Octrooicentrum
Nederland
© 2018741 (21) Aanvraagnummer: 2018741 © Aanvraag ingediend: 19 april 2017 © BI OCTROOI © Int. CL:
A61N 5/06 (2017.01)
| 0 Aanvraag ingeschreven: | © Octrooihouder(s): |
| 29 oktober 2018 | JOBAST B.V. te Eelderwolde. |
| © Aanvraag gepubliceerd: | |
| - | © Uitvinder(s): |
| Selma Aletta van Dijk te Eelderwolde. |
| © Octrooi verleend: | |
| 29 oktober 2018 | |
| © Gemachtigde: |
| © Octrooischrift uitgegeven: | mr. ir. J. van Breda c.s. te Amsterdam. |
| 24 januari 2019 | |
© Light emitting device
Light emitting device for illuminating a tissue of a subject, wherein the light emitting device is arranged to homogenously illuminate malignant cells, infectious agents or inflammatory cells of the tissue. For which purpose the light emitting device comprises a plurality of light emitting elements and wherein the plurality of light emitting elements comprises at least one light generating source.
NL Bl 2018741
Dit octrooi is verleend ongeacht het bijgevoegde resultaat van het onderzoek naar de stand van de techniek en schriftelijke opinie. Het octrooischrift komt overeen met de oorspronkelijk ingediende stukken.
Light emitting device
The invention relates to a light emitting device for illuminating a tissue of a subject and a method for treating a tissue of a subject.
Light emitting devices for illuminating tissue are known from common practice and applied during treatment of various tissues, in particular tumors.
A disadvantage of current pre- and post-operative treatment of solid tumors by either radio- or chemotherapy or a combination of both is that the efficacy of such a treatment is limited due to various resistance mechanisms. First, pressure inside a tumor is generally higher as compared to surrounding tissue. This limits the influx of any medicines or compounds in the tumor. Second, the tumor is hypoxic, which limits the efficacy of both chemo- and radiotherapy as no oxygen radicals produced by radiotherapy responsible for a cell killing effect can be formed inside the tumor. In addition, multidrug resistance pumps (MDRPs) become active in a hypoxic environment. Third, systemic side effects of chemo- or immunotherapy occur, as the active compound distributes through the whole body with a significant off-target effect. Consequently, current pre- and post-operative treatment of solid tumors by either radio- or chemotherapy or a combination of both is hampered by these effects, both in curative as well as palliative treatment of cancer. After neoadjuvant treatment by radiochemotherapy with unpredictable variable effects (i.e. complete response, partial response, no response), surgery is commonly performed for removing the tumor and its accompanying lymph nodes with the risk of leaving viable cancerous tissue behind due to a (non-) or partial responding tumor and the inability of a surgeon to reliably distinguish tumor tissue from healthy tissue.
It is therefore an object of the invention to provide a device and a method to reduce or diminish the aforementioned resistance mechanisms.
This object is achieved by a light emitting device for illuminating a tissue of a subject that is arranged to homogenously illuminate malignant cells of the tissue. Homoge nous illumination of malignant cells of a tissue, for example a cancer tumor, in combination with a targeted photodynamic agent results in an increased perfusion and oxygenation of the tumor. This enables to install radio- and/or chemotherapy at the optimal moment to allow more efficient cell killing at the tumor location. Homogenous illumination (i.e. uniform energy distribution per tumor area) allows for precise and individual administration of light at the tumor location and the light activatable compound in particular, while minimizing the amount of light and thus potentially a non-bound circulating light activatable compound administered to surrounding healthy tissue .
The light emitting device comprises a plurality of light emitting elements. As tissues vary in volumetric size and optical properties, multiple light emitting elements are advantageous to cover tissue having an uneven surface and to administer a precise field of light to that particular tissue.
The plurality of light emitting elements of the light emitting device comprises at least one light generating source. The at least one light generating source can be a xenon-based, laser-based or any other type of light source.
The light emitting device comprises at least one light generating source that is optically connected to the plurality of light emitting elements. Optically connecting the at least on light generating source to the plurality of light emitting elements is advantageous, as at least one light generating source is required and may also suffice for multiple light emitting elements. This reduces the complexity and required costs of the device.
The light emitting elements can be arranged in a twodimensional array. Such an orientation of light emitting elements is particularly suited for illuminating a flat surface of a tissue, for example the skin of a patient or a surface like the internal abdominal wall.
The light emitting elements can also be arranged in a three-dimensional array, wherein the light emitting elements are for example, arranged in a cylindrical orientation. This allows 360° illumination of internal tissues. The light emitting device can be endoscopically applied to treat internal tissues and organs such as oral tissues, respiratory tracts, esophagus, duodenum, pancreas, bile ducts, liver, small bowel, large bowel, sigmoid, rectum, anus, genitourinary system, and others. Moreover, such a light emitting device is compatible with magnetic resonance imaging (MRI).
The light emitting device comprises a controller that is arranged to control an emitted radiant flux of the device. A light dosimetry algorithm is used to control this emitted radiant flux. This algorithm is based on a preoperative clinical positron emission tomography (PET), and/or computed tomography (CT) X-ray, and/or ultrasound, and/or optoacoustic and/or magnetic resonance imaging (MRI) volumetric tissue map and its derived imaging properties per tissue type which are correlated with known optical properties of tissue described in terms of the absorption coefficient, μΆ (cm1), the scattering coefficient μ3 (cm1) , wherein the absorption coefficient and scattering coefficient can be influenced by the presence and amount of tumor tissue, fat, muscle tissue, blood, oxyhemoglobin, vasculature, bone, etc., the scattering function p(0, ψ) (sr1), where Θ is the deflection angle of scatter and ψ is the azimuthal angle of scatter and the real refractive index of the tissue, n'. The algorithm takes into account the individual optical properties of the tissue to be illuminated and the optical properties of the surrounding tissue to deliver a precision light bundle creating a controlled field of light delivery.
The plurality of light emitting elements of the light emitting device can be embodied as fiber-optic cables. This is a cost effective solution to distribute the light from the at least one light generating source to multiple light emitting elements .
The light emitting device is arranged to emit light having a wavelength between 350 to 900 nm, preferably between 660 and 740 nm, most preferable about 700 nm. In order to induce photo-immunotherapy, light having a wavelength from 350 to 900 nm is needed to activate a photodynamic therapy compound or photo-pharmacological agent. Generally, a suitable dose of irradiation is at least 1 J cmz at a wavelength of 660 - 740 nm. Near infrared light (light having a wavelength of approximately 700 nm) has the advantage that it penetrates deeper into tissue and has reduced light scattering and absorption properties. Such a wavelength allows penetration varying from millimeters to centimeters of otherwise inaccessible diseased tissues, such as tumors, infection sites, cardiovascular or inflammatory diseases located within the body of a subj ect.
The at least one light generating source of the light emitting device can comprise at least one light emitting diode. Light emitting diodes are cheap to manufacture and are flexible with regard to their emitted wavelength. This provides additional possibilities to precisely control the light output of the light emitting device for various tissue types.
Preferably, the at least one light emitting diode is a near-infrared (NIR) light emitting diode. Besides deeper tissue penetration and reduced light scattering and absorption, NIR is able to activate tumor-targeted agents, such as NIR 700DX, or other photodynamic therapy agents. These agents can be injected as an individual compound or conjugated to antibodies, nanobodies, polymers, nanoparticles (e.g. micells) or peptides which target a specific tissue. The agent is as such a targeted photo-immunotherapy or photo-activatable (nanoswitch) compound.
The light emitting device is arranged to emit light having a total radiant flux per unit surface area between 20 mW/cm2 and 500 mW/cm2. Near infrared (NIR) light with a density of 2.2 mW cm”2 (2.2 mJ s”1 cm”2) induces cell death. Assuming an attenuation coefficient of 4 cm”1, corrected for absorption (μ3) and scattering properties (μ3) , the intensity of the light applied would be down to 10% at a distance from the light emitting device to the to be treated tissue of 5.8 mm and down to 1% at 12 mm. Therefore, the dose of light emitted by the light emitting device is preferably at least 20 mW cm”z or higher, such as at least 50 mW cm”y 100 mW cm'/ 150 mW cm”2, 2 00 mW cm”2, 2 50 mW cm”2, or 300 mW cm”/
The light emitting device has a shape selected from the group consisting of a cylindrical shape, a bracelet-like shape, a strip shape, a dome-like shape. A cylindrical shape allows endoscopic application of the light emitting device, whereas a bracelet-like shape allows illumination of external areas of the body, such as upper and lower arms, joints, such as knees and elbows, upper and lower leg, neck, and other areas of the body. A strip-like shape can be placed at various positions on the body and its size and length can be varied. A dome-like shape, which can be based on a collapsible design with incorporated fiber optics at connection points of overlapping areas of illumination, can be applied to the breast of a patient to treat tissue of the breast. Due to the collapsible design, the device can be conveniently stored when not in use .
In another aspect the invention relates to a method for treating a tissue of a subject, comprising: bringing a light emitting device in proximity of the tissue of the subject and illuminating the tissue with the light emitting device with light having a wavelength between 350 nm and 900 nm. The subject is preferably a human who has cancer, a cardiovascular disease, an infection, or another disease or condition.
Preferably, a photo-activatable agent is administered to the subject prior to illumination of the tissue. The photoactivatable agent can be an agent suited for photodynamic therapy (PDT), photo-immunotherapy (PIT) and/or photopharmacology (i.e. activation or de-activation of chemical compounds or light-sensing nanoswitches), plasmonic nanostructures and phase change materials, light activatable nanomotors for drug delivery purposes by light or any other electromagnetic wave. The type of administration can be topical, by injection (such as subcutaneous, intramuscular, intradermal, intraperitoneal, intratumoral, intravenous), oral, sublingual, rectal, transdermal, intranasal, vaginal, via inhalation routes, or other types. As a specific tissue area is illuminated, any photo-activatable agent in that area is activated by the light emitting device and acts on the specific tissue area, while in surrounding tissue areas, the photo-activatable agent remains inactive.
In another embodiment of the invention, the administered the photo-activatable agent is a targeted agent such as a nanobody, or peptide. The targeted agent binds specifically to a desired tissue and is activated by the light emitting de vice in a controlled manner provided by the light dosimetry algorithm. Similarly, the light emitting device can also be used for photo-deactivation of medical compounds for purposes of photo-pharmacology. The combination of administering a targeted agent and the decreased pressure and increased oxygen content in the treated tissue, makes this method suitable to treat tissues affected by, but not limited to, breast cancer, head- and neck cancer, pancreatic cancer, esophageal cancer, gastric cancer, rectal cancer, vulvar cancer, cervical cancer, endometrial cancer, bladder and prostate cancer, and other conditions .
Preferably, the light emitting device is introduced endoscopically in the subject's body. Endoscopic introduction does not require surgery, while tissues can be accessed with relative ease.
The invention will hereinafter be further elucidated with reference to the drawing of exemplary embodiments of a light emitting device according to the invention that is not limiting as to the appended claims.
In the drawing:
- figure 1 shows a light emitting device according to the invention that can be externally applied to a subject;
- figure 2 shows another light emitting device according to the invention;
- figure 3 shows a light emitting device according to figure 1 wherein both ends are connected to each other;
- figure 4A shows a light emitting device according to the invention having a dome-like shape; and
- figure 4B shows a light emitting device according to figure 4A wherein that is collapsed.
whenever in the figures the same reference numerals are applied, these numerals refer to the same parts.
With reference to figure 1 the light emitting device 1 is arranged to homogenously illuminate malignant cells of a tissue. The light emitting device 1 is shaped as a strip having an attachment means 2, such that one end of the light emitting device 1 can be attached to another end of the light emitting device to form a bracelet-like shape suitable to wrap around an external body part such as an arm, leg, or neck.
The light emitting device 1 comprises a plurality of light emitting elements 3. This plurality of light elements 3 allows the homogenous illumination of a tissue of a patient wherein the size of the tissue exceeds the size of a single light emitting element 3.
With reference to figure 2, the plurality of light emitting elements 3 of the light emitting device comprises at least one light generating source 4. The plurality of light emitting elements 3 are embodied as panels having multiple LED/laser-based light points. These panels are connected to each other by tread clicking connections 5.
The at least one light generating source 4 is optically connected to the plurality of light emitting elements 3. This allows the usage of a single light generating source 4 to distribute light to all light emitting elements 3 hence increasing the efficiency of the light emitting device 1.
Referring to figure 1 and 2 the light emitting elements 3 are arranged in a two-dimensional array. In this arrangement, the light emitting device 1 is suited to illuminate a substantially flat surface of a tissue.
By connecting the light emitting device 1 to itself, the light emitting elements 3 can be arranged in a threedimensional array, as shown in figure 3. The light emitting device 1 is covered by a transparent cover sheet 7 and a cooling tube 6 is placed within the circumference of the light emitting device 1 to dissipate heat from the light emitting elements by circulation of circulation of a cooling medium such as water or any other coolant or cooling technology.
The light emitting device 1 comprises a controller that is arranged to control an emitted radiant flux of the device. This controller can be embodied as a computer that is electrically connected to the light emitting device 1 and that uses a light dosimetry algorithm to determine and set the emitted radiant flux of the light emitting device based on characteristics of the to be illuminated tissue.
The plurality of light emitting elements 3 can be embodied as fiber-optic cables. Fiber-optic cables form a costeffective solution to distribute light from one or a few sources efficiently over a larger surface.
The light emitting device 1 is arranged to emit light having a wavelength between 350 to 900 nm, preferably between 660 and 740 nm, most preferable about 700 nm. The advantage of light having a wavelength of approximately 700 nm is that it penetrates deeper into tissue and has reduced light scattering and absorption properties which is advantageous as less power is required to emit an effective amount of light. This reduces the required cooling capacity to maintain a temperature of the light emitting device that is suited for the body of a patient .
The at least one light generating source 4 comprises at least one light emitting diode. Light emitting diodes (LEDs) are efficient in their conversion of electric energy into light, and as such generate little heat in comparison to their light output, which in turn reduces the required cooling capacity.
The at least one light emitting diode is preferably a near-infrared (NIR) light emitting diode. NIR LEDs emit nearinfrared light having a wavelength of approximately 700 nm.
The light emitting device 1 is arranged to emit light having a total radiant flux per unit surface area between 20 mW/cirt and 500 mW/ciri. This range of radiant flux is sufficient to thoroughly illuminate most tissues of a patient.
The light emitting device 1 has a shape selected from the group consisting of a cylindrical shape, a bracelet-like shape, a strip shape, a dome-like shape. With reference to figure 4A, a light emitting device having a dome-like shape is shown. The light emitting device is suitable to illuminate a breast of a patient and can be collapsed as shown in figure 4B to ensure easy storage of the device 1.
Although the invention has been discussed in the foregoing with reference to an exemplary embodiment of the light emitting device of the invention, the invention is not restricted to this particular embodiment which can be varied in many ways without departing from the invention. The discussed exemplary embodiment shall therefore not be used to construe the appended claims strictly in accordance therewith. On the contrary the embodiment is merely intended to explain the wording of the appended claims without intent to limit the claims to this exemplary embodiment. The scope of protection of the invention shall therefore be construed in accordance with the appended claims only, wherein a possible ambiguity in the wording of the claims shall be resolved using this exem- plary embodiment.