Fiber optic detection system for delivery of photobiomodulation therapy

Abstract

A system for cochlear photobiomodulation (PBM) therapy, including: an illumination probe including a proximal end and a distal end, the illumination probe including an optical fiber including a spacer and a lens at the distal end, and the distal end of the illumination probe being configured to deliver light to a tissue.

Description

FIBER OPTIC DETECTION SYSTEM FOR DELIVERY OF PHOTOBIOMODULATION THERAPYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application is based on and claims priority from U.S. Patent Application No. 63 / 532,830, filed on August 15, 2023. The entire disclosure of which is incorporated herein by reference.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under HU00011920056 awarded by the Musculoskeletal Injury Rehabilitation Research for Operational Readiness (MIRROR), Department of Physical Medicine Rehabilitation of the Uniformed Services University. The government has certain rights in the invention.BACKGROUND

[0003] Photobiomodulation (PBM) therapy is a light-based therapy that has been shown to reduce inflammation and induce tissue repair. Cochlear inflammation has been shown to occur commonly after noise overexposure, a potential component of sensorineural hearing loss (SNHL). Few reports of successful administration of PBM therapy in animals or humans for hearing loss exist, and those that do have shown mixed results. Successfully administering PBM to tissues such as the human cochlea directly is challenging, because the cochlea is encased in the temporal bone and is not accessible except by invasive surgical approach, typically through a mastoidectomy. Researchers have used divergent beams using small fiber optic cables inserted into the external auditory canal (EAC) and illuminated through the tympanic membrane, although concentrated high irradiance light directed onto the tympanic membrane (TM) can cause tissue damage. Further, there is a need for methods to quantify the amount of light that reaches the inside of a tissue such as the cochlea during PBM therapy. Thus, procedures whichcan both directly deliver light safely and non-invasively as well as measure and characterize the attenuated light inside the cochlea are needed.SUMMARY

[0004] Accordingly, new systems, methods, and apparatus for tissue photobiomodulation (PBM) treatment are desirable.

[0005] In one embodiment, a system for cochlear photobiomodulation (PBM) therapy, including: an illumination probe including a proximal end and a distal end, the illumination probe comprising an optical fiber including a spacer and a lens at the distal end, and the distal end of the illumination probe being configured to deliver light to a tissue.

[0006] In some embodiments of the system, the distal end of the illumination probe may be configured to deliver light to the tissue as a collimated beam. In some embodiments of the system, the spacer and the lens may be configured to expand and collimate a beam emitted from a distal end of the optical fiber. In some embodiments of the system the illumination probe may be coupled to a light source at the proximal end and the light source may be configured to deliver light to the tissue via the illumination probe.

[0007] In some embodiments of the system, the light source may deliver light in a wavelength range of 400 nm to 2400 nm. In some embodiments of the system, the light source may deliver light at a wavelength of 808 nm. In some embodiments of the system, the light source may include a laser.

[0008] In some embodiments of the system, the optical fiber may be a multi-mode fiber. In some embodiments of the system, the multi-mode fiber may include a 105 pm core, a 125 pm cladding, and a 250 pm buffer.

[0009] In some embodiments of the system, the illumination probe may further include protective tubing surrounding the optical fiber. In some embodiments of the system, the protective tubing may include furcation tubing.

[0010] In some embodiments of the system, the illumination probe may further include an angled surface at the proximal end of the spacer to minimize back reflections. In some embodiments of the system, the diameter of the illumination probe may be 3000 pm.

[0011] In some embodiments of the system, the illumination probe may further include aspooling attachment.

[0012] In some embodiments of the system, the illumination probe may be configured to produce a beam having at least one of a collimated beam profile, a diffusive beam profile, a flat- top beam profile, or a Gaussian beam profile.

[0013] In some embodiments of the system, the lens may include at least one of a planoconvex lens, a plano-concave lens, or a diffusive lens.

[0014] In some embodiments of the system, the illumination probe may be configured to produce a beam having a flat-top beam profile. In some embodiments of the system, a diameter of the beam may be 3 mm.

[0015] In some embodiments of the system, the tissue may include a cochlea.

[0016] In another embodiment, a method for cochlear photobiomodulation (PBM) therapy, including: providing an illumination probe including a proximal end and a distal end, the illumination probe comprising an optical fiber including a spacer and a lens at the distal end; and delivering light to a tissue from the distal end of the illumination probe.

[0017] In some embodiments of the method, delivering light to the tissue may further include: delivering the light to the tissue as a collimated beam. In some embodiments of the method, delivering light to the tissue as the collimated beam may further include: delivering light to the tissue as the collimated beam by using the spacer and the lens to expand and collimate a beam emitted from a distal end of the optical fiber.

[0018] In some embodiments of the method, providing the illumination probe may further include: coupling the illumination probe to a light source at the proximal end, and delivering light to the tissue may further include: delivering light from the light source to the tissue using the illumination probe.

[0019] In some embodiments of the method, delivering light to the tissue may further include: delivering light in a wavelength range of 400 nm to 2400 nm. In some embodiments of the method, delivering light to the tissue may further include: delivering light at a wavelength of 808 nm.

[0020] In some embodiments of the method, coupling the illumination probe to the light source may further include: coupling the illumination probe to a laser.

[0021] In some embodiments of the method, providing the illumination probe mayfurther include: providing the illumination probe, wherein the optical fiber may be a multi-mode fiber. In some embodiments of the method, providing the illumination probe may further include: providing the illumination probe, wherein the multi-mode fiber may include a 105 pm core, a 125 pm cladding, and a 250 pm buffer.

[0022] In some embodiments of the method, providing the illumination probe may further include: providing the illumination probe, wherein the illumination probe may further include protective tubing surrounding the optical fiber. In some embodiments of the method, providing the illumination probe may further include: providing the illumination probe, wherein the protective tubing may include furcation tubing.

[0023] In some embodiments of the method, providing the illumination probe may further include: providing the illumination probe, wherein the illumination probe may further include an angled surface at the proximal end of the spacer to minimize back reflections.

[0024] In some embodiments of the method, providing the illumination probe may further include: providing the illumination probe, wherein the diameter of the illumination probe may be 3000 pm.

[0025] In some embodiments of the method, providing the illumination probe may further include: providing the illumination probe, wherein the illumination probe may further include a spooling attachment.

[0026] In some embodiments of the method, delivering light to the tissue may further include: delivering light to the tissue as a beam having at least one of a collimated beam profile, a diffusive beam profile, a flat-top beam profile, or a Gaussian beam profile.

[0027] In some embodiments of the method, providing the illumination probe may further include: providing the illumination probe, wherein the lens may include at least one of a plano-convex lens, a plano-concave lens, or a diffusive lens.

[0028] In some embodiments of the method, delivering light to the tissue may further include: delivering light to the tissue as a beam having a flat-top beam profile. In some embodiments of the method, a diameter of the beam may be 3 mm.

[0029] In some embodiments of the method, delivering light to the tissue may further include: delivering light to a cochlea. In some embodiments of the method, delivering light to the cochlea may further include: inserting the illumination probe into an external auditory canal,placing the distal end of the illumination probe adjacent to a tympanic membrane, and delivering light through the tympanic membrane toward the cochlea. In some embodiments of the method, delivering light to the tissue may further include: accessing a model of light transmission through the cochlea to determine at least one of an intensity or a duration of light delivery, and delivering light to the cochlea using at least one of the intensity or the duration of light delivery determined using the model.

[0030] In still another embodiment, a system for cochlear photobiomodulation (PBM) therapy, including: an illumination probe including a proximal end and a distal end, the illumination probe comprising an optical fiber including a spacer and a lens at the distal end, and the distal end of the illumination probe being configured to deliver light to a tissue; and an isotropic detection probe for detecting the delivered light within the tissue.

[0031] In some embodiments of the system, the distal end of the illumination probe may be configured to deliver light to the tissue as a collimated beam. In some embodiments of the system, the spacer and the lens may be configured to expand and collimate a beam emitted from a distal end of the optical fiber.

[0032] In some embodiments of the system, the illumination probe may be coupled to a light source at the proximal end and wherein the light source is configured to deliver light to the tissue via the illumination probe. In some embodiments of the system, the light source may deliver light in a wavelength range of 400 nm to 2400 nm. In some embodiments of the system, the light source may deliver light at a wavelength of 808 nm. In some embodiments of the system, the light source may include a laser.

[0033] In some embodiments of the system, the optical fiber may be a multi-mode fiber. In some embodiments of the system, the multi-mode fiber may include a 105 pm core, a 125 pm cladding, and a 250 pm buffer. In some embodiments of the system, the illumination probe may further include protective tubing surrounding the optical fiber. In some embodiments of the system, the protective tubing may include furcation tubing.

[0034] In some embodiments of the system, the illumination probe may further include an angled surface at the proximal end of the spacer to minimize back reflections. In some embodiments of the system, the diameter of the illumination probe may be 3000 pm. the illumination probe may further include a spooling attachment.

[0035] In some embodiments of the system, the illumination probe may be configured to produce a beam having at least one of a collimated beam profile, a diffusive beam profile, a flattop beam profile, or a Gaussian beam profile.

[0036] In some embodiments of the system, the lens may include at least one of a planoconvex lens, a plano-concave lens, or a diffusive lens. In some embodiments of the system, the illumination probe may be configured to produce a beam having a flat-top beam profile. In some embodiments of the system, a diameter of the beam may be 3 mm.

[0037] In some embodiments of the system, the tissue may include a cochlea.

[0038] In some embodiments of the system, the isotropic detection probe may include a light-scattering coating. In some embodiments of the system, the light-scattering coating may include metal oxide nanoparticles and a synthetic polymer. In some embodiments of the system, the metal oxide nanoparticles may include titanium oxide.

[0039] In some embodiments of the system, the isotropic detection probe may include an angle of detection of at least 270°. In some embodiments of the system, the isotropic detection probe may be coupled to a multimode fiber. In some embodiments of the system, the system may further include a detector coupled to the isotropic detection probe by the multimode fiber.

[0040] In some embodiments of the system, the isotropic detection probe may include a ball lens. In some embodiments of the system, the ball lens may be formed from a coreless silica fiber. In some embodiments of the system, the ball lens may have an outer diameter of 0.3 mm. In some embodiments of the system, the isotropic detection probe may be configured to be inserted through the round window of a cochlea of a subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Various objects, features, and advantages of the disclosed subject matter can be more fully appreciated with reference to the following detailed description of the disclosed subject matter when considered in connection with the following drawings, in which like reference numerals identify like elements.

[0042] FIG. 1 shows a system schematic for light delivery and detection system inside cadaver temporal bone. The illumination probe is connected to the laser source, while the detection probe is connected to a fiber-coupled photodiode and power meter console.

[0043] FIG. 2A shows a layout of a forward-facing, collimated-illumination probe opticaldesign with flat-top beam profile.

[0044] FIG. 2B shows a ray diagram of the collimated-illumination probe optical design, which features a flat-top beam profile, which is produced by the beam expanding in a spacer before being collimated.

[0045] FIG. 2C shows a photo of a fabricated collimated-illumination probe used for cochlear PBM therapy.

[0046] FIG. 3A shows a beam intensity profile of the illumination probe with no spools and no motion in the fiber.

[0047] FIG. 3B shows a beam intensity profile of the illumination probe with no spools and motion in the fiber.

[0048] FIG. 3C shows a beam intensity profile of the illumination probe with spools and no motion in the fiber.

[0049] FIG. 3D shows a beam intensity profile of the illumination probe with spools and motion in the fiber.

[0050] FIG. 4A shows a ray diagram of the traditional ball lens optical design without application of any specialized external scattering coating.

[0051] FIG. 4B shows a ray diagram of a detection probe which includes a specialized external scattering coating.

[0052] FIG. 4C shows a photo of a fabricated detection probe used for isotropic light detection contained within a protective sheath.

[0053] FIG. 4D shows a photo of a close up view of a fabricated detection probe used for isotropic light detection contained within a protective sheath.

[0054] FIG. 4E shows theoretical relative angular collection efficiencies of ideal, good, and bad ball lenses.

[0055] FIG. 4F shows a comparison of relative angular collection efficiency of an uncoated ball lens (left) and the detection probe with an optical coating (right) plotted on polar plots. The relative collection area is determined by the numerical integral of the area below the collection curve. This area is compared to the uncoated ball lens demonstrating the improvement in isotropic collection of the detection probe with an optical coating.

[0056] FIG. 4G shows the irradiance detection response of a detection probe when placedwithin an integrating sphere.

[0057] FIG. 4H shows the absolute collection efficiency of a detection probe when placed within an integrating sphere.

[0058] FIG. 41 shows a photograph of an illuminated detection probe inside a 3D cochlea spiral phantom.

[0059] FIG. 4J shows a photograph of maximum position of a detection probe after being inserted into a 2D cochlea spiral phantom to demonstrate flexibility and size of a detection probe compared to the cochlea.

[0060] FIG. 4K shows a diagram of the detection probe after sheath assembly, showing the coated ball lens, flexible, and ultra-flexible region of the probe (top) as well as a grip attachment for the rigid insertion tool (bottom).

[0061] FIG. 4L shows a schematic of the angular characterization setup to measure the relative angular collection efficiency of the DP along its coronal plane.

[0062] FIG. 5 shows a labeled diagram of probe placement for characterization of PBM therapy overlaid on a CT scan of the ear canal and cochlea region. The illumination probe is placed into the external ear canal (EAC), placed against the TM, and pointed at the cochlear spiral. The detection probe is placed through the RW and enters the cochlea to detect the power delivered to the cochlea at various positions within the spiral. The CT scan distinguishes bone (white) from surrounding tissue and water (gray) and air (black).

[0063] FIG. 6A shows an example of experimental detected intracochlear irradiances as the probe is inserted further into the cochlea, including data for three separate detection probes.

[0064] FIG. 6B shows preliminary experimental data measured by the system (top) and a surface fitting of the experimental data to estimate intracochlear irradiance produced by the illumination probe and detected by the detection probe at various depths into the cochlea, which is related to specific frequencies related to hearing (bottom).

[0065] FIG. 7A shows an alternative optical design of a diffused-illumination probe with an approximate beam profile, featuring a plano-concave lens.

[0066] FIG. 7B shows an alternative design of a collimated-illumination probe with flat- top beam profile that features a rotating mechanical driveshaft and side-viewing capability.

[0067] FIG. 7C shows an alternative design of a collimated-illumination probe with flat-top beam profile that features a static housing integrated with a 360° viewing collimated- illumination probe.

[0068] FIG. 8 shows an alternative optical design of bare fiber illumination with a Gaussian beam profile.DETAILED DESCRIPTION

[0069] In accordance with some embodiments of the disclosed subject matter, mechanisms (which can include apparatus, systems, and methods) for tissue photobiomodulation (PBM) treatment are described herein.

[0070] As part of procedures for using PBM to treat various tissues including, but not limited to, the cochlea, there is a need to measure and quantify the amount of light that is actually reaching the particular tissue being treated. Given the complexities of most tissues, such as the presence of different tissue types including tissues having varying degrees of absorption of the therapeutic light, it is unlikely that simple mathematical modeling can be used to accurately predict the amount of light that will reach the tissue. To date, there have yet to be satisfactory methods developed to quantify the amount of light that reaches inside of a tissue such as the cochlea during PBM therapy. Thus, systems, methods, and apparatus which can directly deliver light to tissue both safely and non-invasively, as well as measure and characterize the attenuated light inside the tissue, are needed.

[0071] Accordingly, described herein are various embodiments of systems, methods, and apparatus for PBM light delivery treatment. In various embodiments, a PBM therapy system may include one or more of a light source, an illumination probe, a detection probe, a detector, and a controller and processing system (FIG. 1). During an initial phase of development, the illumination probe and detection probe may be used together in a sample or test system (e.g., a phantom or cadaver tissue) to characterize how light travels through a particular tissue such as the cochlea. The information gathered at this stage can then be used to assemble a database of information which can in turn be used to prepare a model for developing PBM therapy treatments in a subject (see below). In general, it may not be practical to use the detection probe to obtain measurements of actual light delivered to the tissue in question (e.g., the cochlea) and therefore the model developed during the development stage is useful for guiding clinicians and other users who are setting up PBM treatment regimens for their subjects.

[0072] In certain embodiments, the model may be included as part of a PBM treatment system. Thus, in some embodiments a PBM therapy system may include a light source coupled to an illumination probe along with a software system for determining a light emission level (and information regarding a direction in which the probe should be aimed, if applicable). The light emission level and direction may be based on information such as the location of where the PBM therapy should be applied (e g., where the subject’s tissue injury is located) as well as any structural information available for the subject (e.g., CT, MRI, or ultrasound scans, or other medical information). The PBM therapy light is applied for a given amount of time which is determined based on the known extent of the injury and / or the amount of light that is predicted to reach the tissue.

[0073] In some embodiments, the PBM system may include two probes, namely an illumination probe and a detection probe. FIG. 1 shows a schematic diagram of an embodiment of a system having both an illumination probe and a detection probe. As noted above, the illumination probe and the detection probe can be used together to characterize the amount of light that is delivered into a particular tissue by the illumination probe, prior to PBM therapy, to determine how light travels through the tissue and determine how much light must be emitted from the illumination probe in order to provide sufficient PBM treatment. Once the tissue has been sufficiently characterized, the illumination probe can be used independently without the detection probe to provide PBM therapy (e.g., a system in use may include only the components on the left half of FIG. 1 including the light source and the illumination probe in communication with a controller).

[0074] In some embodiments, the illumination probe is a collimated fiber-optic illumination probe that can be inserted into the EAC to deliver PBM therapy to the cochlea via a trans-tympanic approach in humans. The “flat-top” beam profile from a collimated beam of light minimizes the irradiance at the entry point into the tissue (e g., the tympanic membrane for the cochlea) by expanding the beam to a larger cross-sectional area to spread the energy over a larger area while ensuring maximum uniformity of illumination at the tissue (e.g., cochlea) due to the collimated profile. In contrast, the illumination from divergent (non-collimated) beam profiles dissipates quickly as a function of distance, making the amount that reaches the tissue of interest much lower than with the collimated beam. A tradeoff between a collimated beam profile and adivergent beam is that it may be more important to properly aim and position the collimated beam in order to deliver the therapeutic PBM illumination to the tissue (or sub-portion of tissue) of interest. In this context, the data-derived model of how the PBM light moves from the illumination probe through the tissue is important for properly aligning the illumination probe and for setting the correct illumination levels.

[0075] In the specific instance of using PBM therapy on the cochlea, the correctly- positioned illumination probe illuminates the basal turn of the cochlea, which is the area where the majority of hair cell damage from SNHL occurs. In other embodiments, the illumination probe may be used to target the RW, which is the cochlear region most vulnerable to noise trauma (e.g., trauma caused by noise commonly experienced by military service members).

[0076] In some embodiments, the detection probe is a flexible and isotropic fiber optic probe used in targeted measurement of irradiance. This probe can me used to verify the amount of light reaching the cochlea. An isotropic detection efficiency is needed to accurately measure the amount of light present at any position, because the angle of light incident to the probe will be variable at different locations of the shell-shaped spiral path of the cochlea. The diameter of the detection probe is small enough to fit within the cochlea up to the medial turn.

[0077] Due to the nature of the illumination and detection probes, which are scalable at a variety of small diameters and which may have catheter-like properties, the methods and systems described herein can be adapted from the specific examples relating to the cochlea to a more generalized (e.g., endoscopic) PBM system with modifiable illumination probes depending on the target tissue for treatment and the detection probe to characterize light delivery to the target tissue.

[0078] Illumination System

[0079] FIG. 2A shows a schematic of an embodiment of an illumination probe. The illumination probe (IP) includes three main components: an optical fiber, spacer, and lens, where the spacer and lens may be coupled to the optical fiber using a protective strain relief and the optical fiber may be surrounded by a protective tubing. The illumination source can also include a light source (e.g., a laser) coupled to the optical fiber. The illumination probe has a proximal end (e.g., at the light source) and a distal end (e.g., at the lens). Accordingly, the optical fiber has a proximal end and a distal end. The light source may deliver light in a wavelength range of 400nm to 2400 nm. In some embodiments, the light source is a laser and in one particular embodiment the laser may emit 808 nm light. The diameter of the rigid portion of the probe (i.e., the portion which includes the spacer and lens) is selected such that it fits within the minimum EAC diameter of 90% of adult humans; in some embodiments, the diameter can range from 125- 15000 pm (15 mm) and in some embodiments the probe diameter is 3000 pm. In general, the diameter of the spacer defines the overall width / diameter of the probe.

[0080] The optical fiber may be a multi-mode fiber. In one particular embodiment, the multi-mode fiber has a 105 pm core, 125 pm cladding, and 250 pm buffer, although in other embodiments different fiber types and dimensions can also be used. In some embodiments, the multi-mode fiber has a diameter of 150 pm.

[0081] In some embodiments, the illumination probe includes protective tubing surrounding the fiber optic cable. The protective tubing can also be referred to as a protective sheath, or simply as a sheath. In various embodiments, the protective tubing may be furcation tubing to reduce mechanical strain. In various embodiments, the protective tubing may be formed of suitable polymer materials, a flexible driveshaft, or thick coating with polyamide. In some embodiments, flexible driveshaft materials may include braided stainless steel, titanium, or other metal alloys optionally including a biocompatible coating such as a biocompatible PTFE or polyamide coating. In certain embodiments the protective tubing diameter can range from 500- 3000 pm and in some embodiments the protective tubing diameter is 900 pm.

[0082] The rigid length of the spacer is determined using optical simulation based on the fiber type, lens type, and spacer material, and is determined based on factors such as the dimensions of the tissue into which the illumination probe is inserted as well as the intensity of the light that is transmitted. In certain embodiments the spacer diameter can range from 125- 15000 pm (15 mm) and in some embodiments the spacer diameter is 3000 pm. In various embodiments the spacer length may range from 100 pm to 50 mm, and the spacer may be made of glass, specialized high-index glass (e.g., GRIN lens), or any other transparent material, although in one embodiment the preferred material is high quality optical glass such as SCHOTT BK7 glass.

[0083] The lens may be at least one of a plano-convex lens, a plano-concave lens, or a diffusive lens. In some embodiments, the lens is a plano-convex lens (e.g., FIGS. 2A-2C), wherethe thickness and curvature of the lens is adaptable to provide a variety of different beam diameters and degrees of divergence. In some embodiments, the lens is selected to deliver collimated light to ensure that light is delivered at an even intensity across the beam diameter (FIG. 2B).

[0084] Reflected light may return to the laser system through the fiber due to the interfaces between materials of different refractive index. Therefore, the illumination probe can also include an angled surface to minimize coupled back-reflections, located at the proximal end of the spacer (e.g., close to the multi-mode fiber, distant from the lens). In some embodiments, the angled surface can be angled at 8°, although in other embodiments the angle of the angled surface can range from greater than 0° to as much as 20°.

[0085] The illumination probe may also include a component to reduce strain between the optical fiber and the spacer. For instance, epoxy resin may be used at the junction of the protective tubing and the spacer to provide strain relief. The angled surface can be located at or near the protective strain relief. With specialized equipment (e.g., a fiber splicer), the fiber can be directly fusion spliced onto the spacer. Fusion splicing involves heating and melting the ends together so the glass components are “welded” together.

[0086] FIG. 2B shows an example ray-tracing diagram of the illumination probe shown in FIG. 2A, showing how the spacer and lens create an expanded beam with a “flat-top” beam profile. A flat-top beam profile, also referred to as an approximately near-field collimated beam, refers to a beam that has a relatively uniform irradiance profile through the cross-section of the light beam as well as a cross-sectional profile that remains relatively consistent at various distances from the probe (i.e., the beam is neither expanding nor converging). In one embodiment, the custom optical illumination probe expands the beam to a diameter of up to 3 mm and collimates it within a 10 mrad divergence, as shown in FIG. 2B. Generally, beam diameters are dependent on the size of the lens and spacer, as well as the divergence and acceptance angle (mrad). This expanded and collimated beam profile minimizes the irradiance at the tympanic membrane by distributing the light over a larger cross-sectional area than the output of the optical fiber while ensuring the maximum uniformity of illumination at the cochlea by delivering the beam in a collimated or approximately near-field collimated profile. In some embodiments, the beam profile may be a low divergence beam profile (e.g., having a divergencehalf angle in a range from 0 to 100 mrad) and a long-focal length focusing beam, in which the acceptance half angle ranges from 0 to 100 mrad. An embodiment of the fabricated illumination probe is shown in FIG. 2C. In another embodiment, the diffuser lens or plano-concave lens (FIG. 7A) can be used with an approximately collimated beam in near-field applications.

[0087] Although the combination of the spacer and the lens is expected to create a uniform beam profile as in FIG. 2B, the beam profile may nevertheless include nonhomogeneities due to certain components such as step index multimode fibers and laser diode light sources, where the non-homogeneities may be caused by interference between the modes traveling through the optical fiber. To address this, a mode scrambler based on a “step index with bends” design may be used. To this end, a spooling attachment with a diameter of 13 mm that has grooves for up to 25 spools around it may be introduced between the light source and the distal end of the probe, where motion may also be introduced into the optical fiber. The spooling attachment can be introduced anywhere along the length of the fiber of the IP. In some embodiments, the spooling attachment is located near the proximal end of the probe, which makes it easier to handle the distal optics without the spooling attachment near them. Motion may be introduced to the fiber by fixing the spooling attachment to an oscillating motor which can be programmed to invert its direction after every 0.5-20 rotations. This motion will change the orientation of the fiber spool continuously, inducing additional mode scrambling and further homogenizing the beam.

[0088] The spooling attachment helps create higher order modes to improve the homogeneity of the flat top profile by improving the intensity flatness factor score. A comparison of beam intensity profiles of illumination probes with and without spooling, and with and without motion in the fiber, are shown in FIGS. 3A-3D. FIG. 3A shows a cross-section of the beam with no spools and no motion, FIG. 3B shows a cross-section of the beam with no spools but with motion in the fiber, FIG. 3C shows a cross-section of the beam with 25 spools and no motion, and FIG. 3D shows a cross-section of the beam with 25 spools and motion of the fiber. As can be seen by comparing the beam profiles, the probe having both spools and motion in the fiber produces a beam having the highest intensity flatness factor (see FIG. 3D; see FIG. 4L for a schematic of the system with a spooling attachment). The output irradiance may range between 1 nW / cm2to 1000 mV / cm2and the desired output irradiances from the probe rangefrom 10-20000 mW / cm2, depending on the target tissue location. The desired irradiance at the target tissue (particularly for the cochlea) is estimated to be between 1-20 nW / cm2.

[0089] Characterization of Light System

[0090] In the specific embodiment of using PBM therapy in the cochlea, the light system may be characterized using cochlea spiral phantoms and / or human cadaver tissue. As indicated above, the detection probe is used during characterization of the system in order to collect measurements which indicate how light travels through the tissue. This information can then be aggregated into a tissue model that can be accessed by clinicians and other users to help them design a treatment protocol for their PBM treatment subjects / patients. However, due to the invasiveness of inserting the probe into the cochlear region, the detection probe would likely not be used routinely during treatment of live subjects.

[0091] For non-cochlear application, the detection probe is versatile and has many potential applications. With its flexibility and small size, it can fit into small spaces and be used to measure attenuation from tissue or bone (to better develop and validate model laser-tissue interactions). This can also allow for more “in-vivo” applications, where a small cut may be made on the surface of a subject’s skin into which the detection probe can be inserted to get a better isotropic “point” measurement that is not one-directional, which is the current limitation of sensors.

[0092] One use of the technology is in the scalp to treat hair loss, since it has been indicated that PBM therapy can stimulate hair growth. Another use is via intranasal or intracranial applications that can be used to target therapy of the brain, e.g., to treat traumatic (stroke, TBI) as well neurodegenerative and psychiatric diseases. In a different vein, in applications separate from the illumination probe, the detection probe can also be used as a way to validate how much of the therapy light is actually hitting the target area “in-vivo” in real time. Given an endoscope that is providing PBM therapy but with a light that is not locally collimated (and therefore not well-characterized), the detection probe can be used to measure the power / irradiance of the therapy laser at the point of treatment.

[0093] Detection Probe

[0094] The detection probe (DP) is a ball lens. In some embodiments, the DP is fabricated using a 125 um “coreless” silica fiber spliced onto the end of a separate 32 pm core,80 pm cladding gradient-index multimode core fiber optic cable; the ball lens includes an external optical coating that internally scatters the light which enters the probe to maximize light detection from all angles. Without such a coating, a conventional ball lens has a focal point directly in front of its axial tip, as shown in FIG. 4A, such that a probe using a conventional ball lens can only detect light which enters the lens directly in front of the probe within its focal length while light entering from other directions exits the lens. The thin, externally-applied optical coating disperses the light within the probe, allowing the probe to act as an isotropic detector, as shown in FIG. 4B. The coated isotropic probe can detect light which enters the lens around the ball surface from various incidence angles, where embodiments of the fabricated detection probe are shown in FIGS. 4C-4D.

[0095] Once fabricated and properly coated, the detection probe is characterized for its relative angular collection efficiency, irradiance response, and absolute collection efficiency; this information may then be factored into any model that is developed based on the collected tissue characterization data. FIG. 4E shows a polar plot of angular collection efficiencies, where regions corresponding to “ideal,” “good,” and “bad” collection efficiencies are shown. High collection efficiencies at all possible angles is considered to be the ideal, while high collection efficiencies at a small range of angles is considered bad. The intermediate range in FIG. 4E which is labeled “good” represents an approximate collection angular range of 270°. Relative angular collection efficiency is measured through unilaterally even illumination at 10-degree intervals along the coronal plane of the DP, as shown in FIG. 4F; the left panel of FIG. 4F shows a line at 180° for an uncoated ball lens which indicates that only light from this one narrow angle is collected by the probe whereas the larger area shown in the right panel shows that a probe with the coated ball lens can collect light from a much wider range of angles. The results are normalized, plotted, and calculated using a numerical integral to estimate how much a detection probe (DP) with the isotropic collection coated ball lens (FIG. 4G) improved with respect to an uncoated ball lens (FIG. 4H).

[0096] The detection probe and in particular the coating are also tested for their durability through insertion tests in cochlea phantoms. FIG. 41 shows an illuminated detection probe inside a cochlea phantom. A protective sheath may be added to increase the rigidity of the probe and reduce the friction between the scala tympani walls and the optical fiber. In variousembodiments the protective sheath may be made of two materials: a Hytrel furcation tube for the main body, and a silicone, ultra-flexible, optically transparent sheath for the portion of the probe that goes inside the cochlea. The combination of a reduced diameter fiber, protective sheath, and unique coating formulation of metal oxide nanoparticles (such as titanium oxide), toluene, and a polymer (polyurethane of UV-curable photopolymer resin) allows the detection probe to reach up to the medial turn in the cochlea prior to snapping, as show in FIG. 4J. This combination also allows the probe to be re-used several times, as there is little to no damage shown during the insertion testing. A modified cannula is used to assist in the insertion of the DP into the cochlea. The tip is so flexible that it is prone to bending outside of the round window early into insertion, for which a rigid tube is required for guidance and bending prevention. FIG. 4K shows a diagram of an embodiment of the detection probe, showing the flexible region and the rigid region (top). The bottom diagram also shows a grip attachment for the insertion tool.

[0097] FIG. 4L shows a schematic diagram of a device for measuring the angular collection efficiency of the detection probe along its coronal plane to generate data such as that shown in FIG. 4F. The schematic includes a spooling attachment (which can also be used to introduce motion to further homogenize the beam), located at the proximal end of the illumination probe. In addition, a beam block is included in the detection probe. A rotation stage is included in the schematic, located at the detection probe tip.

[0098] Experimental Measurements

[0099] The illumination probe and the detection probe are used together to characterize the system. During characterization of light transmission in the cochlear region, the illumination probe is connected to a laser source and is placed against the TM and pointed at the detection probe, which is connected to a highly sensitive, fiber-coupled photodiode and a power meter console which processes the signal and records the measured values (see system schematic in FIG. 1). FIG. 5 shows a diagram of the operation of the illumination probe and the detection probe overlaid on a CT scan of a human cadaver temporal bone. Prior to insertion of the detection probe, the temporal bone is prepared by drilling a facial recess through the round window (RW), after which the detection probe is inserted into the cochlea through the RW.

[0100] Using a therapeutic wavelength that penetrates tissue, it is possible to illuminate the cochlea via a trans-tympanic approach. One such therapeutic wavelength is 808 nm. In thisapproach, an optical probe connected to a flexible fiber optic cable is inserted into the EAC and placed in contact with the TM to deliver a collimated or slightly-diverging beam of light for a particular amount of time. Light penetrates through the TM and is scattered by the ossicles of the middle ear and mastoid air cells, among other tissues, resulting in a uniform illumination of cochlear hair cells. This approach allows for PBM therapy applications outside the operating room, allowing for immediate medical treatment of an affected subject. Preliminary data captured using the disclosed illumination probe and detection probe system is shown in FIG. 6A, with irradiation associated with insertion depth into the cochlea starting at the round window.

[0101] Illumination probes can be validated as part of the characterization process using the detection probe. Several DPs may be used within a single temporal bone and several temporal bones can be used to gather the entire dataset. With this, there are several intracochlear irradiance curves at different depths. See FIG. 6A for example irradiance curves at insertion depths for a single temporal bone. Each curve represents a DP at a specific illumination probe power level. The data is averaged and a 3D surface is built by stacking the average curves for each power level. Polynomial surface fitting is applied to obtain an expression that can approximate the intracochlear irradiance from a given depth and a given output from the IP. See FIG. 6B for example surface maps. Using a surface map, the proper PBM irradiance dose can be determined for treatment based on where the tissue damage is located, which for the cochlea is determined by conducting hearing tests on the subject to identify specific deficiencies in hearing. The irradiance dose is selected based on one or more of the extent of damage, the targeted area, and / or the mechanism of repair. When considering the target area, potential obstacles between the target and where the illumination probe is are taken into account. As one example, to treat oral mucositis (directly within mouth) treatment can be performed with 5 and 150 nW / cm2for 30 s to 60 s per point. As another example, to treat the cochlea (through the eardrum), one group has used light at output levels ranging from 165 mW / cm2(for 30 min / day for 5 consecutive days) to 1300 mW / cm2(for 30 min / day over 14 days), with varying success. The intracochlear irradiance for these cases was estimated to be 0.1-3% of the output.

[0102] Data such as that shown in FIG. 6B may be incorporated into a system for helping clinicians and other users develop a PBM therapy treatment plan by indicating (based on experimental data from sources such as phantoms or cadaver tissue) how much light from theillumination probe will reach a particular region of the tissue. While the data in FIG. 6B is directed at the cochlea, a skilled person will understand that similar models can be developed for other tissue types.

[0103] Design variations

[0104] Nonlimiting examples of a light system, including illumination probes and detection probes, are described below. These examples are illustrative and are not meant to be limiting.

[0105] For the detection system, any illumination beam profile is supported so long as the beam’s power density can be accurately calculated at a specified distance and location within the tissue of interest. The illumination probe can be modified to function with different operating wavelengths, fiber types, spacer materials, lens types, probe diameters, and probe lengths, depending on the application.

[0106] An example of an alternative illumination probe design using a plano-concave or diffusive lens is show in FIG. 7A. The orientation of the illumination probe can be adjusted and re-designed to be side viewing, as shown in FIGS. 7B-7C. One use of the illumination probes shown in FIG. 7B and FIG. 7C is to deliver light homogenously when inside a lumen, and when the target tissue is at or within the walls of this tissue.

[0107] FIG. 7B shows a design of collimated-illumination probe with a flat-top beam profile, featuring a rotating mechanical driveshaft and side-viewing capability. This design can be used to either pinpoint a location on the lumen and provide illumination at one spot, or it can rotate continuously and treat an entire slice; further, while being pulled back slowly and rotating, the probe can be used to treat a volume of tissue within a lumen. This design may include one or more of a protective sheath, flexible driveshaft, optical fiber, spacer, lens, and / or micro-prism. The diameter of the protective sheath may range between 600-2000 pm, with the remaining components having a diameter no larger than the diameter of the protective tubing. In one particular embodiment, the diameter is 850 pm. The flexible driveshaft can range between 300- 1000 pm. In some embodiments, the flexible driveshaft diameter is 550 pm. In some embodiments, the optical fiber is a multi-mode fiber which includes a 50 pm core, 125 pm cladding, and 250 pm buffer. The spacer diameter may range between 125-5000 pm. In some embodiments, the spacer diameter may be 250 pm. The lens may be a gradient-index rod lens,which is scalable up to 2 mm. In some embodiments, the lens diameter is 250 pm. The probe may also include a coated glass micro-prism which can range between 100-5000 pm. In some embodiments, coated glass micro-prism is 180 pm.

[0108] FIG. 7C shows a design of a collimated-illumination probe with a flat-top beam profile that features a static housing integrated with a 360° collimated-illumination probe which uses a cone reflector at the distal end to emit light in all directions. FIG. 7C is an alternative embodiment in which rotation is not needed (in contrast to the embodiment of FIG. 7B) and which produces illumination that can be collimated or diffuse and it is directed at a full 360° region surrounding the probe, treating a slice of the lumen. Similarly, this probe can be moved slowly through the luminal structure to treat an entire volume region. This lumen can be part of, but is not limited to, the G1 tract (e.g., esophagus, stomach, small intestine, colon, etc.), the cardiovascular system (e.g., arteries and veins), and / or the pulmonary system (e.g., trachea, pharynx, larynx, bronchi). The probe includes one or more of a protective tubing, an optical fiber, a spacer, a 3D printed housing, a lens, and / or a reflector. The protective tubing diameter may range between 600-2000 pm, with the remaining components having a diameter no larger than the diameter of the protective tubing. In one particular embodiment, the protective tubing diameter is 900 pm. In some embodiments, the multi-mode fiber includes a 50 pm core, 125 pm cladding, and 250 pm buffer, although other fiber types may be used. In various embodiments, the spacer diameter may range between 125-5000 pm, and in one particular embodiment the spacer diameter is 250 pm. In certain embodiments, the 3D printed housing can be custom designed. The lens may be a gradient-index rod lens, which is scalable between 200 pm to 2 mm. In some embodiments, the lens diameter is 250 pm. The reflector can be a gold-coated cone reflector, scalable between 200-1500 pm. In some embodiments, the cone reflector is 250 pm.

[0109] Yet another alternative optical design is shown in FIG. 8, which shows an optical design of a bare fiber illumination emitted from the end of the fiber creating a Gaussian beam profile. While many applications of the disclosed PBM therapy systems preferentially utilize collimated beams, in certain embodiments (e.g., depending on the tissue type) a diverging beam may be desired.

[0110] PBM therapy can be expanded to application outside of the cochlea. For example, this illumination system can be modified to fit into a side-viewing, capsule-like body to be usedfor endoscopic-based PBM therapy to speed up healing and reduce inflammation within the GI system. Characterization can be done similarly to the ex vivo cochlea setup to understand how much irradiance will reach the targeted area within the epithelial tissue. Other uses of this technology include for PBM therapy in the brain (via intracranial and / or intranasal routes); artery repair; oral tissue (e.g., bones and / or teeth) repair; airway repair; and / or the scalp (e.g., to treat hair loss).[0U1] Thus, while the invention has been described above in connection with particular embodiments and examples, the invention is not necessarily so limited, and that numerous other embodiments, examples, uses, modifications and departures from the embodiments, examples and uses are intended to be encompassed by the claims attached hereto.

Claims

CLAIMSWhat is claimed is:

1. A system for cochlear photobiomodulation (PBM) therapy, comprising: an illumination probe including a proximal end and a distal end, the illumination probe comprising an optical fiber including a spacer and a lens at the distal end, and the distal end of the illumination probe being configured to deliver light to a tissue.

2. The system of claim 1, wherein the distal end of the illumination probe is configured to deliver light to the tissue as a collimated beam.

3. The system of claim 2, wherein the spacer and the lens are configured to expand and collimate a beam emitted from a distal end of the optical fiber.

4. The system of any one of claims 1-3, wherein the illumination probe is coupled to a light source at the proximal end and wherein the light source is configured to deliver light to the tissue via the illumination probe.

5. The system of claim 4, wherein the light source delivers light in a wavelength range of 400 nm to 2400 nm.

6. The system of any one of claims 4 or 5, wherein the light source delivers light at a wavelength of 808 nm.

7. The system of any one of claims 4-6, wherein the light source comprises a laser.

8. The system of any one of claims 1-7, wherein the optical fiber is a multi-mode fiber.

9. The system of claim 8, wherein the multi-mode fiber comprises a 105 pm core, a 125 pm cladding, and a 250 pm buffer.

10. The system of any one of claims 1-9, wherein the illumination probe further comprises protective tubing surrounding the optical fiber.

11. The system of claim 10, wherein the protective tubing comprises furcation tubing.

12. The system of any one of claims 1-11, wherein the illumination probe further comprises an angled surface at the proximal end of the spacer to minimize back reflections.

13. The system of any one of claims 1-12, wherein the diameter of the illumination probe is 3000 pm.

14. The system of any one of claims 1-13, wherein the illumination probe further comprises a spooling attachment.

15. The system of claim 1, wherein the illumination probe is configured to produce a beam having at least one of a collimated beam profile, a diffusive beam profile, a flat-top beam profile, or a Gaussian beam profile.

16. The system of claim 1, wherein the lens comprises at least one of a plano-convex lens, a plano-concave lens, or a diffusive lens.

17. The system of claim 1, wherein the illumination probe is configured to produce a beam having a fl at- top beam profile.

18. The system of claim 17, wherein a diameter of the beam is 3 mm.

19. The system of any one of claims 1-18, wherein the tissue comprises a cochlea.

20. A method for cochlear photobiomodulation (PBM) therapy, comprising: providing an illumination probe including a proximal end and a distal end, the illumination probe comprising an optical fiber including a spacer and a lens at the distal end; and delivering light to a tissue from the distal end of the illumination probe.

21. The method of claim 20, wherein delivering light to the tissue further comprises: delivering the light to the tissue as a collimated beam.

22. The method of claim 21, wherein delivering light to the tissue as the collimated beam further comprises: delivering light to the tissue as the collimated beam by using the spacer and the lens to expand and collimate a beam emitted from a distal end of the optical fiber.

23. The method of any one of claims 20-22, wherein providing the illumination probe further comprises: coupling the illumination probe to a light source at the proximal end, and wherein delivering light to the tissue further comprises: delivering light from the light source to the tissue using the illumination probe.

24. The method of claim 23, wherein delivering light to the tissue further comprises: delivering light in a wavelength range of 400 nm to 2400 nm.

25. The method of any one of claims 23 or 24, wherein delivering light to the tissue further comprises: delivering light at a wavelength of 808 nm.

26. The method of any one of claims 23-25, wherein coupling the illumination probe to the light source further comprises: coupling the illumination probe to a laser.

27. The method of any one of claims 20-26, wherein providing the illumination probe further comprises: providing the illumination probe, wherein the optical fiber is a multi-mode fiber.

28. The method of claim 27, wherein providing the illumination probe further comprises: providing the illumination probe, wherein the multi-mode fiber comprises a 105 pm core, a 125 pm cladding, and a 250 pm buffer.

29. The method of any one of claims 20-28, wherein providing the illumination probe further comprises: providing the illumination probe, wherein the illumination probe further comprises protective tubing surrounding the optical fiber.

30. The method of claim 29, wherein providing the illumination probe further comprises: providing the illumination probe, wherein the protective tubing comprises furcation tubing.

31. The method of any one of claims 20-30, wherein providing the illumination probe further comprises: providing the illumination probe, wherein the illumination probe further comprises an angled surface at the proximal end of the spacer to minimize back reflections.

32. The method of any one of claims 20-31, wherein providing the illumination probe further comprises: providing the illumination probe, wherein the diameter of the illumination probe is 3000 pm.

33. The method of any one of claims 20-32, wherein providing the illumination probe further comprises: providing the illumination probe, wherein the illumination probe further comprises a spooling attachment.

34. The method of claim 20, wherein delivering light to the tissue further comprises: delivering light to the tissue as a beam having at least one of a collimated beam profile, a diffusive beam profile, a flat-top beam profile, or a Gaussian beam profile.

35. The method of claim 20, wherein providing the illumination probe further comprises: providing the illumination probe, wherein the lens comprises at least one of a plano-convex lens, a planoconcave lens, or a diffusive lens.

36. The method of claim 20, wherein delivering light to the tissue further comprises: delivering light to the tissue as a beam having a flat-top beam profile.

37. The method of claim 36, wherein a diameter of the beam is 3 mm.

38. The method of any one of claims 20-37, wherein delivering light to the tissue further comprises: delivering light to a cochlea.

39. The method of claim 38, wherein delivering light to the cochlea further comprises: inserting the illumination probe into an external auditory canal,placing the distal end of the illumination probe adjacent to a tympanic membrane, and delivering light through the tympanic membrane toward the cochlea.

40. The method of claim 38, wherein delivering light to the tissue further comprises: accessing a model of light transmission through the cochlea to determine at least one of an intensity or a duration of light delivery, and delivering light to the cochlea using at least one of the intensity or the duration of light delivery determined using the model.

41. A system for cochlear photobiomodulation (PBM) therapy, comprising: an illumination probe including a proximal end and a distal end, the illumination probe comprising an optical fiber including a spacer and a lens at the distal end, and the distal end of the illumination probe being configured to deliver light to a tissue; and an isotropic detection probe for detecting the delivered light within the tissue.

42. The system of claim 41, wherein the distal end of the illumination probe is configured to deliver light to the tissue as a collimated beam.

43. The system of claim 42, wherein the spacer and the lens are configured to expand and collimate a beam emitted from a distal end of the optical fiber.

44. The system of any one of claims 41-43, wherein the illumination probe is coupled to a light source at the proximal end and wherein the light source is configured to deliver light to the tissue via the illumination probe.

45. The system of claim 44, wherein the light source delivers light in a wavelength range of 400 nm to 2400 nm.

46. The system of any one of claims 44 or 45, wherein the light source delivers light at a wavelength of 808 nm.

47. The system of any one of claims 44-46, wherein the light source comprises a laser.

48. The system of any one of claims 41-47, wherein the optical fiber is a multi-mode fiber.

49. The system of claim 48, wherein the multi-mode fiber comprises a 105 pm core, a 125 pm cladding, and a 250 pm buffer.

50. The system of any one of claims 41-49, wherein the illumination probe further comprises protective tubing surrounding the optical fiber.

51. The system of claim 50, wherein the protective tubing comprises furcation tubing.

52. The system of any one of claims 41-51, wherein the illumination probe further comprises an angled surface at the proximal end of the spacer to minimize back reflections.

53. The system of any one of claims 41-52, wherein the diameter of the illumination probe is 3000 pm.

54. The system of any one of claims 41-53, wherein the illumination probe further comprises a spooling attachment.

55. The system of claim 41, wherein the illumination probe is configured to produce a beam having at least one of a collimated beam profile, a diffusive beam profile, a flat-top beam profile, or a Gaussian beam profile.

56. The system of claim 41, wherein the lens comprises at least one of a plano-convex lens, a plano-concave lens, or a diffusive lens.

57. The system of claim 41, wherein the illumination probe is configured to produce a beam having a flat-top beam profile.

58. The system of claim 57, wherein a diameter of the beam is 3 mm.

59. The system of any one of claims 41-58, wherein the tissue comprises a cochlea.

60. The system of any one of claims 41-59, wherein the isotropic detection probe comprises a light-scattering coating.

61. The system of claim 60, wherein the light-scattering coating comprises metal oxide nanoparticles and a synthetic polymer.

62. The system of claim 61, wherein the metal oxide nanoparticles comprise titanium oxide.

63. The system of any one of claims 41-62, wherein the isotropic detection probe comprises an angle of detection of at least 270°.

64. The system of any one of claims 41-63, wherein the isotropic detection probe is coupled to a multimode fiber.

65. The system of claim 64, further comprising a detector coupled to the isotropic detection probe by the multimode fiber.

66. The system of any one of claims 64 or 65, wherein the isotropic detection probe comprises a ball lens.

67. The system of claim 66, wherein the ball lens is formed from a coreless silica fiber.

68. The system of claim 67, wherein the ball lens has an outer diameter of 0.3 mm.

69. The system of any one of claims 41-68, wherein the isotropic detection probe is configured to be inserted through the round window of a cochlea of a subject.

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