Detection of NT-proBNP Using Optical Fiber Back-Reflection Plasmonic Biosensors.

Heart failure (HF) is a clinical entity included in cardiovascular diseases affecting millions of people worldwide, being a leading cause of hospitalization of older adults, and therefore imposing a substantial economic burden on healthcare systems. HF is characterized by dyspnea, fatigue, and edema associated with elevated blood levels of natriuretic peptides, such as N Terminal pro-B-type Natriuretic Peptide (NT-proBNP), for which there is a high demand for point of care testing (POCT) devices. Optical fiber (OF) biosensors offer a promising solution, capable of real-time detection, quantification, and monitoring of NT-proBNP concentrations in serum, saliva, or urine. In this study, immunosensors based on plasmonic uncladded OF tips were developed using OF with different core diameters (200 and 600 µm). The tips were characterized to bulk refractive index (RI), anddetection tests were conducted with NT-proBNP concentrations varying from 0.01 to 100 ng/mL. The 200 µm sensors showed an average total variation of 3.6 ± 2.5 mRIU, an average sensitivity of 50.5 mRIU/ng·mL-1, and a limit of detection (LOD) of 0.15 ng/mL, while the 600 µm sensors had a response of 6.1 ± 4.2 mRIU, a sensitivity of 102.8 mRIU/ng·mL-1, and an LOD of 0.11 ng/mL. Control tests were performed using interferents such as uric acid, glucose, and creatinine. The results show the potential of these sensors for their use in biological fluids.

Insulin biotrapping using plasmofluidic optical fiber chips: A benchmark.

Plasmonic optical fiber-based biosensors are currently in their early stages of development as practical and integrated devices, gradually making their way towards the market. While the majority of these biosensors operate using white light and multimode optical fibers (OFs), our approach centers on single-mode OFs coupled with tilted fiber Bragg gratings (TFBGs) in the near-infrared wavelength range. Our objective is to enhance surface sensitivity and broaden sensing capabilities of OF-based sensors to develop in situ sensing with remote interrogation. In this study, we comprehensively assess their performance in comparison to the gold-standard plasmonic reference, a commercial device based on the Kretschmann-Raether prism configuration. We present their refractive index sensitivity and their capability for insulin sensing using a dedicated microfluidics approach. By optimizing a consistent surface biotrapping methodology, we elucidate the dynamic facets of both technologies and highlight their remarkable sensitivity to variations in bulk and surface properties. The one-to-one comparison between both technologies demonstrates the reliability of optical fiber-based measurements, showcasing similar experimental trends obtained with both the prismatic configuration and gold-coated TFBGs, with an even enhanced limit of detection for the latter. This study lays the foundation for the detection of punctual molecular interactions and opens the way towards the detection of spatially and temporally localized events on the surface of optical probes.

Gold-coated tilted fiber Bragg gratings for lead ion sensing.

Surface plasmon resonance sensor based on gold-coated tilted fiber Bragg gratings (SPR-TFBGs) are perfectly suited for fine refractometry. Thanks to the functionalization of the gold layer, they can be used for label-free biosensing. They have been largely used for the specific detection of proteins and cells. In this work, we experimentally demonstrate that they are enough sensitive to detect a very small entity like an environmental pollutant. In this context, we report here a bio-functionalization of the SPR-TFBG with thrombin aptamers for lead ion detection. We used aqueous solutions of lead ions with increasing concentrations from 0.001 ppb to 10 ppb. Based on the affinity bending of Pb2+ ions to the thrombin aptamer, we experimentally demonstrated low detection level of lead ion concentration (0.001 ppb) while the saturation limit is meanly fixed by the physical dimension of the sensor and the binding efficiency.

From Whispering Gallery Mode Resonators to Biochemical Sensors.

Optical biosensors are frontrunners for the rapid and real-time detection of analytes, particularly for low concentrations. Among them, whispering gallery mode (WGM) resonators have recently attracted a growing focus due to their robust optomechanical features and high sensitivity, measuring down to single binding events in small volumes. In this review, we provide a broad overview of WGM sensors along with critical advice and additional "tips and tricks" to make them more accessible to both biochemical and optical communities. Their structures, fabrication methods, materials, and surface functionalization chemistries are discussed. We propose this reflection under a pedagogical approach to describe and explain these biochemical sensors with a particular focus on the most recent achievements in the field. In addition to highlighting the advantages of WGM sensors, we also discuss and suggest strategies to overcome their current limitations, leaving room for further development as practical tools in various applications. We aim to provide new insights and combine different knowledge and perspectives to advance the development of the next generation of WGM biosensors. With their unique advantages and compatibility with different sensing modalities, these biosensors have the potential to become major game changers for biomedical and environmental monitoring, among many other relevant target applications.

Electro-plasmonic-assisted biosensing of proteins and cells at the surface of optical fiber.

An electro-plasmonic biosensor is used to attract proteins and cells on the surface of a fiber optic probe by controlled biomolecular migration. Concentrating targets on a high performance plasmon-assisted fiber grating sensor leads to a drastic enhancement of the limit of detection. This architecture relies on a biofunctionalized gold coated tilted fiber Bragg grating (TFBG) that operates as a working electrode to enable electrophoresis in the probed medium. The applied electric field triggers the attraction of proteins over a distance of almost 250 µm from the sensor surface, which is more than two orders of magnitude larger than the intrinsic penetration depth of the plasmon wave. Quantitative determination of target analytes was performed by cyclic voltammetry measurements using the gold coated fiber as an electrode, simultaneously with optical transmission measurements of the underlying fiber grating. In our work, these electro-plasmonic optrodes were used against a clinically-relevant biomarker in breast cancer diagnosis, namely HER2 (Human Epidermal Growth Factor Receptor-2). In vitro assays confirm that their limit of detection lies in the subpicomolar range for proteins, which is beyond reach of similar sensors without voltammetry. The improved detection limit is further facilitated by an improvement of the signal-to-noise ratio of the read-out process. Whole cell capture is finally demonstrated by the same micro-system.

Phase interrogation of plasmonic tilted fiber Bragg grating biosensors through the Jones formalism.

Gold-coated tilted fiber Bragg gratings (TFBG) are refined plasmonic biosensors, highly sensitive to surrounding refractive index (RI) changes. Their interrogation usually relies on insertion loss measurements for single input polarized light, limiting the set of exploitable features. To overcome this limitation, we trigger the Jones formalism to retrieve the polarization enabling optimized plasmonic excitation for both phase and amplitude measurements. We present an experimental phase shift with a sensitivity as high as 45835°/RIU and further assess this approach to HER2 proteins sensing at 1µg/ml. We compare this angular modality with the one relying on the insertion loss using a quality factor that takes the shift as well as the dispersion into account. This strengthens its relevance in terms of precision for ultra-small RI variations.

Partially gold-coated tilted FBGs for enhanced surface biosensing.

To date, there is clear experimental evidence that gold-coated tilted fiber Bragg gratings (TFBGs) are highly sensitive plasmonic biosensors that provide temperature-compensated detection of analytes at concentrations in the picomolar range. As most optical biosensors, they bring an evanescent wave in the surrounding medium, which makes them sensitive to both surface refractive index variations (= the useful biosensing signal) and to bulk refractive index changes (= the non-useful signal for biosensing). This dual sensitivity makes them prone to drift. In this work, we study partially gold-coated TFBGs around their cross-section. These gratings present the ability to discriminate both volume and surface refractive index changes, which is interesting in biosensing to enhance the signal-to-noise ratio. The effects induced in the TFBGs transmitted amplitude spectra were analyzed for surrounding refractive index (SRI) changes in the range 1.3360-1.3370. Then, the gold film was biofunctionalized with human epidermal growth factor receptor (HER2) aptamers using thiol chemistry. The detection of HER2 proteins (a relevant cancer biomarker) at 10-9 g/mL, 10-8 g/mL and 10-6 g/mL demonstrated the advantage to identify environmental perturbations through the bare area of the TFBGs, which is left not functionalized. The non-specific drifts that could exist in samples are eliminated and a wavelength shift only related to the surface modification is obtained.

Label-free plasmonic immunosensor for cortisol detection in a D-shaped optical fiber.

Measuring cortisol levels as a stress biomarker is essential in many medical conditions associated with a high risk of metabolic syndromes such as anxiety and cardiovascular diseases, among others. One technology that has a growing interest in recent years is fiber optic biosensors that enable ultrasensitive cortisol detection. Such interest is allied with progress being achieved in basic interrogation, accuracy improvements, and novel applications. The development of improved cortisol monitoring, with a simplified manufacturing process, high reproducibility, and low cost, are challenges that these sensing mechanisms still face, and for which solutions are still needed. In this paper, a comprehensive characterization of a D-shaped fiber optic immunosensor for cortisol detection based on surface plasmon resonance (SPR) enabled by gold coating is reported. Specifically, the sensor instrumentation and fabrication processes are discussed in detail, and a simulation with its complete mathematical formalism is also presented. Moreover, experimental cortisol detection tests were performed for a detection range of 0.01 to 100 ng/mL, attaining a logarithmic sensitivity of 0.65 ± 0.02 nm/log(ng/mL) with a limit of detection (LOD) of 1.46 ng/mL. Additionally, an investigation of signal processing is also discussed, with the main issues addressed in order to highlight the best way to extract the sensing information from the spectra measured with a D-shaped sensor.

Relevance of the Spectral Analysis Method of Tilted Fiber Bragg Grating-Based Biosensors: A Case-Study for Heart Failure Monitoring.

Optical fiber technology has rapidly progressed over the years, providing valuable benefits for biosensing purposes such as sensor miniaturization and the possibility for remote and real-time monitoring. In particular, tilted fiber Bragg gratings (TFBGs) are extremely sensitive to refractive index variations taking place on their surface. The present work comprises a case-study on the impact of different methods of analysis applied to decode spectral variations of bare and plasmonic TFBGs during the detection of N-terminal B-type natriuretic peptide (NT-proBNP), a heart failure biomarker, namely by following the most sensitive mode, peaks of the spectral envelopes, and the envelopes' crossing point and area. Tracking the lower envelope resulted in the lowest limits of detection (LOD) for bare and plasmonic TFBGs, namely, 0.75 ng/mL and 0.19 ng/mL, respectively. This work demonstrates the importance of the analysis method on the outcome results, which is crucial to attain the most reliable and sensitive method with lower LOD sensors. Furthermore, it makes the scientific community aware to take careful attention when comparing the performance of different biosensors in which different analysis methods were used.

Overview and emerging trends in optical fiber aptasensing.

Optical fiber biosensors have attracted growing interest over the last decade and quickly became a key enabling technology, especially for the detection of biomarkers at extremely low concentrations and in small volumes. Among the many and recent fiber-optic sensing amenities, aptamers-based sensors have shown unequalled performances in terms of ease of production, specificity, and sensitivity. The immobilization of small and highly stable bioreceptors such as DNA has bolstered their use for the most varied applications e.g., medical diagnosis, food safety and environmental monitoring. This review highlights the recent advances in aptamer-based optical fiber biosensors. An in-depth analysis of the literature summarizes different fiber-optic structures and biochemical strategies for molecular detection and immobilization of receptors over diverse surfaces. In this review, we analyze the features offered by those sensors and discuss about the next challenges to be addressed. This overview investigates both biochemical and optical parameters, drawing the guiding lines for forthcoming innovations and prospects in this ever-growing field of research.

PfHRP2 detection using plasmonic optrodes: performance analysis.

BACKGROUND: Early malaria diagnosis and its profiling require the development of new sensing platforms enabling rapid and early analysis of parasites in blood or saliva, aside the widespread rapid diagnostic tests (RDTs). METHODS: This study shows the performance of a cost-effective optical fiber-based solution to target the presence of Plasmodium falciparum histidine-rich protein 2 (PfHRP2). Unclad multimode optical fiber probes are coated with a thin gold film to excite Surface Plasmon Resonance (SPR) yielding high sensitivity to bio-interactions between targets and bioreceptors grafted on the metal surface. RESULTS: Their performances are presented in laboratory conditions using PBS spiked with growing concentrations of purified target proteins and within in vitro cultures. Two probe configurations are studied through label-free detection and amplification using secondary antibodies to show the possibility to lower the intrisic limit of detection. CONCLUSIONS: As malaria hits millions of people worldwide, the improvement and multiplexing of this optical fiber technique can be of great interest, especially for a future purpose of using multiple receptors on the fiber surface or several coated-nanoparticles as amplifiers.

Plasmonic sensors based on tilted Bragg gratings in multicore optical fibers.

Bare and gold-coated tilted fiber Bragg gratings (TFBGs) can nowadays be considered as a mature technology for volume and surface refractometric sensing, respectively. As for other technologies, a continuous effort is made towards the production of even more sensitive sensors, thereby enabling a high-resolution screening of the surroundings and the possible detection of rare events. To this aim, we study in this work the development of TFBG refractometers in 4-core fibers. In particular, we show that the refractometric sensitivity of the cut-off mode can reach 100 nm/RIU for a bare grating. Using another demodulation method, a tenfold sensitivity increase is obtained when tracking the extremum of the SPR (surface plasmon resonance) envelope for a gold-coated TFBG configuration. Immobilization of DNA probes was performed as a proof-of-concept to assess the high surface sensitivity of the device.

HER2 breast cancer biomarker detection using a sandwich optical fiber assay.

Optical fiber-based surface plasmon resonance (OF-SPR) sensors have demonstrated high versatility and performances over the last years, which propelled the technique to the heart of numerous and original biosensing concepts. In this work, we contribute to this effort and present our recent findings about the detection of breast cancer HER2 biomarkers through OF-SPR optrodes. 1 cm-long sections of 400 µm core-diameter optical fibers were covered with a sputtered gold film, yielding enhanced sensitivity to surface refractive index changes. Studying the impacts of the gold film thickness on the plasmonic spectral response, we improved the quality and reproducibility of the sensors. These achievements were correlated in two ways, using both the central wavelengths of the plasmon resonance and its influence on the bulk refractive index sensitivity. Our dataset was fed by additional biosensing experiments with a direct and indirect approach, relying on aptamers and antibodies specifically implemented in a sandwich layout. HER2 biomarkers were specifically detected at 0.6 µg/mL (5.16 nM) in label-free while the amplification with HER2-antibodies provided a nearly hundredfold signal magnification, reaching 9.3 ng/mL (77.4 pM). We believe that these results harbinger the way for their further use in biomedical samples.

HER2 biosensing through SPR-envelope tracking in plasmonic optical fiber gratings.

In the biomedical detection context, plasmonic tilted fiber Bragg gratings (TFBGs) have been demonstrated to be a very accurate and sensitive sensing tool, especially well-adapted for biochemical detection. In this work, we have developed an aptasensor following a triple strategy to improve the overall sensing performances and robustness. Single polarization fiber (SPF) is used as biosensor substrate while the demodulation is based on tracking a peculiar feature of the lower envelope of the cladding mode resonances spectrum. This method is highly sensitive and yields wavelength shifts several tens of times higher than the ones reported so far based on the tracking of individual modes of the spectrum. An amplification of the response is further performed through a sandwich assay by the use of specific antibodies. These improvements have been achieved on a biosensor developed for the detection of the HER2 (Human Epidermal Growth Factor Receptor-2) protein, a relevant breast cancer biomarker. These advanced developments can be very interesting for point-of-care biomedical measurements in a convenient practical way.

Multimodal plasmonic optical fiber grating aptasensor.

Tilted fiber Bragg gratings (TFBGs) are now a well-established technology in the scientific literature, bringing numerous advantages, especially for biodetection. Significant sensitivity improvements are achieved by exciting plasmon waves on their metal-coated surface. Nowadays, a large part of advances in this topic relies on new strategies aimed at providing sensitivity enhancements. In this work, TFBGs are produced in both single-mode and multimode telecommunication-grade optical fibers, and their relative performances are evaluated for refractometry and biosensing purposes. TFBGs are biofunctionalized with aptamers oriented against HER2 (Human Epidermal Growth Factor Receptor-2), a relevant protein biomarker for breast cancer diagnosis. In vitro assays confirm that the sensing performances of TFBGs in multimode fiber are higher or identical to those of their counterparts in single-mode fiber, respectively, when bulk refractometry or surface biosensing is considered. These observations are confirmed by numerical simulations. TFBGs in multimode fiber bring valuable practical assets, featuring a reduced spectral bandwidth for improved multiplexing possibilities enabling the detection of several biomarkers.

Rapid Detection of Circulating Breast Cancer Cells Using a Multiresonant Optical Fiber Aptasensor with Plasmonic Amplification.

The detection of circulating tumor cells (CTCs), which are responsible for metastasis in several forms of cancer, represents an important goal in oncological diagnosis and treatment. These cells remain extremely challenging to detect, despite numerous previous studies, due to their low concentration (1-10 cells/mL of blood). In this work, an all-fiber plasmonic aptasensor featuring multiple narrowband resonances in the near-infrared wavelength range was developed to detect metastatic breast cancer cells. To this aim, specific aptamers against mammaglobin-A were selected and immobilized as receptors on the sensor surface. In vitro assays confirm that the label-free and real-time detection of cancer cells [limit of detection (LOD) of 49 cells/mL] occurs within 5 min, while the additional use of functionalized gold nanoparticles allows a 2-fold amplification of the biosensor response. Differential measurements on selected optical resonances were used to process the sensor response, and results were confirmed by microscopy. The detection of only 10 cancer cells/mL was achieved with relevant specificity against control cells and with quick response time.

Non-enzymatic D-glucose plasmonic optical fiber grating biosensor.

Saccharide sensors represent a broad research area in the scope of sensing devices and their involvement in the medical diagnosis field is particularly relevant for cancer detection at early stage. In that context, we present a non-enzymatic optical fiber-based sensor that makes use of plasmon-assisted tilted fiber Bragg gratings (TFBGs) functionalized for D-glucose biosensing through polydopamine (PDA)-immobilized concanavalin A (Con A). Our probe allows a live and accurate monitoring of the PDA layer deposition leading improved surface biochemistry. The SPR shift observed was assessed to 3.83 ±â€¯0.05 nm within 20 min for a 2 mg/mL dopamine solution. Tests performed in different D-Glucose solutions have revealed a limit of detection close to 10-7 M with the highest sensitivity in the 10-6 to 10-4 M range. This configuration has the capability to overcome the limitations of current enzyme-based solutions.

Optical Fiber Gratings Immunoassays.

Optical fibers are of growing interest for biosensing, especially for point-of-care and biomedical assays. Their intrinsic properties bestow them sought-after assets for the detection of low concentrations of analytes. Tilted fiber Bragg gratings (TFBGs) photo-inscribed in the core of telecommunication-grade optical fibers are known to be highly-sensitive refractometers. In this work, we present different strategies to use them for label-free immunoassays. Bare, gold-sputtered, gold-electroless-plated (ELP) and hybrid configurations are biofunctionalized with antibodies, aiming at the detection of cancer biomarkers. We discuss the relative performances of the tested configurations and show that each leads to singular key features, which therefore drives their selection as a function of the target application. The most sensitive configuration presents a limit of detection of 10-12 g/mL in laboratory settings and was successfully used ex vivo in freshly resected lung tissues.

In situ cancer diagnosis through online plasmonics.

Most cancer diagnoses rely on biomarkers detection. This could be improved if directly conducted in suspicious cancer spots, preventing the need for biopsy. Lung cancer remains a perfect study-case for such a development, as it is generally detected at advanced stage and is in the need for early diagnosis techniques. To this aim, we have designed a minimally invasive catheter-embedded biosensor. It combines a specific grating structure photo-imprinted in a telecommunication-grade optical fiber and an overlay made of a thin metal coating on which receptors are grafted, yielding plasmonic coupling. Our optrode targets a type of cytokeratins, overexpressed at the surface of cancer cells. It was assayed ex vivo in resected lung tissues collected from a dozen of patients. Biosensing responses were confirmed by immunohistochemistry, conducted on the same samples. In addition to accurate biosensing, our gratings inherently enable force-sensing features, which also allow a fine positioning of the probe in the tissue. Finally, the in vivo navigation of the bronchoscope-embedded sensor was validated into pig lungs. These achievements are a critical milestone towards the development of this micro/nano biosensor as a cost-effective and weakly invasive diagnostic tool for applications in areas of critical access such as brain, liver or prostate.

Cytokeratins Biosensing Using Tilted Fiber Gratings.

Optical fiber gratings have widely proven their applicability in biosensing, especially when they are coupled with antibodies for specific antigen recognition. While this is customarily done with fibers coated by a thin metal film to benefit from plasmonic enhancement, in this paper, we propose to study their intrinsic properties, developing a label-free sensor for the detection of biomarkers in real-time without metal coatings for surface plasmon resonances. We focus on the inner properties of our modal sensor by immobilizing receptors directly on the silica surface, and reporting the sensitivity of bare tilted fiber Bragg gratings (TFBGs) used at near infrared wavelengths. We test different strategies to build our sensing surface against cytokeratins and show that the most reliable functionalization method is the electrostatic adsorption of antibodies on the fiber, allowing a limit of detection reaching 14 pM by following the guided cladding modes near the cut-off area. These results present the biodetection performance that TFBGs bring through their modal properties for different functionalizations and data processing strategies.