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.

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.

Optical fiber technology enables smart needles for epidurals: an in-vivo swine study.

Nowadays, epidural space identification is made by using subjective and manual techniques characterized by failure rates up to 7%. In this work, we propose a fiber optic sensor technology based needle guidance system, that is directly inspired by the most common technique currently used for epidurals; through real-time strain measurements, the fiber Bragg grating integrated inside the needle lumen is able to effectively perceive the typical force drop occurring when the needle enters the epidural space. An in vivo swine study demonstrates the validity of our approach, paving the way for the development of lab-in-a-needle systems.

Smart Optical Catheters for Epidurals.

Placing the needle inside the epidural space for locoregional anesthesia is a challenging procedure, which even today is left to the expertise of the operator. Recently, we have demonstrated that the use of optically sensorized needles significantly improves the effectiveness of this procedure. Here, we propose an optimized configuration, where the optical fiber strain sensor is directly integrated inside the epidural catheter. The new design allows the solving of the biocompatibility issues and increases the versatility of the former configuration. Through an in vivo study carried out on a porcine model, we confirm the reliability of our approach, which also opens the way to catheter monitoring during insertion inside biological spaces.

Optimization Strategies for Responsivity Control of Microgel Assisted Lab-On-Fiber Optrodes.

Integrating multi-responsive polymers such as microgels onto optical fiber tips, in a controlled fashion, enables unprecedented functionalities to Lab-on-fiber optrodes. The creation of a uniform microgel monolayer with a specific coverage factor is crucial for enhancing the probes responsivity to a pre-defined target parameter. Here we report a reliable fabrication strategy, based on the dip coating technique, for the controlled realization of microgel monolayer onto unconventional substrates, such as the optical fiber tip. The latter was previously covered by a plasmonic nanostructure to make it sensitive to superficial environment changes. Microgels have been prepared using specific Poly(N-isopropylacrylamide)-based monomers that enable bulky size changes in response to both temperature and pH variations. The formation of the microgel monolayer is efficiently controlled through the selection of suitable operating pH, temperature and concentration of particle dispersions used during the dipping procedure. The effect of each parameter has been evaluated, and the validity of our procedure is confirmed by means of both morphological and optical characterizations. We demonstrate that when the coverage factor exceeds 90%, the probe responsivity to microgels swelling/collapsing is significantly improved. Our study opens new paradigms for the development of engineered microgels assisted Lab-on-Fiber probes for biochemical applications.

Optical fiber meta-tips.

We report on the first demonstration of a proof-of-principle optical fiber 'meta-tip', which integrates a phase-gradient plasmonic metasurface on the fiber tip. For illustration and validation purposes, we present numerical and experimental results pertaining to various prototypes implementing generalized forms of the Snell's transmission/reflection laws at near-infrared wavelengths. In particular, we demonstrate several examples of beam steering and coupling with surface waves, in fairly good agreement with theory. Our results constitute a first step toward the integration of unprecedented (metasurface-enabled) light-manipulation capabilities in optical-fiber technology. By further enriching the emergent 'lab-on-fiber' framework, this may pave the way for the widespread diffusion of optical metasurfaces in real-world applications to communications, signal processing, imaging and sensing.

Nanosphere lithography for optical fiber tip nanoprobes.

This paper reports a simple and economical method for the fabrication of nanopatterned optical fiber nanotips. The proposed patterning approach relies on the use of the nanosphere lithography of the optical fiber end facet. Polystyrene (PS) nanospheres are initially self-assembled in a hexagonal array on the surface of water. The created pattern is then transferred onto an optical fiber tip (OFT). The PS monolayer colloidal crystal on the OFT is the basic building block that is used to obtain different periodic structures by applying further treatment to the fiber, such as metal coating, nanosphere size reduction and sphere removal. Ordered dielectric and metallo-dielectric sphere arrays, metallic nanoisland arrays and hole-patterned metallic films with feature sizes down to the submicron scale are achievable using this approach. Furthermore, the sizes and shapes of these periodic structures can be tailored by altering the fabrication conditions. The results indicate that the proposed self-assembly approach is a valuable route for the development of highly repeatable metallo-dielectric periodic patterns on OFTs with a high degree of order and low fabrication cost. The method can be easily extended to simultaneously produce multiple fibers, opening a new route to the development of fiber-optic nanoprobes. Finally, we demonstrate the effective application of the patterned OFTs as surface-enhanced Raman spectroscopy nanoprobes.