Methods and apparatus for phototherapy

Abstract

To provide methods and apparatus for phototherapy.SOLUTION: An implantable phototherapy device includes a power receiver element configured to receive power from an external power transmitter, a light delivery element powered by the power receiver and configured to deliver phototherapy to a target treatment area, and a tether element coupled to the light delivery element and the power receiver element. The tether element is configured to deliver power between the power receiver element and the light delivery element. In one embodiment, the power receiver element comprises a coil configured to receive the power from the external power transmitter, and the power comprises radiofrequency energy.SELECTED DRAWING: Figure 14

Description

[Technical Field]

[0001] (Priority Claim) This application claims the benefit of U.S. Provisional Patent Application No. 62 / 923,738, filed October 21, 2019, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Light delivery as therapy is an essential part of human survival. Light from the sun regulates circadian rhythms and produces vital vitamin D in the skin throughout the day. Light is used in therapy to treat eye and skin conditions, or to reduce bilirubin levels and treat neonatal jaundice. Light delivery can also be used to treat several other conditions. Summary of the Invention [Means for solving the problem]

[0003] In the drawings, which are not necessarily drawn to scale, like numbers may describe similar components in different figures. Like numbers with different letter suffixes may represent different instances of similar components. The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed in the present document. The present invention provides, for example, the following. (Item 1) 1. An implantable phototherapy device, comprising: a power receiver element configured to receive power from an external power transmitter; a light delivery element powered by the power provided by the power receiver and configured to deliver phototherapy to a target treatment area; a tether element operably coupled to the light delivering element and the receiver element; Equipped with The device, wherein the tether element is configured to deliver the power from the power receiver element to the light delivering element. (Item 2) Item 10. The device of claim 1, wherein the receiver element comprises a coil configured to receive the power from the external power transmitter, the power comprising radio frequency energy. (Item 3) Item 10. The device of claim 1, wherein the receiver element comprises a sealed housing operably coupled to the tether, and the device further comprises an electronic component disposed within the sealed housing, the electronic component configured to control the power delivered to the light delivering element. (Item 4) Item 10. The device of item 1, wherein the light delivery element comprises a light source encapsulated within an optical material, the optical material configured to protect the light source, and the optical material facilitating the transmission of light from the light delivery element to the target treatment area. (Item 5) Item 1, the device further comprising an optical light guide coupled to the light delivery element, the optical light guide being shaped to facilitate delivery of light from the light delivery element to the target treatment area. (Item 6) Item 10. The device of item 1, wherein the light delivery element comprises a plurality of light sources disposed on a substrate, the substrate being configured to be shaped to conform to the target treatment area. (Item 7) Item 7. The device of item 6, wherein the substrate is a light guide configured to direct light to the target treatment area, and the substrate is configured to be trimmed to a desired shape to fit the target treatment area. (Item 8) Item 10. The device of item 1, wherein the light delivering element comprises multiple light sources configured to be independently controllable with respect to each other. (Item 9) Item 10. The device of item 1, wherein the light delivery element further comprises a temperature sensor configured to measure a temperature in the target treatment area. (Item 10) Item 10. The device of item 1, wherein the light delivering element is disposed within a radially expandable member having an expanded configuration and a collapsed configuration, wherein in the expanded configuration, the radially expandable member conforms to the target treatment area. (Item 11) Item 10. The device of item 1, wherein the light delivery element further comprises a port configured to releasably receive an optical fiber optically coupled to an external light source, wherein light from the external light source is delivered to the light delivery element via the optical fiber for illumination of the target treatment area. (Item 12) 1. A phototherapy system, comprising: an implantable phototherapy device according to item 1; an external power transmitter configured to wirelessly transmit the power to the power receiver element; A system comprising: (Item 13) Item 13. The system of item 12, further comprising a planar immersion lens disposed between the external power transmitter and the receiver element, the planar immersion lens configured to focus energy from the external power transmitter toward the receiver element. (Item 14) 13. The system of claim 12, further comprising an electrode configured to provide electrical stimulation to the target treatment area. (Item 15) 13. The system of claim 12, further comprising at least one support element, the support element configured to align with and support tissue in the target treatment area. (Item 16) Item 13. The system of item 12, further comprising a photosensitizer. (Item 17) 1. A method of delivering phototherapy to a target treatment area within a patient, the method comprising: providing an implantable phototherapy device comprising a receiver element, a light delivery element, and a tether element; implanting the phototherapy device within the patient at the target treatment area; wirelessly transmitting power from an external power transmitter to the power receiver element; transmitting the power from the receiver element to the light delivering element via the tether; illuminating the target treatment area with light from the light delivery element; and A method comprising: (Item 18) Item 18. The method of item 17, wherein wirelessly transmitting the power from the external power transmitter to the power receiver element includes receiving radio frequency energy with a coil. (Item 19) Item 18. The method of item 17, wherein the illuminating comprises illuminating the target treatment area with a plurality of independently controllable light emitting elements. (Item 20) Item 18. The method of item 17, wherein wirelessly transmitting the power includes transmitting the power from the external power transmitter and focusing the power toward the receiver element using a planar immersion lens. (Item 21) 18. The method of claim 17, further comprising electrically stimulating tissue in the target treatment area with energy provided by an electrode adjacent to the light delivery element. (Item 22) 18. The method of claim 17, wherein the target therapeutic area comprises the patient's brain. (Item 23) releasably coupling an optical fiber to the light delivering element; inputting light from an external light source into the light delivering element via the optical fiber; illuminating the target tissue with the light from the external light source; Item 18. The method of item 17, further comprising: (Item 24) Item 18. The method of item 17, wherein the light delivery element comprises a plurality of light sources disposed on a substrate, the method further comprising shaping the substrate to conform to the target treatment area and directing light in a plurality of directions to illuminate the target treatment area. (Item 25) 25. The method of claim 24, further comprising trimming the substrate to a desired size or shape to fit the target treatment area. (Item 26) 18. The method of claim 17, further comprising measuring the temperature in the target treatment area with a temperature sensor. (Item 27) Item 18. The method of item 17, wherein the light delivery element comprises a plurality of light sources encapsulated in an optical material, the optical material being a light guide that directs light from the plurality of light sources to the target treatment area. (Item 28) Item 18. The method of item 17, wherein the light delivering element is disposed within a radially expandable member, the method further comprising radially expanding the radially expandable member to align with and conform to the target treatment area. (Item 29) 18. The method of claim 17, further comprising positioning a support element within the target treatment area to support tissue within the target treatment area and help ensure the tissue is illuminated. [Brief explanation of the drawings]

[0004] [Figure 1] FIG. 1 illustrates an optical illumination system.

[0005] [Figure 2] FIG. 2 illustrates an optical illumination system coupled to the patient's head.

[0006] [Figure 3] FIG. 3 illustrates an optical illumination system coupled to the patient's head.

[0007] [Figure 4] FIG. 4 shows some examples of electronic components within the housing.

[0008] [Figure 5] FIG. 5 illustrates some examples of lighting elements.

[0009] [Figure 6] 6A-6D show examples of optical guide geometries.

[0010] [Figure 7] FIG. 7 shows one example of lighting elements disposed on a customizable substrate.

[0011] [Figure 8] FIG. 8 shows another example of the shape of the optical guide.

[0012] [Figure 9] 9A-9D show examples of customized light guides that can be coupled to lighting elements.

[0013] [Figure 10] FIG. 10 shows another example of a lighting element.

[0014] [Figure 11] FIG. 11 illustrates the use of a planar immersion lens.

[0015] [Figure 12] FIG. 12 illustrates the use of multiple light sources in a lighting system.

[0016] [Figure 13] FIG. 13 shows an example of light source control.

[0017] [Figure 14] FIG. 14 illustrates one example of an illumination system that may also include electrical stimulation to the targeted treatment area.

[0018] [Figure 15A] FIG. 15A illustrates one example of a reinforced substrate.

[0019] [Figure 15B] FIG. 15B shows the reinforced substrate of FIG. 15A placed within a tumor cavity.

[0020] [Figure 16] FIG. 16 shows another example of a reinforced substrate.

[0021] [Figure 17] FIG. 17 illustrates the use of additional support elements within the tumor cavity.

[0022] [Figure 18] FIG. 18 illustrates another example of an additional support element within a tumor cavity.

[0023] [Figure 19] FIG. 19 illustrates a second port for coupling an external light source to the lighting element.

[0024] [Figure 20] 20A-20B illustrate the use of multiple light sources within a lighting element and the resulting lighting pattern.

[0025] [Figure 21] FIG. 21 illustrates an example of a method for treating a tumor. DETAILED DESCRIPTION OF THE INVENTION

[0026] Light delivery as therapy is an essential part of human survival. Light from the sun regulates circadian rhythms and produces vital vitamin D in the skin throughout the day. Light is used in forms of therapy to treat eye and skin conditions, or to reduce bilirubin levels and treat neonatal jaundice. More recently, light has been seen as a potential source for new therapies paired with light-activated drugs, leading to new advances not only in skin cancer, but also in several internal tumors and other conditions.

[0027] A major challenge with using light to treat medical diseases is that light does not travel very far within the body. Light is absorbed by skin and tissue, which limits the penetration depth of visible and near-infrared (NIR) wavelengths to 3-5 millimeters. Applying phototherapy to tumors or stimulating neurons to treat movement disorders may require light at depths of 10-25 cm, shallower, or even deeper, and an implanted light source adjacent to the target treatment area is the only practical way for light to reach such depths within the human body.

[0028] This disclosure describes novel powering, light delivery, and integration aspects of implantable phototherapy devices, systems, and methods of use. Implants can be designed to deliver a single therapy and / or can be integrated with other forms of stimulation and / or therapeutic agents besides light, thereby delivering innovative combination therapies. Implants can also be modified to include sensing features, such as for modulating therapeutic drug dosage in response to the patient's physiological state.

[0029] FIG. 1 illustrates an example of a light illumination system 100 that can be used to deliver phototherapy inside a patient's body, for example, in the treatment of tumors deep within the body, such as glioblastoma in the brain. While the examples disclosed herein are primarily directed to implantation of a device within the brain as a treatment for brain cancer, this is not intended to be limiting, and those skilled in the art will understand that the device can be implanted within any other part of the body to deliver phototherapy inside the body as part of a treatment for other medical conditions. Thus, the devices and systems described herein can be surgically implanted within a tumor cavity created by tumor resection, or they can be placed within natural body cavities or natural tissue adjacent to the affected area without surgical modification (e.g., by direct tissue implantation). In either situation, light can be used to activate various therapeutic agents that help fight tumors or provide other therapeutic effects to treat disease, thereby providing localized therapy. For example, in photodynamic therapy, light can be used to activate a therapeutic agent (also called a photosensitizer) that is absorbed by cells, resulting in the production of reactive oxygen species (ROS), which are toxic to host cells and lead to cell death in tumors and other conditions, as has been well documented in the patent and scientific literature. ROS production can be quantified by titration methods known in the art. The wavelength of light must overlap with the activation spectrum of the photosensitizer.

[0030] The lighting system includes a receiver element, which may include a wireless coil 101 and a housing 200. The system may also include a tether wire 300 and a light source (also referred to as a light element or lighting element, or light source) 400.

[0031] The receiver element in this or any example may or may not include any energy storage device (e.g., a battery, capacitor, or other storage element). If no storage device is present, therapy is provided only when the external power source is activated. If an energy storage device is included, the device can be turned on as needed, and the lighting element is powered by the energy storage device. The wireless coil 101 is configured to receive radio frequency energy from an external transmitter coil in the external power source and may have one or more turns of conductive wire coated with insulation. The turns may have any geometric shape, such as a circular or helical coil, and the coil may be made of any material that is conductive to electromagnetic energy. The wireless coil may optionally be made from a printed circuit board or a flexible printed circuit board with metal or conductive traces in a circular or other coil pattern. The coil is sized for wireless power transmission through tissue, such as through the patient's scalp at any depth, such as less than about 5 cm, 4 cm, 3 cm, 2 cm, or 1 cm, and the coil can tolerate variations in intervening tissue thickness. The wireless transmitter and receiver may optionally be capable of two-way authentication, so that only approved devices can cooperate and transmit power to the implanted device. Optionally, secure encryption techniques may be used to ensure that the device cannot be activated by an unauthorized user or transmitter.

[0032] The wireless coil 101 may be electrically and mechanically coupled to an optional housing 200, and energy captured by the coil 101 is delivered to the housing 200, which contains various electronic components for managing the power and controlling the duty cycle of the light source 400. The electronics within the housing may be mounted on a printed circuit board.

[0033] The housing may be any size or shape and may be formed from any number of materials, such as titanium, or any material that is biocompatible. Wires from coil 101 or tether 300 may be coupled to the housing via ceramic feedthroughs. Additional disclosure regarding the electronic components within housing 200 is provided hereinafter.

[0034] The tether wire 300 is operably coupled to both the housing 200, the electronics within the housing 200, and the light source 400. The tether can be formed from any material that is conductive and has adequate strength to ensure that the light source 400 remains coupled to the housing. The tether wire can be soldered to an electronic feedthrough in a hermetically sealed housing (sometimes referred to as a "can") that encloses the power electronics. The tether 300 can be several wires that extend linearly between the housing and the lighting element, or the wires can be coiled, helically wound, braided, twisted together, or any configuration, and the wires can be long enough to ensure that the housing can be anchored in one position and the light source can be positioned where desired. The tether can include multiple electrical wires passing through multi-lumen tubing resulting in a single filament, or the tether can have two or more filaments.

[0035] Light source 400 may be a single light source or may include multiple light sources. For example, multiple light sources may be included within the light source, configured to be adjusted to various intensities, all having the same wavelength or different wavelengths of light, which may be controlled together or independently of each other. The wavelengths may be selected to maximize photoactivation of the therapeutic agent.

[0036] FIG. 2 shows the phototherapy system of FIG. 1 coupled to a patient's skull 1000. Here, the phototherapy system includes a receiver element having a coil 101 for receiving RF energy from an external power source and a housing 200 containing electronic components for controlling the device. A tether 300 operably couples the housing to an illumination element that is placed within a tissue cavity in the patient's brain after tumor resection. The illumination element is not visible in this view. The tether may be coiled (301) along any portion of its length to remove excess slack or provide strain relief. In this example, the receiver element is attached to the patient's skull using techniques known in the art (with sutures, staples, adhesives, etc., or with fasteners such as screws, etc.) so that the receiver element is positioned under the scalp. A tether is also placed between the scalp and the skull. A burr hole can be drilled through the skull to allow the tether and lighting element to be threaded through the skull and into a tissue cavity, where the lighting element can be attached to the tissue, illuminating the target treatment tissue and either left after resection or anchoring it in a desired location where it would provide therapy, such as activating a drug to reduce or eliminate tumor cells that may recur. The burr hole can be the same as the burr hole used to provide access to the surgeon during tumor resection, or it can be a separate burr hole. In this example, the receiver element can be placed behind the ear as shown, or the receiver can be placed anywhere along the skull.

[0037] Optionally, a fastener (not shown), such as a clip or eyelet, can be used to help protect the tether as it passes through openings in the skull that may have sharp edges. The fastener helps hold the tether in place so it cannot be pulled out and provides cable management to prevent tether tangling. The fastener can be made from any biocompatible material, such as a polymer, silicone, metal, etc.

[0038] FIG. 3 shows the phototherapy system of FIG. 1 in addition to an external power source 700 that wirelessly provides radio frequency power to the phototherapy system. The phototherapy system includes a power source 700, here a receiver element including a coil 101 for receiving radio frequency (RF) energy from an RF wireless transmitter. The receiver element also includes a housing 200 containing electronic components for controlling the phototherapy system. Fasteners 201, such as screws, may be used to secure the housing to the skull 1000 beneath the scalp. A tether 300 electrically couples the housing and the electronic components therein to an illumination element (not visible) placed in a cavity in the brain tissue formed after the tumor is resected. A bone plate 500 may be repositioned within the burr hole to assist in closing the skull, and an eyelet 510 or clip may be used to secure the tether to the skull and help prevent damage to the tether. The tether may be coiled or uncoiled. Here, the receiver element is positioned on the side of the patient's head, at about eye level.

[0039] FIG. 4 illustrates an example of a housing 200 that can be used with any of the examples of the phototherapy system disclosed herein. Some of the electronic components that can be located within the housing to help control the phototherapy system include a rectifier, such as a full-wave bridge rectifier 210 with four diodes arranged to convert alternating current (AC) received from the coil 101 to direct current (DC). A DC / DC converter 220 is coupled to the rectifier and can convert power or voltage levels from one level to another, which is operably coupled to a lighting driver 240 that drives lighting elements (not shown), which can be one or more light sources such as light-emitting diodes. A microcontroller 230 can also be included within the housing and control the system. An impedance matching network 102 can couple the coil to the rectifier to ensure maximum power transfer and minimize losses. The impedance matching network can include capacitors or have active electronics for tuning resonance. The housing may also include a temperature measurement component 250 that monitors the temperature from a sensor placed at the target treatment site (not shown), thereby helping to ensure that the temperature at the light source is not excessive and causes tissue damage. The temperature measurement component 250 may also monitor the temperature of the receiver electronics to ensure overheating is avoided. The housing may be formed from any biocompatible material, such as titanium, and may provide a hermetic seal for the electronic components. The housing may act as a heat dissipation element, or a separate heat dissipation element (not shown) may also be included within the housing. Electrical leads exiting the housing form a tether 300 that is coupled to the illumination source.

[0040] FIG. 5 shows an example of a lighting element 400 that can be coupled to a tether 300 and used within any example of a lighting system. The tether allows power to be delivered to the lighting element from a receiver element and, optionally, electrically couples an optional temperature sensor to the electronics within the housing. The tether also provides a mechanical connection between the lighting element 400 and the receiver element, so the two remain coupled together. Here, the lighting element 400 includes one or more flexible substrates 430, such as a flexible printed circuit board (PCB), that can be molded into any desired configuration to conform to the target treatment area. Polyimide is an example of a suitable PCB material. The target treatment area may be a cavity in the brain created after a tumor is removed, so the substrate should be formable into a three-dimensional shape. Additionally, once formed, the flexible substrate can help support the tissue surrounding the cavity and prevent inward tissue collapse, which could prevent part of the tissue from being illuminated. Here, multiple lighting elements 420 are bonded to a flexible substrate that is bent into an upside-down rectangular U-shaped configuration (or a staple-like section with two vertical legs and one horizontal bar connecting the legs), with one lighting element 420 on each leg of the U-shape and one lighting element on the horizontal connection between the legs of the U-shape. This ensures that the light emitted from the lighting elements is evenly distributed radially outward in several different directions, illuminating the target treatment area. The lighting elements 420 can be one or more LEDs that can be controlled independently of each other or together. The LEDs can emit light of a single wavelength or several wavelengths, and their intensity can also be adjusted, as can the duty cycle of how long they are on and how long they are off. The PCB can contain other electronic components that help control the light and automatically direct power from the tether to each LED continuously in the desired cycle. This allows the light intensity to be increased or decreased as needed to control the illumination of different areas of the tumor cavity. As the LED cycles, more intense light exposure is followed by periods of darkness, which may allow oxygen in the tissue time to recover between cycles of illumination when the cavity is dark, while increasing activation of the photosensitizer.The light source and substrate may be encapsulated (410) within a material that not only protects the device but also acts as a light guide to help deliver light to the target treatment area. For example, the encapsulation 410 may be formed from silicone or another translucent material that acts as a light guide for light delivery, or the encapsulation may help to diffuse the light. The encapsulation material may be any shape, including a flat, planar sheet, a square box, a rectangular box, a rounded shape, a cylinder, a sphere, an oval, etc., and is selected to fit within the tumor cavity.

[0041] Because light can generate heat, and overheating can undesirably damage tissue, an optional temperature sensor 251, such as a thermistor, may also be coupled to the flexible substrate to enable temperature monitoring in the treatment area. If excessive heat is generated, the light may be turned off. As mentioned above, the lighting element 420 and temperature sensor 251 may optionally be encapsulated in a material that protects the light and sensor and provides desirable optical properties for delivering light from the lighting element to the target treatment area. For example, the encapsulating material may be optically transparent, or it may include a diffusing or reflective material (not shown), such as titanium dioxide particles. The encapsulating material may then also function as a light guide or waveguide, ensuring minimal light loss during transmission. The encapsulating material may have a primary layer for light protection and to help dissipate heat. An optional secondary layer of encapsulating material may be provided that acts as a light guide and facilitates distribution of light to the target treatment area. Several example layers of encapsulation are disclosed herein, any of which may be used with any example of a lighting element.

[0042] 6A-6D show examples of optical light guide shapes that can be used with any of the illumination elements disclosed herein. The light guide can be integral with the encapsulation material surrounding the light source, or the light guide can be disposed on top of the encapsulation material. The light guide can be formed from the same material as the encapsulation layer, or a different material can be used. The optical light guide shape helps distribute light to the target treatment area with minimal light loss, is shaped to fit within the cavity left after tumor resection, and ensures that all tissue within the target treatment area is illuminated, thereby activating the therapeutic agent. Additionally, the optical light guide can help provide physical or mechanical support to the tissue and prevent it from collapsing, which also helps ensure that all tissue within the target treatment area is illuminated.

[0043] 6A shows a cloud-shaped optical light guide 451. The cloud shape may include multiple lobes extending radially outward. A light source and a temperature sensor may be disposed within the cloud.

[0044] 6B shows an optical light guide that includes a central spherical ball 453 with spokes extending radially outward. The spokes may be linear spokes or may take any other shape and may help to anchor the optical light guide within tissue and support the tissue, directing light to the target treatment area. A light source and temperature sensor may be disposed within the optical light guide.

[0045] 6C shows a star-shaped polygonal optical light guide 452. The star includes multiple arms extending radially outward, each of which may taper radially outward and terminate in a narrow tip. A light source and a temperature sensor may be disposed within the star.

[0046] 6D shows an eye-shaped optical light guide 454. The optical light guide may have a wide, arcuate middle portion with both sides tapering to a narrower portion. A light source and a temperature sensor may be disposed within the optical light guide.

[0047] FIG. 7 shows an example of an illumination element having multiple light sources, here LEDs 420, disposed on a substrate 430, such as a flexible PCB. The illumination element is coupled to a tether 300 so that it can receive power from a power receiver element, and an optional temperature sensor (not shown) can be operably coupled to electronic components within the housing. The illumination element can be coupled to a flat, planar sheet of material or wallpaper 455, which can be formed from an optical material that can act as a light guide and help distribute light to the target treatment area. Wallpaper can also be referred to as a conformal stretched cavity paper (CTCP) capsule. The flat, planar material can be bent and trimmed / cut to size to conform to and secure the target treatment area. The entire flat, planar material can be trimmable, or only a section can be trimmable. Areas that should not be trimmed are clearly marked (e.g., adjacent to the LEDs). The flat, planar material may then be bonded to the tissue in the cavity left after tumor resection using, for example, adhesives, sutures, friction fits, or other techniques known in the art. If adhesive is used, light, such as ultraviolet light (UV), may be introduced into the wallpaper and distributed by the wallpaper to the target treatment area to help cure the adhesive, such as cyanoacrylate. Light may be provided by an external light source, as will be discussed below.

[0048] Wallpaper may be desirable because surgical cavity dynamics and its impact after resection of brain metastases are known to pose challenges for postoperative radiosurgery in patients with glioblastoma multiforme (GBM). Patients with symptomatic brain metastases are typically treated using surgical resection procedures, followed by postoperative stereotactic radiosurgery to reconstruct the surgical cavity for improved local control. Currently, there is no clear consensus regarding the timing or start date of radiation therapy simulation for these patients based on numerous brain metastasis experts. As an illustrative example of the challenges faced today, some have suggested that there appears to be a theoretical benefit of delayed radiation therapy (4–6 weeks postoperatively) in response to known surgical cavity collapse, thereby potentially reducing the target volume.

[0049] There are numerous studies documenting retrospectively assessed changes in surgical cavities in patients treated with surgery and postoperative radiation therapy. There was substantial cavity collapse (>2 cm) at an average of 24 days postoperatively in this cohort. 3 The rate of RT appears to be in the range of 21-31%. Therefore, some caregivers have concluded that delaying radiation therapy for more than two weeks after surgery does not provide the benefit of a smaller target volume. What appears clear is that a significant portion of the surgical cavity undergoes substantial volume changes during the period up to three to four weeks after surgery for a range of reasons, including edema control, healing, fibrosis, etc. This has been assessed as providing an opportunity to reduce treatment volume by delaying postoperative radiation.

[0050] However, delaying treatment would have a devastating impact on these at-risk patients. There remains a need to maximize the light coverage of surgical cavity edges that endure throughout the treatment cycle in light of known cavity dynamics and cavity collapse. The combination of light sources embedded within the CTCP capsule ensures that the cavity edge surface does not otherwise escape illumination.

[0051] Such CTCP capsules may comprise a multi-material matrix that will be used to paper over the interior edges of the excised cavity with light. The multi-material matrix includes various materials, each with specific properties to maximize the conformal papering effect and, in some cases, function as a waveguide. The matrix base can be a flexible, biocompatible material that uniformly conforms to the shape of the cavity edge but does not impede light transmission or fluence. This matrix acts as a scaffold for various standard or custom components, including a range of higher tensile strength materials, to maximize the expansion effect of the CTCP capsule. Such expansion properties will counter the tendency of the cavity to collapse, thus ensuring uniform, consistent, and personalized distribution of light activation and steering. In some cases, the base matrix's scaffolding function is not limited to only elements for countering cavity collapse. In some cases, the multi-material matrix may include elements that provide scaffolding or anchor the optical elements themselves to optimize the placement of various optical components and system performance. Such capsules may be personalized. In some instances, the higher extension span functions as one or more staves. Each stave can be individually controlled to optimize the papering. The multi-material matrix can be molded or impregnated with the optimized polymer material. In some cases, a higher tensile strength material can be embedded within the matrix base or protrude from it into one or more spans of the cavity-spanning material. In some cases, the cavity-spanning material may or may not anchor or suspend one or more light elements or multiple light systems. Such customization can occur at the time of implantation or function as a modular surgical kit. Such instances can include various multi-material matrices of various shapes, sizes, and configurations. Some CTCP capsules can include one or more radiographic markers to aid visualization, for example, using CT and / or MR scanning. Such an approach would aid in distinguishing the capsule from surrounding tissue, tumor tissue, and allow for the determination of wallpaper and / or lighting element movement or separation.

[0052] Because surgical cavities are known to collapse or shrink, some resection cavities may also have bends and difficult-to-reach pockets. Such custom CTCP capsules can be personalized to combat such challenging cavity conditions and dynamics. Various adhesives, gels, fibrous meshes, and waveguides can also be employed to optimize the CTCP capsule. Light sources can be embedded within the CTCP. CTCP material can be overmolded onto LEDs and printed circuit boards. The capsule can be closed, partially encapsulated, a modular combination of various capsule elements, and / or contain one or more pre-configured openings.

[0053] The multi-material matrix may be a combination of multiple different materials and / or one or more material thicknesses. The multi-material matrix may be multiple different materials configured to be expandable to function as an implantable balloon, as will be described in more detail below. The CTCP paper application kit may include a pre-configured assembly of various components designed to allow caregivers to optimize the CTCP capsule according to the patient's needs.

[0054] FIG. 8 shows another example of a light guide that can be integrated with or coupled to an illumination element. Here, the illumination element includes one or more light sources 420, such as LEDs, mounted on a flexible or rigid PCB substrate 430. The LEDs are powered via a tether 300. The light guide 456 can include a spherical center section with multiple spokes extending radially outward, or the light guide 456 can include a flat, planar, rounded center section with multiple planar spokes extending radially outward. The spokes are formed from an optical material that helps deliver light into the target treatment area with minimal light loss. The spokes also help support tissue within the cavity formed after tumor resection, thereby preventing the cavity from collapsing. This helps ensure illumination of the target treatment area. The spokes can be any shape, including flat, planar rectangular arms, rounded cylindrical arms, or any other shape.

[0055] 9A-9D show examples of customized light guides that can be coupled to lighting elements.

[0056] In FIG. 9A , a tether 300 delivers power to a light source encapsulated in a standard shape 401, such as a sphere or square. The light source is implanted within a cavity 1100 formed after resection of a tumor from the brain within a patient's skull 1000. In some situations, it may be beneficial to provide an additional light guide element, which can be customized to any shape and easily bonded to the encapsulation, to help support the tissue within the cavity 1100 and facilitate delivery of light to the target treatment area. In FIG. 9A , an outer light guide 460, customized to fit the cavity, is bonded to the lighting element to form an outer ovoid light guide. The outer light guide may be snap-fit ​​into engagement with, adhesively bonded to, or otherwise bonded to the inner primary light element.

[0057] 9B-9D show examples of light guides that can be snapped onto, bonded to, or otherwise coupled to a light element.

[0058] 9B, spherical light guide 461 has a smaller, hemispherically shaped recessed area sized to receive the light element. The light element is inserted into the recessed area and then adhesively bonded or snap-fit ​​into place. In this example, the light element is coupled off-center to light guide 461; however, the light element could also be positioned at the center of the spherical light guide.

[0059] 9C shows a cloud-shaped light guide 462 having a hemispherical recessed area sized to receive a light element. The light element is inserted into the recessed area and then adhesively bonded or snap-fit ​​into place. The cloud-shaped light guide may include multiple lobes extending radially outward.

[0060] 9D shows a rectangular-shaped light guide 463 with linear sides and arcuate or wavy top and bottom. The light guide includes a hemispherical recessed area sized to receive a light element. The light element is inserted into the recessed area and then adhesively bonded or snap-fit ​​into place.

[0061] Those skilled in the art will understand that the examples of Figures 9A-9D are not intended to be limiting and that light guides of any shape can be coupled to illumination elements to support tissue within the tumor cavity and ensure light is delivered to the targeted treatment area.

[0062] FIG. 10 shows another example of an illumination element that can be used to conform to a tumor cavity 1100 after a tumor is resected. Here, an illumination element with an encapsulation 401 having any of the configurations described herein is coupled to and powered by a tether 300. The illumination element within the encapsulation 401 may include one or more light sources coupled to a substrate, such as a flexible or rigid PCB. The illumination element is coupled to an expandable member 470, such as a balloon, instead of the solid encapsulation material described above. The expandable member is compliant, so as it radially expands, it conforms to the walls of the tumor cavity, providing uniform support and helping to ensure that the target treatment area is illuminated with light. Additionally, the radially expandable member can be adjusted, either by further expansion or by collapsing, to accommodate changes within the tumor cavity. The expandable member can be expanded with a fluid, such as a liquid or gas. A contrast agent can also be used so that the balloon can be visualized using X-ray imaging.

[0063] FIG. 11 illustrates the use of a planar immersion lens 600 that may be disposed on a substrate. The planar immersion lens 600 may be disposed between an external power source (not shown) and a receiver element 700 in the illumination system and serves to focus energy onto the receiver for efficient transmission of energy. The substrate may be rigid or flexible and may be positioned adjacent to the skull 1000 or attached near the skull 1000 and receiver element. Here, the illumination system includes a wireless receiver 700, which may be any of the examples disclosed herein, either placed in the tumor cavity after the tumor is resected or attached to the skull 1000. The wireless receiver 700 includes an antenna coil 710 for receiving energy from an external energy source, which is focused onto the coil by the immersion lens. The illumination element, which may include one or more light sources such as LEDs, is powered by power delivered to the coil. The light source may be encapsulated within an encapsulant 720, which helps to diffuse the light and also helps to hold the implant in place within the tumor cavity 1100. Any of the encapsulants and light guides disclosed herein may be used with this example of an illumination system.

[0064] FIG. 12 illustrates the use of multiple light sources in a lighting system. Here, the lighting element includes multiple light sources 420 oriented to provide directional light output. In this example, three light sources 420, such as LEDs, are oriented so that light is emitted radially outward and in different directions relative to adjacent light sources. Here, light is emitted in the 3:00 o'clock, 6:00 o'clock, and 9:00 o'clock directions. A tether 300 delivers power to the light sources. The lighting elements are placed within a tumor cavity 1100 formed after resection of a tumor from the brain within a patient's skull 1000. The lights are independently controllable to steer the light, as well as to adjust the light intensity and on / off timing. Some electronics 480 may be disposed on a substrate 430 that holds the light sources 420. The substrate 430 may be a printed circuit board. The lighting elements may be encapsulated 410 within an optical material, which may be It facilitates light delivery by diffusing the light or helping to transmit the light efficiently, as well as by providing a protective cover for the light source. Any of the encapsulants or light guides described herein can be used as the encapsulant. Having multiple lights allows for a variety of light therapies to be provided.

[0065] FIG. 13 shows an example of a light source control 480 that can be used with any example of the lighting system described herein, such as in FIG. 12 . The light source control 480 controls illumination of the target tissue when multiple light sources are used, allowing for independent control of the light sources. The control 480 includes an oscillator 481 and a multiplexer 482 that cycles through each of the four LEDs 483 shown in FIG. 13 at a desired switching frequency. In an alternative example, a microcontroller 484 can control the oscillator 481 and the multiplexer 482. A tether 300 connects the control to the receiver element. The electrical components can be mounted on a PCB 430. The control 480 can also be within the housing instead of the lighting element.

[0066] FIG. 14 illustrates an example of an illumination system that may also include electrical stimulation to a target treatment area. Here, an illumination system is placed within a tumor cavity 1100 after a tumor has been resected from a brain within a patient's skull 1000. The illumination system may be any of the systems disclosed herein and may include a tether 300 for providing power to an illumination element 420, which may have one or more light sources coupled to a substrate, such as a PCB 430. The light source and substrate may be encapsulated (410) within a material that not only protects the device but also facilitates delivery of light to the target treatment area, such as by acting as a light guide or diffusing the light. The encapsulation may be any of the example encapsulations or light guides disclosed herein and may also serve to anchor the device within the tumor cavity. Conductors 801 extend from the PCB and are attached to electrodes 800, which are exposed on the sides of the light element and can provide electrical stimulation (deep brain stimulation) to the target treatment area by direct contact with brain tissue or by conduction through interstitial fluid within the resected cavity. Thus, light therapy and electrical stimulation can be provided simultaneously. Lighting systems such as that of FIG. 14 can be used to provide deep brain stimulation in patients suffering from neurodegenerative diseases such as Parkinson's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, or any other condition in which neurostimulation is beneficial. Stimulation can be provided alone or in combination with light therapy, such as by activating a photosensitizer, which can be used to treat diseases including, but not limited to, brain cancer. Electrodes for tissue stimulation, whether in the brain or elsewhere in the body, can be used with any of the example light therapy systems described herein. Additionally, phototherapy systems with electrodes are not limited to implantation within the tumor cavity formed after tumor resection, but may be placed within any tissue to which phototherapy and / or electrical stimulation is to be delivered to treat any disease or condition.

[0067] FIG. 15A shows an example of a reinforced substrate that can be used with any of the example optical and / or electrical stimulation systems disclosed herein. For any substrates used within these examples, such as a substrate carrying a light source or a light guide substrate, it may be advantageous to use a substrate with reinforcement within it to provide a stiffer substrate or a substrate that can bend, flex, or otherwise molded to conform to the target treatment area and retain its shape. Here, the substrate is similar to substrate 455 of FIG. 7 and is a flat, planar substrate that can be trimmed to a desired size and shape to fit the target treatment area. The substrate can be formed from a material with stiffening features, or stiffening features can be built into the substrate. For example, here, a two-dimensional grid of ribs 457 can be formed into the substrate to provide desirable stiffening properties. This helps the substrate maintain its shape when placed within the tumor cavity created after tumor resection. Illumination elements 430 (which may be any of those disclosed herein) may be positioned anywhere along the substrate, and tethers 300 are coupled to illumination elements 430 for the supply of power. The stiffening features may be formed from different materials (e.g., different polymers) having different mechanical properties (e.g., Young's modulus, durometer, etc.) compared to the base substrate.

[0068] Figure 15B shows the device of Figure 15A with stiffening features in a substrate that is implanted in a tumor cavity 1100 in the skull 1000. A tether 300 provides power to an illumination element (not shown in this figure) that is coupled to the substrate with stiffening or reinforcing members. The substrate is formed into a partially closed loop, if two-dimensional, or a partially closed spheroid, if three-dimensional, to support and conform to the tissue and illuminate it. The substrate acts as a light guide to help illuminate the target treatment area.

[0069] FIG. 16 shows another example of a reinforced substrate, such as the example of FIG. 15A, formed into a closed loop if two-dimensional or a closed spheroid if three-dimensional. Here, power is delivered via tether 300 to an illumination element (not shown, but which may be any illumination element disclosed herein) positioned on reinforced substrate 458 within tumor cavity 1100 in skull 1000. The reinforced substrate may be the same as or different from that shown in FIG. 15A, and the ends may remain juxtaposed to each other in a closed configuration due to reinforcements within the substrate maintaining the desired shape or due to the use of adhesive. This helps maintain the substrate in the desired configuration, supporting the tumor cavity and ensuring proper illumination of the target treatment area.

[0070] FIG. 17 illustrates the use of additional support elements within a tumor cavity 1100 in a patient's skull 1000. The wallpaper substrate concepts described in FIGS. 7, 15A-15B, and 16 can be used with additional support elements positioned within the tumor cavity to help support tissue within the target treatment area and also help distribute light to the target treatment area. Here, a tether 300 provides power to a lighting element, which can be any of those disclosed herein. The lighting element can be encapsulated in a material, and the combination of the lighting element and encapsulation material can be bonded to a flat, planar substrate 457 that can be molded and trimmed to fit the tumor cavity. The flat, planar substrate 457 can be any of those described herein and can be optically transparent to ensure light passes through it. Here, the wallpaper is formed into a partial closed loop if two-dimensional, or a partial sphere if three-dimensional. In some situations, it may be beneficial to provide additional support elements 459 that help support the tissue within the tumor cavity, prevent collapse, and may be formed from an optical material, thereby forming a light guide that also helps distribute light to the target treatment area. The support elements may be thin, planar sheets of material that are trimmed and shaped to fit the tumor cavity, or they may be prefabricated into various desired shapes. The support elements may then be secured to the tissue within the tumor cavity using techniques known in the art, such as with sutures, adhesives, or other techniques. The additional support elements may also function as spacers between the tissue and the illumination element, or as optical devices to help deliver light to the tissue.

[0071] FIG. 18 shows another example of the use of additional support elements 490 within a tumor cavity 1100 in a patient's skull 1000. Again, a tether 300 provides power to the lighting element, which may be any of the lighting elements disclosed herein. Multiple additional support elements 490 may be coupled together (as indicated by the arrows) to form a fully closed or partially open loop (if two-dimensional), or a fully closed or partially open spheroid (if three-dimensional), resulting in a rigid or semi-rigid structure that supports tissue within the tumor cavity and prevents it from collapsing inward. Thus, customization is possible during surgery, ensuring that the light provided by the lighting elements can illuminate the entire target treatment area and support the cavity. The support elements may snap together, interference fit together, adhesively bond together, or form any desired shape using coupling mechanisms known in the art, and they may be formed from optical materials that aid in distributing light to the target treatment area.

[0072] FIG. 19 illustrates a second port for coupling an external light source to an illumination element. Here, a tether 300 connects an illumination element (not shown) disposed within a flat, planar substrate 455, as described in FIG. 7 above. The tether 300 delivers power to the illumination element, which delivers light to the target treatment area through the flat, planar substrate 455. As discussed above, the flat, planar substrate 455 can be shaped and trimmed to conform to the target treatment area, which can be adhesively bonded to tissue. In some cases, light can be used to help cure the adhesive, such as when cyanoacrylate is used. Thus, an external light source 1300 can provide the required curing light, such as ultraviolet light, through port 1210, which can be releasably coupled to the external light source. The light is then delivered to the flat, planar substrate via optical fiber 1200, which then delivers the light to the target treatment area and promotes curing of the adhesive. Once substrate 455 is adhesively bonded to tissue, the external light source can be turned off, uncoupled from second port 1210, and removed. Port 1210 and fiber 1200 can remain bonded to flat, planar substrate 455, or they can also be removed. Other components that can be adhesively bonded, such as the complementary support elements of FIGS. 17-18 , the encapsulation surrounding the illumination element (e.g., of FIG. 5 ), the optical light guide shapes of FIGS. 6A-6D , and the complementary light guides of FIGS. 9A-9D , can also be adhesively bonded and cured using an external light source coupled to light input port 1210 and delivered via optical fiber 1200 to the flat, planar substrate to illuminate and cure the adhesive. In other examples, the second light port can be used to introduce light into the target treatment area through substrate 455 using an external light source to illuminate light-responsive biologicals, chemicals, or other agents.

[0073] 20A-20B illustrate the use of multiple light sources within a lighting element and the resulting lighting pattern that provides desirable control of lighting.

[0074] A uniform light source may not be the optimal solution for asymmetrically distributed disease in human tissue. Depending on the individual patient and the details of the anatomy and tumor, there may be areas within the surgical cavity that are more likely to contain residual tumor. Focusing light towards these areas to focus the photodynamic therapy (PDT) effect may be beneficial. Clinical trials involving the intraoperative application of PDT have shown that the input light (fluence, Joules / cm) 2 ) and clinical outcomes. In a single application (as part of a longer course of treatment), example devices disclosed herein can deliver customized outputs of light, with greater emphasis / power directed toward areas of greater tumor risk.

[0075] The total amount of light available is limited in implanted devices, primarily due to wireless power transfer limitations and tissue heating limitations. Therefore, optimal use of light sources is desirable and can be achieved in devices that can control the output of multiple lights, such as in a manner that has variable combinations of lights in on-off configurations.

[0076] Furthermore, this configuration can be applied not only to an on-off configuration but also to the control of individual LED light output within a defined range. This can be controlled by firmware embedded within the implanted PCB or housing, which will direct the power output of the individual lights within the implant. This control by the user can be accomplished through a user interface designed to control the power delivery and output devices. Planning this "prescription" for each patient can be similar to the spatial and temporal planning of radiotherapy treatments combined with prescriptive imaging of tumor locations within the patient.

[0077] In Figure 20A, tether 300 is coupled to a lighting element that includes, in this example, four independently controllable light sources 420, here LEDs. The LEDs are mounted within a substrate 430, such as a flexible PCB, and the assembly can be encapsulated in any manner, as previously described. Because the LEDs can be independently controlled, they can be turned on or off as needed to direct light in a desired direction for a desired amount of time.

[0078] FIG. 20B illustrates the intensity of light emitted by the four LEDs in all four directions as the light is emitted in a direction away from the center of PCB 430. Each direction has a leaf-shaped pattern that indicates the illumination pattern and emitted light intensity for each LED. When the total power provided by the tether is fixed, the intensity of each LED is higher when only a single LED is activated at a time. Thus, the illumination can be steered in a desired direction and the light intensity can also be controlled.

[0079] (Example of usage)

[0080] 21 illustrates an example of a method for treating a tumor. Treatment may be determined by a team of physicians and surgeons, which may include a neurosurgeon, a neuroradiologist, and a neuro-oncologist. Any of the illumination devices and optional features disclosed herein may be used according to the following methods of use. While this example is directed to the treatment of brain cancer, it is not intended to be limiting, and one skilled in the art will understand that other diseases and conditions may also be treated.

[0081] Magnetic resonance imaging (MRI) scans can be used to determine the size and shape of the tumor, and based on that information, an appropriately sized device can be selected. Other imaging techniques known in the art, such as computed tomography (CT), positron emission tomography (PET), and radiography, can also be used. The illumination dose can also be determined based on the bioavailability of the photosensitizer delivered to the target tissue and the effective light fluence and timing. In some embodiments, artificial intelligence (AI) or AI classifiers can be employed as pattern recognition tools to detect and guide physicians toward optimized targeted therapy to improve patient outcomes. The dose includes the photosensitizer drug dose and frequency and the light fluence from the implanted phototherapy device. The initial dose can be higher or lower depending on the patient's condition and the expected severity of any remaining tumor cells within the tumor margin.

[0082] A craniotomy, often a circular section of bone 5-10 cm in diameter, is removed from the skull, allowing access to the patient's brain. After the tumor is resected (2102), a device is implanted (2104) into the tumor cavity formed after the craniotomy and tumor resection surgery, in which the majority of the glioblastoma tumor or other diseased tissue is removed by a neurosurgeon using standard surgical techniques. The light source portion of the device is fixed in place by the neurosurgeon using methods known in the art, including any of those described herein. The light source may comprise a thin, flexible sheet or wallpaper that is glued into the cavity and allowed to harden in place. The surgeon can trim it (2106) to fit the size and shape of the individual patient's tumor.

[0083] The surgeon may adhesively bond or otherwise secure the device within the tumor cavity using cyanoacrylate, fibrin adhesive glue, or similar biocompatible tissue adhesive 2108. The device may be capable of "self-curing" by emitting light of the wavelength required by the adhesive (adhesive glue). An LED emitter can be built into the device, or an external curing light can be coupled to a light guide so that the curing light can reach where it is needed. For example, if the adhesive (UV-cured adhesive) is cured by light, the light source itself can be its own curing light source. The device may have a fitting connected to a point on the light source and can transmit the curing light through the light source to the adhesive (such as the example already described above with respect to FIG. 19).

[0084] If a trimming step is required, the surgeon can trim the light guide shape of the light source to better fit the patient's individual tumor cavity and the surgical scissors or other cutting instrument. The light source can include visual markers that indicate areas that should not be cut.

[0085] The implantation of lighting elements is at the discretion of the neurosurgeon, but should ensure that light is directed to regions within the target treatment area that contain residual tumor or are likely to suffer from recurrence. For GBM tumors that are arborescent and invasive, an additional margin of up to approximately 2 cm from the known margin may be a good margin. For smaller tumors, it may be possible to install lighting elements so that the entire internal cavity surface is illuminated.

[0086] The device can then be tested 2110 to visually check that the light sources are functional and in the correct location.

[0087] The tether can extend to the outside of the skull, with the wireless power portion of the device secured in place on the outside of the skull and under the scalp anywhere, such as behind the ear. The tether can also be secured to the skull so it cannot be pulled out by the patient. A clip or eyelet can be attached to the skull adjacent to the craniotomy opening, and the tether can be secured using the clip or eyelet to protect the wire from the sharp edges around the craniotomy and also serve to hold the tether in place. Excess wire can be coiled around the clip or eyelet. If needed, additional sutures, screws, adhesives, etc. can be used to help secure the tether and coil. A recessed area in the skull can be formed to accommodate the tether, coil, or housing, thereby helping to prevent or minimize bulging. The coil can be placed on the same side as the craniotomy, or it can be placed on the opposite side. Once the device is implanted and secured to the skull, the skull may be closed and the scalp may also be closed.

[0088] Optionally, the illumination system may include radiopaque markers adjacent to the illumination elements to enable a surgeon or physician to visualize and confirm placement of the device within the patient's tumor cavity using imaging techniques known in the art, such as MRI, PET, X-ray, etc.

[0089] After surgical recovery, photodynamic therapy is activated (2112) by powering the wireless power portion of the implant via an external transmitter in the clinic. The implant can control the power level it receives and direct most of that power to the light source. Administration would be monitored by the transmitter under the observation of a human operator. A sufficient dose for effective photodynamic therapy would be required for each session. Because sessions can last only a few hours at most, patients can utilize regular phototherapy sessions and control the recurrence of their tumors over months and even years. One example duty cycle could include one minute of illumination followed by 30 seconds of no illumination, then repeated. This helps reduce heat and may also allow tissue to re-oxygenate between light cycles. The power-receiving element in any embodiment of the device may include a clock oscillator so that it can manage the cycling of the light source. The energy transmitter may be able to reprogram the power-receiving element and change the timing of light delivery.

[0090] Dose fractionation can occur over several days, distinguishing this method from one-time treatments.

[0091] Using the disclosed devices and methods allows for the efficient transfer of significant power to the device while having the optical device in the center of the brain, where traditional wireless power methods cannot easily reach.

[0092] Phototherapy can optionally be combined with imaging and mapping to facilitate directing the illumination. Because the illumination element can include multiple light sources, steering of light in a desired direction is possible, such that if an area is identified as having more tumor cells or is expected to have more tumor cells, phototherapy can be directed in that direction. Phototherapy can also be combined with algorithms and tumor recurrence modeling to steer light to areas of concern using dosages also predicted by computer modeling. The devices, systems, and methods described herein can be used with any photosensitizer that provides the desired diagnostic or therapeutic effect. Examples of photosensitizers are described below. The patient is then monitored for rejection of the photodynamic therapy or photosensitizer drug at regular intervals, for example, every 3 to 6 months, using brain imaging techniques known in the art to detect tumor recurrence. The patient's dosage and therapy can be adjusted as needed.

[0093] Opportunities for individualized treatment may arise at various times during a patient's therapy, including during resection, the approximately six-week recovery period following resection, the approximately six-week combination of TMZ (temozolomide) chemotherapy and radiation therapy, and the six-month follow-up period. The use of phototherapy may be used alone or in conjunction with any of these periods and treatments to provide improved outcomes.

[0094] (wavelength of light)

[0095] The wavelength of light delivered by the illumination element is selected based on the wavelength and depth of tissue penetration required to activate the photosensitizer. For example, light within the red to near-infrared wavelength range of approximately 600 nm to 940 nm may have sufficient tissue penetration within brain tissue. This wavelength may be used with any of the example devices disclosed herein.

[0096] (Example of Photosensitizer)

[0097] Any photosensitizer that can have a therapeutic effect when exposed to light can be used with any of the example lighting systems described herein. Examples of photosensitizers include, but are not limited to, methylaminolevulinic acid hydrochloride, padeliporfin potassium, talaporfin sodium, SGX-301, fimaporfin + gemcitabine, ledaporfin, aminolevulinic acid + artemisinin, CTT-1700, IVX-MES, IVX-PDT, IVXP-02, JL-103, photovac, YC-9, ADC + fimaporfin, bleomycin sulfate + fimaporfin, lemuteporfin, methylaminolevulinic acid. These include epirubicin hydrochloride, motexafin lutetium, padoporfin, SL-017, vandiolax, deuteporfin, graft-versus-host disease-targeting ABCB1-activating small molecules, tumor-targeting EGFR-targeting recombinant peptides, eNOS-targeting small molecules, tumor-targeting nNOS and NO synthase, epirubicin hydrochloride plus fimaporfin, porfimer sodium, temoporfin, palladium bacteriophephorbide, rostaporfin, verteporfin, and 5-aminolevulinic acid.

[0098] These photosensitizers are useful for treating, but not limited to, basal cell carcinoma (e.g., basal cell epithelioma), squamous cell carcinoma, actinic (e.g., solar) keratosis, skin cancer, solid tumors, prostate cancer, esophageal cancer, transitional cell carcinoma (urothelial cell carcinoma), bile duct cancer (e.g., cholangiocarcinoma), endobronchial cancer, kidney cancer (e.g., renal cell carcinoma), renal cell carcinoma, choroidal neovascularization, brain tumor, glioma, neurofibroma, head and neck cancer, hepatocellular carcinoma, metastatic colorectal cancer, nasopharyngeal carcinoma, pancreatic cancer, benign prostatic hyperplasia, and age-related macular degeneration. The light may be used to illuminate in the treatment of various cancers and other diseases, including coronary artery disease, cutaneous vascular malformations, peripheral arterial disease (PAD), peripheral vascular disease (PVD), mycosis fungoides, psoriasis, glioblastoma multiforme (e.g., GBM), inflammatory bowel disease, colorectal cancer, malignant mesothelioma, ovarian cancer, viral infections, colon cancer, graft-versus-host disease (GVHD), carcinoma, sarcoma, acne vulgaris, coronary artery disease (CAD) (e.g., ischemic heart disease), breast cancer, non-small cell lung cancer, small cell lung cancer, and bladder cancer.

[0099] (experiment)

[0100] A sample device was tested that had a coil for receiving RF energy, a rectifier for converting the received AC power to DC, and an LED. The LED emitted light at a wavelength of about 630 nm with a fluence (energy density) of about 120 J / cm. 2 The radiation power was measured using an optical intensity meter over a range of drive currents from about 0.1 mA to about 20 mA. Based on reported literature, this level of fluence is estimated to have an extrapolated necrotic depth of about 10-20 mm.

[0101] The subject of photosensitizer drug activation is more widely understood in the art. Effective application of photodynamic therapy requires light at an optimal wavelength for photosensitizer (PS) drug activation, at a sufficient intensity, and for a sufficient duration to deliver a minimum light fluence (Joules per square centimeter area).

[0102] When demonstrating efficacy against tumors in preclinical and clinical trials, known experimental protocols use light fluence as a control parameter (i.e., PS activation threshold or target). Therefore, for embodiments of the illumination system disclosed herein to deliver a discrete amount of light fluence consistent with that known in the art, effective activation of PS must ensue. In some embodiments, the target light fluence is between 90 and 500 J / cm. 2 In some embodiments, the target light fluence is between 100 and 200 J / cm 2 It is optimized in

[0103] Fractionated or metronomic PDT (mPDT) has received significant attention in the PDT research community. mPDT can achieve the same dose of PS activation but over a longer period at lower light intensities. Scientific literature has shown that in animal models, mPDT can achieve <100 uW / cm over a 10-day period. 2reported promising results with an intensity 1,000 times lower than typical PDT protocols. By using a much longer duration (1,000 times longer), the intensity x time product remains constant.

[0104] Other literature uses fluence rates (W / cm 2 ) suggests that with the same dose, higher intensity has an effect, indicating that tumor cells are killed to a greater depth. This may also result in more normal cell killing, which supports the concept of a "threshold" for photosensitizer activation.

[0105] Further literature reports that studies using other light fluence rates are possible, ranging from 20 to 400 J / cm. 2 Light fluence rate (100-200J / cm 2 There is evidence that higher rates may correspond to better outcomes.

[0106] Based on the data contained within these references, implanted phototherapy device therapy is 100 J / cm 2 When divided over many hours or even days, the instantaneous power required to deliver this energy is on the order of milliwatts or tens of watts (e.g., 7 mW / cm over a 4-hour period). 2Further details can be found in Brendan J. Quirk et al., "Photodynamic therapy (PDT) for malignant brain tumors - Where do we stand?" Photodiagnosis and Photodynamic Therapy 12.3 (2015): 530-544, and Tudge, SH et al., "Modulation of light delivery in photodynamic therapy of brain tumors," Journal of Clinical Neuroscience, 1999 6(3), 227-232, and Yamagishi, "Tissue-adhesive wirelessly powered optoelectronic device for metronomic photodynamic cancer therapy," Nature Biomedical Engineering, January 2019 (the entire contents of which are incorporated herein by reference). Notes and Examples

[0107] The following non-limiting examples detail certain aspects of the present subject matter to, among other things, solve the problems and provide the benefits discussed herein.

[0108] Example 1 is an implantable phototherapy device, the device comprising: a receiver element configured to receive power from an external power transmitter; a light delivery element powered by power provided by the receiver and configured to deliver phototherapy to a target treatment area; and a tether element operably coupled to the light delivery element and the receiver element, the tether element configured to deliver power from the receiver element to the light delivery element.

[0109] Example 2 is the device of example 1, wherein the receiver element comprises a coil configured to receive power from an external power transmitter, and the power comprises radio frequency energy.

[0110] Example 3 is a device described in any of Examples 1-2, wherein the receiver element comprises a sealed housing operably coupled to the tether, and the device further comprises an electronic component disposed within the sealed housing, the electronic component configured to control the power delivered to the light delivering element.

[0111] Example 4 is a device described in any of Examples 1-3, wherein the light delivery element comprises a light source encapsulated within an optical material configured to protect the light source, and the optical material facilitates the transmission of light from the light delivery element to the target treatment area.

[0112] Example 5 is a device described in any of Examples 1-4, further comprising an optical light guide coupled to the light delivery element, the optical light guide being shaped to facilitate delivery of light from the light delivery element to the target treatment area.

[0113] Example 6 is a device described in any of Examples 1-5, wherein the light delivery element comprises a plurality of light sources arranged on a substrate, and the substrate is configured to be shaped to conform to the target treatment area.

[0114] Example 7 is a device according to any of Examples 1-6, wherein the substrate is a light guide configured to direct light to a target treatment area, and the substrate is configured to be trimmed to a desired shape to fit the target treatment area.

[0115] Example 8 is a device according to any of Examples 1-7, wherein the light delivering element comprises a plurality of light sources configured to be independently controllable with respect to each other.

[0116] Example 9 is the device of any of Examples 1-8, wherein the light delivery element further comprises a temperature sensor configured to measure a temperature at the target treatment area.

[0117] Example 10 is a device described in any of Examples 1-9, wherein the light delivery element is disposed within a radially expandable member having an expanded configuration and a collapsed configuration, and in the expanded configuration, the radially expandable member conforms to the target treatment area.

[0118] Example 11 is a device described in any of Examples 1-10, wherein the light delivery element further comprises a port configured to releasably receive an optical fiber optically coupled to an external light source, and light from the external light source is delivered to the light delivery element via the optical fiber for illumination of the target treatment area.

[0119] Example 12 is a phototherapy system, the system including a device described in any of Examples 1-11, a device described in any of Examples 1-10, and an external power transmitter configured to wirelessly transmit power to a receiver element.

[0120] Example 13 is the device of example 12, further comprising a planar immersion lens disposed between the external power transmitter and the receiver element, the planar immersion lens configured to focus energy from the external power transmitter toward the receiver element.

[0121] Example 14 is the system of any of Examples 12-13, further comprising an electrode configured to provide electrical stimulation to the target treatment area.

[0122] Example 15 is the system of any of Examples 12-14, further comprising at least one support element, the support element configured to align with and support tissue in the target treatment area.

[0123] Example 16 is the system of any of Examples 12-15, further comprising a photosensitizer.

[0124] Example 17 is a method of delivering phototherapy to a target treatment area in a patient, the method including providing an implantable phototherapy device comprising a power receiver element, a light delivery element, and a tether element; implanting the phototherapy device in the patient at the target treatment area; wirelessly transmitting power from an external power transmitter to the power receiver element; transmitting power from the power receiver element via the tether to the light delivery element; and illuminating the target treatment area with light from the light delivery element.

[0125] Example 18 is the method of example 17, in which wirelessly transmitting power from an external power transmitter to the receiver element includes receiving radio frequency energy with a coil.

[0126] Example 19 is the method of any of Examples 17-18, wherein illuminating comprises illuminating the target treatment area with a plurality of independently controllable light emitting elements.

[0127] Example 20 is the method of any of Examples 17-19, wherein wirelessly transmitting power includes transmitting power from an external power transmitter and focusing the power toward the receiver element using a planar immersion lens.

[0128] Example 21 is the method of any of Examples 17-20, further comprising electrically stimulating tissue in the target treatment area with energy provided by an electrode adjacent to the light delivery element.

[0129] Example 22 is the method of any of Examples 17-21, wherein the target therapeutic area comprises the brain of the patient.

[0130] Example 23 is a method described in any of Examples 17-22, further comprising releasably coupling an optical fiber to the light delivery element, inputting light from an external light source into the light delivery element via the optical fiber, and illuminating the target tissue using the light from the external light source.

[0131] Example 24 is the method of any of Examples 17-23, wherein the light delivery element comprises a plurality of light sources disposed on a substrate, and the method further comprises shaping the substrate to conform to the target treatment area and directing the light in a plurality of directions to illuminate the target treatment area.

[0132] Example 25 is the method of any of Examples 17-24, further comprising trimming the substrate to a desired size or shape to fit the target treatment area.

[0133] Example 26 is the method of any of Examples 17-25, further comprising measuring the temperature in the target treatment area with a temperature sensor.

[0134] Example 27 is a method described in any of Examples 17-26, wherein the light delivery element comprises multiple light sources encapsulated within an optical material, and the optical material is a light guide that directs light from the multiple light sources to the target treatment area.

[0135] Example 28 is the method of any of Examples 17-27, wherein the light delivery element is disposed within a radially expandable member, and the method further comprises radially expanding the radially expandable member to align with and conform to the target treatment area.

[0136] Example 29 is the method of any of Examples 17-28, further comprising positioning a support element within the target treatment area to support tissue within the target treatment area and help ensure the tissue is illuminated.

[0137] In Example 30, the device, system, or method of any one or any combination of Examples 1-29 can optionally be configured such that all of the listed elements or options are available for use or selection.

[0138] The above detailed embodiments include reference to the accompanying drawings, which form a part of the detailed description. The drawings show, by way of illustration, specific embodiments in which the invention may be practiced. These embodiments are also referred to herein as "examples." Such examples may include elements in addition to those shown or described. However, the inventors also contemplate examples in which only the elements shown or described are provided. Furthermore, the inventors also contemplate examples using any combination or permutation of those elements (or one or more aspects thereof) shown or described herein, either with respect to the particular example (or one or more aspects thereof) or with respect to other examples (or one or more aspects thereof).

[0139] In the event of a conflicting usage between this document and any document so incorporated by reference, the usage in this document shall control.

[0140] The terms "a" or "an" are used herein, as is common in patent documents, to include "one" or "two or more," independently of any other instance or usage of "at least one" or "one or more." The term "or" is used herein to refer to a non-exclusive or, unless otherwise indicated, such that "A or B" includes "A but not B," "B but not A," and "A and B." The terms "including" and "in which" are used herein as the plain-English equivalents of the respective terms "comprising" and "wherein." Also, in the following claims, the terms "including" and "comprising" are open-ended, i.e., systems, devices, articles, compositions, formations, or processes that include elements in addition to those recited after such terms in a claim are still considered to be within the scope of that claim. Also, in the following claims, the terms "first," "second," and "third," etc. are used as labels only and are not intended to impose numerical requirements on their objects.

[0141] The above description is intended to be illustrative, not restrictive. For example, the above-described embodiments (or one or more aspects thereof) may be used in combination with each other. Other embodiments may also be utilized by those skilled in the art upon review of the above description. The Abstract is provided to enable the reader to quickly ascertain the nature of the present technical disclosure. It should be considered with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. Also in the above Detailed Description, various features may be grouped together for the purpose of streamlining the disclosure. This should not be construed as intending that any unclaimed disclosed feature is essential to any claim. Rather, inventive subject matter may lie in less than all features of a particular disclosed embodiment. Thus, the following claims are herein incorporated into the Detailed Description as an example or embodiment, with each claim standing on its own as a separate embodiment, and it is contemplated that such embodiments can be combined with each other in various combinations or permutations. The scope of the invention should be determined with reference to the appended claims, along with the full range of equivalents to which such claims are entitled.

Claims

1. An implantable phototherapy device, comprising: a power receiver element configured to receive power from an external power transmitter; a light delivering element powered by power provided by the power receiver element, the light delivering element configured to deliver light to a target treatment area; and a tether operably coupled to the light delivering element and the receiver element, the tether configured to deliver the power from the receiver element to the light delivering element; a radially expandable member having an expanded configuration and a collapsed configuration; Equipped with In the expanded configuration, the radially expandable member conforms to the target treatment area and provides uniform support to the target treatment area, whereby the target treatment area is illuminated by the light; The device, wherein the light delivering element is disposed within the radially expandable member.

2. The device described in claim 1, wherein the receiver element comprises a coil configured to receive the power from the external power transmitter, and the power comprises radio frequency energy.

3. The device described in claim 1, wherein the receiver element has a sealed housing operably coupled to the tether, and the device further comprises electronic components disposed within the sealed housing, the electronic components configured to control the power delivered to the light delivery element.

4. The device described in claim 1, further comprising an optical light guide coupled to the light delivery element, the optical light guide being shaped to facilitate delivery of the light from the light delivery element to the target treatment area.

5. The device described in claim 1, wherein the light delivery element comprises multiple light sources.

6. The device described in claim 1, wherein the light delivery element comprises multiple light sources, the multiple light sources being configured to be controllable independently of each other.

7. The device described in claim 1, wherein the light delivery element further comprises a temperature sensor, the temperature sensor configured to measure the temperature in the target treatment area.

8. A phototherapy system, comprising:

10. The implantable phototherapy device of claim 1; the external power transmitter configured to wirelessly transmit the power to the power receiver element; A system comprising:

9. The system of claim 8, further comprising an electrode configured to provide electrical stimulation to the target treatment area.

10. The system described in claim 8, further comprising a photosensitizer configured to be activated by the light.

11. The system described in claim 8, further comprising a fluid disposed within the radially expandable member, the fluid configured to expand within the radially expandable member.

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