabricated using standard microelectronics forms are demonstrated for sensing applications, reporting bulk sensi­ technology by conventional photolithography processes over 2 µm tivities up to 1366 2π rad/RIU cm in a fully etched and low-cost thermally grown thick silicon dioxide cladding layer and depositing the biosensor with waveguide dimensions in the bimodal section around core layer of silicon nitride by low-pressure chemical vapor deposition 10 µm and 12 µm (Liang et al., 2018). (LPCVD) technique. These sensors were reported to have a bulk sensi­ On the other hand, some of the problems that usually must be tivity of 1,350 2π rad/RIU cm by using a photodetector attached to the addressed when dealing with BiMW sensors are related to the excitation bimodal output facet. As a result, the interference bimodal pattern was of the modes. These must be equally excited so that the modulation directly detected without merging again both modes in a single-mode depth is increased, which is desirable to obtain a clear read-out signal in output waveguide, and falsely interpreted results can be obtained in the sensing process. To this end, grating assisted BiMW have been real biosensing experiments. However, it is worth noticing that although introduced providing full control over the power distribution in the these BiMW can be integrated in compact structures, they are designed waveguide mode resulting in nearly lossless mode conversion (Bruck in very long optical waveguides to enhance the sensitivity. To mitigate and Hainberger, 2014). Likewise, vertical polymer tapers are reported some of these integration limitations, interferometric biosensors based for efficient light-coupling in BiMW biosensors to enhance the coupling on two-lateral mode spiral silicon waveguides were proposed on SOI of collimated or divergent beams (Grajales et al., 2019), as well as novel wafers patterned by deep UV lithography, Fig. 3b (Liu et al., 2014). The algorithms to overcome ambiguities that commonly arise from read-out use of horizontal modal splitters simplifies the fabrication process as signals typical of interferometric sensors (Bassols-Cornudella et al., only a single lithography etching step is required. The width of these 2022). structures is found to be 450 nm and 900 nm in the single-mode and bimodal part, respectively. Nonetheless, the bulk sensitivity reported is 2.3. Periodic structures 504 2π rad/RIU cm, more than half the standard BiMW in silicon nitride, although in a more compact footprint. Similarly, low cost BiMW were Light propagation through periodically patterned waveguides is reported in the literature by using optical polymer platforms fabricated feasible under certain conditions. To understand the behavior of light in by soft UV nanoimprint lithography which are transparent at both periodic media, we must first study how the modes evolve for different visible and infrared wavelengths (Liang et al., 2019), and with wave­ wavelengths, see the dispersion diagram of Fig. 4. Here, the ratio be­ guide designs of 2 µm width in the bimodal part. The phase sensitivity tween the wavelength (λ) and the periodicity of the structure (a) is key as reported in this case is 316 2π rad/RIU cm, although the spectral it determines whether reflections are produced or not at the interface in sensitivity of 789 nm/RIU is more competitive compared to other types between the periodic elements (Joannopoulos et al., 1997). For a given of resonant-based IO sensors. Here horizontally confined modes are period, if the wavelength is too large to avoid reflections, we may say we considered to design the BiMW, as in the previous case, so that fully are working in the SWG region. A first approximation to determine etched steps are needed in the fabrication processes of the polymer, whether we are at the SWG regime is considering the next expression: which drastically reduces costs compared to previous configurations. At neff < λ/2a, where neff is the effective index of the propagating mode. If the same time, trimodal polymer waveguides fabricated using direct this condition is fully met so that the effective index is drastically smaller laser writing at 405 nm wavelength were introduced by changing the than the second part of the equation, the periodic waveguide works in standpoint of conventional BiMW (Ramirez et al., 2019; Ramirez et al., the deep-subwavelength region, and it can be modelled as a uniform 2015). Here the second higher order mode with even parity is excited in structure with a pitch much smaller than its wavelength (Cheben et al., the bimodal part because of symmetry conditions with the input single- 2018). IO biosensors made of SWG structures provide several Fig. 4. Periodic waveguide representation and schematic of its dispersion diagram where two main regions are distinguished: subwavelength grating and pho­ tonic crystal. 5 L. Torrijos-Morán et al. Results in Optics 9 (2022) 100285 advantages in terms of sensitivity due to the stronger light-matter ∂λ interaction with the substance of interest (Wangüemert-Pérez et al., S= (4) ∂nc 2019). As a result, several conventional spectral-based sensing struc­ tures were redesigned using SWG elements for high-performance oper­ where ∂λ is the wavelength shift of a certain spectral feature and for a ation. This is the case of ring resonators made of SWGs with reported given change in the bulk cladding refractive index ∂nc . Considering a sensitivities up to 580 nm/RIU (Flueckiger et al., 2016; Luan et al., SWG-based BiMW and that we work on a spectral peak (either 2019). Likewise, BiMWs made of deep SWG elements have been also constructive or destructive interference) we can rewrite Eq. (2) as explored in the literature for biosensing, as it is the case of the perforated silicon nitride waveguide, fabricated using LPCVD, which consists of an Δφ = 2π L η = Nπ (5) array of circular holes about 160 nm diameter formed in the bimodal λ part of the structure of height 300 nm and width 800 nm, see Fig. 5a where η is the effective index difference and N is an integer number, (Uchiyamada et al., 2019). However, as we approximate to the PC even in the case of constructive interference and odd for the destructive regime by increasing the periodicity or reducing the wavelength, case. Using implicit function differentiation, we can calculate the phase properties such as dispersion and anisotropy appear and must be derivative respect to the cladding refractive index as follows considered when designing the SWG waveguides. For instance, the typical dispersion of SWGs has been extensively explored to develop ∂φ 2π L ∂η = , (6) directional couplers (Wang et al., 2016) and beam splitters (Halir et al., ∂nc λ ∂nc 2016) for ultra-broad-band operation in very compact devices. Simi­ and respect to the wavelength as larly, the dispersion of SWG can be used to design highly sensitive ( ) spectral-based BiMW biosensors, with reported sensitivities up to 2,270 ∂φ 2πL ∂η η = − (7) nm/RIU in silicon-based devices fabricated using electron beam ∂λ λ ∂λ λ lithography, see Fig. 5b (Torrijos-Morán et al., 2019). Dispersion engi­ neered structures with a period of 260 nm and bimodal width of 1.4 µm so that dividing Eq. (6) by Eq. (7) we obtain an expression of the spectral are herein conceived to provide a similar dispersion for both modes. This sensitivity as a function of the phase shift φ, the effective index differ­ is translated into an almost constant phase shift as a function of wave­ ences η and wavelength λ: length that provides critical sensitivity points in interferometric-based ( ) ∂λ ∂φ/∂nc ∂η ∂η η sensors (Levy et al., 2009; Levy and Ruschin, 2008). In these configu­ S= = = / − . (8) ∂nc ∂φ/∂λ ∂nc ∂λ λ rations, the spectral-based sensitivity can be expressed as From this equation we can conclude that the sensitivity becomes Fig. 5. Types of periodic BiMW sensors: (a) perforated silicon nitride interferometer. Adapted from (Uchiyamada et al., 2019). (b) SWG spectral-based configuration. Adapted with permission from (Torrijos-Morán et al., 2019) © The Optical Society 2022. (c) 1D PCs with high group index contrast made of corrugated waveguides. Adapted from (Torrijos-Morán et al., 2021). (d) Array of patterned circular holes and multi box-based designs. Adapted with permission from (Torrijos-Morán and García-Rupérez, 2021) © The Optical Society 2022. 6 L. Torrijos-Morán et al. Results in Optics 9 (2022) 100285 theoretically infinite when the slope of the phase as a function of footprints and with very low power consumptions (Torrijos-Moran et al., wavelength reaches zero. This condition is met at the critical sensitivity 2021). Besides, different geometries are further investigated as high point: group-index-contrast single-channel interferometers for all kind of IO purposes, which demonstrates the impact of these BiMWs beyond ∂η η = . (9) sensing applications (Torrijos-Morán and García-Rupérez, 2021). Note ∂λ λ also that the bimodal excitation must be addressed when dealing with Dispersive SWGs provoke this behavior in BiMW interferometers, junctions between uniform and periodic waveguides that could nega­ which in addition to the stronger light-matter interaction explains the tively affect the device performance (Zhao et al., 2017). extremely large sensitivity results obtained by these structures. It is also Table 1 shows a detailed comparison of all aforementioned config­ worth noticing that the duty cycle of the SWG structure is crucial to have urations. Examples of classical interferometric sensors based on Young an active control of the critical working point, as it determines the phase (Schmitt et al., 2007) and Mach-Zehnder (Prieto et al., 2003) in­ shift slope evolution, reported optimized values of duty cycle are around terferometers are also included for the sake of comparison. The former 60 % (Torrijos-Morán and García-Rupérez, 2019). Moreover, as it is presents the lowest detection limit although the read-out measurement shown in Eq. (8), the spectral sensitivity does not depend on the sensor is carried out off-chip and additional optical components are needed. length, so that very short interferometric schemes can be designed. The MZIs have been in turn the standard interferometric sensing configu­ reported spectral sensitivity is notably higher than for other silicon rations over the years due to their ease of design, performance and on- biosensors based on resonant configurations and comparable to plas­ chip measurement. For the case of BiMW configurations, we may monic devices, thus confirming the high potential of SWG bimodal highlight that the periodic configurations (SWG and slow light) exhibit waveguides for label-free biosensing. the highest bulk sensitivities both in terms of spectral and phase shift, As it is depicted in Fig. 4, in the SWG regime the fundamental mode respectively. In detail, SWG BiMW provides a sensitivity 3 times higher becomes dispersive as it nears the photonic bandgap (PBG) region, than low-cost BiMW, and slow light configuration more than 7 and 10 where optical modes cannot be propagated through the structure due to times higher than vertical BiMW, and conventional MZIs, respectively. Bragg reflections at each interface of the periodic waveguide (Pérez- However conventional vertical BiMW presents a better detection limit Armenta et al., 2020). Here both modes are sensitive, and somehow they than the other BiMW configurations, due to the read-out stabilization cancel each other so that almost no phase shift is accumulated at the and low noise, which is highly desirable for biosensing. This is mainly output. To improve the phase sensitivity, the fundamental mode is due to the optimization of the modal excitation in the case of the uni­ supposed to be isolated from changes in the environment, and the higher form BiMW which produces a low-noise read-out signal. In contrast, the order mode to be dispersive. This new approach is feasible when dealing periodic BiMW is much noisier because of the cavity formed in the with periodic structures below the PBG, in the PC region, where optical bimodal part, which produces some ripple in the read-out signal. In modes couple with each other in the dispersion diagram (see Fig. 4) and order to reduce the noise of periodic configurations and thus maximize regions of high group index can be obtained, the so-called slow light the detection limit, further optimization in the bimodal excitation must regions (Krauss, 2007; Baba, 2008). PCs have been widely demonstrated be addressed, specifically in the field mismatch between the funda­ as biosensors by taking advantage of slow light effects, as in the case of mental mode at the input and the higher order mode in the periodic two-dimensional periodic structures made of circular holes and one- waveguide. Another interesting next step would be designing these pe­ dimensional PCs based on corrugated waveguides (Castelló et al., riodic configurations in silicon nitride, as in the case of the perforated 2012; Sabek et al., 2018; Sabek et al., 2019). The latter present a reduced BiMW. This material platform provides a lower refractive index contrast lateral size compared to other PCs which reduces the final footprint and than SOI, so that the light-matter interaction is enhanced, which could fabrication complexity while preserving the slow light benefits. In fact, be beneficial both in terms of sensitivity and detection limit. It should be similar 1D PCs have been incorporated in one of the arms of a MZI to also noted that the sensing length is drastically reduced in the case of the design slow light interferometers (Brimont et al., 2011). The underlying periodic configurations compared to the uniform ones, which demon­ mechanism relies on improving the phase shift accumulated by the PC strates the high potential in the integration of multiple devices in a arm due to the slow light phenomena without the need of increasing the single chip. However, the fact that the sensing performance of BiMW length of the interferometer. As a result, very compact MZI schemes are based on periodic structures depends on their dispersive behavior makes therein designed (Nguyen et al., 2012). A similar device inserting a that their optimal operation bandwidth is reduced to few tens of nano­ highly dispersive 1D PC made of circular holes in one of the MZI arms is meters. Additionally, the need of exciting higher order modes of the demonstrated for high-performance biosensing with phase sensitivity periodic structure in order to achieve the required interferometric values of 13,370 2π rad/RIU cm. In this context, a novel approach was behavior can also have an effect on insertion losses, although they can be introduced by encompassing the ideas of PCs in MZIs and BiMWs kept below 1–2 dB if a proper design of the access coupling elements is (Torrijos-Morán et al., 2021). This is the case of the slow light BiMW carried out. fabricated using electron beam lithography in a 1D PC for high- performance interferometric operation, see Fig. 5c, where sensitivities 3. Lab-on-a-Chip integration and biosensor applications of 10,620 2π rad/RIU cm are demonstrated in single-channel compact structures with a period of 370 nm and bimodal waveguide width of In view of the exceptional sensing performance provided by BiMW 1400 nm. The fundamental and the second order mode both with even interferometers, their application for biomedical and environmental parity are herein excited as in the case of the trimodal waveguide, but sensing holds a great potential toward the advanced on-site testing. The now in a highly dispersive 1D PC so that the design dimensions are implementation of BiMW technologies as portable and multiplexed POC reduced. In order to critically enhance the phase shift in the bimodal biosensors would offer rapid one-step analysis, minimum reagent con­ interferometer, the group index of the higher order mode is drastically sumption, and high reliability and accuracy. However, the development increased compared to the fundamental one. On this matter, PCs allow of fully operative POC biosensors must tackle certain challenges in terms us to engineer bimodal interferometers with high group-index-contrast of optical system engineering, microfluidics design, and surface bio­ waveguides by a proper design of the unit cell and thus its dispersion functionalization. Hereunder, we will discuss the latest advances in this diagram. In this case, the interferometers are exploited to exhibit a large regard, and will give an overall perspective of the achievements in the phase shift at the output, similar to other BiMWs and contrary to SWG demonstration of BiMW biosensors as analytical tools for medical di­ bimodal configurations where the spectral-based sensing is optimized. agnostics and environmental control. Similarly, slow light BiMWs exciting the fundamental and the first high- order mode are also demonstrated as 2x2 switches in really compact 7 L. Torrijos-Morán et al. Results in Optics 9 (2022) 100285 Table 1 Comparison of different types of interferometers, including BiMW biosensors. The most important parameters discussed in this review are shown. N.D. means not determined by the author. Configuration Bulk sensitivity Detection Modal Modal splitter Material Sensing length Ref. limit symmetry platform Young dneff/dnc = 0.22 9 × 10-9 RIU Single-mode none Ta2O5 5 mm (Schmitt et al., 2007) MZI 966 2π rad/RIU cm 7 × 10-6 RIU Single-mode none Si3N4 15 mm (Prieto et al., 2003) (Phase shift) Vertical BiMW 1,350 2π rad/RIU cm 2.5 × 10-7 RIU Even/odd Vertical Si3N4 15 mm (Zinoviev et al., 2011) (Phase shift) -5 Spiral BiMW 504 2π rad/RIU cm 2.2 × 10 RIU Even/odd Horizontal (full- SOI 4.5 mm (Liu et al., 2014) (Phase shift) etch) (185 × 185 µm2) Low-cost BiMW 789 nm/RIU N.D. Even/odd Horizontal (full- Polymer 5 mm (Liang et al., 2019) (Spectral shift) etch) (Ormocore) Trimodal BiMW 1,366 2π rad/RIU cm N.D. Even Horizontal (full- Polymer 15 mm (Liang et al., 2018) (Phase shift) etch) (SU-8) -5 SWG BiMW 2,270 nm/RIU 2 × 10 Even/odd Horizontal (full- SOI 0.125 mm (Torrijos-Morán et al., (Spectral shift) RIU etch) 2019) Perforated 194 nm/RIU 20.4 µm/mL Even/odd Horizontal (full- Si3N4 0.1 mm (Uchiyamada et al., 2019) BiMW (Spectral shift) (Surface DL) etch) Slow light BiMW 10,620 2π rad/RIU 6.6 × 10-6 RIU Even Horizontal (full- SOI 0.078 mm (Torrijos-Morán et al., cm etch) 2021) (Phase shift) 3.1. Integration in lab-on-a-chip (LOC) platforms waveguide with high alignment tolerances, achieving efficient light couplings although this device must be carefully fabricated with high The engineering of photonic biosensor systems must address several resolution lithography techniques in order to achieve sub-micron scales parameters, such as the light in-coupling, optical read-out, data pro­ (De Vos et al., 2007). Duval et al. (Duval et al., 2012) proposed the cessing, and microfluidics integration for sample transport and analysis. incorporation of a nanograting coupler directly in the BiMW chip that Selection of the most appropriate light sources and detectors, their work under the visible spectrum of light for an efficient light coupling miniaturization and incorporation in robust devices – ideally with a low and possible integration at large scale due to the use of standard fabri­ cost –, and the accomplishment of high-efficient and high-resolution cation processes. In this work, a taper is integrated after the grating read-outs are probably the biggest challenges in photonic waveguide coupler to increase coupling efficiency. Waveguide tapers can be lateral, biosensor development. Table 2 summarizes the main advantages and vertical or three-dimensional, employed to increase the waveguide input limitations of different optical components. area and increase the coupling efficiency (Son et al., 2018). Grajales et Different light sources that can be used for BiMW interferometric al. (Grajales et al., 2019) reported a low-cost solution for a vertical taper operation include light emitting diodes (LEDs), diodes bars, and laser made from SU-8 polymer, fabricated in a wafer level and integrated in diodes, being the last ones the most widely employed. Main technical the BiMW sensor with three additional photolithographic mask levels, requirements are the narrow band emission and a directional mode, obtaining an experimental coupling efficiency of 55 % corresponding to while low power consumption and low cost might be preferred for a coupling loss of 2.63 dB. However, they stated certain fabrication implementation in POC biosensors. Further, the light source must be limitations that increase scattering and explain the power loss. This precisely aligned and coupled to micrometer-sized waveguides, and in forefront strategies are usually combined with the use of a direct optical multiplexed sensing, simultaneously illuminate different waveguides. In fiber light source, which can be mechanically directed and focused on order to incorporate a single light source in a multiplex chip, beam the input waveguide to create a more user-friendly and easier to splitters such as Y-branches (Aikio et al., 2015) or multimode interfer­ automatize coupling approach with high efficiency couplers. Collima­ ence branches (MMI) (Guo et al., 2021) are presented as possible tion and polarization lenses can be easily adapted in the fiber output microfabrication approaches. Beam splitters generate uniform power optics (Son et al., 2018). An avant-garde approach for an automated splitting along the several waveguide branches from the input interface. light in-coupling has been proposed by Morichetti et al. (Morichetti The MMI coupler, compared to a matrix of Y-junctions, offers advan­ et al., 2014) using on-chip photodetectors. These devices measure the tages in terms of compactness. Nonetheless, these branches suffer from intensity of the light inside the waveguide and send signals to a self- propagation losses along the path of light hindering an efficient light configuring system of beam coupler (Miller, 2013; Bogaerts et al., coupling. Diode arrays (Laser Diode Technology, n.d.; Shimizu et al., 2020). Results show that light is monitored with a sensitivity of 30 dBm 2014) are an alternative approach to the use of beam splitters as they do and have demonstrated applications for waveguides. Although one not require any extra fabrication process on the chip waveguides. An should note that for medical applications it is required to design single- example of integration of diode arrays in PICs was shown by Theurer et use devices in order to avoid cross-contamination of samples in flow. For al. (Theurer et al., 2020), where the diode, with an optical power of 60 this end, optical integration of the different optical building blocks mW, demonstrated coupling loss of 2.1 dB in silicon nitride waveguides. should be accomplished at a small cost in mass fabrication processes. They employed a hybrid flip-chip integration interface method, which Finally, the propagated light that exits the BiMW has to be collected resulted to be an efficient solution for chip integration and being readily by a detector for signal processing and data acquisition. Devices such as adaptable to other platforms. However, restraints such as polarization of two-section photodetectors can be found as a low-cost, easy to configure, the light or tuning of the wavelength for the specific application in and work as miniaturized devices in single waveguide approach. How­ BiMW could limit their purpose. In terms of alignment, different solu­ ever, the area of the sections and signal–noise ratios can be quite tions have been proposed to achieve compact, simple, easy to built-in limiting factors in terms of sensitivity of the devices. In terms of multi­ and be automated, including grating couplers, tapers, or other free- plexed waveguides, CCD cameras may show improved characteristics, space in-coupling methods (Son et al., 2018). Grating couplers are exhibiting extraordinary features in terms of pixel resolution. Single composed of periodically spaced diffractive elements and these optical light sensitive areas fabricated in a wide matrix enables processing and structures diffract the light in such angles that can be defined by the control of each waveguide output signal separately, even in low-output Bragg condition. This coupling method can enable the light entering the power scenarios (Dante, 2014). This signal output is processed 8 L. Torrijos-Morán et al. Results in Optics 9 (2022) 100285 Table 2 retrieval techniques have been designed. Dante et al. (Dante et al., 2015) Advantages and limitations of BiMW optical schemes for LOC integration. developed an all-optical modulation technique combined with a Fourier Device Advantages Limitations Series deconvolution algorithm to achieve a linear read-out; it allowed a facile implementation by using commercial laser diodes under high- Light Source Light emitting diodes Low power consumption Not directional beam frequency intensity modulation. The technique has been recently (LEDs) Low cost Relatively broad light improved by Bassols-Cornudella et al. (Bassols-Cornudella et al., 2022) Optically safe spectrum with the incorporation of a new modulation algorithm based on simple Incoherent light trigonometric relationships of sinusoidal signals, which could possibly Laser diodes Low power consumption No circular beam shape Low cost Require thermal and be applied to any type of time-dependent sinusoidal signal. As a result, High optical efficiency electrical controllers the sinusoidal interferometric signals are presented as linear responses, Directional beam Single input interface which are simpler and more user-friendly to be applied in a POC Narrow light spectrum coupling biosensor device. Multi-mode operation Can be dangerous for Besides optical engineering, the integration of microfluidics into the regime vision Allows light modulation biosensor system is of high importance as it allows for a minimum of light sample consumption and manipulation, and dynamic and automated Adaptable to beam injection and washing steps. The fabrication of such microfluidic plat­ splitters and gratings forms is complex due to the reduced size of the channels, the need of Diode bars Multi-coupling approach High power consumption Integration during No collimated light channel interface alignment, and the integration of fluidic manipulation fabrication modules for automated sample delivering (and processing) in a flexible In coupling methods and scalable platform (Zeming et al., 2016). Concerning the type of Free-space laser diodes ( Low cost Requires additional materials, polydimethoxysiloxane (PDMS) is the most widely used ma­ Son et al., 2018) Requires higher-power optical components terial for this application as it is biocompatible, robust, transparent, and light source Careful alignment of the Robust in laboratory optical set-up low-cost material (Yavas et al., 2017). In order to achieve an automated environments Collimation of light can platform integrated with photonic biosensors, it has been reported the be challenging use of digital microfluidics (Ceyssens et al., 2013), droplet-based Not robust for portable microfluidics (Hess et al., 2020), or micromechanical valve based applications microfluidic systems (Yavas et al., 2017; Aćimović et al., 2014; Szydzik Fiber-coupled laser diodes Easy alignment Power loss along the (Son et al., 2018) Uniform beam intensity optical fiber length et al., 2017; Parks et al., 2014; Cai et al., 2015; Schudel et al., 2009; profile Ceyssens et al., 2013). Among these, the micromechanical valves have Easy integration in achieved the highest interest for fluidic automation of photonic bio­ optical fibers sensors. Szydzik et al. (Hess et al., 2020) reported an example of an Compact set-up Grating (Duval et al., Solution to free-space Increased fabrication automated microfluidic system containing different modules in a single 2012) couplings cost and time PDMS device (i.e., six fluidic reservoirs connected to the primary Allows tuning of the light Out-of-plane coupling channel through different pneumatic valves, waste channel). Each pri­ spectrum method mary fluidic channel is 250 μm wide and they have automated the Taper (Son et al., 2018) High efficiency coupling Located on the chip pressure regulation for − 900 mbar in actuation and + 50 mbar for valve edges Require chip polishing closure. However, this module only contains a single channel (Fig. 6a). Beam splitters -MMI CMOS compatible High power laser beams Other platforms containing similar valves have been developed, as splitters (Guo et al., fabrication Propagation losses along shown by Acimovic et al. (Szydzik et al., 2017) they have incorporated 2021) Input fiber coupled beam the light path eight sensing channels each of them can be controlled individually or Allows beam polarization Reduction of bulky simultaneously, their work was tested in a clinical application in a electronic components photonic device showing real-time measurements (Fig. 6b). On the other Photodetectors hand, an important function of microfluidic systems for point-of-care Photodiode array Miniaturized device Difficult integration in applications is sample pre-treatment (e.g., separation of plasma from Low cost multiplex approach whole blood). Recent developments in this field have been done High noise CCD camera Low noise and high Bulky component focusing on automated platforms to be simply integrated in point-of-care sensitivity Saturate at low input setting as reliable, safer, and faster approaches. A filtration platform was Low light spectral power reported by Lenz et al. (Lenz et al., 2021) in which they describe as being measures Speed of data acquisition a low-cost device, for processing small volumes of whole blood (90 μL) Individual control of pixel in the matrix and offering minimal loss of sample integrity. This device achieved an ideal spinning velocity of 4500 rpm (during 3 min) for a serum sepa­ ration with few red blood cells when compared with traditional cen­ according to the interferometric effect of light in BiMW sensors, in which trifugated serum (Fig. 6c). Apart from these examples, many other variations in the phase of light of the two propagating modes produce solutions have been developed and demonstrated not only in optical changes in the oscillation of the light modes. The output signal is biosensors but for fluorescent microarrays or other lab-on-a-chip de­ measured as a shift of the two light modes in terms of a photon profile vices, which could motivate their eventual incorporation in BiMW sys­ distribution, showing a sinusoidal signal at a certain amplitude and tems, boosting their exploitation and application in real bioanalytical time. When a binding event occurs on the sensor surface, the sinusoidal scenarios. baseline is altered changing its amplitude and frequency as result of the interferometric phase shift. The shift is directly proportional to the 3.2. Sensor biofunctionalization refractive index variation occurring at the sensor-dielectric interface, which in turn is directly proportional to the concentration of analyte In label-free sensing, the analytical sensitivity and specificity ulti­ binding to the surface. Some methods used to quantify the correspon­ mately depend on the biorecognition element and how it is tethered on dent variation of light phase were based on the number of counts from the sensor surface. Typically, most employed bioreceptors are antibodies maximum and minimum values of the periodical wave. Due to and nucleic acids (i.e., DNA probes), although other molecules such as complexity and time-consuming method to analyze data, new phase aptamers, cell receptors, or polymers can also be used. These 9 L. Torrijos-Morán et al. Results in Optics 9 (2022) 100285 Fig. 6. Schematics of automated microfluidic devices: (a) single channel microfluidic platform fixed to the BiMW biosensor. On the right, the model shows the PDMS interface slab bonded irreversibly to the injection platform and a clamping layer. Reproduced from (Hess et al., 2020) with permission from the Royal Society of Chemistry. (b) Schematics of the flow and control layer of a multiplex microfluidic chip containing 8 flow channels. Image of the connected chip below. Adapted with permission from (Szydzik et al., 2017) © American Chemical Society 2022. (c) Portable filtration unit successful separates serum from blood in different reservoirs by centrifugal forces. On the left is the schematic of the device, containing multiple channels stacked on top of each other and separated by membrane windows. Adapted from (Lenz et al., 2021). bioreceptors show extraordinary affinity and specificity towards their precision and reproducibility (Luchansky and Bailey, 2012; Huang et al., corresponding analyte, allowing the selective capture of the target with 2012). Additionally, some strategies have been applied to enhance the a high sensitivity. However, the immobilization procedure on the sensor antifouling properties of the silanized surface, such as the incorporation surface must take into account several parameters, such as the stability, of polyethylene glycol (PEG) groups in the silane chain (Maldonado the grafting density, the orientation, and the minimization of non- et al., 2020). These molecules offer a high resistance toward non-specific specific adsorption of other substances present in the sample matrix. adsorptions by creating a hydration layer on the surface, being therefore Commonly, the sensor surface biofunctionalization consists in the useful when attempting direct measurement of complex biological fluids chemical modification of the silicon-based waveguide for the immobi­ (Soler and Lechuga, 2022). Nonetheless, the main issue with silanization lization of the appropriate bioreceptors. This chemical modification is is the lack of a standardized and universal protocol to be applied in all carried out through the so-called silanization. This procedure employs type of silicon sensors, as it highly depends on the silicon surface quality, reactive alkoxysilane molecules to form a self-assembled monolayer ambient conditions, solvents, temperatures, etc. onto the silicon surface that display functional end groups (e.g., amine, Upon surface modification, the immobilization of the bioreceptor carboxyl, etc.) at the outer interface (Soler and Lechuga, 2022). A wide must also be optimized in terms of stability, orientation, and grafting variety of protocols have been described to achieve a reproducible density. Conventional strategies are based on the covalent binding of the silanization reaction on silicon surfaces, including liquid and vapor biomolecules to the functional silane layer via cross-linking reactions. A phase reactions (Luchansky and Bailey, 2012). As an example, for the myriad of chemical crosslinkers is available for the covalent binding of case of the amino-functional silanes such as (3-aminopropyl) triethox­ receptors to the modified surface via amine–amine, amine-carboxyl, ysilane (APTES) the protocol can occur in solution with anhydrous thiol-amine, or thiol-thiol binding, among others (Fig. 7b). This cova­ toluene (Moon et al., 1996), or with chemical vapor deposition (CVD) at lent binding method offers important advantages such as the high sta­ room temperature for 4 h (Giraud et al., 2016), or CVD at 150 ◦ C for 5 bility of the bioreceptor layer and the control of the bioreceptor density min (Zhang et al., 2010). The in-solution reactions are prone to result in by tailoring the number of functional groups or including lateral spacers. low ordered or multilayer coatings (González-Guerrero et al., 2013), However, it generally occurs randomly, without any preferred orienta­ therefore some protocols refer to the use of vapor-phase deposition tion. To ensure an oriented immobilization of bioreceptors, it is possible combined with measure tools for tracking the deposition rate with high to make use of affinity ligands, such as protein A or protein G, that bind 10 L. Torrijos-Morán et al. Results in Optics 9 (2022) 100285 Fig. 7. Schematics of different surface biofunctionalization approaches for bioreceptor immobilization: (a) physical adsorption of bioreceptor through electrostatic forces, offers poor orientation for analyte specificity; (b) chemical functionalization employed for strong bond of the bioreceptor on surface, using functionalized silanes to immobilize bioreceptor through chemical bonds of crosslinking reactions. Different type of chemical bonds illustrated, using amine cross-linkers and thiol cross-linkers; (c) biotin/streptavidin pair or the use of protein A/G are mostly employed to achieve oriented affinity of the bioreceptor on surface. antibodies through their constant region, or the use of biotin/strepta­ 3.3. Applications in biomedical and environmental analysis vidin pair (Fig. 7c) (Gunnar and Carl-Fredrik, 2011; Freitag et al., 1998). On the other hand, innovative approaches have also been developed BiMW biosensors can be used in a wide range of applications in both for the application of BiMW technologies as chemical and gas sensors. the biomedical and environmental areas. In medicine, biosensors are Herein, the recognition interface typically consists in chemical matrices, introduced as analytical tools for diagnosis and prognosis of a disease, as such as graphene (Yavari et al., 2011) or carbon nanotubes (Modi et al., well as to monitor the treatment progress through the selective detection 2003) able to selectively capture small organic or gas molecules. of specific biomarkers in the body fluids. Most common biomarkers are Recently, the use of highly porous coatings of Metal-Organic Frame­ proteins and enzymes, as well as genomic molecules, such as micro­ works (MOFs) has also been achieved. Tao et al. (Tao et al., 2017) report RNAs. A few examples have been reported demonstrating and, in some the use of zeolitic imidazolate framework-8 (ZIF-8) film due to its high cases, validating the BiMW biosensor technology for clinical purposes. surface area, good water stability and efficient light transmittance. They One of the first works was published by Gonzalez et al. (González- deposited ZIF-8 layer by layer with an intergrowth process above the Guerrero et al., 2017) reporting the detection of the human growth entire chip. The final pattern on the waveguide was done with lithog­ hormone (hGH) in urine samples as a non-invasive method for di­ raphy and chemical etching (Fig. 8 a-c). The activation of the MOF film agnostics of acromegaly disease. The bioassay was based on the direct is done by immersion in anhydrous methanol for 3 days for the release of interaction of antibody-antigen and different concentrations of hGH unreacted species. The film is then dried under a dynamic vacuum for were tested in buffer urine sample and clinical validation was done with 12 h, reaching a thickness of ZIF-8 coating around 1 μm. Chocarro-Ruiz human spiked urine samples. The results show a limit of detection for et al. (Chocarro-Ruiz et al., 2018) also report the application of ZIF-8 spike urine sample of only 3 pg/mL. The same BiMW biosensor was nanoparticles for coating of the BiMW waveguides (Fig. 8 d-f). Their applied for the diagnostic of bladder cancer through the direct detection deposition method consisted of spin-coating of the ZIF-8 solution, of a specific microRNA marker also in urine samples (Fig. 9a) (Huertas evaluating the desired nanoparticles concentration and spinning speeds. et al., 2016). In this case, an outstanding sensitivity was obtained, They achieved 90 % light transmittance on surface and showed 100 % reaching a limit of detection of 23 aM, and successfully validating the gas sensor response. biosensor with the evaluation of clinical samples from healthy in­ dividuals and cancer patients. More recently, the BiMW biosensor has been demonstrated for diagnosis of bacterial infections. Maldonado et al. (Maldonado et al., 2016) showed an ultrasensitive detection of 11 L. Torrijos-Morán et al. Results in Optics 9 (2022) 100285 Fig. 8. Surface functionalization using MOFs (a) Photonic resonator - MOF sensor device fabrication process by layer deposition of MOF films. (b) Scanning electron microscope image (top view) of the waveguide containing ZIF-8. (c) Chemical structure of the ZIF-8 nanocrystals. Adapted from (Tao et al., 2017). (d) BiMW sensor device coated with nanoZIF-8. (e) FE-SEM image (side view) of the nanoZIF-8-based BiMW sensor, showing the layers of nanoZIF-8 and PDMS built on top of the waveguide. Scale bar: 5 mm. (f) Structure of the ZIF-8 particle. Reproduced from (Chocarro-Ruiz et al., 2018) with permission from the Royal Society of Chemistry. Escherichia coli in ascitic fluid of cirrhotic patients, reaching limit of Morán et al., 2020) for the recognition of bovine serum albumin (BSA) detection of 4 cfu/mL. They also applied the biosensor for detection of protein. A concentration of 10 μg/mL of BSA has been detected using hospital acquired infections through the rapid detection of Pseudomonas protein A/G and antibodies as surface biofunctionalization. These ex­ aeruginosa and Staphylococcus aureus with detection limits below 50 cfu/ amples confirm that although being still in its infancy, the application of mL (Maldonado et al., 2020). Furthermore, they have also been able to BiMW technologies for biomedicine and environmental control is rising identify antibiotic resistance and susceptibility, which is paramount for area of research with a promising and attractive future ahead. Efforts therapy decision making (Fig. 9b) (Maldonado et al., 2020). Finally, it is should now be directed to attain truly operative LOC systems based on worth mentioning that the BiMW system is also being applied for the BiMW biosensor that can be integrated in fully automated and user- detection of coronavirus disease (COVID-19) (Fig. 9c) (Ruiz-Vega et al., friendly POC devices to be operated by non-specialized users. Also, 2021). In environmental applications, BiMW biosensors have been research focus should be placed on the sensor biofunctionalization and employed mainly for detection of contaminants and pollutants either in assay optimization in order to exploit the full potential of the ultrasen­ air or waters. For example, the MOF biosensor developed by Chocarro- sitive detection offered by the different and innovative BiMW designs. Ruiz et al. (Chocarro-Ruiz et al., 2018) was applied for the detection and quantification of CO2 gas, which could be used for room contamination 4. Conclusions measurements. Recently, Ramirez-Priego et al. (Ramirez-Priego et al., 2021) demonstrated the real-time monitoring of fenitrothion in tap In summary, this review provides an overview of BiMW biosensors water samples, achieving a detection limit of 0.29 μg/mL (Fig. 9d). from the fundamentals to its application in LOC devices and detection of More novel types of BiMW technologies are also being demonstrated real samples. Last advances on the topic are presented and discussed for bioanalytical sensing, although validation with real scenarios has not regarding its operating principle, materials employed, detection method been fully accomplished yet. For example, Liu et al. (Liu et al., 2014) and integration capabilities. Specifically, uniform and periodic config­ developed a spiral BiMW sensor that demonstrated quantification of urations are studied to develop BiMWs and compared in terms of per­ biotin-streptadivin interactions over a wide range. The perforated BiMW formance. Uniform schemes are widely demonstrated for different biosensor described by Uchiyamada et al. (Uchiyamada et al., 2019) has biosensing purposes which shows the high degree of maturity within this been tested with the human serum albumin (HSA) in a surface modified area compared to other IO-based devices. In contrast, periodic config­ with molecular imprinted polymers in a label-free approach. In this urations have been recently proposed and have a long way to go in the sensor, the detection limit is calculated at 20.4 μg/mL, which is not high biosensing field. Nevertheless, first results show a promising potential as enough for its use in urine testing. Similarly, SWG BiMW have been a result of outstanding sensitivity performances (aM-fM range) and explored in biosensor experiments by Torrijos-Morán et al. (Torrijos- highly compact design for integration in portable and user-friendly POC 12 L. Torrijos-Morán et al. Results in Optics 9 (2022) 100285 Fig. 9. Applications of the bimodal sensors on biomedical and environmental analysis. a) Bladder cancer patients samples containing selective miRNAs used for the prediction of the disease at attomolar of concentration. Real-time detection of miR-181a at different concentrations. Concentrations of miR-181a in healthy donors and cancer patients. Adapted with permission from (Huertas et al., 2016) © American Chemical Society 2022. (b) Bacteria resistance detections employing a surface of silane-PEG-COOH surface provided a highly specific detection of bacteria (MRSA), while non-specific bacteria (MSSA) was used to demonstrate the microbial- repelling property of the surface. Adapted from (Maldonado et al., 2020). (c) Two strategies used for the SARS-CoV-2 diagnosis with the BiMW biosensor: on the left, the illustration of the intact SARS-CoV-2 virus detection; On the right, the viral genomic material is detected. Adapted from (Ruiz-Vega et al., 2021). (d) Calibration curves for fenitrothion detection from samples diluted in buffer medium (PBST – black curve) and samples collected in the field (tap water – blue curve). Specificity of the assay is not altered. Adapted from (Ramirez-Priego et al., 2021). devices. BiMWs encompasses the benefits from evanescent-wave sensors References and interferometric configurations in a single-channel structure that addresses the requirements of miniaturization and integration of LOC Aćimović, S.S., Ortega, M.A., Sanz, V., Berthelot, J., Garcia-Cordero, J.L., Renger, J., Maerkl, S.J., Kreuzer, M.P., Quidant, R., 2014. LSPR chip for parallel, rapid, and portable devices. Overall, they pave the road towards the realization of sensitive detection of cancer markers in serum. Nano Lett. 14, 2636–2641. https:// new generation bio-recognition tools that will have a profound impact in doi.org/10.1021/nl500574n. several applications such as health-care diagnostics, environmental Aikio, S., Hiltunen, M., Hiltunen, J., 2015. Compensation of drift by using a multichannel integrated Young interferometer. Appl. Opt. 54, 4771. https://doi.org/10.1364/ pollution identification or food quality control. AO.54.004771. Baba, T., 2008. Slow light in photonic crystals. Nat. Photonics 2, 465–473. https://doi. Declaration of Competing Interest org/10.1038/nphoton.2008.146. Barrios, C.A., Bañuls, M.J., González-Pedro, V., Gylfason, K.B., Sánchez, B., Griol, A., Maquieira, A., Sohlström, H., Holgado, M., Casquel, R., 2008. Label-free optical The authors declare that they have no known competing financial biosensing with slot-waveguides. Opt. Lett. 33, 708. https://doi.org/10.1364/ interests or personal relationships that could have appeared to influence OL.33.000708. Bassols-Cornudella, B., Ramirez-Priego, P., Soler, M., Estevez, M.C., Luis-Ravelo, H.J.D., the work reported in this paper. Cardenosa-Rubio, M., Lechuga, L.M., 2022. Novel sensing algorithm for linear read- out of bimodal waveguide interferometric biosensors. J. Lightwave Technol. 40, Acknowledgements 237–244. https://doi.org/10.1109/JLT.2021.3118103. Bogaerts, W., Pérez, D., Capmany, J., Miller, D.A.B., Poon, J., Englund, D., Morichetti, F., Melloni, A., 2020. Programmable photonic circuits. Nature 586, 207–216. https:// LTM and JGR acknowledge the support from the Spanish MCIN/AEI/ doi.org/10.1038/s41586-020-2764-0. 10.13039/501100011033 through the PID2019-106965RB-C21 project Brimont, A., Thomson, D.J., Sanchis, P., et al., 2011. High speed silicon electro-optical and by the European Union through the operational program of the modulators enhanced via slow light propagation. Opt. Express 19, 20876. https:// doi.org/10.1364/OE.19.020876. European Regional Development Fund (FEDER) of the Valencia Bruck, R., Hainberger, R., 2014. Sensitivity and design of grating-assisted bimodal Regional Government 2014-2020. BDL, MS, and LML acknowledge interferometers for integrated optical biosensing. Opt. Express 22, 32344. https:// support of FLAG-ERA grant LEGOCHIP, funded by the Spanish Research doi.org/10.1364/oe.22.032344. Cai, H., Parks, J.W., Wall, T.A., Stott, M.A., Stambaugh, A., Alfson, K., Griffiths, A., Agency (AEI, Ref. PCI2019-111890-2), and financial support from Mathies, R.A., Carrion, R., Patterson, J.L., Hawkins, A.R., Schmidt, H., 2015. EROICA project (Spanish Ministry of Science and Innovation MCIN, Optofluidic analysis system for amplification-free, direct detection of Ebola Ref. PID2019-105132RB-I00). The ICN2 is funded by the CERCA pro­ infection. Sci. Rep. 5, 14494. https://doi.org/10.1038/srep14494. Castelló, J.G., V. Toccafondo, J. Escorihuela, M.J. Bañuls, A. Maquieira, J. García- gram/Generalitat de Catalunya and supported by the Severo Ochoa Rupérez, 2012. Real-time analysis of antigen-antibody association kinetics using a Centers of Excellence program, funded by the Spanish Research Agency low-cost SOI photonic biosensor, IEEE International Conference on Group IV (AEI, grant SEV-2017-0706). Photonics GFP. 297–299. 10.1109/GROUP4.2012.6324165. Ceyssens, F., Witters, D., Van Grimbergen, T., Knez, K., Lammertyn, J., Puers, R., 2013. Integrating optical waveguides in electrowetting-on-dielectric digital microfluidic chips. Sensors Actuators, B Chem. 181, 166–171. https://doi.org/10.1016/j. snb.2013.01.078. 13 L. Torrijos-Morán et al. Results in Optics 9 (2022) 100285 Cheben, P., Halir, R., Schmid, J.H., Atwater, H.A., Smith, D.R., 2018. Subwavelength Heideman, R.G., Kooyman, R.P.H., Greve, J., 1991. Development of an optical integrated photonics. Nature 560, 565–572. https://doi.org/10.1038/s41586-018- waveguide interferometric immunosensor. Sens. Actuators, B 4, 297–299. https:// 0421-7. doi.org/10.1016/0925-4005(91)80126-5. Chocarro-Ruiz, B., Pérez-Carvajal, J., Avci, C., Calvo-Lozano, O., Alonso, M.I., Herranz, S., Gavela, A.F., Lechuga, L.M., 2017. Label-free biosensors based on bimodal Maspoch, D., Lechuga, L.M., 2018. A CO2 optical sensor based on self-assembled waveguide (BiMW) interferometers. Methods Mol. Biol. 1571, 161–185. https://doi. metal-organic framework nanoparticles. J. Mater. Chem. A 6, 13171–13177. https:// org/10.1007/978-1-4939-6848-0_11. doi.org/10.1039/c8ta02767f. Hess, D., Yang, T., Stavrakis, S., 2020. Droplet-based optofluidic systems for measuring Chow, E., Grot, A., Mirkarimi, L.W., Sigalas, M., Girolami, G., 2004. Ultracompact enzyme kinetics. Anal. Bioanal. Chem. 412, 3265–3283. https://doi.org/10.1007/ biochemical sensor built with two-dimensional photonic crystal microcavity. Opt s00216-019-02294-z. Lett. 29, 1093–1095. https://doi.org/10.1364/ol.29.001093. Huang, C.S., Chaudhery, V., Pokhriyal, A., George, S., Polans, J., Lu, M., Tan, R., Chrostowski, L., S. Grist, J. Flueckiger, W. Shi, X. Wang, E. Ouellet, H. Yun, M. Webb, B. Zangar, R.C., Cunningham, B.T., 2012. Multiplexed cancer biomarker detection Nie, Z. Liang, K.C. Cheung, S.A. Schmidt, D.M. Ratner, N.A.F. Jaeger, 2012. Silicon using quartz-based photonic crystal surfaces. Anal. Chem. 84, 1126–1133. https:// photonic resonator sensors and devices, Laser Resonators, Microresonators, and doi.org/10.1021/ac202817q. Beam Control XIV, SPIE. 823620. 10.14288/1.0107567. Huertas, C.S., Fariña, D., Lechuga, L.M., 2016. Direct and label-free quantification of Dante, S., 2014. All-optical phase modulation for advanced interferometric point-of-care micro-RNA-181a at attomolar level in complex media using a nanophotonic biosensors. UAB http://hdl.handle.net/10803/285191. biosensor. ACS Sensors 1, 748–756. https://doi.org/10.1021/acssensors.6b00162. Dante, S., Duval, D., Fariña, D., González-Guerrero, A.B., Lechuga, L.M., 2015. Linear Irace, A., Breglio, G., Alvarez-Herrero, A., Guerrero, H., Belenguer, T., Levy, D., Rao, Y., readout of integrated interferometric biosensors using a periodic wavelength Kalli, K., Brady, G., Webb, D., Jackson, D., Zhang, L., 2003. All-silicon optical modulation. Laser Photonics Rev. 9, 248–255. https://doi.org/10.1002/ temperature sensor based on Multi-Mode Interference. Opt. Express 11, 2807–2812. lpor.201400216. https://doi.org/10.1364/OE.11.002807. De Vos, K., Bartolozzi, I., Schacht, E., Bienstman, P., Baets, R., 2007. Silicon-on-Insulator Joannopoulos, J.D., Villeneuve, P.R., Fan, S., 1997. Photonic crystals: putting a new twist microring resonator for sensitive and label-free biosensing. Opt. Express 15, 7610. on light. Nature 386, 143–149. https://doi.org/10.1038/386143a0. https://doi.org/10.1364/oe.15.007610. Krauss, T.F., 2007. Slow light in photonic crystal waveguides. J. Phys. D Appl. Phys. 40, Duval, D., González-Guerrero, A.B., Dante, S., Osmond, J., Monge, R., Fernández, L.J., 2666–2670. https://doi.org/10.1088/0022-3727/40/9/S07. Zinoviev, K.E., Domínguez, C., Lechuga, L.M., 2012. Nanophotonic lab-on-a-chip Ksendzov, A., Lin, Y., 2005. Integrated optics ring-resonator sensors for protein platforms including novel bimodal interferometers, microfluidics and grating detection. Opt. Lett. 30, 3344. https://doi.org/10.1364/OL.30.003344. couplers. Lab Chip 12, 1987–1994. https://doi.org/10.1039/c2lc40054e. Lenz, K.D., Jakhar, S., Chen, J.W., Anderson, A.S., Purcell, D.C., Ishak, M.O., Harris, J.F., Estevez, M.C., Alvarez, M., Lechuga, L.M., 2012. Integrated optical devices for lab-on-a- Akhadov, L.E., Kubicek-Sutherland, J.Z., Nath, P., Mukundan, H., 2021. chip biosensing applications. Laser Photonics Rev. 6, 463–487. https://doi.org/ A centrifugal microfluidic cross-flow filtration platform to separate serum from 10.1002/lpor.201100025. whole blood for the detection of amphiphilic biomarkers. Sci. Rep. 11, 5287. https:// Fernández Gavela, A., Grajales García, D., Ramirez, J., Lechuga, L., 2016. Last advances doi.org/10.1038/s41598-021-84353-z. in silicon-based optical biosensors. Sensors 16, 285. https://doi.org/10.3390/ Levy, R., Ruschin, S., 2008. Critical sensitivity in hetero-modal interferometric sensor s16030285. using spectral interrogation. Opt. Express 16, 20516. https://doi.org/10.1364/ Flueckiger, J., Schmidt, S., Donzella, V., Sherwali, A., Ratner, D.M., Chrostowski, L., OE.16.020516. Cheung, K.C., 2016. Sub-wavelength grating for enhanced ring resonator biosensor. Levy, R., Ruschin, S., 2009. Design of a single-channel modal interferometer waveguide Opt. Express 24, 15672. https://doi.org/10.1364/oe.24.015672. sensor. IEEE Sens. J. 9, 146–153. https://doi.org/10.1109/JSEN.2008.2011075. Freitag, S., Le Trong, I., Chilkoti, A., Klumb, L.A., Stayton, P.S., Stenkamp, R.E., 1998. Levy, R., Ruschin, S., Goldring, D., 2009. Critical sensitivity effect in an interferometer Structural studies of binding site tryptophan mutants in the high-affinity sensor. Opt. Lett. 34, 3023. https://doi.org/10.1364/OL.34.003023. streptavidin-biotin complex. J. Mol. Biol. 279, 211–221. https://doi.org/10.1006/ Liang, Y., Zhao, M., Wu, Z., Morthier, G., 2018. Investigation of grating-assisted trimodal jmbi.1998.1735. interferometer biosensors based on a polymer platform. Sensors. 18, 1502. https:// Gao, Y., Gan, Q., Xin, Z., Cheng, X., Bartoli, F.J., 2011. Plasmonic Mach-Zehnder doi.org/10.3390/s18051502. interferometer for ultrasensitive on-chip biosensing. ACS Nano 5, 9836–9844. Liang, Y., Zhao, M., Wu, Z., Morthier, G., 2019. Bimodal waveguide interferometer RI https://doi.org/10.1021/nn2034204. sensor fabricated on low-cost polymer platform. IEEE Photonics J. 11, 1–8. https:// García-Rupérez, J., L. Torrijos-Morán, 2021. Bimodal Interferometric Photonic Sensors doi.org/10.1109/JPHOT.2019.2900741. Based On Periodic Configurations, in: OSA Optical Sensors and Sensing Congress, Ligler, F.S., 2009. Perspective on optical biosensors and integrated sensor systems. Anal. OSA, Washington, D.C., 10.1364/SENSORS.2021.SF2D.1. Chem. 81, 519–526. https://doi.org/10.1021/ac8016289. García-Ruperez, J., L. Torrijos-Morán, M. Gomez-Gomez, P. Martinez-Perez, S. Ponce- Liu, Q., Tu, X., Kim, K.W., Kee, J.S., Shin, Y., Han, K., Yoon, Y.J., Lo, G.Q., Park, M.K., Alcantara, 2021. High performance photonic biosensors based on periodic 2013. Highly sensitive Mach-Zehnder interferometer biosensor based on silicon configurations, in: S.M. García-Blanco, P. Cheben (Eds.), Integrated Optics: Devices, nitride slot waveguide. Sens. Actuators, B 188, 681–688. https://doi.org/10.1016/J. Materials, and Technologies XXV, SPIE, 10.1117/12.2576401. SNB.2013.07.053. Giraud, L., Nadarajah, R., Matar, Y., Bazin, G., Sun, J., Zhu, X.X., Giasson, S., 2016. Liu, Q., Kim, K.W., Gu, Z., Kee, J.S., Park, M.K., 2014. Single-channel Mach-Zehnder Amino-functionalized monolayers covalently grafted to silica-based substrates as a interferometric biochemical sensor based on two-lateral-mode spiral waveguide. robust primer anchorage in aqueous media. Appl. Surf. Sci. 370, 476–485. https:// Opt. Express 22, 27910. https://doi.org/10.1364/oe.22.027910. doi.org/10.1016/j.apsusc.2016.02.141. Lohmeyer, M., Wilkens, L., Zhuromskyy, O., Dotsch, H., Hertel, P., 2001. Integrated González-Guerrero, A.B., Alvarez, M., Castaño, A.G., Domínguez, C., Lechuga, L.M., magnetooptic cross strip isolator. Opt. Commun. 189, 251–259. https://doi.org/ 2013. A comparative study of in-flow and micro-patterning biofunctionalization 10.1016/S0030-4018(01)01010-0. protocols for nanophotonic silicon-based biosensors. J. Colloid Interface Sci. 393, Lopez, G.A., Estevez, M.C., Soler, M., Lechuga, L.M., 2017. Recent advances in 402–410. https://doi.org/10.1016/j.jcis.2012.10.040. nanoplasmonic biosensors: applications and lab-on-a-chip integration. González-Guerrero, A.B., Maldonado, J., Herranz, S., Lechuga, L.M., 2016. Trends in Nanophotonics. 6, 123–136. https://doi.org/10.1515/nanoph-2016-0101. photonic lab-on-chip interferometric biosensors for point-of-care diagnostics. Anal. Luan, E., Shoman, H., Ratner, D., Cheung, K., Chrostowski, L., 2018. Silicon photonic Methods 8, 8380–8394. https://doi.org/10.1039/c6ay02972h. biosensors using label-free detection. Sensors. 18, 3519. https://doi.org/10.3390/ González-Guerrero, A.B., Maldonado, J., Dante, S., Grajales, D., Lechuga, L.M., 2017. s18103519. Direct and label-free detection of the human growth hormone in urine by an Luan, E., Yun, H., Ma, M., Ratner, D.M., Cheung, K.C., Chrostowski, L., 2019. Label-free ultrasensitive bimodal waveguide biosensor. J. Biophotonics 10, 61–67. https://doi. biosensing with a multi-box sub-wavelength phase-shifted Bragg grating waveguide. org/10.1002/jbio.201600154. Biomed. Opt. Express 10, 4825. https://doi.org/10.1364/boe.10.004825. Grajales, D., Fernández Gavela, A., Domínguez, C., Sendra, J.R., Lechuga, L.M., 2019. Luchansky, M.S., Bailey, R.C., 2012. High-Q optical sensors for chemical and biological Low-cost vertical taper for highly efficient light in-coupling in bimodal analysis. Anal. Chem. 84, 793–821. https://doi.org/10.1021/ac2029024. nanointerferometric waveguide biosensors. J. Phys.: Photonics 1, 025002. https:// Maldonado, J., González-Guerrero, A.B., Domínguez, C., Lechuga, L.M., 2016. Label-free doi.org/10.1088/2515-7647/aafebb. bimodal waveguide immunosensor for rapid diagnosis of bacterial infections in Gunnar, B., Carl-Fredrik, M., 2011. Orientation and capturing of antibody affinity cirrhotic patients. Biosens. Bioelectron. 85, 310–316. https://doi.org/10.1016/j. ligands: applications to surface plasmon resonance biochips. Sens. Actuators, B 158, bios.2016.04.095. 265–270. https://doi.org/10.1016/j.snb.2011.06.017. Maldonado, J., González-Guerrero, A.B., Fernández-Gavela, A., González-López, J.J., Guo, Y., Guo, Y., Li, C., Zhang, H., Zhou, X., Zhang, L., 2021. Integrated optical phased Lechuga, L.M., 2020. Ultrasensitive label-free detection of unamplified multidrug- arrays for beam forming and steering. Appl. Sci. 11, 4017. https://doi.org/10.3390/ resistance bacteria genes with a bimodal waveguide interferometric biosensor. app11094017. Diagnostics 10, 845. https://doi.org/10.3390/diagnostics10100845. Halir, R., Cheben, P., Luque-González, J.M., Sarmiento-Merenguel, J.D., Schmid, J.H., Maldonado, J., Estévez, M.-C., Fernández-Gavela, A., González-López, J.J., González- Wangüemert-Pérez, G., Xu, D.X., Wang, S., Ortega-Moñux, A., Molina-Fernández, Í., Guerrero, A.B., Lechuga, L.M., 2020. Label-free detection of nosocomial bacteria 2016. Ultra-broadband nanophotonic beamsplitter using an anisotropic sub- using a nanophotonic interferometric biosensor. Analyst 145, 497–506. https://doi. wavelength metamaterial. Laser Photonics Rev. 10, 1039–1046. https://doi.org/ org/10.1039/C9AN01485C. 10.1002/lpor.201600213. McDonagh, C., Burke, C.S., MacCraith, B.D., 2008. Optical chemical sensors. Chem. Rev. Heideman, R.G., Lambeck, P.V., 1999. Remote opto-chemical sensing with extreme 108, 400–422. https://doi.org/10.1021/cr068102g. sensitivity: design, fabrication and performance of a pigtailed integrated optical Miller, D.A.B., 2013. Self-aligning universal beam coupler. Opt. Express 21, 6360. phase-modulated Mach-Zehnder interferometer system. Sens. Actuators, B 61, https://doi.org/10.1364/oe.21.006360. 100–127. https://doi.org/10.1016/S0925-4005(99)00283-X. Modi, A., Koratkar, N., Lass, E., Wei, B., Ajayan, P.M., 2003. Miniaturized gas ionization sensors using carbon nanotubes. Nature 424, 171–174. https://doi.org/10.1038/ nature01777. 14 L. Torrijos-Morán et al. Results in Optics 9 (2022) 100285 Moon, J.H., Shin, J.W., Kim, S.Y., Park, J.W., 1996. Formation of uniform aminosilane Soler, M., Huertas, C.S., Lechuga, L.M., 2019. Label-free plasmonic biosensors for point- thin layers: An imine formation to measure relative surface density of the amine of-care diagnostics: a review. Exp. Rev. Mol. Diagnostics 19, 71–81. https://doi.org/ group. Langmuir 12, 4621–4624. https://doi.org/10.1021/la9604339. 10.1080/14737159.2019.1554435. Morichetti, F., Grillanda, S., Carminati, M., Ferrari, G., Sampietro, M., Strain, M.J., Son, G., Han, S., Park, J., Kwon, K., Yu, K., 2018. High-efficiency broadband light Sorel, M., Melloni, A., 2014. Non-invasive on-chip light observation by contactless coupling between optical fibers and photonic integrated circuits. Nanophotonics 7, waveguide conductivity monitoring. IEEE J. Sel. Top. Quantum Electron. 20, 1845–1864. https://doi.org/10.1515/nanoph-2018-0075. 292–301. https://doi.org/10.1109/JSTQE.2014.2300046. Soref, R., 2006. The past, present, and future of silicon photonics. IEEE J. Sel. Top. Muñoz, P., Micó, G., Bru, L.A., Pastor, D., Pérez, D., Doménech, J.D., Fernández, J., Quantum Electron. 12, 1678–1687. https://doi.org/10.1109/JSTQE.2006.883151. Baños, R., Gargallo, B., Alemany, R., Sánchez, A.M., Cirera, J.M., Mas, R., Szydzik, C., Gavela, A.F., Herranz, S., Roccisano, J., Knoerzer, M., Thurgood, P., Domínguez, C., 2017. Silicon nitride photonic integration platforms for visible, near- Khoshmanesh, K., Mitchell, A., Lechuga, L.M., 2017. An automated optofluidic infrared and mid-infrared applications. Sensors 17, 2088. https://doi.org/10.3390/ biosensor platform combining interferometric sensors and injection moulded S17092088. microfluidics. Lab Chip 17, 2793–2804. https://doi.org/10.1039/c7lc00524e. Nguyen, H.C., Hashimoto, S., Shinkawa, M., Baba, T., 2012. Compact and fast photonic Tao, J., Wang, X., Sun, T., Cai, H., Wang, Y., Lin, T., Fu, D., Ting, L.L.Y., Gu, Y., Zhao, D., crystal silicon optical modulators. Opt. Express 20, 22465. https://doi.org/10.1364/ 2017. Hybrid photonic cavity with metal-organic framework coatings for the ultra- OE.20.022465. sensitive detection of volatile organic compounds with high immunity to humidity. Lambeck, P.V., 1992. Integrated opto-chemical sensors. Sens. Actuators, B 8, 103–116. Sci. Rep. 7, 41640. https://doi.org/10.1038/srep41640. https://doi.org/10.1016/0925-4005(92)85016-P. Laser Diode Technology, (n.d.). https://www.newport.com/t/laser-diode-technology Lambeck, P.V., 2006. Integrated optical sensors for the chemical domain. Meas. Sci. (accessed April 13, 2022). Technol. 17, R93–R116. https://doi.org/10.1088/0957-0233/17/8/R01. Theurer, M., Moehrle, M., Sigmund, A., Velthaus, K.O., Oldenbeuving, R.M., Wevers, L., Paniccia, M., 2010. Integrating silicon photonics. Nat. Photonics 4, 498–499. https://doi. Postma, F.M., Mateman, R., Schreuder, F., Geskus, D., Worhoff, K., Dekker, R., org/10.1038/nphoton.2010.189. Heideman, R.G., Schell, M., 2020. Flip-chip integration of InP to SiN photonic Parks, J.W., Olson, M.A., Kim, J., Ozcelik, D., Cai, H., Carrion, R., Patterson, J.L., integrated circuits. J. Lightwave Technol. 38, 2630–2636. https://doi.org/10.1109/ Mathies, R.A., Hawkins, A.R., Schmidt, H., 2014. Integration of programmable JLT.2020.2972065. microfluidics and on-chip fluorescence detection for biosensing applications. Tien, P.K., 1977. Integrated optics and new wave phenomena in optical waveguides. Rev. Biomicrofluidics. 8, 054111 https://doi.org/10.1063/1.4897226. Mod. Phys. 49, 361–420. https://doi.org/10.1103/RevModPhys.49.361. Pérez-Armenta, C., Ortega-Moñux, A., Čtyroký, J., Cheben, P., Schmid, J.H., Halir, R., Torrijos-Moran, L., Brimont, A., Griol, A., Sanchis, P., Garcia-Ruperez, J., 2021. Ultra- Molina-Fernández, Í., Wangüemert-Pérez, J.G., 2020. Narrowband Bragg filters compact optical switches using slow light bimodal silicon waveguides. J. Lightwave based on subwavelength grating waveguides for silicon photonic sensing. Opt. Technol. 39, 3495–3501. https://doi.org/10.1109/JLT.2021.3066479. Express 28, 37971. https://doi.org/10.1364/oe.404364. Torrijos-Morán, L., A. Griol, J. García-Rupérez, 2020. Bimodal waveguide sensors Prieto, F., Sepúlveda, B., Calle, A., Llobera, A., Domínguez, C., Abad, A., Montoya, A., enabled by subwavelength grating structures, in: OSA Advanced Photonics Congress Lechuga, L.M., 2003. An integrated optical interferometric nanodevice based on (AP), OSA, Washington, D.C., 10.1364/IPRSN.2020.ITu4A.4. silicon technology for biosensor applications. Nanotechnology. 14, 907–912. Torrijos-Morán, L., García-Rupérez, J., 2019. Single-channel bimodal interferometric https://doi.org/10.1088/0957-4484/14/8/312. sensor using subwavelength structures. Opt. Express 27, 8168. https://doi.org/ Ramirez, J.C., Lechuga, L.M., Gabrielli, L.H., Hernandez-Figueroa, H.E., 2015. Study of a 10.1364/oe.27.008168. low-cost trimodal polymer waveguide for interferometric optical biosensors. Opt. Torrijos-Morán, L., García-Rupérez, J., 2021. Design of slow-light-enhanced bimodal Express 23, 11985. https://doi.org/10.1364/oe.23.011985. interferometers using dimensionality reduction techniques. Opt. Express 29, 33962. Ramirez, J.C., Gabrielli, L.H., Lechuga, L.M., Hernandez-Figueroa, H.E., 2019. Trimodal https://doi.org/10.1364/oe.425865. waveguide demonstration and its implementation as a high order mode Torrijos-Morán, L., Griol, A., García-Rupérez, J., 2019. Experimental study of interferometer for sensing application. Sensors 19, 2821. https://doi.org/10.3390/ subwavelength grating bimodal waveguides as ultrasensitive interferometric sensors. s19122821. Opt. Lett. 44, 4702. https://doi.org/10.1364/ol.44.004702. Ramirez-Priego, P., Estévez, M.-C., Díaz-Luisravelo, H.J., Manclús, J.J., Montoya, Á., Torrijos-Morán, L., Martínez-Pérez, P., García-Rupérez, J., 2020. Real-time Lechuga, L.M., 2021. Real-time monitoring of fenitrothion in water samples using a functionalization and biosensing in subwavelength grating bimodal waveguides. In: silicon nanophotonic biosensor. Anal. Chim. Acta 1152, 338276. https://doi.org/ 22nd European Conference on Integrated Optics, pp. 1–3. 10.1016/j.aca.2021.338276. Torrijos-Morán, L., Griol, A., García-Rupérez, J., 2021. Slow light bimodal interferometry Ruiz-Vega, G., Soler, M., Lechuga, L.M., 2021. Nanophotonic biosensors for point-of-care in one-dimensional photonic crystal waveguides. Light Sci. Appl. 10, 16. https://doi. COVID-19 diagnostics and coronavirus surveillance. J. Phys.: Photonics 3, 011002. org/10.1038/s41377-020-00460-y. https://doi.org/10.1088/2515-7647/abd4ee. Uchiyamada, K., Okubo, K., Asakawa, K., Kamon, Y., Kitayama, Y., Takeuchi, T., Sabek, J., Torrijos-Morán, L., Griol, A., Díaz Betancor, Z., Bañuls Polo, M.-J., Suzuki, H., 2019. Perforated bimodal interferometric biosensor for affinity sensing. Maquieira, Á., García-Rupérez, J., 2018. Real time monitoring of a UV light-assisted Adv. Mater. Technol. 4, 1800533. https://doi.org/10.1002/admt.201800533. biofunctionalization protocol using a nanophotonic biosensor. Biosensors 9, 6. Wang, Y., Lu, Z., Ma, M., Yun, H., Zhang, F., Jaeger, N.A.F., Chrostowski, L., 2016. https://doi.org/10.3390/bios9010006. Compact broadband directional couplers using subwavelength gratings. IEEE Sabek, J., Díaz-Fernández, F.J., Torrijos-Morán, L., Díaz-Betancor, Z., Maquieira, Á., Photonics J. 8, 1–8. https://doi.org/10.1109/JPHOT.2016.2574335. Bañuls, M.-J., Pinilla-Cienfuegos, E., García-Rupérez, J., 2019. Experimental study of Wangüemert-Pérez, J.G., Hadij-ElHouati, A., Sánchez-Postigo, A., Leuermann, J., Xu, D.- an evanescent-field biosensor based on 1D photonic bandgap structures, Beilstein. X., Cheben, P., Ortega-Moñux, A., Halir, R., Molina-Fernández, Í., 2019. J. Nanotechnol. 10, 967–974. https://doi.org/10.3762/bjnano.10.97. Subwavelength structures for silicon photonics biosensing. Opt. Laser Technol. 109, Schipper, E.F., Brugman, A.M., Dominguez, C., Lechuga, L.M., Kooyman, R.P.H., 437–448. https://doi.org/10.1016/j.optlastec.2018.07.071. Greve, J., 1997. The realization of an integrated Mach-Zehnder waveguide Yavari, F., Chen, Z., Thomas, A.V., Ren, W., Cheng, H.M., Koratkar, N., 2011. High immunosensor in silicon technology. Sens. Actuators, B 40, 147–153. https://doi. sensitivity gas detection using a macroscopic three-dimensional graphene foam org/10.1016/S0925-4005(97)80254-7. network. Sci. Rep. 1, 166. https://doi.org/10.1038/srep00166. Schmitt, K., Schirmer, B., Hoffmann, C., Brandenburg, A., Meyrueis, P., 2007. Yavas, O., Svedendahl, M., Dobosz, P., Sanz, V., Quidant, R., 2017. On-a-chip biosensing Interferometric biosensor based on planar optical waveguide sensor chips for label- based on all-dielectric nanoresonators. Nano Lett. 17, 4421–4426. https://doi.org/ free detection of surface bound bioreactions. Biosens. Bioelectron. 22, 2591–2597. 10.1021/acs.nanolett.7b01518. https://doi.org/10.1016/j.bios.2006.10.016. Ymeti, A., Kanger, J.S., Greve, J., Lambeck, P.V., Wijn, R., Heideman, R.G., 2003. Schudel, B.R., Choi, C.J., Cunningham, B.T., Kenis, P.J.A., 2009. Microfluidic chip for Realization of a multichannel integrated Young interferometer chemical sensor. combinatorial mixing and screening of assays. Lab Chip 9, 1676–1680. https://doi. Appl. Opt. 42 (28), 5649. org/10.1039/b901999e. Zeming, K.K., Thakor, N.V., Zhang, Y., Chen, C.H., 2016. Real-time modulated Sepúlveda, B., Sánchez Del Río, J., Moreno, M., Blanco, F.J., Mayora, K., Domínguez, C., nanoparticle separation with an ultra-large dynamic range. Lab Chip 16, 75–85. Lechuga, L.M., 2006. Optical biosensor microsystems based on the integration of https://doi.org/10.1039/c5lc01051a. highly sensitive Mach-Zehnder interferometer devices. J. Opt. A: Pure Appl. Opt. 8 Zhang, F., Sautter, K., Larsen, A.M., Findley, D.A., Davis, R.C., Samha, H., Linford, M.R., https://doi.org/10.1088/1464-4258/8/7/S41. 2010. Chemical vapor deposition of three aminosilanes on silicon dioxide: Surface Shimizu, T., Hatori, N., Okano, M., Ishizaka, M., Urino, Y., Yamamoto, T., Mori, M., characterization, stability, effects of silane concentration, and cyanine dye Nakamura, T., Arakawa, Y., 2014. Multichannel and high-density hybrid integrated adsorption. Langmuir 26, 14648–14654. https://doi.org/10.1021/la102447y. light source with a laser diode array on a silicon optical waveguide platform for Zhao, X., Dalir, H., Xu, X., Chen, R.T., 2017. Efficient coupling into slow-light one- interchip optical interconnection. Photonics Res. 2, A19. https://doi.org/10.1364/ dimensional fishbone waveguide by mode converter method. Appl. Phys Express 10, prj.2.000a19. 072502. https://doi.org/10.7567/APEX.10.072502/XML. Soler, M., Lechuga, L.M., 2022. Biochemistry strategies for label-free optical sensor Zinoviev, K.E., González-Guerrero, A.B., Domínguez, C., Lechuga, L.M., 2011. Integrated biofunctionalization: advances towards real applicability. Anal. Bioanal. Chem. 414, bimodal waveguide interferometric biosensor for label-free analysis. J. Lightwave 5071–5085. https://doi.org/10.1007/s00216-021-03751-4. Technol. 29, 1926–1930. https://doi.org/10.1109/JLT.2011.2150734. 15