Development of optical quality bioresorbable fibers is an emerging area of study where researchers are trying to advance the field by assessing the suitability of these fibers for various biomedical applications. These types of fiber implants dissolve in the human body over a clinically relevant time scale eliminating the need for extraction surgeries.
We conducted both ex-vivo and in vivo diffuse correlation spectroscopic studies using our fibers to measure blood flow and a preliminary trial to integrate a biocompatible electrode material on the fiber for electrical signal measurements. The results demonstrated the potential of Calcium Phosphate glass-based fiber-optic devices in future physiological monitoring applications which can be implanted inside the body without the need of an explant procedure.
Acknowledgement: This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 860185.
Calcium phosphate glass based single-mode and multi-mode bioresorbable optical fibers were in-house manufactured. Ex-vivo studies were then conducted to test the suitability of these fibers for time gated diffuse optics spectroscopy, photodynamic therapy and diffuse correlation spectroscopy applications which can be respectively employed for the diagnosis, treatment, and monitoring of malignant tissues. The results demonstrated the potential of calcium phosphate glass-based fiber optic devices towards the realization of an implantable multi-functional class of devices with functionalities ranging from cancer detection to monitoring of the healing process all integrated into a single bioresorbable platform.
Acknowledgement: This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 860185
Bioresorbable materials have gained interest for implantable optical components such as fibers for medical devices and have been demonstrated as suitable to perform diffuse optical measurements. In this work, we demonstrate interstitial, broadband, time-domain diffuse optical spectroscopy measurements using bioresorbable fibers, by employing a single-photon avalanche diode operated in an ultrafast time-gate mode for photon detection. Using tissue equivalent liquid phantoms, we test the system absorption linearity as per the MEDPHOT protocol and demonstrate the scattering independent absorption retrieval of the water spectrum in the 600-920 nm range. Consequently, we also attempt to distinguish the spectral changes due to the presence of optically denser speck inclusion in a tissue equivalent liquid phantom.
Calcium phosphate glasses offer an exclusive combination of optical, bioresorbable, and enhanced thermo-mechanical properties, making them an attractive material for fabricating resorbable biomedical devices. In the present study, we report the in vitro dissolution test of a multimode (MM) phosphate fiber and a hollow fiber in phosphate buffered saline (PBS) solution. The power transmission change with the MM fiber’s invitro dissolution is also presented. Then, using the same respective glass compositions of the MM fiber and hollow fiber, we report the realization of a novel bi-functional microstructured optical fiber with a MM core for light delivery and a microfluidic channel for drug delivery. The multistage fabrication process involves the techniques of extrusion, rod-in-tube, and stack-and-draw. The core was tested for light guidance and the channel for liquid delivery. The proposed approach illustrates the vast potentiality of phosphate glassbased micro-structured fibers that could be used as a theranostic device to be implanted at specific areas inside the body without needing an explant procedure.
Sensing using optical fibers is quite an established technology and is increasingly used in the field of bio-medical sensing applications owing to its small size, light weight, immunity towards electromagnetic interference, biocompatibility, sensitivity, and the ease with which it can be integrated with standard catheters leading to a designated point of inspection. Fiber Bragg gratings (FBGs), due to their ease of multiplexing, inherent sensitivity towards strain, and thereby pressure, can be suitably designed to make a novel pressure sensor for diagnosing and monitoring angiogenesis in brain tumors and for assessing vascular lesions inside coronary arteries. However, standard FBGs have a poor pressure sensitivity of 4pm/MPa (0.5fm/mmHg), which is insufficient to detect a few mmHg blood pressure changes. By utilizing the mechanical properties of modified FBGs with an elastomeric material coating, it is possible to improve the transduction mechanism of effectively translating pressure to strain and increase the resolution and sensitivity by two orders of magnitude (53.4 times) compared to standard FBGs. These modified FBGs could then be used to monitor respective pressure indices, i.e., Intracranial Pressure (ICP) and Instantaneous wave-free Ratio (iFR), by integrating them with catheters or endoscopes and using appropriate signal-processing algorithms. Moreover, a simulation of the modification of the blood vessel flow with respect to the secondary vessel formation is done to study the impact of different blood vessel formations during angiogenesis on pressure, thereby co-relating flow patterns to angiogenesis.
Lasers emitting in the visible find applications in biology and medicine. Considering the success of near-infrared fiber lasers, the possibility to optically pump rare-earth-doped fibers in the blue to directly obtain visible emission is attractive. The recent progress in the field of GaN-based blue laser diodes offers new scopes. Dy3+-doped materials have received much interest because of their intense yellow emission originating from the 4F9/2→6H13/2 transition. An involvement of a glass matrix benefiting from enhanced thermo-mechanical properties would ease diode pumping. We report on the synthesis of a series of novel phosphate glasses in the system P2O5-Al2O3–BaO-K2O doped with Dy2O3. The Dy3+ concentrations were 0.05, 0.21, 0.83 and 2.5 [1020 ions/cm3]. The glasses were synthesized by the standard melt-quenching technique and thoroughly characterized in their physical, thermo-mechanical and optical properties. A Dy3+-doped optical fiber was drawn by preform drawing from the developed glasses, with the preform being obtained by rod-in tube technique, combining a cast core and an extruded cladding. Preliminary emission results in the visible from the fabricated fiber will be reported.
State-of-the-art optical fiber pressure sensors use displacement diaphragms and mechanical transducers to enhance pressure sensitivity, however, due to their bulkiness and large size they can’t be easily integrated inside pressure guide wire for intravital monitoring. Fiber Bragg Gratings (FBGs) due to their inherent advantages can be designed in a way that is suitable for monitoring Intracranial Pressure (ICP) and Instantaneous Wave-Free Ratio (iFR) pressure indices. The main disadvantage of FBG is that it has a low-pressure sensitivity of 3.04pm/MPa, which is insufficient for these applications and is made worse by the cross-sensitivity caused by temperature. We hereby present a two-pronged strategy to tackle this issue. The first step in improving sensitivity is to modify FBGs, and the second is to use signal processing methods to recover minor wavelength shifts. A frequency-selective detection technique can be used to measure sub-pm wavelength shifts for small modulated pressure signals. This technique was used to establish a test bench for measuring the pressure sensitivity of standard acrylate and polyimide coated FBGs as well as to confirm a linear relationship between the pressure range of interest and Bragg wavelength shift.
The continuous improvement of interferometric gravitational-wave detectors (GWDs) and the preparations for next generation of GWDs set highly demanding requirements on their laser sources. A promising candidate to fulfill the challenging requirements of GWD laser sources is the hybrid master-oscillator power fiber amplifier (MOPFA) configuration. The implementation of a MOPFA relies principally on commercial silica glass-based optical fiber technology, which has been key in the successful development of high-power fiber amplifiers but that poses also a limitation to power scaling of these devices. It is well known that erbium (Er) ions tend to cluster in silica glass leading to ion-ion interactions and degradation of performance. The limited concentration of RE ions per unit length implies a limited optical gain per unit length and thus the requirement for long amplifying fiber lengths that enforce deleterious nonlinear effects, foremost stimulated Brillouin scattering (SBS).
Numerous SBS suppression techniques have been proposed, alongside investigation of specialty optical fibers. One of the most promising solutions is the use of highly doped optical fibers based on multicomponent phosphate glass that allows the fabrication of ultra-compact active devices with minimized nonlinearities.
To realize compact optical fiber amplifiers operating at 1.5 µm, a series of highly Er3+-doped custom phosphate glass compositions was designed and fabricated to be used as active materials for the core of the fiber amplifiers. Suitable cladding compositions were explored.
Core and cladding glasses were synthesized by melt-quenching method. The core glass was cast into a cylindrical mold to form a rod, whereas the cladding tube was fabricated by extrusion technique. Phosphate fibers were then manufactured by drawing the preform assembled by rod-in-tube technique.
Preliminary results of the application of the Er3+-doped phosphate fiber as laser active medium in a fully monolithic single-mode single-frequency core-pumped MOPFA setup resonantly pumped at around 1480 nm are presented.
In recent years, there has been a growing interest towards compact high peak-power pulsed laser sources for applications such as LIDAR, range findings, remote sensing, communications and material processing.
A common laser architecture used to realize these sources is the Master Oscillator Power Amplifier (MOPA), in which a master oscillator produces a highly coherent beam and a fiber amplifier boosts the output power, while preserving its main spectral properties.
Phosphate glasses are recognized to be an ideal host material for engineering the amplification stage of a pulsed MOPA since they enable extremely high doping levels of rare-earth ions to be incorporated in the glass matrix without clustering, thus allowing the fabrication of compact active devices with high gain per unit length.
With the aim of realizing compact optical fiber amplifiers operating at 1 and 1.5 µm, a series of highly Yb3+- and Yb3+/Er3+-doped custom phosphate glass compositions were designed and fabricated to be used as active materials for the core of the amplifiers. Suitable cladding glass compositions were explored and final core/cladding glass pairs were selected to realize single-mode and multi-mode optical fibers.
Core and cladding glasses were synthesized by melt-quenching technique. The core glass was then cast into a cylindrical mold to form a rod, while the cladding glass was shaped into a tube by rotational casting method or extrusion technique. The latter has been extensively employed for the manufacturing of tellurite and germanate glass preforms, but only recently the first example of active phosphate fiber preform fabricated by this method has been reported by our research team.
Phosphate fibers were then manufactured by preform drawing, with the preform being obtained by the rod-in-tube technique.
Preliminary results of pulsed optical amplification at 1 and 1.5 µm are presented for a single-stage MOPA.
The well-known enhancement effect of surface-enhanced Raman spectroscopy (SERS) is associated with the presence of metallic nanostructures at the substrate surface. Different bottom-up and top-down processes have been proposed to impart the substrate with such a nanostructured layer. The former approaches are low cost but may suffer from reusability and stability. The latter strategies are expensive, time consuming and require special equipment that complicate the fabrication process.
Here, we present the possibility to obtain stable and reusable SERS substrates by a low-cost silver-sodium ion-exchange process in soda-lime glass microrods. The microrods were obtained by cutting the tip of the ion-exchanged soda-lime fiber, resulting in disks of about few millimeters in length and one hundred microns in diameter. A thermal annealing post-process was applied to trigger the reduction of Ag+ ions into nanoparticles (AgNPs) within the ion-exchanged glass microrods. Afterwards, ion-exchange and thermal treatments were carefully tuned to assure the presence of silver NPs exposed on the surface of the microrods, without using any chemical etching. An AFM analysis confirmed the presence of AgNPs with size of tens of nm on the surface of the fiber probe.
A SERS affinity bioassay was developed on the probe with the final aim of detecting microRNA fragments acting as biomarkers of different diseases. Specifically a DNA hybridization assay was built up by anchoring a molecular beacon containing a Raman tag on the Ag surface via thiol chemistry. Initial SERS experiments confirmed the presence of the beacon on the NPs embedded on the microrods surface, as monitored by detecting main spectral bands ascribed to the oligonucleotide chain. Finally, the ability of the platform to interact with the target microRNA sequence was assessed. The analysis was repeated on a number of miRNA sequences differing from the target to evaluate the specificity of the proposed assay.
The steps toward the fabrication of directly-extruded microstructured fibre preforms made of a bioresorbable phosphate glass are herein presented. Microstructured fibres show a wide range of applications, i.e. photonic crystal fibres, large mode area fibres, hollow gas/liquid sensors, etc. Nevertheless, the fabrication of bioresorbable microstructured fibres has not been feasible so far due to a lack of bioresorbable transparent glass and more flexible fibre preform fabrication techniques. A custom developed calcium-phosphate glass has been designed and carefully prepared in our laboratory to be dissolvable in a biological fluid while being optically transparent and suitable for both preform extrusion and fibre drawing. This glass has been characterised both in terms of mechanical and optical properties as well as for dissolution in aqueous medium. Furthermore, the proposed glass is thermally stable, i.e. can be processed both in the extruder and in the drawing tower. Several extrusion experiments have been carried out with different glass preforms’ shapes. Analyses of these preforms by means of Optical Profilometry and Atomic Force Microscopy have been carried out to assess the roughness of the surface of the extrudate. To support the production of an optimized die for the preform extrusion, a simplified laminar flow model simulation has been employed. This model is intended as a tool for a fast and reliable way to catch the complex behaviour of glass flow during each extrusion and can be regarded as an effective design guide for the dies to fulfil specific needs for preform fabrication. After die optimisation, extrusion of a capillary was realised, and a stacking of extruded tubes was drawn to produce a microstructured optical fibre made of bioresorbable phosphate glass. The combination of bioresorbability and fibre microstructure, show a promising pathway toward a new generation of implantable biomedical devices.
This Conference Presentation, “Bioresorbable phosphate glass microstructured optical fiber for simultaneous light and drug delivery,” was recorded for the SPIE Photonics Europe 2020 Digital Forum.
The combination of fiber-optic–based platforms for biosensing with nanotechnologies is opening up the chance for the development of in situ, portable, lightweight, versatile, reliable and high-performance optical sensing devices. The route consists of the generation of lossy mode resonances (LMRs) by means of the deposition of nm-thick absorbing metaloxide films on special geometric-modified fibers. This allows measuring precisely and accurately the changes in surface refractive index due to the binding interaction between a biological recognition element and the analyte, with very high sensitivity compared to other optical technology platforms, such as fiber gratings or surface plasmon resonance. The proposed methodology, mixed with the use of specialty fiber structures such as D-shaped fibers, allows improving the light-matter interaction in a strong way. The shift of the LMR has been used to monitor in real-time the biomolecule interactions thanks to a conventional wavelength-interrogation system and an ad-hoc developed microfluidics. A big leap in performance has been attained by detecting femtomolar concentrations in real samples of human serum. The biosensor regeneration has been also studied by using a solution of sodium dodecyl sulphate (SDS), proving the device reusability. Therefore, this technology possibly represents a paradigm shift in the development of a simple, high-specificity and label-free biosensing platform, which can be applied to speed up diagnostic healthcare processes of different diseases toward an early diagnostic and personalized treatment system.
The design, fabrication and characterization of phosphate based bioresorbable optical fibers is reported. Applications in diffuse optics, pH sensing and temperature sensing have been demonstrated paving the way to the use for a new generation of implantable and degradable devices for theranostics.
Optical fibers and optical fiber bundles are often used for endoscopy and related (minimally invasive) medical methods because they offer good transparency together with flexibility. The ability to perform the operation, monitoring and chemical analysis of tissues with minimal disruption of the skin or internal organs of the patient is very promising in the medical field. Traditionally, silica optical fibers are used. Although silicon oxide is a biocompatible material, its use involves a serious health risk due to its fragility and the fact that potential fiber fragments can freely move inside the body and they are not detectable by conventional methods such as X-ray imaging. A possible solution to this issue can be the development of optical fibers based on biodegradable materials. Important benefit of bioresorbable fibers is that they do not need to be explanted after their use. We report on the optical power transmission tests of recently developed bioresorbable optical fibers based on phosphate glasses. Continuous-wave fiber lasers at 1080 and 1060 nm with output powers up to 7 W and a picosecond laser source at 515 nm with MW pulse peak power were used.
The development of compact eye-safe optical amplifiers has been recently triggered by the need of airborne LIght Detection And Ranging systems (LIDARs) for environmental monitoring and surveillance. Among potential candidate materials, phosphate glasses can incorporate high amounts of rare earth ions, thus allowing for high optical gain per unit length which would result in few-cm long optical amplifier sections. Another advantage guaranteed by a short length optical amplifier is the possibility to reduce the unwanted non-linear effects, e.g. Stimulated Brillouin Scattering, which cause distortion in the beam profile and affect the performance of the device.
We report on the design and fabrication of Yb/Er-doped phosphate glasses to be used as active materials for the core of a waveguide amplifier. The prepared glasses were characterized in their physical and optical properties and the best composition selected for the fabrication of the amplifier. Suitable cladding compositions were explored, and the final core/cladding glass pair was processed by melt-quenching the glasses into the desired shapes: core rods were obtained by casting the glass into preheated cylindrical glass molds, while the cladding glass tubes were fabricated by extrusion using an in-house developed equipment. The optical waveguide was then obtained using a custom induction heated optical fiber drawing tower. Preliminary results of optical amplification are presented for the single stage Master Oscillator Power Amplifier (MOPA), using a CW source as seed laser.
The reported activity was carried out in the framework of the NATO Science for Peace and Security project “Caliber”, grant no. SPS G5248.
The use of bioresorbable fibers represents an innovative way to build optical implantable devices and to look inside the body. Recently, a new kind of bioresorbable fibers, based on calcium-phosphate glasses, has been introduced by some of us. They show a good biocompatibility and improved attenuation loss coefficient with respect to other bioresorbable fibers. In this work, we used those fibers to explore their suitability in diffuse optics. Indeed, the time-domain technique is a non-invasive methodology which allows to have an absolute estimate of the absorption and reduced scattering spectra of the diffusive medium. It allows to bring information about concentration of chemical components (water, oxyand deoxy-hemoglobin), thus conveying information about the functional status and/or the scattering properties (changes in tissue microstructure, edema). Such information can then be related to the tissue regeneration, healing process, or to a harmful evolution. This makes the time domain optical spectroscopy coupled to bioresorbable fibers a good candidate for future medical devices. Here we demonstrate the suitability of these fibers for diffuse optics by means of standardized tests and then we use them for a proof-of-principle measurement on ex-vivo chicken breast, obtaining results comparable with standard fibers. Thanks to the encouraging results, we are working on a system based on a single fiber (serving as both injection and collection fiber) to go closer to a single interstitial fiber which can lessen the effect of the implant.
Optical fibers have been employed for several years in biomedicine and mainly used for light delivery and collection with high efficiency and selectivity. So far most of the research effort has been devoted to the optical configurations and the functions of the fibers rather than on the materials employed. Indeed, this aspect has been mainly considered to assure biocompatibility with tissues and non-toxic behavior limiting the choice mostly to silicate fibers.
We report on the recent advances in engineering inorganic glass optical and hollow fibers fabricated with optical glasses which are also resorbable in body fluids. Suitable phosphate glass compositions were designed to combine resorbability and optical transparency. Glasses were fabricated by melt-quenching inside a chamber furnace under a flux of dried air and cast into preheated brass molds. The fibers were obtained by preform drawing, with the core rod fabricated by melt quenching whilst the cladding tube by rotational casting. Extrusion techniques were also applied to obtain more complex cross sections with increased functionalities.
Glasses and fibers were characterized in their physical and optical properties. The materials showed high stability toward crystallization and a wide optical transmission window, ranging from the ultraviolet to the near infrared wavelength regions. Hollow fibers were employed to demonstrate multifunctional fiber probes, able to provide drug delivery and light excitation in the prospect of developing resorbable endoscopes for intravital monitoring and therapy, such as photodynamic therapy. Optimization of drug delivery was carried out using functionalization procedures on the surface of both bulk glasses and hollow fibers, aiming to modify the release kinetics: a silanization protocol was developed and successfully tested using different organic compounds. The modification of the surface roughness was monitored using atomic force microscopy, while surface energy changes verified using contact angle measurements. The possibility of performing drug excitation was assessed by guiding light through the capillary using optical beams produced by different wavelength sources covering the visible spectrum. Finally, mechanical characterization of the prepared optical fibers and hollow fibers was carried out to measure the elastic moduli, the tensile strength and the minimum radius of curvature attainable. The overall results allowed to demonstrate the reliability of the proposed optical fibers and hollow fibers for biomedical applications.
We report on the employment of a biodegradable phosphate-based optical fiber as a pH sensing probe in physiological environment. The phosphate-based optical fiber preform was fabricated by the rod-in-tube technique. The fiber biodegradability was first tested in-vitro and then its biodegradability and toxicity were tested in-vivo. Optical probes for pH sensing were prepared by the immobilization of a fluorescent dye on the fiber tip by a sol-gel method. The fluorescence response of the pH-sensor was measured as a ratio of the emission intensities at the excitation wavelengths of 405 and 450 nm.
We show for the first time the aptness of Calcium Phosphate Glass-based bioresorbable fibers for time-domain diffuse optics using tests described by a standardized protocol and we also present a spectroscopic measurement on a chicken breast.
A hollow bioresorbable phosphate glass fiber was developed and used for drug and light delivery.
The interaction between organic molecules and the fiber’s internal surface was studied. Promising
results for the release of Rose Bengal were obtained.
A theoretical and experimental analysis of group velocity reduction in periodic super-structured Bragg gratings
is presented. Experimental demonstration of group velocity reduction of sub-nanosecond pulses at the 1.5 μm wavelength of optical communications is reported using either a 20-cm-long Moire and a periodically-spaced πphase shift fiber gratings. Time delays up to approximately 690 ps for 250-ps-duration optical pulses have been achieved leading to the realization of an optical buffer.
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