Implantable phototherapy device, implantable photodynamic therapy system, phototherapy system and surgical kit

Abstract

An implantable phototherapy device, an implantable photodynamic therapy system, a phototherapy system, and a surgical kit are disclosed. 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 provided by the power receiver element, the light delivery element configured to deliver light therapy to a target treatment region, where the light delivery element includes a plurality of light sources configured to distribute light radially outward to illuminate the treatment region, the plurality of light sources configured to be adjusted to different light intensities and wavelengths; and a tether operably coupled with the light delivery element and the power receiver element, the tether configured to deliver power from the power receiver element to the light delivery element.

Description

[0001] This application is a divisional application of the patent application No. 202080076126.0, with the invention name of "Methods and Devices for Phototherapy", which has an application date of October 21, 2020, an international application number of PCT / US2020 / 056609, and entered the Chinese national phase on April 29, 2022.

[0002] Priority Claims

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 923,738, filed on October 21, 2019; the entire content of which is incorporated herein by reference. Technical Field

[0004] This application relates to methods and devices for phototherapy. Background Art

[0005] Light delivery as a therapeutic modality is an integral part of human existence. Light from the sun helps regulate our circadian rhythms and produces key vitamins D in our skin throughout the day. Light is used in therapeutic forms to treat eye and skin conditions, or to reduce bilirubin levels to treat neonatal jaundice. Light delivery can be used to treat many other conditions. Summary of the Invention

[0006] A first aspect of the present disclosure provides an implantable phototherapy device, comprising:

[0007] A power receiver element configured to receive power from an external power transmitter;

[0008] A light delivery element powered by the power provided by the power receiver element, the light delivery element being configured to deliver phototherapy to a target treatment area,

[0009] wherein the light delivery element includes a plurality of light sources configured to radially distribute light outwardly to irradiate the treatment area, the plurality of light sources being configured to be adjusted to different light intensities and wavelengths; and

[0010] A tether operably coupled to the light delivery element and the power receiver element, the tether being configured to deliver the power from the power receiver element to the light delivery element.

[0011] A second aspect of the present disclosure provides an implantable photodynamic therapy system, comprising:

[0012] The device according to the first aspect of the present disclosure; and

[0013] A photosensitizer,

[0014] Wherein, the light distributed from the light delivery element is configured to activate the photosensitizer to react with oxygen in the tissue at the treatment area, and the oxygen generates reactive oxygen species (ROS) that induce tumor cell death.

[0015] A third aspect of the present disclosure provides an implantable phototherapy device, comprising:

[0016] A power receiver coil configured to receive power from an external power transmitter;

[0017] A light delivery element powered by the power provided by the power receiver coil and configured to deliver phototherapy to a target treatment area;

[0018] A flat planar sheet including an optical material removably coupled to the light delivery element, wherein the flat planar sheet is an optical waveguide facilitating the distribution of light from the light delivery element to the target treatment area,

[0019] wherein the flat planar sheet is flexible and can be trimmed to conform to the target treatment area; and

[0020] A tether element operably coupled to the light delivery element and the power receiver coil, the tether element being configured to deliver the power from the power receiver coil to the light delivery element.

[0021] A fourth aspect of the present disclosure provides a phototherapy system, comprising:

[0022] The implantable phototherapy device provided according to the third aspect of the present disclosure; and

[0023] An external power transmitter configured to wirelessly transmit power to the power receiver coil.

[0024] A fifth aspect of the present disclosure provides a surgical kit for providing phototherapy to a patient, comprising:

[0025] A power receiver element configured to receive power from an external power transmitter, the power receiver element being configured to be attached to the patient;

[0026] A light delivery element powered by the power provided by the power receiver element, the light delivery element being configured to deliver phototherapy to a target treatment area;

[0027] A conformal stretchable cavity paper capsule (CTCP) coupled to the light delivery element and formed of an optical material serving as a waveguide to facilitate the distribution of light from the light delivery element to the target treatment area,

[0028] Wherein, the CTCP is configured to be bent and trimmed to conform to the target treatment area and is configured to be coupled to the target treatment area;

[0029] A tether operably coupled to the light delivery element and the power receiver element, the tether configured to deliver the power from the power receiver element to the light delivery element; and

[0030] A pre-configured assembly of various components configured to enable a caregiver to personalize the CTCP according to patient needs.

[0031] A sixth aspect of the present disclosure provides an implantable phototherapy device, comprising:

[0032] A power receiver element configured to receive power from an external power transmitter;

[0033] A light delivery element powered by the power provided by the power receiver element, the light delivery element configured to deliver phototherapy to a target treatment area;

[0034] A tether operably coupled to the light delivery element and the power receiver element, the tether configured to deliver the power from the power receiver element to the light delivery element;

[0035] An electrode adjacent to the light delivery element, the electrode configured to provide electrical stimulation to tissue in or adjacent to the treatment area; and

[0036] A sensor configured to monitor tissue adjacent to the device.

[0037] A seventh aspect of the present disclosure provides an implantable photodynamic therapy system, comprising:

[0038] The device according to the sixth aspect of the present disclosure; and

[0039] A photosensitizer, wherein the light distributed from the light delivery element is configured to activate the photosensitizer to react with oxygen in the tissue at the treatment area, and the oxygen generates reactive oxygen species (ROS) that induce tumor cell death. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] In the drawings, which are not necessarily drawn to scale, like reference numerals may describe like components in different views. Like reference numerals with different letter suffixes may represent different instances of like components. The drawings generally illustrate, by way of example and not limitation, the various embodiments discussed in this document.

[0041] Figure 1 A light irradiation system is shown.

[0042] Figure 2 Shows a light irradiation system coupled to a patient's head.

[0043] Figure 3 Shows a light irradiation system coupled to a patient's head.

[0044] Figure 4 Shows an example of electronic components in a housing.

[0045] Figure 5 Shows an example of an irradiation element.

[0046] Figures 6A to 6D Shows an example of the shape of an optical light guide.

[0047] Figure 7 Shows an example of an irradiation element disposed on a customizable substrate.

[0048] Figure 8 Shows another example of the shape of an optical light guide.

[0049] Figures 9A to 9D Shows an example of a customized light guide that can be coupled to an irradiation element.

[0050] Figure 10 Shows another example of an irradiation element.

[0051] Figure 11 Shows the use of a planar immersion lens.

[0052] Figure 12 Shows the use of multiple light sources in an irradiation system.

[0053] Figure 13 Shows an example of a light source control device.

[0054] Figure 14 Shows an example of an irradiation system that may further include electrical stimulation of a target treatment area.

[0055] Figure 15A Shows an example of a reinforcement substrate.

[0056] Figure 15B Shows disposed in a tumor cavity Figure 15A of the reinforcement substrate.

[0057] Figure 16 Shows another example of a reinforcement substrate.

[0058] Figure 17 Shows the use of additional support elements in a tumor cavity.

[0059] Figure 18 Shows another example of additional support elements in a tumor cavity.

[0060] Figure 19 shows a second port for coupling an illumination element to an external light source.

[0061] Figures 20A to 20B shows the use of multiple light sources in an illumination element and the resulting illumination pattern.

[0062] Figure 21 shows an example of a method of treating a tumor. DETAILED DESCRIPTION

[0063] Light delivery as a therapeutic modality is an integral part of human existence. Light from the sun helps regulate our circadian rhythms and produces crucial vitamin D in our skin throughout the day. Light is used in therapeutic forms to treat eye and skin disorders or to reduce bilirubin levels to treat neonatal jaundice. More recently, light has been seen as a potential source of new therapies paired with photoactivatable drugs, leading to new advances in skin cancer as well as some internal tumors and other disorders.

[0064] The main challenge in using light to treat internal diseases is that light cannot penetrate very far into the body. Light is absorbed by the skin and tissues, which limits the penetration depth of visible and near-infrared (NIR) wavelengths to 3 millimeters to 5 millimeters. Applying phototherapy to tumors or stimulating neurons to treat movement disorders may require light at a depth of 10 cm to 25 cm, a smaller depth, or even a greater depth, and an implantable light source adjacent to the target treatment area is the only practical way for light to reach such depths in the human body.

[0065] This disclosure describes novel power supply, light delivery, and integration aspects of implantable phototherapy devices, systems, and methods of use. The implant can also be designed to deliver a single therapy and / or in combination with other forms of stimulation and / or therapeutic agents other than light, and in so doing deliver innovative combination therapies. The implant can also be modified to include sensing characteristics, such as regulating the treatment dose in response to the patient's physiological state.

[0066] Figure 1An example of a light irradiation system 100 is shown, which can be used to deliver phototherapy in a patient's body, for example, for treating tumors deep within the body (such as glioblastoma in the brain). Although the examples disclosed herein mainly relate to implanting the device into 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 into any other part of the body to deliver phototherapy in the body as part of the treatment for other conditions. Thus, the devices and systems described herein can be surgically implanted into the tumor cavity created by tumor resection, or the devices and systems described herein can be placed in a natural body cavity adjacent to the diseased area or in natural tissue (e.g., by direct implantation into the tissue) without surgical modification. In either case, light can be used to activate various therapeutic agents that help combat tumors or provide other therapeutic effects to treat diseases, thereby providing local therapy. For example, in photodynamic therapy, light can be used to activate a therapeutic agent (also known as a photosensitizer) that is taken up by cells, which causes the production of reactive oxygen species (ROS), which are toxic to host cells and cause, for example, cell death in tumors, as is well reported in the patent and scientific literature. The production of ROS can be quantified by titration methods known in the art. The wavelength of the light must overlap with the activation spectrum of the photosensitizer.

[0067] The irradiation system includes a power receiver element, which can include a wireless coil 101 and a housing 200. The system can also include a tether line 300 and a light source (also referred to as a light element or irradiation element or light source) 400.

[0068] The power receiver element in this or any example may or may not include any energy storage device (such as a battery, capacitor, or other storage element). If no storage device is present, treatment is provided only when an external power source is activated. If an energy storage device is included, the device can be turned on as needed, and the illumination 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 an external power source and may have one or more turns of wire covered by an insulator. The turns can take any geometry such as a circular or helical coil, and the coil can be made of any material that is conductive to electromagnetic energy. The wireless coil can optionally be made of a flexible printed circuit board or a printed circuit board with a metal or conductive trace having a circular or other coil pattern. The size of the coil is adapted for wireless power transfer through tissue, such as through any depth of a patient's scalp, for example, a depth 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 can optionally be capable of two-way authentication such that only approved devices can work together and send power to the implanted device. Optionally, secure cryptographic techniques can be used to ensure that the device cannot be activated by unauthorized users or transmitters.

[0069] The wireless coil 101 can be electrically and mechanically coupled to an optional housing 200 such that the energy captured by the coil 101 is delivered to the housing 200, which includes various electronic components for managing power and controlling the duty cycle of the light source 400. The electronics in the housing can be mounted on a printed circuit board.

[0070] The housing can be any size or shape and can be formed from any number of materials (such as titanium or any biocompatible material). Wires from the coil 101 or the tether 300 can be coupled to the housing via ceramic feedthroughs. Additional disclosure regarding the electronic components in the housing 200 is provided later in this specification.

[0071] The tether wire 300 is operably coupled to the housing 200, the electronics in the housing 200, and the light source 400. The tether ensures that the light source 400 remains coupled to the housing and can be formed from any material having an appropriate strength for the tether and being conductive. The tether wire can be welded to an electronic feedthrough in an airtight sealed housing (sometimes also referred to as a "can") that encapsulates the power electronics. The tether 300 can be several wires that linearly extend between the housing and the illumination element, or the wires can be coiled, helically wound, braided, twisted together, or take any configuration and have a sufficient length to ensure that the housing can be anchored in one position and the light source can be positioned as desired. The tether can include multiple electrical wires passing through a multi-lumen tube to form a single filament, or the tether can have more than one filament.

[0072] The light source 400 can be a single light source or can include multiple light sources. For example, multiple light sources can be included in the light source and be configured to be adjusted to various intensities and can all have light of the same or different wavelengths, which can be controlled together or independently of each other. The wavelength can be selected to maximize the photoactivation of the therapeutic agent.

[0073] Figure 2 shown coupled to the patient's skull 1000 Figure 1 of a phototherapy system. Here, the phototherapy system includes a power receiver element having a coil 101 for receiving RF energy from an external power source and a housing 200 containing electronic components for the control device. A tether 300 operably couples the housing to the illumination element, which is disposed in a tissue cavity in the patient's brain after tumor resection. The illumination element is not visible in this view. The tether can be coiled 301 at any portion of its length to absorb excess slack or provide strain relief. In this example, the power receiver element is attached to the patient's skull using techniques known in the art (such as using sutures, staples, adhesives, or fasteners such as screws) such that the power receiver element is disposed beneath the scalp. The tether is also disposed between the scalp and the skull. A bore can be drilled through the skull to enable the tether and the illumination element to pass through the skull into the tissue cavity, where the illumination element can be attached to the tissue to fix the illumination element in a desired position, at which position the illumination element will illuminate a target treatment tissue to provide treatment, such as activating a drug for reducing or eliminating tumor cells that may remain after resection or may recur. The bore can be the same bore used to provide access for the surgeon during tumor resection or the bore can be a separate bore. In this example, the power receiver element can be disposed behind the ear as shown, or the power receiver can be disposed anywhere along the skull.

[0074] Optionally, fasteners such as clips or grommets (not shown) can be used to help protect the tether when it passes through an opening in the skull that may have sharp edges. The fastener helps keep the tether in place such that the tether cannot be pulled out and provides cable management to prevent the tether from tangling. The fastener can be formed of any biocompatible material such as polymers, silicone, metals, etc.

[0075] Figure 3 shown Figure 1A phototherapy system and an external power supply 700 that wirelessly supplies RF power to the phototherapy system. The phototherapy system includes a power receiver element that includes a coil 101 for receiving radio frequency energy (RF) from the power supply 700 (here an RF wireless transmitter). The power receiver element also includes a housing 200 that contains electronic components for controlling the phototherapy system. A fastener 201 such as a screw can be used to fix the housing to the skull 1000 under the scalp. A tether 300 electrically couples the housing and the electronic components in the housing to an irradiation element (not shown) that is disposed in the cavity of the brain tissue formed after tumor resection. A bone plate 500 can be repositioned in the drill hole to help close the skull, and a grommet 510 or clip can be used to help fix the tether to the skull and prevent damage to the tether. The tether can be coiled or unrolled. Here, the power receiver element is positioned on one side of the patient's head, approximately at eye level.

[0076] Figure 4 An example of the housing 200 that can be used in any example of the phototherapy system disclosed herein is shown. Some of the electronic components that can be disposed in the housing to help control the phototherapy system include a rectifier 210 such as a full-wave bridge rectifier that includes four diodes arranged to convert alternating current (AC) received from the coil 101 to direct current (DC). A DC / DC converter 220 can be coupled to the rectifier and convert the power or voltage level from one level to another, and the DC / DC converter is operably coupled to an irradiation driver 240 that drives an irradiation element (not shown) that can be one or more light sources such as light-emitting diodes. A microcontroller 230 can also be included in the housing to 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 can have active electronic devices to tune the resonance. The housing can also include a temperature measurement component 250 that helps monitor the temperature from a sensor disposed at the target treatment site (not shown) to ensure that the temperature at the light source does not become excessive and cause tissue damage. The temperature measurement component 250 can also monitor the temperature of the receiver electronics to ensure overheating is avoided. The housing can be formed of any biocompatible material such as titanium and provides an airtight seal for the electronic components. The housing can act as a heat sink, or a separate heat sink (not shown) can also be included in the housing. Electrical leads exiting the housing form a tether 300 that is coupled to the irradiation source.

[0077] Figure 5Shows an example of an illumination element 400 that can be coupled to a tether 300 and can be used in any example of an illumination system. The tether enables power to be delivered from a power receiver element to the illumination element and optionally also electrically couples an optional temperature sensor to the electronics in the housing. The tether also provides a mechanical coupling between the illumination element 400 and the power receiver element such that both the illumination element 400 and the power receiver element remain coupled together. Here, the illumination element 400 includes one or more flexible substrates 430 such as a flexible printed circuit board (PCB), which can be shaped in any desired configuration to conform to the target treatment area. Polyimide is one example of a suitable PCB material. The target treatment area can be a cavity created after removing a tumor in the brain, so the substrate should be formable into a three-dimensional shape. Additionally, once formed, the flexible substrate helps support the tissue around the cavity to prevent the tissue from collapsing inward, which can prevent some tissue from being irradiated. Here, a plurality of illumination elements 420 are coupled to the flexible substrate, and the substrate is bent into an inverted square U-shaped configuration (or a U-shaped staple with two vertical legs and a horizontal bar connecting the legs) such that one illumination element 420 is on each leg of the U and one illumination element is on the horizontal connecting piece between the legs of the U. This ensures that the light emitted from the illumination elements will be radially outward and evenly distributed in several different directions to irradiate the target treatment area. The illumination 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 the intensity of the light, as well as the duty cycle of how long the LEDs are on and how long they are off, can be adjusted. The PCB can include other electronic components that help control the light source and automatically direct power from the tether to each LED continuously in a desired cycle. This enables the light intensity to be increased or decreased as needed to control the irradiation of different areas of the tumor cavity. When the LEDs cycle, a more intense light exposure is followed by a dark period, which can increase the activation of photosensitizers while giving the oxygen in the tissue time to recover between irradiation cycles when the cavity is dark. The light source and the substrate can be encapsulated 410 in a protective device and a material that acts as an optical waveguide to help deliver the light to the target treatment area. For example, the encapsulation 410 can be formed of silicone or another translucent material that acts as an optical waveguide for delivering light, or the encapsulation can help diffuse the light. The seal can be any shape, including a flat sheet, a square box, a rectangular box, a circle, a cylinder, a sphere, an oval, etc., and is chosen to fit the tumor cavity.

[0078] An optional temperature sensor 251 (e.g., a thermistor) can also be coupled to the flexible substrate to enable temperature monitoring at the target treatment area, as light can generate heat and overheating is undesirable and can damage tissue. If too much heat is generated, the light source can be turned off. As mentioned above, the illumination element 420 and the temperature sensor 251 can optionally be encapsulated in a material that protects the light source and sensor and provides the desired optical properties for delivering light from the illumination element to the target treatment area. For example, the encapsulating material can be optically transparent, or the encapsulating material can include a diffusing or reflective material (not shown) such as titanium dioxide particles. The seal can then also act as an optical waveguide to ensure minimal light loss during transmission. The seal can have a primary layer that protects the light and aids in heat dissipation. An optional secondary layer of the seal can be provided, and the secondary layer of the seal acts as an optical waveguide and facilitates the distribution of light to the target treatment area. Examples of multi-layer encapsulation are disclosed herein, and any of them can be used for any example of the illumination element.

[0079] Figures 6A to 6D Examples of optical waveguide shapes that can be used for any illumination element disclosed herein are shown. The optical waveguide can be integral with the seal surrounding the light source, or the optical waveguide can be disposed on top of the seal. The optical waveguide can be formed of the same material as the encapsulating layer, or a different material can be used. The optical waveguide shape helps to distribute light to the target treatment area with minimal light loss and is shaped to fit the cavity left after tumor resection to ensure that all tissue in the target treatment area is irradiated to activate the therapeutic agent. Additionally, the optical waveguide can physically or mechanically support the tissue and help prevent tissue collapse, which also helps ensure that all tissue in the target treatment area is irradiated.

[0080] Figure 6A A cloud-shaped optical waveguide 451 is shown. The cloud can include a plurality of protrusions extending radially outward. The light source and the temperature sensor can be disposed in the cloud.

[0081] Figure 6B An optical waveguide including a central spherical ball 453 having spokes extending radially outward is shown. These spokes can be linear spokes or take any other form and can help to anchor the optical waveguide in the tissue and support the tissue and direct the light directly to the target treatment area. The light source and the temperature sensor can be disposed in the optical waveguide.

[0082] Figure 6C A star-shaped polygon optical waveguide 452 is shown. The star includes a plurality of arms extending radially outward, and each arm can radially taper outward and terminate in a narrow tip. The light source and the temperature sensor can be disposed in the star.

[0083] Figure 6DAn eye-shaped optical light guide 454 is shown. The optical light guide can have a wide bow-shaped middle portion and relatively tapered sides that narrow to a narrower portion. A light source and a temperature sensor can be disposed within the optical light guide.

[0084] Figure 7 An example of an illumination element having multiple light sources is shown, where an LED 420 is disposed on a substrate 430 such as a flexible PCB. The illumination element is coupled to a tether 300 such that the illumination element can receive power from a power receiver element, and an optional temperature sensor (not shown) can be operatively coupled to electronic components within a housing. The illumination element can be coupled to a flat planar material sheet or wallpaper 455 formed of an optical material that can act as a light guide to help distribute light to a target treatment area. The wallpaper can also be referred to as a conformal stretch cavity paper (CTCP) capsule. The flat planar material can be bent and trimmed / cut to conform to the dimensions of the target treatment area and affixed to the target treatment area. The entire flat planar material can be trimable, or only certain portions can be trimable. Areas that should not be trimmed are clearly marked (e.g., areas adjacent to the LED). The flat planar material can then be coupled to tissue within a cavity left after tumor resection using techniques such as adhesives, sutures, friction fit, or other techniques known in the art. If an adhesive is used, light such as ultraviolet light (UV) can be introduced into the wallpaper and distributed by the wallpaper to the target treatment area to help cure the adhesive (e.g., cyanoacrylate). The light can be provided by an external light source, which will be discussed below.

[0085] Wallpaper may be desirable because the known surgical cavity dynamics after resection of brain metastases and their implications are a challenge for postoperative radiosurgery in patients with glioblastoma multiforme (GBM). Patients with symptomatic brain metastases are typically treated with a surgical resection procedure followed by postoperative stereotactic radiosurgery of the surgical cavity to improve local control. Based on many brain metastasis expert panels, there is currently no clear consensus on the timing or start date of radiotherapy simulation for these patients. As an illustrative example of the challenges faced today, some believe that delayed radiotherapy (4 to 6 weeks postoperatively) appears to have theoretical advantages in dealing with surgical cavity collapse, which can thereby reduce the target volume.

[0086] A large number of studies have confirmed that the surgical cavity changes in patients undergoing surgery and postoperative radiotherapy have been retrospectively evaluated. The rate of parenchymal cavity collapse (>2 cm^3) in this cohort at an average of 24 days postoperatively appears to be between 21% and 31%. Therefore, some caregivers have concluded that delaying radiotherapy for more than two weeks after surgery does not provide the benefit of a smaller target volume. It seems obvious that due to a series of reasons including edema control, healing, fibrosis, etc., during the time period including 3 to 4 weeks after surgery, the volume of a considerable part of the surgical cavity changes significantly. This has been evaluated as an opportunity to reduce the treatment volume by delaying postoperative radiation.

[0087] However, treatment delay will have a profound impact on these at-risk patients. Given the known cavity dynamics and cavity collapse, there is still a need to maximize the light coverage of the surgical cavity margin that persists throughout the treatment cycle. The combination of light sources embedded in the CTCP capsule ensures that the cavity margin surface is not otherwise escaped from irradiation.

[0088] Such CTCP capsules can include a multi-material matrix that will be used to conformally line the inner edges of the resection cavity using light. The multi-material matrix includes various materials, each with specific properties to maximize the conformal lining effect and in some cases to act as waveguides. The base of the matrix can be a flexible biocompatible material that conforms evenly to the cavity edge shape without impeding light transmission or flux. The matrix serves as a scaffold for various standard or custom components, including spans of higher tensile strength materials to maximize the expansion effect of the CTCP capsule. Such expansion properties will counteract the tendency of the cavity to collapse, ensuring a uniform, consistent, and personalized distribution of light activation and light guidance. In some cases, the scaffolding function of the base matrix is not limited to components that counteract cavity collapse. In some cases, the multi-material matrix can include components that support or anchor the light elements themselves with a scaffold to optimize the placement of various optical components and system performance. Such capsules can be personalized. In some examples, the higher tensile spans serve as one or more slats. Each slat can be individually controlled to optimize the lining. The multi-material matrix can be molded or impregnated with optimized polymeric materials. In some cases, the higher tensile strength material can be embedded in the base of the matrix or protrude from the base of the matrix in the span of one or more cavity expansion materials. In some cases, the cavity expansion materials can anchor or suspend one or more light elements or multiple optical systems, or can not anchor or suspend one or more light elements or multiple optical systems. Such customization can occur at the time of implantation or when working as a modular surgical kit. Such examples can include various multi-material matrices of various shapes, sizes, and configurations. Some CTCP capsules can include one or more radioisotope labels to assist with visualization, for example, using CT and / or MR scans. Such methods will assist in differentiating the capsule from surrounding tissue, tumor tissue, and will enable the determination of the migration or detachment of the wallpaper and / or irradiation elements.

[0089] Due to known surgical cavity collapse or contraction, some resection cavities may also have curvatures and hard-to-reach recesses. Such customized CTCP capsules can be personalized to address such challenging cavity conditions and dynamics. Various adhesives, gels, fiber meshes, and waveguides can also be employed to optimize the CTCP capsule. The light source can be embedded within the CTCP. The CTCP material can be overmolded onto the LED and printed circuit board. The capsule can be enclosed, partially enclosed, a modular combination of various capsule components, and / or can contain one or more pre-configured holes.

[0090] The multi-material substrate can be a combination of a variety of different materials and / or one or more material thicknesses. The multi-material substrate can be a variety of different materials configured to be inflatable for use as an implantable balloon, as will be described in more detail below. The CTCP application kit can include a pre-configured assembly of various components designed such that a caregiver can optimize the CTCP capsule according to patient needs.

[0091] Figure 8 Another example of an optical waveguide that can be integrated with or coupled to an illumination element is shown. Here, the illumination element includes one or more light sources 420 (e.g., LEDs) mounted to a flexible or rigid PCB substrate 430. The LEDs are powered via a tether 300. The optical waveguide 456 can include a spherical central portion with a plurality of spokes extending radially outward, or the optical waveguide 456 can include a flat planar circular central portion with a plurality of planar spokes extending radially outward. The spokes are formed of an optical material that facilitates delivering light to the target treatment area with minimal light loss, and the spokes also help support tissue in the cavity formed after tumor resection, thereby preventing cavity collapse. This helps ensure illumination of the target treatment area. The spokes can be of any shape including flat planar rectangular arms, circular cylindrical arms, or any other shape.

[0092] Figures 9A to 9D An example of a customized optical waveguide that can be coupled to an illumination element is shown.

[0093] In Figure 9A , the tether 300 delivers power to a light source encapsulated in a standard shape 401 such as spherical or square. The light source is implanted in a cavity 1100 formed after tumor resection from the brain of a patient's skull 1000. In some cases, it may be beneficial to provide an additional optical waveguide element customized to any shape and easily coupled to the encapsulation to help support tissue in the cavity 1100 and facilitate delivering light to the target treatment area. In Figure 9A , an external optical waveguide 460 customized to fit the cavity is coupled to the illumination element, thereby forming an external oval optical waveguide. The external optical waveguide can be snap-fitted, adhesively bonded, or otherwise coupled to the internal main optical element.

[0094] Figures 9B to 9D Examples of optical waveguides that can be snapped onto, bonded to, or otherwise coupled to an optical element are shown.

[0095] In Figure 9B , the spherical optical waveguide 461 has a smaller hemispherical recessed area sized to accommodate the optical element. The optical element is inserted into the recessed area and then adhesively bonded or snapped in place. In this example, the optical element is coupled to the optical waveguide 461 eccentrically, however the optical element can also be disposed at the center of the spherical optical waveguide.

[0096] Figure 9C A cloud-shaped light guide 462 is shown having a hemispherical recessed area sized to receive an optical element. The optical element is inserted into the recessed area and then adhesively bonded or snapped into place. The cloud-shaped light guide may include a plurality of protrusions extending radially outward.

[0097] Figure 9D A rectangular light guide 463 is shown having linear sides and arcuate or fan-shaped top and bottom. The light guide includes a hemispherical recessed area sized to receive an optical element. The optical element is inserted into the recessed area and then adhesively bonded or snapped into place.

[0098] Those skilled in the art will understand that Figures 9A to 9D the examples in [[ ]] are not intended to be limiting, and a light guide of any shape may be coupled to the illumination element to support tissue in the tumor cavity and ensure that light is delivered to the target treatment area.

[0099] Figure 10 Another example of an illumination element that can be used to conform to the tumor cavity 1100 after tumor resection is shown. Here, an illumination element of a package 401 having any of the configurations described herein is coupled to a tether 300 and powered by electricity from the tether 300. The illumination element in the package 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, rather than the solid seal described above. The expandable member is malleable, so that when the expandable member expands radially, it will conform to the wall of the tumor cavity and provide uniform support, thus helping to ensure that the target treatment area is irradiated with light. Additionally, to accommodate changes in the tumor cavity, the radially expandable member can be adjusted by further expanding or by contracting it. The expandable member can be inflated with a fluid such as a liquid or a gas. A contrast material may also be used so that the balloon can be visualized using radiographic imaging.

[0100] Figure 11Shows the use of a planar immersion lens 600 that can be disposed on a substrate. The planar immersion lens 600 can be disposed between an external power source (not shown) and a power receiver element 700 in an illumination system, and helps to focus energy onto the receiver for efficient energy transfer. The substrate can be ridged or flexible and can be disposed adjacent to or attached to the skull 1000 and near the power receiver element. Here, the illumination system can be any of the examples disclosed herein and includes a wireless receiver 700 that is disposed in or attached to the tumor cavity after tumor resection and attached to the skull 1000. The wireless receiver 700 includes an antenna coil 710 that is configured to receive energy from an external energy source and the energy is focused onto the coil through the immersion lens. An illumination element that can include one or more light sources such as LEDs is powered by the power delivered to the coil. The light source can be encapsulated in a seal 720 that helps to diffuse the light and also helps to hold the implant in place within the tumor cavity 1100. Any of the seals and light guides disclosed herein can also be used for this example of the illumination system.

[0101] Figure 12 Shows the use of multiple light sources in an illumination system. Here, the illumination element includes multiple light sources 420 that are oriented to provide a directional light output. In this example, three light sources 420 (e.g., LEDs) are oriented such that they emit light 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 illumination element is disposed in a tumor cavity 1100 formed after tumor resection from the brain of a patient's skull 1000. The light sources can be independently controlled to direct the light and also independently adjust the light intensity and on / off timing. Some electronics 480 can be disposed on a substrate 430 that holds the light sources 420. The substrate 430 can be a printed circuit board. The illumination element can be encapsulated 410 in an optical material that promotes light delivery, for example, by helping to diffuse the light or efficiently transmit the light and providing a protective covering for the light sources. Any of the seals or light guides described herein can be used as the seal. Having multiple light sources enables different light therapies to be provided.

[0102] Figure 13 Shows an example of a light source control device 480 that can be used for any of the examples of the illumination systems such as Figure 12 described herein. When multiple light sources are used, the light source control device 480 controls the illumination of the target tissue and is capable of independently controlling the light sources. The control device 480 includes an oscillator 481 and a multiplexer 482 that cycles through Figure 13Each of the four LEDs 483 shown. In an alternative example, the microcontroller 484 may control the oscillator 481 and the multiplexer 482. The tether 300 connects the control device to the power receiver element. The electrical components may be mounted on the PCB 430. The control device 480 may also be in the housing rather than the illumination element.

[0103] Figure 14 An example of an illumination system is shown that may also include electrical stimulation of the target treatment area. Here, after removing a tumor from the brain of a patient's skull 1000, the illumination system is disposed in the tumor cavity 1100. The illumination system may be any system 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 the substrate may be encapsulated 410 in a material that protects the device and facilitates delivery of light to the target treatment area, for example by acting as an optical waveguide or by diffusing the light. The encapsulation may be any encapsulation example or optical waveguide disclosed herein and may also help to secure the device in the tumor cavity. Extending from the PCB is a conductor 801 attached to an electrode 800 that is exposed on the side of the illumination element and may provide electrical stimulation (deep brain stimulation) to the target treatment area either by direct contact with the brain tissue or by conduction via interstitial fluid in the resection cavity. Thus, phototherapy and electrical stimulation may be provided simultaneously. The illumination system (e.g., Figure 14 the illumination system) may 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, and any other condition in which nerve stimulation is beneficial. The stimulation may be provided alone or in combination with phototherapy, in which light may be used to treat diseases, including but not limited to brain cancer, for example by activating photosensitizers. Electrodes for tissue stimulation, whether in the brain or elsewhere in the body, may be used in any example of the phototherapy systems described herein. Additionally, a phototherapy system having an electrode is not limited to being implanted in a tumor cavity formed after tumor resection. The phototherapy system may be placed in any tissue in which phototherapy and / or electrical stimulation will be delivered to treat any disease or condition.

[0104] Figure 15A An example of a reinforced substrate is shown that may be used in any example of the light and / or electrical stimulation systems disclosed herein. For any substrate used in these examples, such as a substrate on which a light source is mounted or an optical waveguide substrate, it may be advantageous to use a substrate having reinforcement in the substrate to provide a stiffer substrate or a substrate that can be bent, folded, or otherwise shaped to fit the target treatment area and maintain that shape. Here, the substrate is similar to Figure 7a substrate 455 therein, 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 of a material having reinforcement features, or the reinforcement features can be built into the substrate. For example, herein, a two-dimensional grid of ribs 457 can be formed in the substrate to provide the desired reinforcement characteristics. This helps the substrate maintain its shape once placed in the tumor cavity created after tumor resection. The irradiation element 430 (which can be any of the irradiation elements disclosed herein) can be positioned anywhere along the substrate, and the tether 300 is coupled to the irradiation element 430 to supply power. The reinforcement features can be formed of a different material (e.g., a different polymer) having different mechanical properties (such as Young's modulus, durometer, etc.) compared to the base substrate.

[0105] Figure 15B shows Figure 15A a device having reinforcement features in a substrate within a tumor cavity 1100 implanted in a skull 1000. The tether 300 supplies power to an irradiation element (not shown in this view), which is coupled to a substrate having reinforcement members or strengthening members. In two dimensions, the substrate is formed as a partially closed loop, or in three dimensions, the substrate is formed as a partially closed spheroid, to support and conform to tissue and irradiate the tissue. The substrate serves as an optical waveguide to assist in irradiating the target treatment area.

[0106] Figure 16 shows another example of a reinforced substrate formed as a closed loop in two dimensions or a closed spheroid in three dimensions (e.g., Figure 15A example). Here, power is delivered via the tether 300 to an irradiation element (not shown and which can be any of the irradiation elements disclosed herein) that is disposed on a reinforced substrate 458 within the tumor cavity 1100 in the skull 1000. The reinforced substrate can be the same as or different from that shown in Figure 15A , and the ends can be held juxtaposed to each other in a closed configuration due to a stiffener in the substrate that maintains the desired shape or due to the use of an adhesive. This helps maintain the substrate in the desired configuration for supporting the tumor cavity to ensure proper irradiation of the target treatment area.

[0107] Figure 17 shows the use of additional support elements within a tumor cavity 1100 in a patient's skull 1000. Figure 7 , Figures 15A to 15B and Figure 16The wallpaper substrate concept described herein can be used for additional support elements disposed in a tumor cavity to help support tissue in a target treatment area and also help distribute light to the target treatment area. Here, the tether 300 provides power to an illumination element that can be any of the illumination elements disclosed herein. The illumination element can be encapsulated in a material, and the combination of the illumination element and the seal can be coupled to a flat planar substrate 457 that can be shaped and trimmed to fit flat in the tumor cavity. The flat planar substrate 457 can be any of the flat planar substrates described herein and can be optically transparent to ensure light passes through the flat planar substrate. Here, the wallpaper is formed as a partially closed loop in two dimensions or as a partially spherical shape in three dimensions. In some cases, it may be beneficial to provide additional support elements 459 that help support tissue in the tumor cavity and prevent collapse, and the additional support elements can also be formed of an optical material to form an optical waveguide that helps distribute light to the target treatment area. The support element can be a thin sheet of planar material trimmed and shaped to fit the tumor cavity, or the support element can be preformed into various desired shapes. The support element can then be secured to the tissue in the tumor cavity using techniques known in the art (such as using sutures, adhesives, or other techniques). The additional support element can also act as a spacer between the tissue and the illumination element or act as an optical instrument to help deliver light to the tissue.

[0108] Figure 18 Another example of using additional support elements 490 in a tumor cavity 1100 in a patient's skull 1000 is shown. Again, the tether 300 provides power to an illumination element that can be any of the illumination elements disclosed herein. Multiple additional support elements 490 can be coupled together (as indicated by the arrows) to form a fully closed loop or a partially open loop (in two dimensions) or a fully closed spheroid or a partially open spheroid (in three dimensions), which results in a rigid or semi-rigid structure that supports the tissue in the tumor cavity and prevents the tissue from collapsing inward. Thus, customization can be performed during surgery to ensure that the light provided by the illumination element can irradiate the entire target treatment area and support the cavity. The support elements can be snapped together, press fit together, adhesively coupled together, or using coupling mechanisms known in the art to form any desired shape, and these support elements can be formed of an optical material to help distribute light to the target treatment area.

[0109] Figure 19 A second port for coupling the illumination element to an external light source is shown. Here, the tether 300 is coupled to be disposed as described above Figure 7The illumination element (not shown) in the flat planar substrate 455. The tether 300 delivers power to the illumination element, which delivers light through the flat planar substrate 455 to the target treatment area. As described above, the flat planar substrate 455 can be shaped and trimmed to conform to the target treatment area, and the flat planar substrate can be adhesively bonded to tissue. In some cases, such as when using cyanoacrylate, light can be used to help cure the adhesive. Thus, an external light source 1300 can provide the required curing light, such as ultraviolet light, via a port 1210 that can be releasably coupled to the external light source. The light is then delivered to the flat planar substrate via an optical fiber 1200, which then delivers the light to the target treatment area, facilitating the curing of the adhesive. Once the substrate 455 is adhesively bonded to the tissue, the external light source can be turned off and decoupled and removed from the second port 1210. The port 1210 and the optical fiber 1200 can remain coupled to the flat planar substrate 455, or the port and the optical fiber can also be removed. An external light source coupled to the light input port 1210 and delivering light via the optical fiber 1200 to the flat planar substrate for illuminating and curing the adhesive can also be used to adhesively bond and cure other components that can be adhesively bonded, such as Figures 17 to 18 the auxiliary support element in, surrounding (e.g., Figure 5 the) encapsulation of the illumination element, Figures 6A to 6D the optical light guide shape in, and Figures 9A to 9D the auxiliary light guide in. In other examples, a second light port can be used to introduce light into the target treatment area via the substrate 455 using an external light source to illuminate a photosensitive biologic agent, chemical, or other reagent.

[0110] Figures 20A to 20B The use of multiple light sources in the illumination element and the resulting illumination pattern providing desired illumination control is shown.

[0111] A uniform light source may not be the best solution for asymmetrically distributed diseases in human tissue. Depending on the individual patient and the details of the anatomy and the tumor, there may be areas in the surgical cavity that are more likely to contain residual tumor. To focus the photodynamic therapy (PDT) effect, it may be beneficial to concentrate the light in these areas. Clinical trials of intraoperative PDT have shown a direct relationship between the input light (fluence, joules / cm^2) and the clinical outcome. In a single application (as part of a longer series of treatments), examples of the devices disclosed herein can deliver a customized light output, where areas with a greater risk of tumor are emphasized / output more.

[0112] The total amount of light available in an implant device is limited, mainly due to wireless power transfer limitations and tissue heating limitations. Therefore, optimal use of the light source is desired and can be achieved in a device capable of controlling the output of multiple light sources in a manner such as with variable combinations of light sources in an on and off configuration.

[0113] In addition, this configuration can be applied not only to the on and off configuration, but also to controlling the individual LED light output within a defined range. This can be controlled by firmware embedded in the implanted PCB or housing, which will direct the power output of the individual light sources in the implant. User control of this can be achieved through a user interface designed to control the power delivery and output device. The planning of this "prescription" for each patient can be similar to the spatial and temporal planning of radiotherapy, in combination with prior imaging of the tumor location in the patient.

[0114] In Figure 20A , the tether 300 is coupled to an illumination element that, in this example, includes four independently controllable light sources 420, here LEDs. The LEDs are mounted in a substrate 430 such as a flexible PCB, and the components can be encapsulated in any manner as previously described. Since the LEDs can be independently controlled, the LEDs can be turned on or off as needed to direct light in a desired direction for a desired amount of time.

[0115] Figure 20B Shows the intensity of the light emitted by the four LEDs in all four directions when light is emitted in a direction away from the center of the PCB 430. Each direction has a leaf-shaped pattern that shows the illumination pattern of each LED and the intensity of the light emitted. With the total power provided by the tether fixed, the intensity of each LED is higher when only a single LED is activated at a time. Therefore, illumination can be directed in a desired direction and the light intensity can also be controlled.

[0116] Example of method of use

[0117] Figure 21 Shows an example of a method of treating a tumor. The treatment can be determined by a team of physicians and surgeons, which can include neurosurgeons, neuroradiologists, and neuro-oncologists. Any of the illumination devices and optional features disclosed herein can be used according to the following method of use. This example relates to the treatment of brain cancer, but this is not intended to be limiting, and those skilled in the art will understand that other diseases and conditions can also be treated.

[0118] MRI (Magnetic Resonance Imaging) scans can be used to determine the size and shape of a tumor, and based on this information, an appropriately sized device can be selected. Other imaging techniques known in the art can also be used, such as computed tomography (CT), positron emission tomography (PET), radiographic imaging, etc. The irradiation dose can also be determined based on the bioavailability of the photosensitizer delivered to the target tissue, as well as the effective light flux and timing. In some examples, artificial intelligence (AI) or an AI classifier can be used at least as a pattern recognition tool to perform detection and guide the physician in performing optimized targeted therapy, thereby improving patient outcomes. The dose includes the photosensitizer drug dose and frequency, as well as the light flux from the implantable phototherapy device. Depending on the patient's condition and the expected severity of any remaining tumor cells in the tumor margin, the initial dose can be higher or lower.

[0119] Craniotomy typically removes a circular bone segment with a diameter of 5 cm to 10 cm from the skull and enables access to the patient's brain. After removing the tumor 2102, the device is implanted 2104 into the tumor cavity formed after craniotomy and tumor resection surgery, where most of the glioblastoma tumor or other diseased tissue is removed by a neurosurgeon using standard surgical procedures. The light source portion of the device is fixed in place by a neurosurgeon using methods known in the art (including any of these methods described herein). The light source can include a thin flexible sheet or wallpaper that is adhered to the cavity and cured in place. The surgeon can trim the thin flexible sheet or wallpaper to fit the tumor size and shape 2106 of the individual patient.

[0120] The surgeon can adhesively bond or otherwise fix the device to the tumor cavity using cyanoacrylate, fibrin glue, or similar biocompatible tissue adhesives 2108. The device is capable of "self-curing" by emitting the light wavelength required for the adhesive (glue). The LED emitter can be built into the device, or an external curing light can be coupled to the light guide such that the curing light can reach where it is needed. For example, in the case where the adhesive (such as a UV-curing adhesive) is cured by light, the light source itself can be the source of its own curing light. The device can have an attachment connected to a point on the light source, and the curing light can be sent to the adhesive through the light source, such as in the example previously described above regarding Figure 19 the example.

[0121] If trimming is required, the surgeon can trim the shape of the light guide of the light source with surgical scissors or other cutting instruments to better fit the corresponding tumor cavity of the patient. The light source can include visual markings indicating areas that should not be cut.

[0122] The implantation of the irradiation element is determined by the neurosurgeon, but it should be ensured that the light is directed to the area containing the residual tumor or the area that may experience recurrence in the target treatment area. For dendritic and infiltrative GBM tumors, an additional margin of about 2 cm from the known margin may be a good boundary. For smaller tumors, the light element can be attached so that all lumen surfaces are irradiated.

[0123] Then, the device 2110 can be tested to visually check that the light source is working and in the correct position.

[0124] The tether can extend outside the skull, and the wireless power part of the device is fixed in place anywhere outside the skull and under the scalp (such as behind the ear). The tether can also be fixed to the skull so that it cannot be pulled out by the patient. Clips or grommets can be attached to the skull adjacent to the craniotomy opening, and the tether can be fixed with the clips or grommets to protect the wire from the sharp edges around the craniotomy and also to keep the tether in place. The excess wire can be wound around the clip or grommet. If needed, additional sutures, screws, adhesives, etc. can be used to help fix the tether and the coil. A recessed area in the skull can be formed to help accommodate the tether, the coil, or the housing, thus preventing or minimizing bulging. The coil can be placed on the same side as the craniotomy, or the coil can be placed on the opposite side. Once the device is implanted and fixed to the skull, the skull can be closed, and the scalp can also be closed.

[0125] Optionally, the irradiation system can include a radiopaque marker adjacent to the irradiation element to allow the surgeon or physician to visualize and confirm the placement of the device in the tumor cavity of the patient using imaging techniques known in the art (such as MRI, PET, x-ray, etc.).

[0126] After surgical recovery, the photodynamic therapy 2112 is activated by powering the wireless power part of the implant via an external transmitter in the clinic. The implant can control the power level it receives and direct most of this power to the light source. Under the observation of the operator, the transmitter will monitor the dose. Each treatment session will require a sufficient dose for effective photodynamic therapy. Since the treatment sessions may be at most only a few hours, the patient can use regular phototherapy sessions to control the recurrence of their tumor over months or even years. Examples of the duty cycle can include one minute of irradiation and thirty seconds without irradiation, and then repeat. This helps reduce heat and also allows the tissue to re-oxygenate between light cycles. The power receiving element in any example of the device can include a clock oscillator so that it can manage the cycle of the light source. The energy transmitter is capable of reprogramming the power receiver element to change the timing of light delivery.

[0127] The fractionation of the dose can occur over several days, distinguishing this method from single - treatment.

[0128] Using the disclosed devices and methods enables the efficient transmission of a large amount of electrical power to the device while still positioning the optical device at the center of the brain where traditional wireless power methods do not easily reach.

[0129] Phototherapy can optionally be combined with imaging and mapping to assist in guiding the irradiation. Since the irradiation element can comprise multiple light sources, the light can be directed to the desired direction such that if an area with more tumor cells or an area expected to have more tumor cells is identified, phototherapy can be directed in that direction. Additionally, phototherapy can be combined with algorithms and tumor recurrence modeling to direct the light to areas of concern, where the dose is 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. Then, known brain imaging techniques in the art are used to monitor the patient for adverse reactions to the photodynamic therapy or photosensitizer drug at regular intervals (e.g., every 3 to 6 months) to look for tumor recurrence. The patient dose and treatment can be adjusted as needed.

[0130] Possible opportunities for personalized treatment can occur at different times during the patient's treatment, including during resection, during the recovery period of about 6 weeks after resection, during the period of about 6 weeks of a combination of TMZ (temozolomide) chemotherapy and radiotherapy, and during the 6 - month follow - up period. The use of phototherapy can be used alone or in combination with any of these time periods and treatments to provide enhanced results.

[0131] Wavelength of light

[0132] The wavelength of the light delivered by the irradiation element is selected based on the wavelength required to activate the photosensitizer and the depth of tissue penetration. For example, light in the range of red to near - infrared wavelengths from about 600 nm to 940 nm can have sufficient tissue penetration in brain tissue. This wavelength can be used for any example of the devices disclosed herein.

[0133] Examples of photosensitizers

[0134] Any photosensitizer that can have a therapeutic effect when exposed to light can be used in any example of the irradiation systems described herein. Examples of photosensitizers include, but are not limited to, methyl aminolevulinate hydrochloride; padoporfin potassium; talaporfin sodium; SGX-301; nemorubicin + gemcitabine; ridoporfin; aminolevulinic acid + artemisinin; CTT-1700; IVX-MES; IVX-PDT; IVXP-02; JL-103; Photobacterium; YC-9; ADC + nemorubicin; bleomycin sulfate + nemorubicin; lutetium texaphyrin; methyl aminolevulinate hydrochloride; motexafin lutetium; padoporfin; SL-017; Vangiolux; deuteroporphyrin; small molecule for activated ABCB1 for graft-versus-host disease; recombinant peptide targeting EGFR for oncology; small molecule targeting eNOS; nNOS and NO synthase for oncology; epirubicin hydrochloride + nemorubicin; porfimer sodium; temoporfin; palladium bacteriochlorophyll; rotaporfin; verteporfin; and 5-aminolevulinic acid.

[0135] These photosensitizers can be irradiated with light in the treatment of various cancers and other diseases, including 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); biliary tract cancer (e.g., cholangiocarcinoma); bronchial cancer; kidney cancer (e.g., renal cell carcinoma); renal cell cancer; choroidal neovascularization; brain tumors; gliomas; neurofibromas; head and neck cancer; hepatocellular carcinoma; metastatic colorectal cancer; nasopharyngeal cancer; pancreatic cancer; benign prostatic hyperplasia; age-related macular degeneration; coronary heart disease; cutaneous vascular malformations; peripheral artery 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.

[0136] Experiment

[0137] A sample device having a coil for receiving RF energy, a rectifier for converting the received alternating current of the electric power into direct current, and an LED was tested. The LED emitted light having a wavelength of about 630 nm, and the measured fluence (energy density) was about 120 J / cm^2. The radiant power was measured using an optical power meter in a driving current range of about 0.1 mA to about 20 mA. According to the reported literature, the extrapolated necrosis death depth at this fluence level was estimated to be about 10 mm to 20 mm.

[0138] The topic of photosensitizer drug activation is well known in the art. Effective application of photodynamic therapy requires light at the optimal wavelength, sufficient intensity, and sufficient duration for photosensitizer (PS) drug activation to deliver a minimum light fluence (joules per square centimeter of area).

[0139] When demonstrating efficacy against tumors in preclinical and clinical testing, known experimental protocols have used light fluence as a control parameter (i.e., the PS activation threshold or target). Thus, since the examples of illumination systems disclosed herein deliver discrete amounts of light fluence consistent with those known in the art, effective activation of the PS must be followed. In some examples, the target light fluence is from 90 J / cm² to 500 J / cm². In some examples, the target light fluence is optimized to be from 100 J / cm² to 200 J / cm².

[0140] Fractionated or rhythmic PDT (mPDT) has received considerable attention in the PDT research community. For PS activation, mPDT can achieve the same dose but over a longer period at lower light intensities. The scientific literature has reported promising results in animal models over a 10-day period with light intensities of <100 μW / cm², 1000 times lower than typical PDT protocols. By using a much longer period (1000x), the product of intensity and time remains constant.

[0141] Other literature has shown that the fluence rate (W / cm²) does have an impact, showing that at the same amount of dose, the higher the intensity, the deeper the tumor cells are killed. This can also lead to more normal cell death, but this does support the concept of a "threshold" for photosensitizer activation.

[0142] Other literature has also reported that studies of other light fluence rates are possible. Light fluence rates of 20 J / cm² to 400 J / cm² were used (mostly between 100 J / cm² and 200 J / cm²), and there is some evidence that higher light fluence rates correspond to better outcomes.

[0143] Based on the data contained in these references, the implanted phototherapy device is targeted to a light fluence of 100 J / cm^2. When dispensed over many hours or even days, the instantaneous power required to deliver this energy can be on the order of mW or tens of mW (e.g., 7 mW / cm^2 over 4 hours). Additional details can be found in "Photodynamic therapy (PDT) for malignant brain tumors - Where do we stand" by Brendan J. Quirk et al., Photodiagnosis and Photodynamic Therapy 12.3 (2015): 530 - 544. And "Modulation of light delivery in photodynamic therapy of brain tumours" by Tudge, S.H. et al., Journal of Clinical Neuroscience, 1999 6(3), 227 - 232; and "Tissue - adhesive wirelessly powered optoelectronic device for metronomic photodynamic cancer therapy" by Yamagishi, Nature Biomedical Engineering, January 2019; the entire contents of which are incorporated herein by reference.

[0144] Notes and Examples

[0145] The following non - limiting examples detail certain aspects of the subject matter to address challenges and provide the benefits discussed herein, etc.

[0146] Example 1 is 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; and a tether element operatively coupled to the light delivery element and the power receiver element, the tether element being configured to deliver the power from the power receiver element to the light delivery element.

[0147] Example 2 is the device of Example 1, wherein the power receiver element comprises a coil configured to receive the power from the external power transmitter, and wherein the power comprises radio - frequency energy.

[0148] Example 3 is the device according to any one of Examples 1 to 2, wherein the power receiver element includes a sealed housing operably coupled to the tether, and the device further includes electronic components disposed in the sealed housing, the electronic components being configured to control the power delivered to the light delivery element.

[0149] Example 4 is the device according to any one of Examples 1 to 3, wherein the light delivery element includes a light source encapsulated in an optical material, the optical material being configured to protect the light source, and wherein the optical material facilitates transmission of light from the light delivery element to the target treatment area.

[0150] Example 5 is the device according to any one of Examples 1 to 4, further including 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.

[0151] Example 6 is the device according to any one of Examples 1 to 5, wherein the light delivery element includes a plurality of light sources disposed on a substrate, and wherein the substrate is configured to be shaped to match the target treatment area.

[0152] Example 7 is the device according to any one of Examples 1 to 6, wherein the substrate is an optical light guide configured to direct light to the target treatment area, and wherein the substrate is configured to be trimmed to a desired shape to fit the target treatment area.

[0153] Example 8 is the device according to any one of Examples 1 to 7, wherein the light delivery element includes a plurality of light sources, the plurality of light sources being configured to be independently controllable relative to each other.

[0154] Example 9 is the device according to any one of Examples 1 to 8, wherein the light delivery element further includes a temperature sensor configured to measure the temperature at the target treatment area.

[0155] Example 10 is the device according to any one of Examples 1 to 9, wherein the light delivery element is disposed in a radially expandable member having an expanded configuration and a contracted configuration, wherein in the expanded configuration, the radially expandable member conforms to the target treatment area.

[0156] Example 11 is the device according to any one of Examples 1 to 10, wherein the light delivery element further includes a port configured to releasably receive an optical fiber optically coupled to an external light source, and wherein light from the external light source is delivered to the light delivery element via the optical fiber for irradiating the target treatment area.

[0157] Example 12 is a phototherapy system including the device according to any one of Examples 1 to 11, and is the device according to any one of Examples 1 to 10, and an external power transmitter is configured to wirelessly transmit power to a power receiver element.

[0158] Example 13 is the system according to Example 12, further including a planar immersion lens disposed between the external power transmitter and the power receiver element, and the planar immersion lens is configured to focus energy from the external power transmitter toward the power receiver element.

[0159] Example 14 is the system according to any one of Examples 12 to 13, further including an electrode configured to provide electrical stimulation to the target treatment area.

[0160] Example 15 is the system according to any one of Examples 12 to 14, further including at least one support element configured to juxtapose and support tissue in the target treatment area.

[0161] Example 16 is the system according to any one of Examples 12 to 15, further including a photosensitizer.

[0162] Example 17 is a method for delivering phototherapy to a target treatment area of a patient, the method including: providing an implantable phototherapy device including a power receiver element, a light delivery element, and a tether element; implanting the phototherapy device at the target treatment area of the patient; wirelessly transmitting power from an external power transmitter to the power receiver element; transmitting the power from the power receiver element to the light delivery element via the tether; and irradiating the target treatment area with light from the light delivery element.

[0163] Example 18 is the method according to Example 17, wherein wirelessly transmitting power from an external power transmitter to the power receiver element includes receiving radio frequency energy with a coil.

[0164] Example 19 is the method according to any one of Examples 17 to 18, wherein the irradiating includes irradiating the target treatment area with a plurality of independently controllable light emitting elements.

[0165] Example 20 is the method according to any one of Examples 17 to 19, wherein wirelessly transmitting the power includes transmitting the power from the external power transmitter and focusing the power toward the power receiver element with a planar immersion lens.

[0166] Example 21 is the method according to any one of Examples 17 to 20, further including electrically stimulating tissue in the target treatment area with energy provided by an electrode adjacent to the light delivery element.

[0167] Example 22 is the method according to any one of Examples 17 to 21, wherein the target treatment area includes the brain of the patient.

[0168] Example 23 is the method according to any one of Examples 17 to 22, wherein an optical fiber is releasably coupled to the light delivery element; light from an external light source is input into the light delivery element via the optical fiber; and the target tissue is irradiated with the light from the external light source.

[0169] Example 24 is the method according to any one of Examples 17 to 23, wherein the light delivery element includes a plurality of light sources disposed on a substrate, and the method further includes: shaping the substrate to conform to the target treatment area and guiding light in a plurality of directions to irradiate the target treatment area.

[0170] Example 25 is the method according to any one of Examples 17 to 24, further including trimming the substrate to a desired size or shape to fit the target treatment area.

[0171] Example 26 is the method according to any one of Examples 17 to 25, further including measuring the temperature at the target treatment area with a temperature sensor.

[0172] Example 27 is the method according to any one of Examples 17 to 26, wherein the light delivery element includes a plurality of light sources encapsulated in an optical material, and the optical material is an optical waveguide that guides the light from the plurality of light sources to the target treatment area.

[0173] Example 28 is the method according to any one of Examples 17 to 27, wherein the light delivery element is disposed in a radially expandable member, and the method further includes radially expanding the radially expandable member to be juxtaposed with and conform to the target treatment area.

[0174] Example 29 is the method according to any one of Examples 17 to 28, further including disposing a support element in the target treatment area to assist in supporting the tissue in the target treatment area to ensure that the tissue is irradiated.

[0175] In Example 30, the devices, systems, or methods of any one or any combination of Examples 1 to 29 can optionally be configured such that all of the recited elements or options are available for use or selection therefrom.

[0176] The above detailed embodiments include reference to the accompanying drawings, which form a part of the detailed embodiments. The accompanying drawings illustrate, by way of example, specific embodiments in which the present invention may be practiced. Such embodiments are also referred to herein as "examples". Such examples may include elements other than those shown or described. However, the inventors also contemplate examples in which only those elements shown or described are provided. In addition, the inventors also contemplate examples using any combination or arrangement of those elements (or one or more aspects thereof) shown or described with respect to a particular example (or one or more aspects thereof) or with respect to other examples (or one or more aspects thereof) shown or described herein.

[0177] In the event of any inconsistency in usage between this document and any document incorporated by reference, the usage in this document shall prevail.

[0178] In this document, as is common in patent literature, the term "a" or "an" is used to include one or more than one, regardless of any other instances or uses of "at least one" or "one or more". In this document, unless otherwise indicated, the term "or" is used to refer to a non-exclusive or, such that "A or B" includes "A but not B", "B but not A", and "A and B". In this document, the terms "comprising" and "in" are used as the plain English equivalents of the corresponding terms "including" and "wherein". Further, in the appended claims, the terms "comprising" and "including" are open-ended, that is, a system, apparatus, article, composition, formulation or process that includes elements other than those listed after such a term in the claims is still considered to fall within the scope of that claim. Further, in the appended claims, the terms "first", "second", "third", etc. are used merely as labels and are not intended to impose numerical requirements on their objects.

[0179] The above description is intended to be illustrative and not restrictive. For example, the above examples (or one or more aspects of the examples) can be used in combination with each other. For example, those of ordinary skill in the art can use other embodiments after reviewing the above description. The abstract is provided to enable the reader to quickly ascertain the nature of the technical disclosure. The abstract submitted should be understood not to be used to interpret or limit the scope or meaning of the claims. Additionally, in the above detailed description, various features can be combined to organize the present disclosure. This should not be construed to mean that for any claim, the disclosed features not claimed are necessary. Rather, the inventive subject matter may lie in less than all of the features of a particular disclosed embodiment. Thus, the appended claims are hereby incorporated by way of example or embodiment into the detailed description, where each claim stands 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 present invention should be determined with reference to the appended claims and the full scope of equivalents to such claims.

[0180] Additionally, the present technology can also be configured as follows.

[0181] (1) An implantable phototherapy device, comprising:

[0182] A power receiver element configured to receive power from an external power transmitter;

[0183] A light delivery element powered by the power provided by the power receiver and configured to deliver phototherapy to a target treatment area; and

[0184] A tether element operably coupled to the light delivery element and the power receiver element, the tether element configured to deliver the power from the power receiver element to the light delivery element.

[0185] (2) The device according to (1), wherein the power receiver element includes a coil configured to receive the power from the external power transmitter, and wherein the power includes radio frequency energy.

[0186] (3) The device according to (1), wherein the power receiver element includes a sealed housing operably coupled to the tether, and the device further includes electronic components disposed in the sealed housing, the electronic components configured to control the power delivered to the light delivery element.

[0187] (4) The device according to (1), wherein the light delivery element includes a light source encapsulated in an optical material, the optical material configured to protect the light source, and wherein the optical material facilitates transmission of light from the light delivery element to the target treatment area.

[0188] (5) The device according to (1) further includes 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.

[0189] (6) The device according to (1), wherein the light delivery element includes a plurality of light sources disposed on a substrate, and wherein the substrate is configured and shaped to match the target treatment area.

[0190] (7) The device according to (6), wherein the substrate is a light guide configured to direct light to the target treatment area, and wherein the substrate is configured to be trimmed into a desired shape to fit the target treatment area.

[0191] (8) The device according to (1), wherein the light delivery element includes a plurality of light sources, the plurality of light sources being configured to be independently controllable relative to each other.

[0192] (9) The device according to (1), wherein the light delivery element further includes a temperature sensor configured to measure the temperature at the target treatment area.

[0193] (10) The device according to (1), wherein the light delivery element is disposed in a radially expandable member having an expanded configuration and a contracted configuration, wherein in the expanded configuration, the radially expandable member conforms to the target treatment area.

[0194] (11) The device according to (1), wherein the light delivery element further includes a port configured to releasably receive an optical fiber optically coupled to an external light source, and wherein light from the external light source is delivered to the light delivery element via the optical fiber for irradiating the target treatment area.

[0195] (12) A phototherapy system, comprising:

[0196] (1) The implantable phototherapy device as described above; and

[0197] An external power transmitter configured to wirelessly transmit power to a power receiver element.

[0198] (13) The system according to (12) further includes a planar immersion lens disposed between the external power transmitter and the power receiver element, the planar immersion lens being configured to focus energy from the external power transmitter towards the power receiver element.

[0199] (14) The system according to (12) further includes an electrode configured to provide electrical stimulation to the target treatment area.

[0200] (15) The system according to (12) further includes at least one support element configured to juxtapose and support tissue in the target treatment area.

[0201] (16) The system according to (12) further includes a photosensitizer.

[0202] (17) A method for delivering phototherapy to a target treatment area of a patient, the method comprising:

[0203] providing an implantable phototherapy device including a power receiver element, a light delivery element, and a tether element;

[0204] implanting the phototherapy device at the target treatment area of the patient;

[0205] wirelessly transmitting power from an external power transmitter to the power receiver element;

[0206] transmitting the power from the power receiver element to the light delivery element via the tether; and

[0207] irradiating the target treatment area with light from the light delivery element.

[0208] (18) The method according to (17), wherein wirelessly transmitting power from an external power transmitter to the power receiver element includes receiving radio frequency energy with a coil.

[0209] (19) The method according to (17), wherein the irradiating includes irradiating the target treatment area with a plurality of independently controllable light emitting elements.

[0210] (20) The method according to (17), wherein wirelessly transmitting the power includes transmitting the power from the external power transmitter and focusing the power towards the power receiver element with a planar immersion lens.

[0211] (21) The method according to (17) further includes electrically stimulating tissue in the target treatment area with energy provided by an electrode adjacent to the light delivery element.

[0212] (22) The method according to (17), wherein the target treatment area includes the brain of the patient.

[0213] (23) The method according to (17) further includes:

[0214] Releaseably couple an optical fiber to the light delivery element;

[0215] Input light from an external light source into the light delivery element via the optical fiber; and

[0216] Irradiate a target tissue with light from the external light source.

[0217] (24) The method according to (17), wherein the light delivery element includes a plurality of light sources disposed on a substrate, and the method further includes: shaping the substrate to conform to the target treatment area and guiding light in a plurality of directions to irradiate the target treatment area.

[0218] (25) The method according to (24), further including trimming the substrate to a desired size or shape to fit the target treatment area.

[0219] (26) The method according to (17), further including measuring the temperature at the target treatment area with a temperature sensor.

[0220] (27) The method according to (17), wherein the light delivery element includes a plurality of light sources encapsulated in an optical material, and the optical material is an optical waveguide that guides light from the plurality of light sources to the target treatment area.

[0221] (28) The method according to (17), wherein the light delivery element is disposed in a radially expandable member, and the method further includes radially expanding the radially expandable member to juxtapose with the target treatment area and conform to the target treatment area.

[0222] (29) The method according to (17), further including disposing a support element in the target treatment area to assist in supporting the tissue in the target treatment area to ensure that the tissue is irradiated.

Claims

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 received by the power receiver element, the light delivery element being configured to deliver phototherapy to a target treatment area; Wherein the light delivery element includes a plurality of light sources configured to radially distribute light outwardly to irradiate the treatment area, and the plurality of light sources are configured to be adjusted to different light intensities and wavelengths; And A tether operably coupled to the light delivery element and the power receiver element, the tether being configured to deliver the power from the power receiver element to the light delivery element.

2. The device according to claim 1, further comprising a temperature sensor configured to monitor the temperature of tissue adjacent to the device.

3. The apparatus according to claim 1, wherein, The plurality of light sources are encapsulated in a material configured to provide protection thereto.

4. The device according to claim 1, wherein, An irradiation element is disposed in an inflatable member configured to conform to and provide support for the wall of a tumor cavity in the treatment area.

5. An implantable photodynamic therapy system, comprising: The device according to claim 1; And A photosensitizer, Wherein the light distributed from the light delivery element is configured to activate the photosensitizer to react with oxygen in the tissue at the treatment area, which generates reactive oxygen species (ROS) that cause tumor cell death.

6. An implantable phototherapy device, comprising: A power receiver coil configured to receive power from an external power transmitter; A light delivery element powered by the power provided by the power receiver coil and configured to deliver phototherapy to a target treatment area; A flat planar sheet including an optical material removably coupled to the light delivery element, wherein the flat planar sheet is an optical waveguide that facilitates distributing light from the light delivery element to the target treatment area, Wherein the flat planar sheet is flexible and can be trimmed to conform to the target treatment area; and A tether element operably coupled to the light delivery element and the power receiver coil, the tether element being configured to deliver the power from the power receiver coil to the light delivery element.

7. A phototherapy system, comprising: The implantable phototherapy device according to claim 6; And An external power transmitter configured to wirelessly transmit power to the power receiver coil.

8. A surgical kit for providing phototherapy to a patient, comprising: A power receiver element configured to receive power from an external power transmitter, the power receiver element being configured to be attached to the patient; A light delivery element powered by the power provided by the power receiver element, the light delivery element being configured to deliver phototherapy to a target treatment area; A conformal stretch cavity paper capsule (CTCP) coupled to the light delivery element and formed of an optical material that serves as a waveguide to facilitate distributing light from the light delivery element to the target treatment area. Wherein, the CTCP is configured to be bent and trimmed to conform to the target treatment area and is configured to be coupled to the target treatment area; A tether operably coupled to the light delivery element and the power receiver element, the tether being configured to deliver the power from the power receiver element to the light delivery element; and A preconfigured assembly of various components configured to enable a caregiver to personalize the CTCP according to patient needs.

9. 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 element, the light delivery element being configured to deliver phototherapy to a target treatment area; A tether operably coupled to the light delivery element and the power receiver element, the tether being configured to deliver the power from the power receiver element to the light delivery element; An electrode adjacent to the light delivery element, the electrode being configured to provide electrical stimulation to tissue in or adjacent to the treatment area; And A sensor configured to monitor tissue adjacent to the device.

10. An implantable photodynamic therapy system, comprising: The device according to claim 9; And A photosensitizer, wherein the light distributed from the light delivery element is configured to activate the photosensitizer to react with oxygen in the tissue at the treatment area, which generates reactive oxygen species (ROS) that cause tumor cell death.

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