WO2020141431A1

WO2020141431A1 - Bio-resorbable microstructured optical fiber to release fluids, in particular drugs, and to transmit light

Info

Publication number: WO2020141431A1
Application number: PCT/IB2019/061428
Authority: WO
Inventors: Daniel Milanese; Davide Janner; Diego PUGLIESE; Edoardo CECI GINISTRELLI; Nadia Giovanna BOETTI
Original assignee: Fondazione Links Leading Innovation & Knowledge For Society; Politecnico di Torino
Current assignee: Fondazione Links Leading Innovation & Knowledge For Society; Politecnico di Torino
Priority date: 2018-12-31
Filing date: 2019-12-30
Publication date: 2020-07-09
Anticipated expiration: 2021-06-30
Also published as: IT201800021559A1

Abstract

A microstructured bioresorbable optical glass fiber comprises a compound including phosphorus oxide, magnesium oxide and calcium oxide; so as to provide a loss of no more than 22 dB/m for a radiation having a wavelength of 633 nm when curved with a curvature of 10 cm; and has a longitudinal channel (2) having a diameter such to release and/ or uptake a liquid.

Description

"Bio-resorbable microstructured optical fiber to release fluids, in particular drags, and to transmit light"

DESCRIPTION

TECHNICAL FIELD

The present invention relates to a bioresorbable microstructured optical fiber to conduct light signals and at the same time provide the release and / or withdrawal of drugs or other chemical substances. The function of conducting light signals, in particular to and from the patient, allows the application of diagnostic protocols; the drug release function or the collection of samples in fluid form, for example in solution, allows the application of therapeutic and diagnostic protocols. Both protocols are therefore applicable on the same device of the invention, i.e. the microstructured optical fiber. In addition, bioabsorbability is defined as the ability of a material to dissolve within a living organism (especially the human body) without causing harmful effects and / or significant metabolic alterations.

STATE OF THE ART

It is known to make bioresorbable optical fibers of phosphate glass with additions of calcium and magnesium oxides for the transmission of light signals. The addition of further oxides, e.g. of Boron and Sodium, provides a compromise between bioabsorbability, light transmission and thermo-mechanical properties.

It is also known to employ a bioabsorbable hollow fiber of phosphate glass for the release of some drugs.

In particular, in 'Hollow resorbable fiber for combined light and drug delivery: fiber development and analysis of relase kinetics', Progress in biomedical optics and imaging, SPIE - International Society for optical engineering, Bellingham, WA, US 28 July 2017, is discussed a phosphate glass capillary with a light attenuation at 1300 nm and no mention of the measurement conditions, ie curved capillary or straight capillary. There are no attenuation measures but only the detection of a transmitted light, without indicating the power of the source of such light. It is not obvious that what has been found for light at 1300 nm also happens at other wavelengths.

In 'Novel biocompatible and resorbable UV-transparent phosphate glass based optical fiber¹, Optical Material Express vol. 6, no. 6, 23 majority 2016, a phosphate glass optical fiber having a core / cladding configuration is discussed: the relative measurement of optical losses are therefore not referred to a capillary and the measurement condition is that of the straight optical fiber.

In 'Resorbable hollow phosphate glass fibers as controlled release systems for biomedical applications', Materials Letters, vol. 99, February 26, 2013, the mentioned glass is opaque to the light as it contains relatively high percentages of titanium dioxide: the great impact that this oxide has on light transmission is known, in particular the increase in opacity. Furthermore, the crucible used for melting is not suitable for melting of optical phosphate glass, since it has impurities: indeed, the glass capillary has no optical uses but exclusively adducts fluids.

In 'Effect of biodegradation on spectroscopic properties of Smdoped 45S5 bioglass', Microfluidics, Biomems, and Medical Microsystems XI: 3-5 February 2013, Proceedings of SPIE, vol. 8615 is described a silicate glass, i.e. the glass lattice is not formed by phosphorus oxide and Strontium is not mentioned but Samarium. Furthermore, the bioactivity measure refers to the fact that it is possible to grow cells on this glass, not the bioabsorbability, which instead refers to the dissolution of the glass.

SCOPES AND SUMMARY OF THE INVENTION The purpose of the present invention is to create a new bioabsorbable component capable of providing the application of both diagnostic and therapeuhc protocols by defining a single operating platform.

The object of the present invention is achieved by a micro structured glass optical fiber having at least one longitudinal channel, preferably with a minimum cross section of 300 mm² corresponding to a diameter of about 20 mm, to add or withdraw a fluid, comprising a compound with Phosphorus, Magnesium, Calcium oxides and with a maximum optical loss of 22 dB / meter measured via the cut-back technique using a laser light source having a wavelength of 633 nm when the fiber is placed at a curvature radius of 10 cm.

This optical fiber provides manufacturing of multifunctional devices capable of measuring, for example, optical properties of tissues by coupling with an optical spectroscope; apply fluorescence spectroscopy to diagnose the beginning of diseases such as tumors, arteriosclerosis or local inflammation states; to measure the local temperature at the tip or along the fiber by using Bragg gratings made in the fiber itself; locally release medicines, contrast agents or photosensitizing substances; activate with light photosensitive substances used for photodynamic therapy and monitor the status of therapy; carry out, thanks to the high transparency in the near UV region, the sterilization of tissues or photodynamic therapy by irradiation with light sources having wavelengths even lower than 400 nm. In fact, the fiber in its basic composition has an absorption coefficient less than or equal to 1 cm^-1 at a wavelength of 200 nm. In this way it is possible to execute e.g. spectroscopic analysis of fluorescence.

Furthermore, this fiber exhibits good optical performance at a radius of curvature of 10 cm, compatible with the most common conditions of use providing for example the release of drugs or tracers in the medical analysis sector. In particular, it should be noted that in this sector the optical fibers for the release of the drugs do not exceed 3 m and, preferably, do not exceed 2 m in length.

According to a preferred embodiment, the optical fiber has a minimum radius of curvature equal to at least 25 times the external diameter of the fiber itself. This radius of curvature guarantees handling without excessive risk of breakage by e.g. of medical personnel when the fiber is manipulated at all stages of application on a patient.

According to a preferred embodiment of the present invention, the molar percentages of the components of the optical fiber are equal to: Phosphorus oxide 40- 80%; calcium oxide 5-55%; 5-55% magnesium oxide; Silicon oxide 0-10%; Sodium, Potassium, Lithium or other alkaline earth metal and Boron oxides in a molar percentage of no more than 30% and 10% respectively to obtain one or more of the following physical / mechanical properties thanks to the construction in a spinning tower:

In particular, Calcium oxide provides a particular contribution to biocompatibility which is also provided by the addition of other alkaline earth metal oxides such as Potassium, Sodium and Lithium. In addition, the variation of Magnesium oxide impacts the dissolution rate.

According to a preferred embodiment of the present invention, Strontium oxide is also present in a molar quantity not exceeding 5% to increase the refractive index and also induce, where necessary, a certain degree of bioactivity.

According to a preferred embodiment of the present invention, the optical fiber comprises one or more non-hollow internal cores having a diameter of between 0.1 mm and 2 mm and a hollow cladding having a diameter between 20 gm and 9 mm, wherein the cavity for adducting the fluid is made in the cladding. The percentage of Magnesium oxide is higher in the cladding than in the core so that the refractive index of the core is higher than that of the cladding. Other compositional variations are possible to obtain the necessary difference of refractive index for the realization of a fiber capable of efficiently guiding light signals. In this way the light signal is conveyed more effectively in the core.

Furthermore, the cores can be at least two and have a different composition one another.

According to a preferred embodiment, the surface of the optical fiber is coated with a single externally self-assembled layer and / or layer self-assembled in the adduction channel. This layer comprising molecular entities that adhere to the glass surface comprises molecules that change the character of the surface from hydrophobic to hydrophilic or vice versa depending on the type of molecule used and the specific composition of the glass used. This possibility of varying the surface properties by functionalizing the multifunctional device allows to control the movement of the fluid in the channel with greater precision. By way of example, the internal channel of a multifunctional optical fiber can be functionalized by means of a single self-assembled layer of Octadecyl-trichlorosilane which changes the surface of the device to become hydrophobic. Such a device releases a drug - e.g. Rosa Bengal - in a slower and more controlled manner than a device that has not undergone such treatment, thus significantly increasing the therapeutic efficacy of the treatment protocol.

According to a preferred embodiment, the composition of the glass is such that the optical fiber withstands the pressure of a flow rate through the channel of 100 mΐ / h for a cross section of the channel of 1 mm². Such pressure is for example applied manually by means of a syringe fluidly connected to the optical fiber. There are additional pumping / administration devices used in the medical field for the release of drugs that provides this flow.

According to a preferred embodiment, it is possible to bundle together a plurality of fibers according to the preceding paragraphs.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be described below by means of some preferred embodiments, given as a non-limiting example, with reference to the attached drawings. Such drawings illustrate different aspects and examples of the present invention and, where appropriate, structures, components, materials and / or similar elements in different figures are indicated by similar reference numbers.

In particular:

- Figure 1 shows the cross sections a), b), c), d), e), f) of alternative and non limiting embodiments of a microstructured optical fiber according to the present invention;

- Figure 2a-f shows, in a clockwise direction, the contact angle of a drop of distilled water and the topology and the signal by Atomic Force Microscopy for a flat surface of calcium-phosphate glass according to an exemplary composition respectively without and with silanization, i.e. functionalization;

- Figures 3a and 3b respectively show the graphs of the absorption coefficient of the light power as a function of the wavelength and the light output power in different sections of the fiber (squares); and

Figure 4 shows a comparative test of the cumulative release of a drug over time for a silanized optical fiber, i.e. functionalized, and not silanized, i.e. not functionalized. DETAILED DESCRIPTION OF THE INVENTION

Figure 1 shows some non-limiting alternatives of cross sections of a bioresorbable microstructured optical fiber 1 for conduting light and adducting drugs, through a longitudinal cavity 2. Through the cavity or channel 2 it is possible, depending on the applications, to release or withdraw organic substances such as cells, and / or bacteria, and / or chemicals such as drugs and reagents. Channel 2 has a minimum size of about 20 mm and is such to make microstructured the fiber of Figure la. Optical fiber 1 is also able to conduct from ultraviolet to infrared light to perform, according to non-limiting examples, sterilization, spectroscopic analysis of fluorescence, activation of photosensitizing substances e.g. for photodynamic therapies of tumors or photochemical adhesion of tissues.

Calcium-phosphate glass has proven to be a suitable material for obtaining a good compromise between bioabsibility and the mechanical and physical properties necessary to create a flexible conduit, which can be manipulated by medical personnel and versatile for the transmission of a wide spectrum of visible light frequencies and not visible.

According to an embodiment of the present invention, the microstructured optical fiber comprises, in molar percentages, 50 of P₂O₅, 11.5 of Na₂O, 30 of CaO, 3 of

T_s is the softening temperature;

CTE is the thermal expansion coefficient;

E is the elastic modulus or Young's modulus.

In addition, the microstructured optical fiber according to the previous composition has an absorption coefficient less than or equal to 1 cm^-1 at a wavelength of 200 nm. This property can be modified by adding the following oxides: Na₂0, Li₂O, K2O, TiO₂, CuO and ZnO making the fiber more or less transparent at this wavelength. As an example, adding an amount of TiO₂ greater than 1% increases the absorption coefficient to 200 nm bringing it to values greater than or equal to 5 cm^-1. The possibility of changing the absorption at this wavelength has the consequence of moving the lower transparency threshold, giving the possibility to use the microstructured optical fiber as a spectral filter. For example, a multinucleus fiber in which a core carries the UV light with a relative composition and another core collects fluorescence light by absorbing the ultraviolet light and letting pass the wavelength at which biological tissues are fluorescent that typically is at a higher wave length (e.g. 500 nm). This other core has a further composition, in particular comprising TiO₂ greater than 0.5 mol% in addition to the other oxides indicated above.

Furthermore, the glass fiber according to the example is reabsorbable in physiological conditions [37 ºC and pH of 7.4] with a dissolution rate of about 2-4 mm / day when the maximum cross-sectional size is 200 mm and is transparent at wavelengths between 250 and 2600 nm. An example of geometry obtainable according to Figure la is 220 mm of external diameter and 110 mm of diameter of channel 2. More generally, the technical characteristics are obtained by varying the composition to obtain the desired optical effects and / or mechanical characteristics within the following limits (in molar percentages):

. It is also possible to provide further oxides in variable quantities but less than 30% in molar percentage.

For example, it is possible to provide an amount of Strontium oxide not exceeding 5% to increase the refractive index of the glass of the core.

Further exemplary and non-limiting compositions according to the invention are

Ti0₂. Preferably, when the Phosphorus oxide drops below 50% it is appropriate to introduce or increase the Boron and / or Silicon oxides. In addition, a variation of Calcium oxide is compensated by an opposite variation of Magnesium and / or Strontium oxides.

In addition, the optical fiber made according to the composition indicated above, has a relatively high flexibility and suitable for manipulation or application on the human body. It should be noted that the optical fiber of the invention has relatively low losses even as a result of bending. In particular, it has been verified that the loss at a wavelength of 633 nm does not exceed 22 dB per linear meter of fiber when subjected to a radius of curvature of 10 cm. In addition, with the same curvature, the loss is less than or equal to 15 dB when measured at a wavelength of 1300 nm. These loss values represent an upper limit that is valid in the numerous possible configurations of the cross section of the microstructured optical fiber according to the invention, as indicated in a non-limiting way by Figures la-e. Furthermore, these losses are suitable for use in the medical analysis sector where the length of the fiber within the human body does not exceed 2 m. According to a variant of the present invention, the optical fiber 1 (Figures lb-d) can comprise a compact core 3 substantially intended for the transmission of light and a cladding 4 defining channel 2 and incorporating core 3. Core 3 has a composition substantially optimized for the transmission of visible and / or non-visible light and, for this purpose, the percentage of Magnesium oxide in core 3 is greater than that in cladding 4, for example greater than 5% . More generally, the core and the cladding both have compositions based on Phosphorus oxide, Calcium and Magnesium but the percentages and / or further oxides among those listed above are different or can be added. Likewise, in the case of multi-core fibers, the respective compositions are based on Phosphorus, Calcium and Magnesium oxide but the percentages and / or further oxides among those listed above are different or can be added.

The manufacturing alternatives of Figures lc and Id refer respectively to a configuration of the concentric core with respect to channel 2, with the core surrounding the channel, and to the presence of both a plurality of cores and a plurality of channels.

The manufacturing alternatives of Figures le and If refer to photonic crystal fiber configurations in which the light is guided by confinement obtained thanks to a suitable arrangement of microchannels 5. These microchannels can be made of glass (e.g. core glass such as 3 ), each microchannel 5 being obtainable with a different glass composition, or empty as microchannel 2. Microchannels 5 that are empty can also be used for the release of liquids. A dedicated release channel 2 can be provided in addition to microchannels 5 as indicated in the construction alternative of Figure If.

Preferably, the optical fiber 1 is made by means of a spinning tower starting from one or more hollow or full glass tubes made using the casting, extrusion or chemical vapor deposition technique. When the optical fiber includes a core and a cladding, the optical guide function is more efficient and the maximum loss measured with a radius of curvature of 10 cm and light with a wavelength equal to 633 nm does not exceed 7 dB / meter. The corresponding loss value when the radiation has a wavelength equal to 1300 nm is 3 dB / meter.

Preferably, the surface of the optical fiber 1, in particular of the channel 2, is functionalized to control the liquid release procedure, e.g. of the drug. The functionalization can be carried out to deposit either a hydrophilic layer or a hydrophobic layer depending on the characteristics of the liquid to be released.

According to an exemplary embodiment, the micro structured optical fiber 1 with molar percentages of 50 P₂O₅, 30 CaO, 11.5 Na₂0, 3 MgO, 3 S12O, 2.5 B2O has been made according to the scheme of Figure la with an external diameter of 220 ± 3 mm and an internal diameter of 110 ± 6 mm.

To determine Young's modulus and fiber resistance 1, the tensile tests were performed using a universal testing machine according to the ASTM C1557 standard methodology. Every single sample was glued on assembly tabs cut from thin cardboard to facilitate positioning and fixing to the machine for mechanical tests. All tensile tests were carried out in environmental conditions (T = 23 ºC, Relative Humidity = 50% ). Average values of 40 GPa of Young's modulus and 250 MPa of yield strength were obtained, congruent with a minimum breaking radius of curvature of 2.5 cm.

The ability to guide the light by optical fiber 1 was assessed by launching a visible laser light (wavelength of 405, 532 and 650 nm) through a i m long section of the microstructured fiber 1. The quality of the end faces of the fibers was assessed by optic microscopy of the respective cross section. A series of images were also taken near the end faces using red laser light at 660 nm wavelength. Hollow fiber loss was estimated at a wavelength of 660 nm by the cut-back method using a multimode pigtailed hber laser diode source (QFLD-660-10S). The attenuation value was calculated by linear fithng of the experimental data taken at different fiber lengths (Figure 3b).

Furthermore, the surface was cleaned and the glass was activated by sonicahon in an alkaline solution NH40H + H202 + H20 for 10 minutes at room temperature. The silanizahon of the glass was obtained by dipping the sample in a solution of 10 mΐ of OTS in 25 ml of hexane for 1 hour. The sample was finally carefully rinsed with, in order, hexane, acetone and ethanol. In particular, the treatment indicated above was also performed on planar glass sheets to perform contact angle measurements in order to characterize the silane monolayer on the surface. Measurements using Atomic Force Microscopy were performed using an Akiyama silicon probe in contact mode before and after the silanization procedure. The contact angle measurements were performed on a silanized and a non-silanized sample (Figure 2). Three measurements per surface were carried out on different points of the circular sample.

Initially, a combined test for the release of a fluorophore (fluorescein isothiocyanate) and its excitation were carried out with the hollow Hber 1 according to the composition indicated above. For this purpose, the release and guiding action of the light were achieved at the same time by connecting the fibers to a syringe and coupling a diode laser to the hollow fiber on one side. The fluorophore was diluted in water and was excited using a laser diode at 405 nm wavelength producing an emission centered at 520 nm. The solution for the drug release tests was prepared by dissolving Rose Bengal in ethanol at a concentration of 9.4 mM. Both the non-silanized and silanized fibers were cut into sections of 20 mm (internal volume V = 0.19 mΐ), filled with the immersion solution and finally vacuum dried at 40 ° C for 24 hours to remove the solvent. Subsequently, to test the release behavior, the fibers filled with the drug were placed in closed Eppendorf tubes containing 1 ml of saline phosphate buffer solution (PBS) at pH = 7.4. During the tests the temperature was constantly maintained at 37 ° C. After an initial waiting time of 1 minute, the solution containing the released drug was taken from the hollow fiber for UV absorption spectroscopic analysis and then replaced with the same volume of fresh PBS. The procedure was repeated at fixed time intervals until complete release and at least 3 measurements were taken for each point. The concentration of the drug released was then obtained by interpolating the appropriate calibration curve (R2> 0.999). To obtain the time scale characteristic of the release process for non-silanized and silanized hollow fibers, the data were adapted using the Weibull distribution and the typical time for a cumulative release of 62.2% was extrapolated from the interpolation.

According to the present invention, it is possible to make a microstructured optical fiber with a photonic crystal, i.e. in which the guiding effect is obtained by a plurality of hollow cores for index contrast or for the creation of a photonic "bandgap". In this case, one or more of the same hollow cores can act as a release channel or channel 2 is surrounded or adjacent to these hollow cores and has a larger diameter than these cores.

With reference to bioabsorbability, a photonic crystal fiber has substantially identical performances to a corresponding fiber according to the geometries of figure 1 with the same properties of the guided optical modes and channel diameter.

A microstructured fiber with a photonic crystal has electromagnetic radiation power losses on average greater than both the configuration of Figure la and, above all, of the configurations with core and mantle of Figures lb-d. In a similar way to what is described above, the micro structured photonic crystal fiber can receive a surface treatment to be functionalized and, using the same mechanism, allow to release in a more controlled way any drugs or chemical substances such as for example contrast agents, nano-crystals and nano-particles.

Claims

1. Microstructured bioresorbable optical glass fiber comprising a compound including phosphorus oxide, magnesium oxide and calcium oxide; so as to provide a loss of no more than 22 dB/m for a radiation having a wavelength of 633 nm when curved with a curvature of 10 cm; and having a longitudinal channel (2) having a diameter such to release and/ or uptake a liquid.

2. Microstructured glass fiber according to claim 1, wherein the channel (2) has a cross-section between 300 mm ² and 1 mm².

3. Microstructured glass fiber according to any of claims 1 or 2, wherein the composition is such to withstand the pressure of a flow rate through the channel (2) of 100 mΐ/h for a cross-section of the channel of l mm².

4. Microstructured glass fiber according to any of the preceding claims, wherein the composition is such that the loss is no more than 15 dB/m for a radiation having a wavelength of 1300 nm.

5. Microstructured glass fiber according to any of the preceding claims, wherein the composition is such that the dissolution rate at pH = 7.4 and T = 37 °C is between 0.1 and 20 mm /day for a fiber having a maximum cross-sectional dimension of 200 mm².

6. Microstructured glass fiber according to any of the preceding claims, wherein the composition further comprises another oxide of an alkaline metal in a molar percentage of no more than 30% and/or Boron oxide in a molar percentage of no more than 10% and/ or Silica in a molar percentage of no more than 10% .

7. Microstructured glass fiber according to any of the preceding claims, wherein the composition further comprises Strontium oxide in a molar percentage of no more than 5% .

8. Microstructured glass fiber according to any of the preceding claims, comprising at least a core comprising the composition and having a diameter between 0.1 mm and 2 mm and a hollow cladding comprising the composition and embedding the at least one core and having a diameter between 1 mm and 9 mm and wherein a Magnesium oxide molar percentage is greater in the cladding than in the core.

9. Microstructured glass fiber according to claim 8, wherein the at least one core comprises the composition such that the absorption is no more than 1 cm^-1 for a radiation with a wavelength of 200 nm.

10. Microstructured glass fiber according to claim 9, wherein the fiber comprises a further core having the composition further including Titanium oxide such that the absorption of the further core is greater than 3 cm^-1 for a radiation with a wavelength of 200 nm.

11. Microstructured glass fiber according to claim 8, wherein the core is hollow and surrounds the channel (2).

12. Microstructured glass fiber according to any of the preceding claims, wherein the surface is functionalized to be either hydrophobic or hydrophilic.