Optrode-Assisted Multiparametric Near-Infrared Spectroscopy for the Analysis of Liquids.

We demonstrate a sensing scheme for liquid analytes that integrates multiple optical fiber sensors in a near-infrared spectrometer. With a simple optofluidic method, a broadband radiation is encoded in a time-domain interferogram and distributed to different sensing units that interrogate the sample simultaneously; the spectral readout of each unit is extracted from its output signal by a Fourier transform routine. The proposed method allows performing a multiparametric analysis of liquid samples in a compact setup where the radiation source, measurement units, and spectral readout are all integrated in a robust telecom optical fiber. An experimental validation is provided by combining a plasmonic nanostructured fiber probe and a transmission cuvette in the setup and demonstrating the simultaneous measurement of the absorption spectrum and the refractive index of water-methanol solutions.

Assessment of Primary Human Liver Cancer Cells by Artificial Intelligence-Assisted Raman Spectroscopy.

We investigated the possibility of using Raman spectroscopy assisted by artificial intelligence methods to identify liver cancer cells and distinguish them from their Non-Tumor counterpart. To this aim, primary liver cells (40 Tumor and 40 Non-Tumor cells) obtained from resected hepatocellular carcinoma (HCC) tumor tissue and the adjacent non-tumor area (negative control) were analyzed by Raman micro-spectroscopy. Preliminarily, the cells were analyzed morphologically and spectrally. Then, three machine learning approaches, including multivariate models and neural networks, were simultaneously investigated and successfully used to analyze the cells' Raman data. The results clearly demonstrate the effectiveness of artificial intelligence (AI)-assisted Raman spectroscopy for Tumor cell classification and prediction with an accuracy of nearly 90% of correct predictions on a single spectrum.

Development of High-Loading Trastuzumab PLGA Nanoparticles: A Powerful Tool Against HER2 Positive Breast Cancer Cells.

Background: Trastuzumab, a therapeutic monoclonal antibody directed against HER2, is routinely used to treat HER2-positive breast cancer with a good response rate. However, concerns have arisen in the clinical practice due to adverse side effects. One way to overcome these limitations is to encapsulate trastuzumab in nanoparticles to improve cytotoxic activity, increase intracellular drug concentrations, escape the immune system and avoid systemic degradation of the drug in vivo. Methods: A double emulsion method was used to encapsulate trastuzumab into poly(lactic-co-glycolic) nanoparticles, effective for their biocompatibility and biodegradability. These nanocarriers, hereafter referred to as TZPs, were characterised in terms of size, homogeneity, zeta potential and tested for their stability and drug release kinetics. Finally, the TZPs cytotoxicity was assessed in vitro on the HER2 positive SKBR3 breast cancer cell line and compared to free trastuzumab. Results: The TZPs were stable, homogeneous in size, with a reduced zeta potential. They showed higher encapsulation efficiency and drug loading, a prolonged trastuzumab release kinetics that retained its physicochemical properties and functionality. TZPs showed a stronger cytotoxicity and increased apoptosis than similar doses of free trastuzumab in the cell line analysed. Confocal microscopy and flow cytometry assessed TZPs and trastuzumab cellular uptake while Western blot evaluated downstream signalling, overall HER2 content and shedding. Conclusion: TZPs exert more robust effects than free trastuzumab via a dual mode of action: TZPs are taken up by cells through an endocytosis mechanism and release the drug intracellularly for longer time. Additionally, the TZPs that remain in the extracellular space release trastuzumab which binds to the cognate receptor and impairs downstream signalling. This is the sole modality used by free trastuzumab. Remarkably, half dose of TZPs is as efficacious as the highest dose of free drug supporting their possible use for drug delivery in vivo.

Sorafenib-Loaded PLGA Carriers for Enhanced Drug Delivery and Cellular Uptake in Liver Cancer Cells.

Introduction: Currently, conventional treatments of hepatocellular carcinoma (HCC) are not selective enough for tumor tissue and lead to multidrug resistance and drug toxicity. Although sorafenib (SOR) is the standard first-line systemic therapy approved for the clinical treatment of HCC, its poor aqueous solubility and rapid clearance result in low absorption efficiency and severely limit its use for local treatment. Methods: Herein, we present the synthesis of biodegradable polymeric Poly (D, L-Lactide-co-glycolide) (PLGA) particles loaded with SOR (PS) by emulsion-solvent evaporation process. The particles are carefully characterized focusing on particle size, surface charge, morphology, drug loading content, encapsulation efficiency, in vitro stability, drug release behaviour and tested on HepG2 cells. Additionally, PLGA particles have been coupled on side emitting optical fibers (seOF) integrated in a microfluidic device for light-triggered local release. Results: PS have a size of 248 nm, tunable surface charge and a uniform and spherical shape without aggregation. PS shows encapsulation efficiency of 89.7% and the highest drug loading (8.9%) between the SOR-loaded PLGA formulations. Treating HepG2 cells with PS containing SOR at 7.5 µM their viability is dampened to 40%, 30% and 17% after 48, 129 and 168 hours of incubation, respectively. Conclusion: The high PS stability, their sustained release profile and the rapid cellular uptake corroborate the enhanced cytotoxicity effect on HepG2. With the prospect of developing biomedical tools to control the spatial and temporal release of drugs, we successfully demonstrated the potentiality of seOF for light-triggered local release of the carriers. Our prototypical system paves the way to new devices integrating microfluidics, optical fibers, and advanced carriers capable to deliver minimally invasive locoregional cancer treatments.

An Innovative Fiber-Optic Hydrophone for Seismology: Testing Detection Capacity for Very Low-Energy Earthquakes.

An innovative fiber-optic hydrophone (FOH) was developed and investigated via an experiment at sea; it is capable of operating at a very low frequency of the seismic spectrum and detecting small magnitude earthquakes. The FOH exploits an optical fiber coil wrapped around a sensitive mandrel in a Michelson interferometric configuration. The FOH operated for about seven days at a water depth of 40 m, in the Campi Flegrei volcanic area (Southern Italy), and a few meters from a well-calibrated PZT hydrophone used as a reference. Thirty-three local earthquakes occurred during the simultaneous operation of the two hydrophones, allowing a straightforward comparison of the recordings. The local earthquakes occurred at an epicentral distance less than 2.5 km from the site of recording, and were estimated to be in the range of magnitude from -0.8 to 2.7. The analysis of the recorded earthquake waveforms in the frequency and time domains allowed retrieving the response function of the FOH in the frequency range from 5 to 70 Hz. The FOH responsivity in terms of acoustic pressure reached about 230 nm/Pa and was flat in the studied frequency range. Due to the high quality of the FOH recordings, this equipment is suitable for applications addressing submarine volcanic activity and the background seismicity of active faults in the ocean.

Innovative Photonic Sensors for Safety and Security, Part II: Aerospace and Submarine Applications.

The employability of photonics technology in the modern era's highly demanding and sophisticated domain of aerospace and submarines has been an appealing challenge for the scientific communities. In this paper, we review our main results achieved so far on the use of optical fiber sensors for safety and security in innovative aerospace and submarine applications. In particular, recent results of in-field applications of optical fiber sensors in aircraft monitoring, from a weight and balance analysis to vehicle Structural Health Monitoring (SHM) and Landing Gear (LG) monitoring, are presented and discussed. Moreover, underwater fiber-optic hydrophones are presented from the design to marine application.

Innovative Photonic Sensors for Safety and Security, Part I: Fundamentals, Infrastructural and Ground Transportations.

Our group, involving researchers from different universities in Campania, Italy, has been working for the last twenty years in the field of photonic sensors for safety and security in healthcare, industrial and environment applications. This is the first in a series of three companion papers. In this paper, we introduce the main concepts of the technologies employed for the realization of our photonic sensors. Then, we review our main results concerning the innovative applications for infrastructural and transportation monitoring.

Innovative Photonic Sensors for Safety and Security, Part III: Environment, Agriculture and Soil Monitoring.

In order to complete this set of three companion papers, in this last, we focus our attention on environmental monitoring by taking advantage of photonic technologies. After reporting on some configurations useful for high precision agriculture, we explore the problems connected with soil water content measurement and landslide early warning. Then, we concentrate on a new generation of seismic sensors useful in both terrestrial and under water contests. Finally, we discuss a number of optical fiber sensors for use in radiation environments.

Advanced Lab-on-Fiber Optrodes Assisted by Oriented Antibody Immobilization Strategy.

Lab-on-fiber (LoF) optrodes offer several advantages over conventional techniques for point-of-care platforms aimed at real-time and label-free detection of clinically relevant biomarkers. Moreover, the easy integration of LoF platforms in medical needles, catheters, and nano endoscopes offer unique potentials for in vivo biopsies and tumor microenvironment assessment. The main barrier to translating the vision close to reality is the need to further lower the final limit of detection of developed optrodes. For immune-biosensing purposes, the assay sensitivity significantly relies on the capability to correctly immobilize the capture antibody in terms of uniform coverage and correct orientation of the bioreceptor, especially when very low detection limits are requested as in the case of cancer diagnostics. Here, we investigated the possibility to improve the immobilization strategies through the use of hinge carbohydrates by involving homemade antibodies that demonstrated a significantly improved recognition of the antigen with ultra-low detection limits. In order to create an effective pipeline for the improvement of biofunctionalization protocols to be used in connection with LoF platforms, we first optimized the protocol using a microfluidic surface plasmon resonance (mSPR) device and then transferred the optimized strategy onto LoF platforms selected for the final validation. Here, we selected two different LoF platforms: a biolayer interferometry (BLI)-based device (commercially available) and a homemade advanced LoF biosensor based on optical fiber meta-tips (OFMTs). As a clinically relevant scenario, here we focused our attention on a promising serological biomarker, Cripto-1, for its ability to promote tumorigenesis in breast and liver cancer. Currently, Cripto-1 detection relies on laborious and time-consuming immunoassays. The reported results demonstrated that the proposed approach based on oriented antibody immobilization was able to significantly improve Cripto-1 detection with a 10-fold enhancement versus the random approach. More interestingly, by using the oriented antibody immobilization strategy, the OFMTs-based platform was able to reveal Cripto-1 at a concentration of 0.05 nM, exhibiting detection capabilities much higher (by a factor of 250) than those provided by the commercial LoF platform based on BLI and similar to the ones shown by the commercial and well-established bench-top mSPR Biacore 8K system. Therefore, our work opened new avenues into the development of high-sensitivity LoF biosensors for the detection of clinically relevant biomarkers in the sub-ng/mL range.

Design and Optimization of All-Dielectric Fluorescence Enhancing Metasurfaces: Towards Advanced Metasurface-Assisted Optrodes.

The need for miniaturized biological sensors which can be easily integrated into medical needles and catheters for in vivo liquid biopsies with ever-increasing performances has stimulated the interest of researchers in lab-on-fiber (LOF) technology. LOF devices arise from the integration of functional materials at the nanoscale on the tip of optical fibers, thus endowing a simple optical fiber with advanced functionalities and enabling the realization of high-performance LOF biological sensors. Consequently, in 2017, we demonstrated the first optical fiber meta-tip (OFMT), consisting of the integration of plasmonic metasurfaces (MSs) on the optical fiber end-face which represented a major breakthrough along the LOF technology roadmap. Successively, we demonstrated that label-free biological sensors based on the plasmonic OFMT are able to largely overwhelm the performance of a standard plasmonic LOF sensor, in view of the extraordinary light manipulation capabilities of plasmonic array exploiting phase gradients. To further improve the overall sensitivity, a labelled sensing strategy is here suggested. To this end, we envision the possibility to realize a novel class of labelled LOF optrodes based on OFMT, where an all-dielectric MS, designed to enhance the fluorescence emission by a labelled target molecule, is integrated on the end-face of a multimode fiber (MMF). We present a numerical environment to compute the fluorescence enhancement factor collected by the MMF, when on its tip a Silicon MS is laid, consisting of an array of cylindrical nanoantennas, or of dimers or trimers of cylindrical nanoantennas. According to the numerical results, a suitable design of the dielectric MS allows for a fluorescence enhancement up to three orders of magnitudes. Moreover, a feasibility study is carried out to verify the possibility to fabricate the designed MSs on the termination of multimode optical fibers using electron beam lithography followed by reactive ion etching. Finally, we analyze a real application scenario in the field of biosensing and evaluate the degradation in the fluorescence enhancement performances, taking into account the experimental conditions. The present work, thus, provides the main guidelines for the design and development of advanced LOF devices based on the fluorescence enhancement for labelled biosensing applications.

Ultrasound waves in tumors via needle irradiation for precise medicine.

Grounded in the interdisciplinary crosstalk among physics and biological sciences, precision medicine-based diagnosis and treatment strategies have recently gained great attention for the actual applicability of new engineered approaches in many medical fields, particularly in oncology. Within this framework, the use of ultrasounds employed to attack cancer cells in tumors to induce possible mechanical damage at different scales has received growing attention from scholars and scientists worldwide. With these considerations in mind, on the basis of ad hoc elastodynamic solutions and numerical simulations, we propose a pilot study for in silico modeling of the propagation of ultrasound waves inside tissues, with the aim of selecting proper frequencies and powers to be irradiated locally through a new teragnostic platform based on Lab-on-Fiber technology, baptized as a hospital in the needle and already the object of a patent. It is felt that the outcomes and the related biophysical insights gained from the analyses could pave the way for envisaging new integrated diagnostic and therapeutic approaches that might play a central role in future applications of precise medicine, starting from the growing synergy among physics, engineering and biology.

Liquid Resin Infusion Process Validation through Fiber Optic Sensor Technology.

In the proposed work, a fiber-optic-based sensor network was employed for the monitoring of the liquid resin infusion process. The item under test was a panel composed by a skin and four stringers, sensorized in such a way that both the temperature and the resin arrival could be monitored. The network was arranged with 18 Fiber Bragg Gratings (FBGs) working as temperature sensors and 22 fiber optic probes with a modified front-end in order to detect the resin presence. After an in-depth study to find a better solution to install the sensors without affecting the measurements, the system was investigated using a commercial Micron Optics at 0.5 Hz, with a passive split-box connected in order to be able to sense all the sensors simultaneously. The obtained results in terms of resin arrival detection at different locations and the relative temperature trend allowed us to validate an infusion process numerical model, giving us better understanding of what the actual resin flow was and the time needed to dry preform filling during the infusion process.

Feasibility analysis of an ultrasound on line diagnostic approach for oral and bone surgery.

During implant surgery procedures, surgical precision is an essential prerequisite for the functional and aesthetic success of the prosthetic crown to be placed on the dental implant. A modern implant surgical approach should be standardized as much as possible to guarantee extreme precision in the insertion of the implant into the upper and lower bone jaws. Among the most common surgical errors during implant surgery there is the over-preparation of the surgical alveolus with possible damage to the contiguous anatomical structures. To avoid this problem, in the recent years, there has been an increasing attention to the development of new control techniques. In this paper, we describe an innovative ultrasound approach, which exploits the integration of an electro-acoustic transducer with the surgical drill used for realizing the alveolus in the bone that will host the implant. Specifically, he proposed approach is based on the "time-of-flight" detection technique for measuring the thickness of the residual bone subjected to the drilling. In order to demonstrate the feasibility of the proposed approach, here we report on a detailed numerical analysis aimed at studying the propagation of ultrasonic waves through the drill-bit and through the involved tissues. The obtained results confirm the validity of our approach, and enable for a future first prototype implementation of a hi-tech surgical drill-bit, which in general is suitable not only for dental implant surgery but also for other uses in oral surgery, maxillofacial surgery and for bone surgery.

Human Serum Albumin Nanoparticles as a Carrier for On-Demand Sorafenib Delivery.

BACKGROUND: Drug delivery systems based on Human Serum Albumin (HSA) have been widely investigated due to their capability to interact with several molecules together with their nontoxicity, non-immunogenicity and biocompatibility. Sorafenib (SOR) is a kinase inhibitor used as the firstline treatment in hepatic cancer. However, because of its several intrinsic drawbacks (low solubility and bioavailability), there is a growing need for discovering new carriers able to overcome the current limitations. OBJECTIVES: To study HSA particles loaded with SOR as a thermal responsive drug delivery system. METHODS: A detailed spectroscopy analysis of the HSA and SOR interaction in solution was carried out in order to characterize the temperature dependence of the complex. Based on this study, the synthesis of HSA particles loaded with SOR was optimized. Particles were characterized by Dynamic Light Scattering, Atomic Force Microscopy and by spectrofluorometer. Encapsulation efficiency and in vitro drug release were quantified by RP-HPLC. RESULTS: HSA particles were monodispersed in size (≈ 200 nm); encapsulation efficiency ranged from 25% to 58%. Drug release studies that were performed at 37 °C and 50 °C showed that HS5 particles achieved a drug release of 0.430 µM in 72 hours at 50 °C in PBS buffer, accomplishing a 4.6-fold overall SOR release enhancement following a temperature increase from 37 °C to 50 °C. CONCLUSION: The system herein presented has the potential to exert a therapeutic action (in the nM range) triggering a sustained temperature-controllable release of relevant drugs.

Optical meta-waveguides for integrated photonics and beyond.

The growing maturity of nanofabrication has ushered massive sophisticated optical structures available on a photonic chip. The integration of subwavelength-structured metasurfaces and metamaterials on the canonical building block of optical waveguides is gradually reshaping the landscape of photonic integrated circuits, giving rise to numerous meta-waveguides with unprecedented strength in controlling guided electromagnetic waves. Here, we review recent advances in meta-structured waveguides that synergize various functional subwavelength photonic architectures with diverse waveguide platforms, such as dielectric or plasmonic waveguides and optical fibers. Foundational results and representative applications are comprehensively summarized. Brief physical models with explicit design tutorials, either physical intuition-based design methods or computer algorithms-based inverse designs, are cataloged as well. We highlight how meta-optics can infuse new degrees of freedom to waveguide-based devices and systems, by enhancing light-matter interaction strength to drastically boost device performance, or offering a versatile designer media for manipulating light in nanoscale to enable novel functionalities. We further discuss current challenges and outline emerging opportunities of this vibrant field for various applications in photonic integrated circuits, biomedical sensing, artificial intelligence and beyond.

Miniaturized optical fiber probe for prostate cancer screening.

Tissue elasticity is universally recognized as a diagnostic and prognostic biomarker for prostate cancer. As the first diagnostic test, the digital rectal examination is used since malignancy changes the prostate morphology and affects its mechanical properties. Currently, this examination is performed manually by the physician, with an unsatisfactory positive predictive value of 42%. A more objective and spatially selective technique is expected to provide a better prediction degree and understanding of the disease. To this aim, here we propose a miniaturized probe, based on optical fiber sensor technology, for mechanical characterization of the prostate with sub-millimeter resolution. Specifically, the optical system incorporates a customized Fiber Bragg Grating, judiciously integrated in a metallic cannula and moved by a robotic arm. The probe enables the local measurement of the force upon tissue indentation with a resolution of 0.97 mN. The system has been developed in such a way to be potentially used directly in vivo. Measurements performed on phantom tissues mimicking different stages of the prostatic carcinoma demonstrated the capability of our device to distinguish healthy from diseased zones of the prostate. The study on phantoms has been complemented with preliminary ex vivo experiments on real organs obtained from radical surgeries. Our findings lay the foundation for the development of advanced optical probes that, when integrated inside biopsy needle, are able to perform in vivo direct mechanical measurements with high sensitivity and spatial resolution, opening to new scenarios for early diagnosis and enhanced diagnostic accuracy of prostate cancer.

Improving the width of lossy mode resonances in a reflection configuration D-shaped fiber by nanocoating laser ablation.

The full width at half maximum (FWHM) of lossy mode resonances (LMRs) in the optical spectrum depends on the homogeneity of the thin film deposited. In this Letter, a method for improving the FWHM is applied for an LMR generated by a D-shaped optical fiber in reflection configuration. For this purpose, three samples with different attenuation were deposited with DC sputtering thin films of SnO2-x, and a further controlled immersion of the samples in water was performed. A laser-cleaner method was used to improve the FWHM characteristics of one of the samples from 106 to 53 nm. This improvement can be applied to thin-film-based sensors where there is a problem with the inhomogeneity of the coating thickness. Moreover, with this technique, it was proved that a coated length of just 3-4 mm permits the generation of an LMR, with implications for the miniaturization of the final device.

Lab-On-Fiber Technology: A Roadmap toward Multifunctional Plug and Play Platforms.

This review presents an overview of the "lab-on-fiber technology" vision and the main milestones set in the technological roadmap to achieve the ultimate objective of developing flexible, multifunctional plug and play fiber-optic platforms designed for specific applications. The main achievements, obtained with nanofabrication strategies for unconventional substrates, such as optical fibers, are discussed here. The perspectives and challenges that lie ahead are highlighted with a special focus on full spatial control at the nanoscale and high-throughput production scenarios. The rapid progress in the fabrication stage has opened new avenues toward the development of multifunctional plug and play platforms, discussed here with particular emphasis on new functionalities and unparalleled figures of merit, to demonstrate the potential of this powerful technology in many strategic application scenarios. The paper also analyses the benefits obtained from merging lab-on-fiber (LOF) technology objectives with the emerging field of optomechanics, especially at the microscale and the nanoscale. We illustrate the main advances at the fabrication level, describe the main achievements in terms of functionalities and performance, and highlight future directions and related milestones. All achievements reviewed and discussed clearly suggest that LOF technology is much more than a simple vision and could play a central role not only in scenarios related to diagnostics and monitoring but also in the Information and Communication Technology (ICT) field, where optical fibers have already yielded remarkable results.

Detection of small DNA fragments by biolayer interferometry.

Small molecular weight species such as miRNAs and other nucleic acid fragments are gaining an increased interest as biomarkers for relevant diseases. Also, cheap and rapid assays for their routine detection are becoming an urgent need. We have investigated the usability and convenience of a price affordable, label free and fast technique for their detection on a laboratory scale small device based on Bio-Layer Interferometry. Using a model DNA fragment (7 kDa), we have found that the technique is effectively fast and sensitive enough for the detection of nucleic acid fragments having a MW below the stated molecular size detection limit (10 kDa). The test molecule has been detected in solution at 100 nM in a direct capture experiment and up to about 10 nM following an improved approach where an enhancing probe is used to increase the apparent molecular dimensions of the analyte. The technique, following further optimizations, can be applied for the routine, cheap and fast analysis of small nucleic acid fragments that have a relevance in diagnosis and in therapy.

Analysis of uncoated LPGs written in B-Ge doped fiber under proton irradiation for sensing applications at CERN.

In this contribution, a complete dissertation concerning the behavior of a Long Period Grating (LPG) inscribed in a B-Ge co-doped optical fiber by means of an excimer laser and exposed to proton irradiation during a recent extensive campaign performed at the European Organization for Nuclear Research (CERN) with a fluence of 4.4·1015 p∙cm-2 is provided. The experimental results have been thus combined for the first time to the best of our knowledge with numerical simulations in order to estimate the variations of the major parameters affecting the grating response during the ultra-high dose proton exposure. From the correlation between experimental and numerical analysis, the irradiation exposure was found to induce a maximal variation of the core effective refractive index of ~1.61·10-4, responsible of a resonance wavelength red shift of ~44 nm in correspondence of the highest absorbed radiation dose of 1.16 MGy. At the same time, a relevant decrease close to ~0.93·10-4 in the refractive index modulation pertaining to the grating was estimated, leading to a reduction of the resonant dip visibility of ~12 dB. The effect of the proton beam on the spectral response of the LPG device and on the optical fiber parameters was assessed during the relaxation phases, showing a partial recovery only of the wavelength shift without any relevant change in the dip visibility revealing thus a partial recovery only in the refractive index of the core while the reduction of the refractive index modulation observed during the irradiation remained unchanged.