WO2010039886A1 - Procédés et dispositifs de modulation de lumière visible d'une fonction mitochondriale dans une hypoxie et une maladie - Google Patents

Procédés et dispositifs de modulation de lumière visible d'une fonction mitochondriale dans une hypoxie et une maladie Download PDF

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Publication number
WO2010039886A1
WO2010039886A1 PCT/US2009/059104 US2009059104W WO2010039886A1 WO 2010039886 A1 WO2010039886 A1 WO 2010039886A1 US 2009059104 W US2009059104 W US 2009059104W WO 2010039886 A1 WO2010039886 A1 WO 2010039886A1
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tissue
light
radiation
subject
electromagnetic radiation
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PCT/US2009/059104
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English (en)
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John Dunning
Vivian Dullien
Robert O. Poyton
Richard Samuel Murdoch
Michael H. B. Stowell
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Clarimedix
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Priority to EP09793208A priority Critical patent/EP2364182A1/fr
Publication of WO2010039886A1 publication Critical patent/WO2010039886A1/fr
Priority to US13/076,114 priority patent/US20120065709A1/en
Priority to US14/339,335 priority patent/US20160008627A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/0618—Psychological treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0635—Radiation therapy using light characterised by the body area to be irradiated
    • A61N2005/0643—Applicators, probes irradiating specific body areas in close proximity
    • A61N2005/0645—Applicators worn by the patient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/065—Light sources therefor
    • A61N2005/0651—Diodes
    • A61N2005/0653—Organic light emitting diodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
    • A61N2005/0662—Visible light
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment

Definitions

  • Diabetic peripheral neuropathies are some of the most common long-term complications of diabetes (Pop-Busui et al. 2006). They are a major cause of pain associated with diabetes and often result in lower extremity amputations. Although studies have reported that many patients with diabetic peripheral neuropathies are responsive to near infrared radiation (NIR) therapy (Delellis et al. 2004; Powell et al. 2004; Harkless et al. 2006; Powell et al. 2006) the therapeutic mode of action of photobiomodulation in treating these neuropathies is not yet clear.
  • NIR near infrared radiation
  • NIR is effective in these therapies.
  • Light in the NIR has significant advantages over visible or ultraviolet light because it penetrates tissues more deeply than visible light and at the same time lacks the carcinogenic and mutagenic properties of ultraviolet light (Whelan et al, 2001, 2002).
  • the cellular and molecular mechanisms that underlie the therapeutic benefits of NIR are still poorly understood.
  • several studies have revealed that the most effective wavelengths for therapeutic photobiomodulation are between 600 and 830 nm (Karu, 1999; Karu, 2005).
  • Photobiomodulation using light emitting diode (LEDs) arrays or low energy lazers, has been shown to have a variety of therapeutic benefits (DeLellis et al., 2005; Harkless et al., 2006; Powell et al., 2004; Powell et al., 2006; Sommer et al., 2001; Yu et al., 1997).
  • This non-invasive therapy has been used to accelerate wound healing, improve recovery rates from ischemia, slow degeneration of injured optic nerves, and improve sensitivity and reduce pain in various types of neuropathies.
  • ROS reactive oxygen species
  • ROS are normally sequestered at the binuclear reaction center within the holocytochrome c oxidase molecule and are not released. However, under some pathological conditions (Poyton, 1999) they are released and can either act destructively (to induce oxidative stress, a condition that lies at the heart of many diseases as well as aging), or constructively (in intracellular signaling pathways (Poyton and McE wen, 1996)). Because light can affect the oxidation state of cytochrome c oxidase (Winterrle and Einarsdottir, 2006, Tachtsidis et al. 2007) it can also alter the conformation of the binuclear reaction center and cause the release of reactive oxygen species.
  • the invention relates to the use of visible electromagnetic radiation to modulate NO production and to reduce the level or production of reactive oxygen species in hypoxia.
  • the invention relates to the absorption of visible light by cytochrome c mediating the effect of electromagnetic radiation on mitochondria and that the wavelength(s) of electromagnetic radiation to use in modulating mitochondrial function are those wavelengths preferentially absorbed by cytochrome c oxidase.
  • the effects of the radiation are mediated by the absorption of the visible light by cytochrome c oxidase.
  • the effects of the electromagnetic radiation are mediated by the ability of the radiation to promote the phosphorylation or conversion of cytochrome c oxidase into a form which more readily generates NO.
  • the invention provides a method of treating hypoxia in a tissue of a mammalian subject by diagnosing the hypoxia or a condition associated with hypoxia and exposing the hypoxic tissue of the mammal to electromagnetic radiation. Exposure to the radiation improves tissue blood flow in the hypoxic state by increasing the production of NO thereby reducing vascular resistance in the tissue. Accordingly, in one embodiment, the invention provides a method of preventing or repairing tissue damage in a hypoxic tissue by exposing the tissue to electromagnetic radiation. In related embodiments, the invention provides methods of increasing mitochondrial nitrite reductase activity or NO production in the exposed tissue by exposing the tissue to electromagnetic radiation.
  • the invention provides an in vivo or in vitro method of modulating NO production by neurons or endothelial cells in a mammalian tissue capable of producing NO under hypoxic conditions and/or high concentrations of glucose by cyctochrome c nitrite reductase activity by exposing the neurons or endothelial cells to the radiation.
  • the invention relates to combination therapy of electromagnetic radiation with a second agent (e.g, nitrite, NO donors, nitroglycerin, organic nitrites, arginine) which promotes NO activity in reducing vascular resistance.
  • a second agent e.g, nitrite, NO donors, nitroglycerin, organic nitrites, arginine
  • the radiation is in the visible portion of the electromagnetic radiation spectrum.
  • the hypoxia is as low as 1- 2% to 80%, 2 to 10%, about 10% to 80% or 10% to 50% normoxia for a given tissue, in other embodiments it is from 10% to 30% normoxia for a given tissue, or 10-15% normoxia for a given tissue.
  • the hypoxia corresponds to 20 to 100 micromolar oxygen, 20 to 80 micromolar oxygen, 20 to 50 micromolar oxygen, or 22 to 35 micromolar oxygen (e.g., 30 to 50 torr) in a tissue (e.g., blood).
  • the invention provides a method of improving energy metabolism in a hypoxic tissue by exposing the tissue to electromagnetic radiation.
  • the exposure to electromagnetic radiation alters cytochrome C oxidase or the phosphorylation of cytochrome c oxidase in such a way as to modulate its nitrite reductase activity.
  • the electromagnetic radiation exposure leads to the increased expression of mitochondrial proteins leading to an increase in mitochondrial biogenesis in the tissue.
  • the invention provides a method of modulating respiration mediated by cytochrome c oxidase in a cell of a tissue or of modulating the phosphorylation of cytochrome c oxidase in a cell of a tissue by exposing the tissue to electromagnetic radiation.
  • the amount or expression of one or more subunits selected from the group of subunits of cytochrome c oxidase, cytochrome c, cytochrome c reductase or ATP synthetase in the tissue is increased.
  • the invention provides a method of reducing oxidative stress or toxic stress in a tissue of a mammal by exposing the tissue to electromagnetic radiation.
  • the toxic stress is caused by exposure to a chemical which is metabolized to a reactive species or to generate an oxygen radical.
  • the invention provides a method of monitoring the effect of treatment with electromagnetic radiation on a mammalian subject, said method comprising exposing a tissue of the subject to electromagnetic radiation and measuring the effect of the radiation on the production of NO on NO-induced vasodilators by the tissue.
  • the invention provides a method of prognosis and/or diagnosis for poor blood circulation or diabetic peripheral neuropathy (DPN) in a tissue or organ, said method comprising measuring the tissue or blood NO, VEGF, or protein carbonylation levels.
  • DPN diabetic peripheral neuropathy
  • the NO and VEGF levels indicate early stage DPN prior to loss of sensation and pain.
  • the invention provides a method of treating a mammalian subject for diabetic peripheral neuropathy said method comprising exposing an affected tissue to electromagnetic radiation.
  • the invention provides a method of monitoring the response to exposure of a tissue to electromagnetic radiation by measuring blood flow in the tissue, or measuring the tissue or blood NO, VEGF, or protein carbonylation levels.
  • the response is a response according to a method of any of aspects one through six above.
  • the invention provides methods of reducing ROS in a tissue by exposing the tissue to electromagnetic radiation.
  • the invention provides methods of improved control of hyperglycemia or blood glucose levels in diabetes patients by exposing the subject o electromagnetic radiation. In some aspects, the invention provides methods of treating a neurodegenerative condition or a peripheral neuropathy by exposing the subject to electromagnetic radiation in the visible radiation range.
  • the invention provides methods for treating diseases or conditions which may be exacerbated or caused by hypoxia or oxidative stress.
  • diseases or conditions include neurodegenerative diseases (such as Parkinson's disease), Huntington's disease, other neurological/degenerative disease such as Alzheimer's disease, fronto-temporal dementia, stroke, non-diabetic peripheral neuropathies and dementias; macular degeneration; traumatic brain injury; ischemia/reperfusion disease; migraine; tissue injury; cardiovascular diseases including atherosclerosis and hypertension, diabetes and diabetic complications of the eye (e.g., macular degeneration), kidney, and nerves (e.g., diabetic peripheral neuropathy); inflammation, arthritis, radiation injury, aging, burns/wound healing; spine/back disease such as herniated discs; peripheral vascular disease, and vasospasm.
  • the invention also provides methods for treating obesity.
  • the wavelength of electromagnetic radiation or light to be used is visible radiation. Accordingly, in such embodiment, the wavelength of electromagnetic radiation light to be used comprises wavelengths from about 400 to 625 nm, 500 to 650 nm, from 550 to 625 nm, from 575 nm to about 625 nm in wavelength, or from 500 to 600 nm, 550 to 600 nm, from 575 to 600 nm.
  • the wavelength of electromagnetic radiation to be used is substantially free of light having a wavelength greater than 595 nm, 600 nm, 610 nm, 615 nm, 625nm, 630 nm, 650 nm, or 675 nm.
  • the applied electromagnetic radiation is substantially free of radiation in the 615 to 750 nm range, the 620 to 700 nm range, 630 to 700nm range, 630 to 750 nm range, 630 to 675 nm range, the 650 and 700 nm range, or 625 to 800 nm range.
  • the wavelengths of light used fall within or are principally comprised of wavelengths falling within the primary band of mitochondrial cytochrome C oxidase. In some embodiments, the wavelengths of light used fall within the band of such wavelengths stimulating production of NO by cytochrome C oxide. In some embodiments, the light or radiation specifically targets the haem absorption bands of cyctochrome c oxidase. In further embodiments of such, the wavelengths of light are free or substantially free of wavelengths which inhibit the product of NO by cytochrome c oxidase. The period and/or intensity and/or intensity of this light can be adjusted to fit the individual subject or therapeutic objective as described further herein.
  • the mammalian subject does not have diabetes.
  • the above methods can stimulate NO production in treated tissue. Accordingly, in a further aspect of any of the above, the invention further provides for a combination therapy comprising use of any one of the above methods in combination with therapy to modulate NO activity in the subject.
  • This therapy may include administration of NO donors and other compounds (substrates for NO synthetase, inhibitors of NO degradative pathways) which modulate NO levels in a subject.
  • FIG. 1 Model relationships between hyperglycemia, hypoxia, vasoconstriction and photobiomodulation. Elements of this model are as follows: (1) the increased blood glucose levels in diabetes patients promotes endothelial cell aerobic fermentation reactions which promote hypoxia. (2) Under hypoxic conditions the levels of reactive oxygen species, especially superoxide, increase. (3) This superoxide reacts with NO in the blood to produce peroxynitrite. (4) The production of peroxynitrite from blood NO effectively reduces the concentration of NO in the blood., and results in protein nitration (5) Because NO is a vasodilator reduction in blood NO levels results in the constriction of blood vessels (especially micro vasculature) .
  • Figure 6. Power dependence of late phase light-stimulated nitric oxide production in yeast cells.
  • Figure 7. Overall rates of nitric oxide production during the late phase as a function of wavelength.
  • Figure 8 Model depicting intra and extra cellular actions of NO.
  • Figure 9 Model depicting a suitable placement of LED device for purposes of phototherapy affecting CNS.
  • Figure 13 Effects of broadband light on Cco/NO activity in HUVEC cells.
  • Figure 14 Effects of light intensity on cerebrum mitochondrial cytochrome c oxidase NO synthesis.
  • Figure 15 Differential effects of light at different wavelengths on cerebrum mitochondrial cytochrome c oxidase NO synthesis.
  • the invention relates to the use of electromagnetic radiation in the visible portion of the spectrum to modulate cytochrome c oxidase (Ceo), cytochrome c oxidase phosphorylation and, also, particularly, to modulate the ability of mitochondria to make NO, and additionally, the ability of this NO to modulate circulation in a tissue exposed to the electromagnetic radiation.
  • cytochrome c oxidase cytochrome c oxidase
  • the mitochondrion, and more particularly, cytochrome c oxidase is a major control point for cell energy production (Poyton, 1988). Accordingly, TER modulation of cytochrome c oxidase and mitochondrial function can also produce signal molecules that provide immediate benefits to cell and tissue function in hypoxic tissue.
  • electromagnetic radiation in the visible portion of the spectrum is useful in modulating cell viability or reproduction in hypoxic tissue and protecting cells and tissues from hypoxia. Whereas the former effects should have immediate short-term effects on cell and tissue physiology the latter effects would be expected to have more long-term effects.
  • Mitochondrial cytochrome c oxidase in human endothelial and mouse neuronal cells catalyzes nitrite-dependent NO synthesis under those hypoxic conditions that accompany some pathophysiological states.
  • results provide support for the use of light to modulate mitochondrial NO synthesis and in the therapeutic photobiomodulation of mitochondrial function as it relates to disease in general, including, but not limited to, metabolic disorders mediated by, or characterized by, impaired mitochondrial function, aging, neurogenerative dieases associated with aging, (e.g., Parkinsons' disease and Alzhemier's disease).
  • the methods provide means for improving blood flow in hypoxic tissues, and reducing blood pressure.
  • modulate means to decrease or increase.
  • the modulatory stimulus may be dynamic (varying over time) during application or constant.
  • the visible light modulation of mitochondrial function is illustrated in figure 1.
  • the modulation can be therapeutic in nature and result in the treatment (e.g., amelioration, reduction (as to either frequency or severity) or prevention (e.g., delay in on-set or failure to develop) of the recited adverse condition or the signs, symptoms, or adverse sequelae of the recited adverse condition. Modulation can also promote the health of a tissue or subject with respect to a particular condition.
  • the invention relates to the Applicants' discovery that visible light falling within the wavelength range of 400 to 625 nm (e.g., 400 ⁇ 25 nm, 500 ⁇ 25 nm, 550 ⁇ 25 nm, and 600 ⁇ 25), including 550 to 625 nm, benefits mitochondrial function under anoxic conditions and that light within a wavelength range of about 625 nm to 750 nm inhibits this therapeutic effect.
  • the invention provides for improved methods of promoting mitochondrial function under conditions of reduced oxygen by applying to a target tissue monochromatic or polychromatic light of a wavelength from about 400 to 625 or 550 nm to 625 nm. In some further embodiments, this light is substantially free of electromagnetic radiation having longer wavelengths or free of radiation having a wavelength from about 630 nm to 700 nm in wavelength.
  • the invention provides methods of treating hypoxia in a tissue of a mammalian subject, said method comprising exposing the hypoxic tissue of the mammal to electromagnetic radiation in the form of visible light.
  • the response to the treatment is assessed by measuring the blood flow of the affected tissue.
  • blood or tissue levels of NO or a NO- induced vasodilator or VEGF is monitored to assess the response to the treatment.
  • the radiation increases NO production by mitochondria of the exposed tissue and blood flow in the exposed tissue increases.
  • mitochondrial oxygen efficiency in the exposed tissue is increased by the exposure.
  • the hypoxia is due to poor circulation of the extremities.
  • tissue is that of a subject with diabetes.
  • the treatment alleviates a sign or symptom of peripheral neuropathy in diabetic or non-diabetic patients on in patients with normal glucose control.
  • the treatment alleviates sensory disturbances (e.g., pin and needle sensation, numbness, burning, or other unpleasant sensations) in the extremities (e.g., feet or hands).
  • the invention provides a method of treating a mammalian subject for diabetic peripheral neuropathy by exposing an affected tissue of the subject to electromagnetic radiation in the visible portion of the spectrum.
  • the invention provides a method of improving energy metabolism in a hypoxic tissue by exposing the tissue to this radiation.
  • the invention provides a method of reducing oxidative stress in a tissue of a mammal by exposing the tissue to electromagnetic radiation in the visible portion of the spectrum..
  • the invention provides a method of modulating respiration mediated by cytochrome c oxidase in a cell of a tissue or of modulating the phosphorylation of cytochrome c oxidase in a cell of a tissue by exposing the tissue to electromagnetic radiation in the visible portion of the spectrum.
  • the invention provides a method of modulating mitochondrial function in a tissue, said method comprising exposing the tissue to electromagnetic radiation in the visible portion of the spectrum.
  • the modulation increases mitochondrial nitrite reductase activity, NO production in the exposed tissue or mitochondrial biogenesis, including, for instance, the amount or expression of mitochondrial proteins.
  • the amount or expression of one or more subunits selected from the group of subunits of cytochrome c oxidase, cytochrome c, cytochrome c reductase or ATP synthetase is increased.
  • the radiation is visible or near-infrared radiation.
  • the invention provides a method of monitoring the effect of treatment with electromagnetic radiation in the visible portion of the spectrum on a mammalian subject, by exposing a tissue of the subject to the radiation and measuring the effect of the radiation on the production of NO on NO-induced vasodilators in the tissue.
  • the invention provides an in vivo or in vitro method of modulating NO production by cells (e.g., neurons or endothelial cells) in a mammalian tissue capable of producing NO under hypoxic conditions and/or high concentrations of glucose by cyctochrome c nitrite reductase activity, by exposing the neurons or endothelial cells to visible radiation.
  • a neurodegenerative condition can be treated.
  • the invention provides methods for increasing NO production and blood flow in the brain tissue of persons having or at increased risk of Alzheimer's disease or another neurodegenerative disease involving altered APP processing and plaque formation.
  • the invention accordingly provides a method of modulating APP processing or of reducing plaque formation by reducing APP processing in such persons.
  • visible radiation reverses hypoxia-related or oxidative stress induced APP processing to A ⁇ l-40 and A ⁇ l-42, the two major peptides implicated in Alzheimer's.
  • the invention further provides methods of phototherapy which enhance or improve cognitive function in Alzheimer's patients.
  • an extremity is irradiated with the electromagnetic radiation in the visible portion of the spectrum.
  • the extremity in some embodiments is the foot or hand, or lower limb.
  • the tissue can be a tissue of the central nervous system. In some embodiments, the tissue is a brain tissue or spinal cord tissue.
  • the "electromagnetic radiation in the visible portion of the spectrum” comprises light having wavelengths of about 400 to about 625 nm, 400 to 600 nm, 500 to 650 nm, from 550 to 625 nm, from 575 nm to about 625 nm in wavelength, or from 500 to 600 nm, 550 to 600 nm, and from 575 to 600 nm.
  • the wavelength of electromagnetic radiation to be used is substantially free of light having a wavelength greater than 600 nm, 610 nm, 615 nm 625nm, 630 nm, 650 nm, or 675 nm.
  • the electromagnetic radiation is substantially free of radiation of inhibitory wavelengths of light or is substantially free of light in the 615 to 750 nm range, the 620 to 700 nm range, 630 to 700nm range, 630 to 750 nm range, 630 to 675 nm range, the 650 and 700 nm range, 625 to 800 nm range.
  • Light which is "substantially free” of certain wavelengths is light which comprises a small proportion (e.g., less that 25%, 20%, 15%, 10%, 5%, or 1%) of its total energy at the specified wavelengths) or which has a ratio of light energy in the therapeutic range (e.g., 550 nm to 625 nm) which is at least 3-fold, 4-fold, 5-fold or 10-fold greater than that of those wavelengths which inhibit the effect of the therapeutic light on the mitochondria as measured according to stimulation of NO production under anoxic conditions (e.g., inhibitory wavelengths).
  • radiation specifically targets the haem absorption bands of cyctochrome c oxidase.
  • the wavelength of electromagnetic radiation to be used is principally composed of polychromatic light falling within the above wavelength ranges.
  • “principally composed' it is meant that at least 70%, 80%, 90%, or 95% of the energy of the applied light falls within the above wavelength ranges.
  • the monochromatic or polychromatic electromagnetic radiation is substantially free of radiation having wavelengths in the 615 to 750 nm range, the 620 to 700 nm range, 630 to 700nm range, 630 to 750 nm range, 630 to 675 nm range, the 650 to 700 nm range, or the 625 to 800 nm range.
  • the method employ light filters to remove one or more wavelengths of light having a wavelength from 625 to 700 nm from a polychromatic light source before the radiation from the light source is to be applied to the skin.
  • suitable wavelengths for use according to the invention can principally be composed of 400 ⁇ 25 nm, 500 ⁇ 25 nm, 550 ⁇ 25 nm, and 600 ⁇ 25 or from 375 nm to 625 nm light.
  • the electromagnetic radiation in the visible portion of the spectrum is applied at a level of about 0.5 to 40, 1 to 20, or 2 to 10 joules/cm 2 per treatment.
  • the radiation is modulated to provide pulses of the light at a pulse frequency of 4 to 10,000 Hz.
  • the wavelength of visible light has a peak in the transmission spectrum from about 400 to 600 nm, 500 to 650 nm, from 550 to 625 nm, from 575 nm to about 625 nm in wavelength, or from 500 to 600 nm, 550 to 600 nm, from 575 to 600 nm, from 590 to 610 nm, or from 595 to 605nm.
  • the light has a bandwidth of about 10, 20, 25, 30, 40, or 50 nm.
  • the wavelength of electromagnetic radiation to be used is principally composed of one or more sources of monochromatic light within the above wavelengths.
  • the applied light can have a peak in the transmission spectrum of about 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610 nm and a bandwidth of from about 5, 10, or 20 nm or less than 5, 10, or 20 nm.
  • the administered light can be continuous or pulsed.
  • the light source in any of the above embodiments can be a xenon-halogen bulb, a light emitting diode (LED), organic LED, a semiconductor-based light emitting device, or a laser diode.
  • LED light emitting diode
  • organic LED organic LED
  • semiconductor-based light emitting device or a laser diode.
  • the dosage regimen for the electromagnetic radiation in the visible portion of the spectrum can be adjusted to fit the individual subject.
  • the period and intensity of treatment can be individualized for each subject and/or tissue.
  • the frequency, duration, and intensity of the radiation can adjusted according to the severity of the condition, the responsiveness of the patient, and/or according to the thickness and coloration of the skin at the point of exposure.
  • the tissue is irradiated over a treatment period of from 10 sec to 1 hour in length.
  • the treatment is given once- or twice-a-day; 1-, 2-, 3-, 4-, or 5-times a week, or once- or twice- a month.
  • the treatment is given once or a few times to treat an acute condition. In other embodiments, the treatment is given on a chronic basis (lasting months to years). In yet other embodiments, the treatment may be intermittent and/or as needed to alleviate the signs and symptoms of the condition to be alleviated. Accordingly, treatments may vary in duration from the acute to the chronic.
  • the radiation may be applied internally (e.g., via glass fiber optics) or externally to the tissue or subject. The electromagnetic radiation in the visible portion of the spectrum is preferably not associated with any significant heating of the tissue by the energy of the radiation. In some embodiments, the radiation may be applied locally or proximal to the affected tissue or applied at a location at some distance from the affected tissue to foster a release of NO that acts upon a target tissue at a location not contacted with the applied light.
  • the invention provides a method of prognosis and diagnosis for poor blood circulation or DPN in a tissue or organ by measuring the tissue or blood NO, VEGF, or protein carbonylation levels.
  • the NO and VEGF levels serve to indicate early stage DPN prior to loss of sensation and pain.
  • the invention provides a method of monitoring the response to exposure of a tissue to electromagnetic radiation in the visible portion of the spectrum by measuring blood flow in the tissue, or measuring the tissue or blood NO, VEGF, protein carbonylation, nitration, or nitroslylation levels in the blood or tissue.
  • this aspect can be used in evaluating the response of a tissue or subject exposed to radiation according to any of the other aspects and embodiments of the invention.
  • the monitoring is used to adjust the radiation treatment regimen for a tissue or subject on either an acute or chronic basis.
  • the invention provides for the use of electromagnetic radiation in the visible portion of the spectrum in the therapeutic photomodulation of diabetic peripheral neuropathy.
  • LEDs light emitting diode arrays or low energy lasers
  • the applied radiation can be coherent or non-coherent.
  • the invention further provides for a combination therapy comprising use of any one of the above phototherapeutic methods in combination with administration of NO donors and other compounds (substrates for NO synthetase, inhibitors of NO degradative pathways) which modulate NO levels in a subject.
  • modulate means to decrease or increase.
  • the modulatory stimulus may be dynamic (varying over time) during application or constant.
  • the visible light modulation of mitochondrial function is illustrated in figure 1.
  • the modulation can be therapeutic in nature and result in the treatment (e.g., amelioration, reduction (as to either frequency or severity) or prevention (e.g., delay in on-set or failure to develop) of the recited adverse condition or the signs, symptoms, or adverse sequelae of the recited adverse condition. Modulation can also promote the health of a tissue or subject with respect to a particular condition.
  • Hypoxia is a condition in which the body as a whole or in part lacks an adequate oxygen supply.
  • the term includes ischemic hypoxia or ischemia as from a restriction in blood supply as may occur in circulatory disorders (e.g. atherosclerosis, macro or microcirculatory disorders) affecting blood flow , edema, or tissue perfusion.
  • cerebral hypoxia refers to a reduced or indequate oxygen supply to brain tissue. Mild or moderate cerebral hypoxia can cause confusion and fainting.
  • the hypoxia is characterized by increased susceptibility to visible light induced mitochondrial induction of NO production.
  • electromagnetic radiation in the visible portion of the spectrum comprises light having wavelengths of about 400 to 650 nm, 500 to 650 nm, from 550 to 625 nm, from 575 nm to about 625 nm in wavelength, or from 500 to 600 nm, 550 to 600 nm, from 575 to 600 nm.
  • the wavelength of electromagnetic radiation to be used is substantially free of light having a wavelength greater than 600 nm, 610 nm, 615 nm 625nm, 630 nm, 650 nm, or 675 nm.
  • the electromagnetic radiation is substantially free of radiation of inhibitory wavelengths of light or is substantially free of light in the 615 to 750 nm range, the 620 to 700 nm range, 630 to 700nm range, 630 to 750 nm range, 630 to 675 nm range, the 650 and 700 nm range, 625 to 800 nm range.
  • Light which is "substantially free” of certain wavelengths is light which comprises a small proportion (e.g., less that 25%, 20%, 15%, 10%, 5%, or 1%) of its total energy at the specified wavelengths) or which has a ratio of light energy in the therapeutic range (e.g., 550 nm to 625 nm) which is at least 3-fold, 4-fold, 5-fold or 10-fold greater than that of those wavelengths which inhibit the effect of the therapeutic light on the mitochondria as measured according to stimulation of NO production under anoxic conditions (e.g., inhibitory wavelengths).
  • a small proportion e.g., less that 25%, 20%, 15%, 10%, 5%, or 1%) of its total energy at the specified wavelengths
  • a ratio of light energy in the therapeutic range e.g., 550 nm to 625 nm
  • the therapeutic radiation can be applied at a level of about 0.5 to 40, 1 to 20, or 2 to 10 joules/cm 2 per treatment.
  • the radiation can be continuous or pulsed.
  • the radiation can also be modulated to provide pulses of radiation at a pulse frequency of 4 to 10,000 Hz.
  • visible radiation is applied as an intensity per treatment of 0.5 to 40 joules /cm 2 per treatment period and is modulated at a frequency of from 1 to 100 Hz, 4 to 10,000Hz, 40 to 2000Hz, 1000 to 5000 Hz, orlOO to 1000 Hz.
  • the treatments can be of varying duration (e.g., ranging from 1 to 5 minutes to an hour or more). For instance, a treatment can last for 5 to 10 minutes, 5 to 20 minutes or 20 to 40 minutes.
  • the light source used to apply the light preferably generates light in the visible range.
  • the wavelength of electromagnetic radiation light to be used comprises wavelengths from about 400 to 625 nm, 400 to 525 nm, 500 to 650 nm, from 550 to 625 nm, from 575 nm to about 625 nm in wavelength, or from 500 to 600 nm, 550 to 600 nm, from 575 to 600 nm.
  • the wavelength of electromagnetic radiation to be used is substantially free of light having a wavelength greater than 600 nm, 610 nm, 615 nm 625nm, 630 nm, 650 nm, or 675 nm. In some embodiments, the electromagnetic radiation is substantially free of radiation in the 615 to 750 nm range, the 620 to 700 nm range, 630 to 700nm range, 630 to 750 nm range, 630 to 675 nm range, the 650 and 700 nm range, or the 625 to 800 nm range.
  • the light source comprises one or more laser diodes, which each provide coherent light.
  • the emitted light may produce "speckling" due to coherent interference of the light.
  • This speckling comprises intensity spikes which are created by constructive interference and can occur in proximity to the target tissue being treated.
  • the average power density may be approximately 10 mW/cm 2
  • the power density of one such intensity spike in proximity to the brain tissue to be treated may be approximately 300 mW/cm 2 .
  • this increased power density due to speckling can improve the efficacy of treatments using coherent light over those using incoherent light for illumination of deeper tissues.
  • the light source provides incoherent light.
  • Exemplary light sources of incoherent light include, but are not limited to, incandescent lamps or light-emitting diodes.
  • a heat sink can be used with the light source (for either coherent or incoherent sources) to remove heat from the light source and to inhibit temperature increases at the scalp.
  • the light source generates light which is substantially monochromatic (i.e., light having one wavelength, or light having a narrow band of wavelengths).
  • the light source generates or provides light having a plurality of wavelengths, but with the proviso that the light is substantially free of light having wavelengths ranging from 650 to 750 nm.
  • one or more optical filters are used to remove a portion of light having a wavelength falling between 625 and 750 nm.
  • the light source is capable of emitting light energy at a power sufficient to achieve a predetermined power density at the subdermal target tissue (e.g., at a depth of approximately 2 centimeters from the dura with respect to the brain). It is presently believed that phototherapy of tissue is most effective when irradiating the target tissue with power densities of light of at least about 0.01 mW/cm 2 and up to about 1 W/cm 2 .
  • the subsurface power density is at least about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, or 90 mW/cm 2 , respectively, depending on the desired clinical performance.
  • the subsurface power density is preferably about 0.01 mW/cm 2 to about 100 mW/cm 2 , more preferably about 0.01 mW/cm 2 to about 50 mW/cm 2 , and most preferably about 2 mW/cm 2 to about 20 mW/cm 2 . It is believed that these subsurface power densities are especially effective at producing the desired biostimulative effects on the tissue being treated.
  • surface power densities preferably between about 10 mW/cm 2 to about 10 W/cm 2 , or more preferably between about 100 mW/cm 2 to about 500 mW/cm 2 , can typically be used to attain the selected power densities at the subdermal target tissue.
  • the light source is preferably capable of emitting light energy having a total power output of at least about 25 m to about 100 W. In various embodiments, the total power output is limited to be no more than about 30, 50, 75, 100, 150, 200, 250, 300, 400, or 500 mW, respectively.
  • the light source comprises a plurality of sources used in combination to provide the total power output.
  • the actual power output of the light source is preferably controllably variable. In this way, the power of the light energy emitted can be adjusted in accordance with a selected power density at the subdermal tissue being treated.
  • Certain embodiments utilize a light source that includes only a single laser diode that is capable of providing about 10, 20, 25, 30, 40, or 5OmW to about 100 W of total power output at the skin surface.
  • the laser diode can be optically coupled to the scalp via an optical fiber or can be configured to provide a sufficiently large spot size to avoid power densities which would burn or otherwise damage the skin.
  • the light source utilizes a plurality of sources (e.g., laser diodes) arranged in a grid or array that together are capable of providing at least 10, 20, 25, 30, 40, or 5OmW to about 100 W of total power output at the skin surface.
  • sources e.g., laser diodes
  • the light source of other embodiments may also comprise sources having power capacities outside of these limits.
  • the light source generates light which cause eye damage if viewed by an individual.
  • the light source apparatus can be configured to provide eye protection so as to avoid viewing of the light by individuals. For example, opaque materials can be appropriately placed to block the light from being viewed directly.
  • interlocks can be provided so that the light source apparatus is not activated unless the protective element are in place, or other appropriate safety measures are taken.
  • the therapy apparatus for delivering the light energy includes a handheld probe.
  • the application of the light is controlled programmable controller comprising a logic circuit, a clock coupled to the logic circuit, and an interface coupled to the logic circuit.
  • the clock of certain embodiments provides a timing signal to the logic circuit so that the logic circuit can monitor and control timing intervals of the applied light. Examples of timing intervals include, but are not limited to, total treatment times, pulse width times for pulses of applied light, and time intervals between pulses of applied light.
  • the light sources can be selectively turned on and off to reduce the thermal load on the skin and to deliver a selected power density to particular areas of the brain or other target tissue/organ.
  • the applied light source is controlled by a logic circuit coupled to an interface.
  • the interface can comprise a user interface or an interface to a sensor monitoring at least one parameter of the treatment.
  • the programmable controller is responsive to signals from the sensor to preferably adjust the treatment parameters to optimize the measured response.
  • the programmable controller can thus provide closed-loop monitoring and adjustment of various treatment parameters to optimize the phototherapy.
  • the signals provided by the interface from a user are indicative of parameters that may include, but are not limited to, patient characteristics (e.g., skin type, fat percentage), selected applied power densities, target time intervals, and power density/timing profiles for the applied light.
  • the logic circuit is coupled to a light source driver.
  • the light source driver is coupled to a power supply, which in certain embodiments comprises a battery and in other embodiments comprises an alternating current source.
  • the light source driver is also coupled to the light source.
  • the logic circuit is responsive to the signal from the clock and to user input from the user interface to transmit a control signal to the light source driver. In response to the control signal from the logic circuit, the light source driver adjust and controls the power applied to the light sources.
  • the logic circuit is responsive to signals from a sensor monitoring at least one parameter of the treatment to control the applied light.
  • a sensor monitoring at least one parameter of the treatment For example, certain embodiments comprise a temperature sensor thermally coupled to the skin to provide information regarding the temperature of the skin to the logic circuit.
  • the logic circuit is responsive to the information from the temperature sensor to transmit a control signal to the light source driver so as to adjust the parameters of the applied light to maintain the scalp temperature below a predetermined level.
  • Other embodiments include exemplary biomedical sensors including, but not limited to, a blood flow sensor, a blood gas (e.g., oxygenation) sensor, an NO production sensor, or a cellular activity sensor. Such biomedical sensors can provide real-time feedback information to the logic circuit.
  • the logic circuit is responsive to signals from the sensors to preferably adjust the parameters of the applied light to optimize the measured response.
  • the logic circuit can thus provide closed-loop monitoring and adjustment of various parameters of the applied light to optimize the phototherapy.
  • Preferred methods of phototherapy for a selected wavelength(s) are based upon recognition that the power density (light intensity or power per unit area, in W/cm 2 ) or the energy density (energy per unit area, in J/cm 2 , or power density multiplied by the exposure time) of the light energy delivered to tissue is an important factor in determining the relative efficacy of the phototherapy.
  • the light source can be adjusted to irradiate different portions of the subject's skin or scalp in order to target underlying brain tissue which, or instance, has been the subject of a pathology or neurodegeneration.
  • neurodegeneration refers to the process of cell destruction or loss of function resulting from primary destructive events such as stroke or CVA, as well as from secondary, delayed and progressive destructive mechanisms that are invoked by cells due to the occurrence of the primary destructive event.
  • Primary destructive events include disease processes or physical injury or insult, including stroke, but also include other diseases and conditions such as multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, Alzheimer's disease, dementia resulting from other causes such as AIDS, cerebral ischemia including focal cerebral ischemia, and physical trauma such as crush or compression injury in the CNS, including a crush or compression injury of the brain, spinal cord, nerves or retina, or any acute injury or insult producing neurodegeneration.
  • the methods according to the invention can be used to treat Huntington disease; Parkinson disease; familial Parkinson disease; Alzheimer disease; familial Alzheimer disease; amyotrophic lateral sclerosis; sporadic amyotrophic lateral sclerosis; mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes; myoclonus epilepsy with ragged-red fibers; Kearns-Sayre syndrome; progressive external ophthalmoplegia; Leber hereditary optic neuropathy (LHON); Leigh syndrome; and Friedreich ataxia, and cytochrome c oxidase (Ceo) deficiency states.
  • Huntington disease Huntington disease
  • Parkinson disease familial Parkinson disease
  • Alzheimer disease familial Alzheimer disease
  • amyotrophic lateral sclerosis sporadic amyotrophic lateral sclerosis
  • mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes myoclonus epilepsy with ragged-red fibers
  • neurodegeneration refers to a therapeutic strategy for slowing or preventing the otherwise irreversible loss of neurons or CNS function due to neurodegeneration after a primary destructive event, whether the neurodegeneration loss is due to disease mechanisms associated with the primary destructive event or secondary destructive mechanisms.
  • inflammation and oxidative stress are important in the pathology of many chronic neurodegenerative conditions, including Alzheimer's disease.
  • This disease is characterized by the accumulation of neurofibrillary tangles and senile plaques, and a widespread progressive degeneration of neurons in brain.
  • Senile plaques are rich in amyloid precursor protein (APP) that is encoded by the APP gene located on chromosome 21.
  • Pathogenesis of AD may be mediated by an abnormal proteolytic cleavage of APP which leads to an excess extracellular accumulation of beta-amyloid peptide which is toxic to neurons (Selkoe et al., (1996), J. Biol. Chem.
  • an object of the present invention is to provide a treatment of dementia which can ameliorating learning and/or memory impairments, or cognitive impairment in Alzheimer-type dementia, cerebrovascular dementia and senile dementia.
  • the invention provides a method of treating a subject having a disorder involving impaired mitochondrial function.
  • the method includes administering a phototherapy of the present invention to such a subject under conditions effective to improve mitochondrial function.
  • This method of the present invention is particularly useful for the treatment or prophylaxis of disorders associated with impaired mitochondrial function.
  • Disorders that can be treated according to this method generally include conditions or diseases characterized by a decreased level of oxidative metabolism.
  • the disorders may be caused by genetic factors, environmental factors, or both. More specifically, such disorders include conditions or diseases of the nervous system (e.g., neurodegenerative, psychoses, etc.), conditions or diseases of other parts of the body, and conditions or diseases of the body as a whole.
  • Such conditions or diseases of the nervous system include not only Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, but also spinocerebellar ataxias, and psychoses (including depression or schizophrenia) associated with oxidative metabolic abnormalities.
  • exemplary conditions or disorders of other parts of the body include cardiovascular disorders (e.g., atherosclerotic and cardiovascular diseases including myocardial infarctions, angina, cardiomyopathies, cardiac valvular disorders, and other conditions or disorders causing cardiac failure), musculoskeletal disorders in which oxidative metabolism is abnormal and other conditions or disorders of non-neural tissues in which oxidative metabolism is abnormal, such as frailty, a geriatric syndrome often associated with metabolic alterations.
  • AD cerebral metabolic insufficiencies
  • impaired cerebral function such as dementia
  • another aspect of the present invention relates to a method of improving cerebral function in a subject having cerebral metabolic insufficiencies.
  • a treatment of the present invention is administered to a subject having impaired cerebral metabolism under conditions effective to improve the cerebral cellular metabolism.
  • treating refers to therapeutic methods involving the application of an agent which benefits a particular disease or condition.
  • a phototherapy according to the invention can be used to slow the progression or onset of the disease or condition, and/or to reduce the signs and/or symptoms or physical manifestations of the disease or condition.
  • a therapeutically effective amount of an agent references a quantity or dose of an agent (e.g., radiation or drug) which is sufficient to treat the disease or condition.
  • an agent e.g., radiation or drug
  • Many models systems for determining the efficacy of neuroprotective agents are known in the art. Such model systems can be used to assess the efficacy of treatments according to the invention. For instance, behavioral assessments as known to one of ordinary skill in the art can be used in humans or test animals for cognitive impairment.
  • the spatial memory test using Y-maze apparatus can be used test the behavioral property of animals to enter into a new arm, avoiding the arm that they entered into just before (alternation behavior), (see, Itoh, J., et al. (Eur. J. Pharmacol., 236, 341-345 (1993)).
  • histopathological methods monitoring cell death, accumulation of neurofibrillary tangles or senile plaque can be used to assess the extent of neurodegeneration.
  • a neuroprotective-effective amount of light energy achieves the goal of reversing, preventing, avoiding, reducing, or eliminating neurodegeneration.
  • the "neuroprotection” involves treating a patient (e.g., Alzheimer's disease) by placing the therapy apparatus in contact with the scalp and adjacent the target area of the patient's brain.
  • the target area of the patient's brain can be previously identified such as by using standard medical imaging techniques.
  • treatment further includes calculating a surface power density at the scalp which corresponds to a preselected power density at the target area of the patient's brain. The calculation of certain embodiments includes factors that affect the penetration of the light energy and thus the power density at the target area.
  • These factors include, but are not limited to, the thickness of the patient's skull, type of hair and hair coloration, skin coloration and pigmentation, patient's age, patient's gender, and the distance to the target area within the brain.
  • the power density and other parameters of the applied light are then adjusted according to the results of the calculation.
  • the power density selected to be applied to the target area of the patient's brain depends on a number of factors, including, but not limited to, the wavelength of the applied light, the location and severity of the pathology, and the patient's clinical condition, including the extent of the affected brain area.
  • the power density of light energy to be delivered to the target area of the patient's brain may also be adjusted to be combined with any other therapeutic agent or agents, especially pharmaceutical neuroprotective agents, to achieve the desired biological effect.
  • the selected power density can also depend on the additional therapeutic agent or agents chosen.
  • the treatment proceeds continuously for a period of about 10 seconds to about 2 hours, more preferably for a period of about 1 to about 10 minutes, and most preferably for a period of about 2 to 5 minutes.
  • the light energy is preferably delivered for at least one treatment period of at least about five minutes, and more preferably for at least one treatment period of at least ten minutes.
  • the light energy can be pulsed during the treatment period or the light energy can be continuously applied during the treatment period.
  • the light is delivered at a rate of from about 0.5 to 8, 2 to 6, or about 4 mW/cm 2 on average to a target site over a given treatment duration.
  • the treatment is for about 0.1, 0.2, 0.4, 0.8, 1, 2, 3, 4, 5, 6, or 8 hours.
  • the light is provided in a total amount from 0.5 to 40 joules/cm 2 /treatment.
  • the treatment may be terminated after one treatment period, while in other embodiments, the treatment may be repeated for at least two treatment periods.
  • the time between subsequent treatment periods is preferably at least about five minutes, more preferably at least about 1 to 2 days, and most preferably at least about one week..
  • the length of treatment time and frequency of treatment periods can depend on several factors, including the functional recovery or response of the patient to the therapy.
  • a method for the neuroprotective treatment of a patient in need of such treatment involves delivering a neuroprotective-effective amount of light energy having a wavelength in the visible range to a target area of the patient's brain.
  • the target area of the patient's brain includes the area of plaque accumulation or ischemia, i.e., to neurons within the "zone of danger.”
  • the target area includes portions of the brain not within the zone of danger.
  • a method provides a neuroprotective effect in a patient that has had an ischemic event in the brain.
  • the method comprises identifying a patient who has experienced an ischemic event in the brain.
  • the method further comprises estimating the time of the ischemic event.
  • the method further comprises commencing administration of a neuroprotective effective amount of light energy to the brain or the affected area of the brain and/or an area proximal thereto.
  • the administration of the light energy is commenced no less than about two hours following the time of the ischemic event.
  • phototherapy treatment can be efficaciously performed preferably within 24 hours after the ischemic event occurs, and more preferably no earlier than two hours following the ischemic event, still more preferably no earlier than three hours following the ischemic event, and most preferably no earlier than five hours following the ischemic event.
  • one or more of the treatment parameters can be varied depending on the amount of time that has elapsed since an ischemic event.
  • the invention also provides a method of treating Alzheimer's disease (e.g., slowing the progression or onset of the condition, or reducing the signs and/or symptoms or physical manifestations of the disease).
  • Alzheimer's disease e.g., slowing the progression or onset of the condition, or reducing the signs and/or symptoms or physical manifestations of the disease.
  • Much evidence indicates that less oxygenated blood flowing to the brain contributes to the build-up of the protein plaques associated with Alzheimer's disease. Alterations in mitochondrial function, including particularly cytochrome c-oxidase activity have also been reported in Alzheimer's disease patients as well.
  • cytochrome c-oxidase activity have also been reported in Alzheimer's disease patients as well.
  • the invention provides phototherapy
  • the external carotid artery and or the vertebral artery are exposed to light by the application of the visible light from the sides of the head (e.g., the temples).
  • the shortest distance to these structures is from the sides.
  • Positioning the treatment heads or light sources directly under the ear and behind the jaw bone would give the most direct access to these structures for the radiant energy applied.
  • the vertebral artery is treated by the application of the light to the from the rear of the skull or from the sides of the skull.
  • the light can be applied to any portion of the skull, including the forehead and any combination of the above, especially when close to the affected or target site for application of the light.
  • the treatment head should be applied to the below the ear and just behind the jaw bone (see, Figure 9). This will maze the irradiation area of the supplying vessels to the brain due to having to traverse less soft tissue. This illustrates that a treatment head of approximately 2" inches in diameter would cover both structures. Other treatment heads may be used, including those of from 0.5 to 4 inches in diameter can be used. The treatment heads need not be circular but can be configured so as to track the location of the targeted arteries more closely. In some embodiments, the treatment heads can have an application surface area of from about one or two square inches to 4, 8 or 10 square inches. In some embodiments, the treatments can be applied to either or both sides of the body.
  • the methods of treatment according to the invention use a light emitting diode (LED), an organic LED (OLED) device formulated into a single-use or multiple use patch to provide the electromagnetic radiation or visible light for use according to the invention, or another semiconductor-based light emitting device.
  • LED light emitting diode
  • OLED organic LED
  • a battery having sufficient power for only a single-use treatment would be incorporated into the patch thereby producing a unit dose of the therapeutic light.
  • other sources of power could be utilized as known to persons of skill in the art.
  • An exemplary patch or bandage may include materials such as textile fabrics, tapes, or films.
  • a patch may include natural or synthetic rubber, fabric, cotton, polyester, and the like.
  • a patch may include an adhesive substance, glue, bonding agent, strap, tie, fastener, or means of fixing the LED or OLED on the patient.
  • a patch may incorporate a natural or synthetic adhesive, a medical adhesive, or a bioadhesive.
  • An adhesive can be coated on a surface of a patch, or impregnated within a dressing or matrix of a patch.
  • a patch may include a curable gel or paste.
  • a patch can serve to secure placement of an LED or OLED at a desired location on a patient.
  • a patch may be flexible or curved, so as to conform with any of a variety of surface shapes.
  • a patch may include one or more layers of material. The patch may be configured so as to maximize or modulate the amount of electromagnetic radiation incident upon the patient.
  • the invention provides a photobiomodulation medical device in the form of a multi- or single-use LED or Organic light emitting diode (OLED) patch.
  • the patch may be charged with a unit dose of energy capable of delivering from 0.5 to 8 mW/cm 2 on average to a target site over a treatment duration.
  • the light can be continuous or pulsatile as described above.
  • the patch when used in therapy for Alzheimer's disease patients may be applied either to the neck or head of the patient:
  • Endothelial Targeting By placing the LED or and patch over the carotid artery of the neck, and targeting CCO in the endothelial cells and/or smooth muscle cells lining the artery, circulation and oxygenation to the brain is increased, thereby reducing oxidative stress, the accumulation of amyloid peptides and slowing or reversing the progression of the disease.
  • Neuronal Targeting By placing the CL ARIMEDIX patch on the head, targeting CCO in neurons within the brain, NO production is increased, to affect gamma secretase activity, causing abeta 40 and 42 to be reduced back to normal levels and slowing or reversing progression of the disease.
  • OLED devices are well known in the technological arts.
  • an organic LED consists of an anode into which current (hole current specifically) is injected, a hole transport layer (that often also serves as an electron blocking layer), then an active medium in which recombination takes place with the electron current that is injected from the cathode through an electron transport medium (that often serves as a hole blocking medium).
  • the active medium consists of efficient recombination centers if the device is to function with high luminescent efficiency.
  • each of these layers are well defined, and in fact, the small molecule organic devices often try to mimic the operation of inorganic devices despite the significantly lower conductivity of the organic conductors.
  • Organic light emitting diodes on flexible substrates for patch application to the head and neck are also contemplated as sources of the light to be administered.
  • these OLEDS can have a peak luminescence, for instance, of 400, 550, 600 and 650 nm and can produce output powers on the order of 1 mW for dosage periods, for instance, of seconds to minutes and possess lifetimes of up to hundreds of hours.
  • the OLED provides a light intensity of 1 to 8 mW/cm 2 is applied to a target site over a treatment duration.
  • the light can be continuous or pulsatile as described above.
  • PVK Polyvinylcarbazole
  • the recombination efficiency (luminescent efficiency) of PVK is not especially high. Recombination on certain dyes (for example, certain laser dyes in particular) can be quite high.
  • the figure below illustrates the stereo chemical formulae of two different dye compounds, GT3--105 (as named by Lumera Incorporated) and Nile Red.
  • OLEDs can be fabricated on a flexible substrates consisting of an acrylate coated with thin enough layers of indium tin oxide (ITO) such that the brittleness of tin oxide does not affect the flexibility of the overall structure.
  • ITO indium tin oxide
  • the ITO material is both transparent in the visible and near infrared and is also a good electrical conductor.
  • ITO in combination with polyethylenenedioxythiophene (PEDOT) that is often doped with polystyrenesulfonate (PSS) is a very efficient hole conduction injection combination due to the relative locations of the lowest unoccupied molecular orbital (LUMOs) and the energy gap between this level and the highest occupied molecular orbital (HOMOs).
  • PEDOT polyethylenenedioxythiophene
  • PSS polystyrenesulfonate
  • OLEDs The fabrication of OLEDs follows general procedures. Pilot fabrication runs will be performed to determine optimal layer thickness, curing times, and the like.
  • OLED devices having emission wavelengths of 400, 500, 550, 600 and 650nm, with conversation efficiencies of >15%, and lifetimes of great than 100 hours are contemplated.
  • the invention provides methods of using the OLED patch device to emit light of a suitable wavelength to treat Alzheimer's disease in the methods according to the invention and/or to improve cerebral blood flow.
  • the device can serve to stimulate the production of NO by endothelial cells that line the vascular system.
  • This NO production in turn, improves circulation and oxygenation in and to the brain, thereby preventing or reducing the low oxygen conditions that can contribute to neurological impairment, including, in the case of Alzheimer's disease, the formation of Alzheimer's plaques and tangles.
  • the ability of NIR light to penetrate the scalp and skull to reach underlying tissue is evidenced by Quan Zhang et al, Journal of Biomedical Optics 5(2), 206-213 (April 2000).
  • the device is also targeting neurons directly, the technology by increasing nitric oxide production within the exposed neurons thereby reducing or preventing harmful APP processing.
  • the effect of the treatment on Alzheimer's disease can be monitored by assessing the effect on the treatment on the disease progression itself or indirectly by monitoring biomarkers of disease progression or pathogenesis (e.g, APP and APP products, gamma secretase (including but not limited to particularly the presenilin subunit) levels; mitochondrial Ceo subunit IV (mammalian, V yeast) isoforms)).
  • biomarkers of disease progression or pathogenesis e.g, APP and APP products, gamma secretase (including but not limited to particularly the presenilin subunit) levels; mitochondrial Ceo subunit IV (mammalian, V yeast) isoforms
  • Example 1 Role of the respiratory chain in NO production in endothelial cells under hypoxic conditions
  • NOS nitric oxide synthase
  • NOS II inducible NOS
  • NOS III endothelial NOS
  • the second pathway for NO production involves nitrite-dependent NO production by the mitochondrial respiratory chain. This pathway is active only at reduced oxygen concentrations.
  • the relative importance of the NOS-dependent and A ⁇ OS-independent NO synthesis in endothelial cells is assessed before and after visible light treatment.
  • the production of NO is evaluated in cells exposed to hypoxic conditions in the presence of physiological concentration of nitrite.
  • the involvement of the respiratory chain in this process is evaluated in the presence of: a) L-NAME, a general NOS inhibitor, b) inhibitors of the respiratory chain, c) disruptors of the mitochondrial membrane potential, d) inhibitors of mitochondrial complex IV, e) inhibitors of constitutive NOS, and e) theophylline.
  • Example 2 NO production by endothelial cells.
  • Endothelial cells are isolated and cultured as described elsewhere (Wang et al, 2007; Wang et al, 2004). Hypoxia (1.5% O 2 , 93.5% N 2 , 5% CO 2 ) or anoxia (5% CO 2 , 4% H 2 , 91% N 2 ) is established in an IN VIVO workstation (Biotrace) or Coy laboratories glove box, pre-equilibrated with the appropriate gas mixture. All cell extracts are prepared inside the workstation or glove box to prevent re-oxygenation. Cells are maintained under anoxic or hypoxic conditions for varying lengths of time (2-8 hr). Nitric oxide production is evaluated with the fluorescent nitric oxide indicator DAF-FM (Molecular Probes, CA).
  • Nutrient media are supplemented with 20 ⁇ M N a N0 2 .
  • the involvement of the respiratory chain in nitrite dependent NO production is evaluated in the presence of: a) the inhibitors of complex III Antimycin A (10 ⁇ M), myxothiazol (10 ⁇ M) and Cyanide (ImM); b) disruptors of the mitochondrial membrane potential FCCP (10 ⁇ M) and dinitrophenol (100 ⁇ M) c) inhibitors of mitochondrial complex V oligomycin 10 uM, and d) L-NAME, an inhibitor of constitutive NOS L-NAME (1 mM).
  • Mitochondria from normal and hypoxic cells is isolated and evaluated for respiratory control, hypoxic production of nitrite dependent NO production, and production of nitrite dependent NO production after incubation with ATP and theophylline, using methods described previously (Castello et al, 2006).
  • Example 4 Stimulation of nitrite reductase activity and subunit phosphorylation of cytochrome c oxidase by visible light
  • Nitrite-dependent NO production Initially, NO levels is measured in isolated mitochondria, using an NO meter or the fluorescent probe DAF-FM (Molecular Probes, CA). Mitochondria exposed to visible light are treated with specific respiratory inhibitors in order to localize NO production to cytochrome c oxidase, as described previously (Castello et al. 2006). Visible light stimulation of NO production in mitochondria is observed.
  • Example 5 Effect of visible light on intracellular levels of oxidative stress and/or mitochondrial biogenesis in endothelial and yeast cells.
  • One way of assessing the effects of visible light on cellular oxidative stress is to measure the production of ROS by the respiratory chain. This is done using isolated mitochondria and an hydrogen peroxide electrode connected to a W.P.I. amplifier.
  • the first makes use of fluorescent dyes (e.g, derivatives of fluorescein or rhodamine) to estimate intracellular ROS levels.
  • the second assesses oxidative damage, caused by ROS, by measuring the accumulation of lipid peroxides (e.g., malonaldehyde and hydroxyalkenals), oxidized nucleosides (e.g., 8-hydroxy-2'-deoxyguanosine (8OH2gG), or oxidized amino acid side chains on proteins (e.g., o-tyrosine, m-tyrosine, dityrosine, and carbonyl derivatives).
  • the third measures the expression of oxidative stress-induced genes.
  • Protein carbonylation is used to indicate overall levels of cellular oxidative stress. Carbonyl content of mitochondrial and cytosolic protein fractions is measured after derivatizing proteins in each fraction with 2,4-dinitrophenyl hydrazine (DNPH) as described (Dirmeier et al. 2002; 2004).
  • DNPH 2,4-dinitrophenyl hydrazine
  • Mitochondrial biogenesis In order to determine if light impacts the synthesis of new mitochondria and, consequently, the level of cellular respiration, oxygen consumption rates are measured using an oxygen electrode. Altered intracellular levels of key mitochondrial proteins (subunits of cytochrome c oxidase, cytochrome c, cytochrome c reductase, and ATP synthase) are measured after cells are exposed to light. Levels of these proteins are determined by immunob lotting SDS-gels of whole cell extracts.
  • Example 7 Visible light increases levels of vasodilators in the blood.
  • NO and VEGF are measured in venous blood and exposed tissues after patients with peripheral neuropathies are exposed to visible light. VEGF levels will be assessed by an immunoassay and NO levels will be measured with an NO meter or the fluorescent NO indicator DAF-FM.
  • VEGF levels VEGF levels in the blood will be determined after running whole blood on an SDS-polyacrylamide gel and immunoblotting the gel with an antibody specific for VEGF.
  • Example 8 The relationship between light and cellular nitrite-dependent nitric oxide production
  • the overall goal of this study was to examine the relationship(s) between light and cellular nitrite-dependent nitric oxide production by mitochondrial cytochrome c oxidase.
  • the yeast Saccharomyces cerevisiae was used as a model for these studies. Specific Aims were to:
  • Condition A cells were pre-conditioned by exposure to light for variable lengths of time, prior to the addition of nitrite. Upon addition of nitrite the light was turned off.
  • Condition B was the same as Condition A except that the light was kept on for the duration of the experiment.
  • the effect of broadband light on nitrite-dependent nitric oxide production under Conditions A and B is shown in Figure 3.
  • a series of broadband interference filters from Edmund Scientific were used to assess the effects of specific wavelengths of light on nitrite-dependent nitric oxide production and hence produce the used action spectrum. These filters had peak transmittance every 50 nm and a full width half maximum bandwidth (FWHM) of 80 nm. The overall rates of nitric oxide production during the late phase are shown in Figure 7. Maximum stimulation of nitric oxide production was observed when cells were stimulated with the 550 ⁇ 40 nm and 600 ⁇ 40 nm filters. Wavelengths transmitted by the 450 and 500 nm filters had no effect on nitric oxide production.
  • those wavelengths transmitted by the 650 and 700 nm filters light had an inhibitory effect on nitrite-dependent nitric oxide production when compared to the no light control.
  • narrow bandwidth interference filters from Cheshire optical. These filters had center wavelengths spaced every 10 ⁇ 2 nm and covered the range between 530 and 850 nm. Unfortunately, because these narrow band filters reduce the level of light transmission to a level that is below that required for light stimulated nitric oxide synthesis they were not suitable for establishing a higher resolution action spectrum.
  • HMVEC Human micro vasculature endothelial cells
  • HUMVEC human umbilical endothelial cells
  • mitochondria from murine brain tissue mitochondria are all found to be capable of nitrite-dependent NO synthesis catalyzed by Ceo.
  • a representative experiment with brain mitochondria is shown below. This reaction requires nitrite, does not occur at oxygen concentrations above lO ⁇ M O 2 , and the NO produced is removed by PTIO, an NO scavenger. As found for yeast, this reaction is stimulated by light in an intensity dependent fashion (see figure below). It is also differentially affected by different wavelengths of light tuned to specific absorption bands of Ceo.
  • Nitrite-dependent NO synthesis by mouse cerebrum mitochondrial Ceo Time of addition of nitrite and PTIO are indicated. Right). Effects of light intensity on cerebrum mitochondrial Ceo NO synthesis.
  • Example 10 Alzheimer 's disease treatment and OLED device
  • AD Alzheimer 's disease
  • a ⁇ Amyloid Beta
  • APP Amyloid Precursor Protein
  • ROS reactive oxygen species
  • Ceo cytochrome c oxidase
  • Ceo is the terminal protein of the mitochondrial respiratory chain in all mammalian cells.
  • mitochondrial Ceo was thought to have only one enzymatic activity; the reduction of oxygen to water. This is an oxidase reaction that occurs under normoxic conditions and involves the addition of 4 electrons and 4 protons to diatomic oxygen.
  • a second enzymatic function for eukaryotic Ceo (Castello et al., 2006; Castello et al, 2008). This activity involves the reduction of nitrite to nitric oxide (NO).
  • This nitrite reductase activity of Ceo is favored under hypoxic conditions, is inhibited by oxygen, and is enhanced by low intracellular pH. So far, this reaction has been demonstrated in yeast cells and yeast mitochondria, rat liver mitochondria, mouse neuronal cells and mitochondria, human endothelial cells and mitochondria, and the mitochondria of hypoxic plant roots. Its presence in a wide variety of organisms and cells suggest that it is a universal method for NO synthesis under hypoxic conditions, like those that accompany several pathophysiological states.
  • the overall goal of this Example is to illustrate how to evaluate the efficacy of various photo-biomodulation therapies for the treatment of Alzheimer's disease.
  • NO nitrite-dependent nitric oxide
  • Ceo cytochrome c oxidase
  • the importance of this mechanism of NO synthesis during hypoxia has been demonstrated in a wide range of cell types including yeast, (rat) liver, (human) endothelial cells and (mouse) neurons.
  • NO synthesis by Ceo can be activated by light tuned to specific absorption bands of Ceo.
  • this experiment is to illustrate the effectiveness of activating the Cco/NO pathway in the treatment of Alzheimer's disease by use of an OLED patch-based treatment device and in two established Alzheimer's mouse models.
  • Patch OLEDs designed for mouse carotid or brain irradiation with optimal emission wavelengths of 550, 600, and 650nm are used. These devices are powered by single 1600mA/hr batteries that will achieve operational lifetimes of weeks to months.
  • ⁇ -amyloid Elisa assays are performed to determine changes in amyloid peptide production following treatment.
  • APP pulldown and mass-spec analysis are used to determine changes in APP processing.
  • the oxidase and nitrite reductase activites of Ceo activities in brain tissue taken from light-treated and untreated mice are determined.
  • Measurements of serum NO levels in light-treated and untreated mice are also made.
  • histological analysis of brain tissue monitor the progression of the disease and the accumulation of amyloid plaques.
  • the first mouse model (Oakley et al., 2006) is the 5xFAD transgenic mouse that overexpresses both mutant human APP(695) with the Swedish (K670N, M671L), Florida (1716V), and London (V717I) Familial Alzheimer's Disease (FAD) mutations and human PSl harboring two FAD mutations, M146L and L286V. These mice accumulate intraneuronal Abeta-42 starting at 1.5 months of age, just prior to amyloid deposition and gliosis, which begins at 2 months of age.
  • mice have reduced synaptic marker protein levels, increased p25 levels, neuron loss, and memory impairment in the Y-maze test and rapidly recapitulate major features of Alzheimer's disease amyloid pathology.
  • the second model (Colton et al., 2006) to be used is a cross between the APPSw expressing transgenic mouse and the NOS2 -/- mouse which results in enhanced disease progression and provides a key link between appropriate NO levels and Alzheimer's. This model allows one to establish the effectiveness of particular treatment methods and regimes at restoring appropriate NO levels in the brain.
  • the treatment protocol is a matrix that provides for a broad initial screen of treatment regimes that affect disease progression. Following this initial screen a large scale more in depth study is to be performed coupled to the biochemical and pathological studies outlined below.
  • Treatment protocols which adjust both irradiation wavelength and dosage matrix are employed (see, table below). Animals are shaved and the OLED adhered using the bio compliant glue 2-octyl cyanoacrylate. The OLED sare monitored for 1 day and then activated by insertion of the battery to begin the treatment regime. Each individual OLED is numerically coded during the fabrication based upon both the emission wavelength and the irradiation protocol. This allows for efficient bookkeeping during cognitive tests.
  • the water task consists of a circular galvanized steel pool approximately 117 cm in diameter and 58 cm deep.
  • a movable escape platform constructed of a Plexiglas base column, having a height of 43 cm and topped by a round platform 15 cm in diameter, is placed in one quadrant of the pool and will be maintained there throughout acquisition of the task.
  • the mouse is trained to find the hidden platform. Training consists of 4 trials a day. On a trial the mouse is taken from its cage and place into the pool for 40 seconds or until it finds the escape platform. If it does not find the platform in 40 sec it will be guided to the platform by the experimenter. 15 sec after reaching the platform the mouse will be gently dried and returned to its cage. The interval between trials is approximately 15 min. Another cohort of mice from each strain will also be tested at 3 different ages on this task (1, 2, and 4 months).
  • Brain tissue derived from treated and untreated mice is to be analyzed for levels of two primary amyloid peptides (A ⁇ l-40 and A ⁇ l-42) using Elisa methods. Tissue samples will be homogenized and extracted and total protein concentration determined. Elisa assays will be performed using the Invitrogen protocol to determine amyloid peptides A ⁇ l- 40 and A ⁇ l-42 concentration and normalized to total protein concentration in the extracts.
  • Brain tissue derived from treated and untreated mice is to be analyzed using MS/MS of APP immunoprecipitates.
  • the anti-c-terminal APP antibody will be used to immunoprecipitate APP from tissue lysate.
  • the immunoprecipiate is then used for MS/MS analysis to determine the types and extent of APP processing occurring.
  • the quantitative MS/MS analysis allows the types and degrees of APP processing in treated and untreated mice to be monitored.
  • mice To determine if light exposure has systemic effect on NO levels in mice, blood is taken from the tail vein of mice weekly and NO levels determined colorimetrically using the Greiss reagent. This allows quantitatively monitoring of the affects on photobiomodulation upon NO levels.
  • Example 11 Ceo of endothelial and nerve cells response to light under hypoxic conditions, including an Alzheimer's disease model
  • the current example investigated the ability of mitochondrial Ceo of endothelial cells and nerve cells to make NO from nitrite under hypoxic conditions.
  • the study investigated the effects of light on mitochondrial Cco/NO activity in both human endothelial cell and mouse cerebrum mitochondria.
  • the study investigated the alteration of Cco/oxidase or Cco/NO activities in the 'Swedish' mouse model for Alzheimer's disease and examined the ability of light to enhance Cco/NO activity in this model.
  • Aim 1 Effects of exposure to light on COX gene expression and respiration.
  • Some cells were grown in the presence of oxygen (normoxia) while others were grown at low oxygen levels (hypoxia) in each of the four conditions described above.
  • hypoxic cultures a constant gas flow of 1% O 2 , 5% CO 2 , 94% N 2 was administered beginning one hour before the experiment began. Gas flow remained constant during the experiments.
  • Nitrite-supplemented samples were dosed 1 hour before the beginning of each experiment.
  • Light from a Broadband 50 watt Xenon/Halogen Floodlight was administered at the beginning of each hour for a total of 3 doses, each at 6.4 J/cm 2 . (105 mW/cm 2 ).
  • Oxygen Consumption Fold Change Oxygen Consumption Fold Sample (nmol/min/mg cells) (%) (nmol/min/mg cells) Change (%)
  • Aim 2 Cco/NO activity in endothelial cells and nerve cells.
  • HMVEC human microvascular endothelial cells
  • HUVEC human umbilical vein endothelial cells
  • Aim 3 Effects of light on mitochondrial Cco/NO activity in endothelial and nerve cells.
  • Endothelial cells To demonstrate the effect of investigate the ask if light has an effect on nitrite-dependent NO synthesis in mammalian cells intact HUVEC cells were used.
  • the source of illumination used was a 50 watt Xenon/Halogen Floodlight. This light source is capable of producing broad spectrum visible and near IR light.
  • Two experimental conditions were examined to assess the effects of light on nitrite-dependent NO synthesis in hypoxic cells. In Condition A cells were preconditioned by exposure to light for variable lengths of time, prior to the addition of nitrite (Figure 13A). Upon addition of nitrite the light was turned off.
  • Condition B was the same as Condition A except that the light was turned on at the same time that nitrite was added and kept on for the duration of the experiment.
  • the cells used were from confluent cultures and they were incubated in the assay chamber until the chamber became hypoxic, at which point they were exposed to light.
  • Cells being assayed were kept at a constant temperature of 37 0 C in a water jacketed chamber and a heat filter was placed between the light source and the cells in order to insure that the effects observed were due to light and not a change in temperature due to illumination.
  • Light intensity at the surface of the assay chamber was measured with a Newport Instruments 918D-SL Power meter. All studies were done in a darkened room.
  • Nerve cells To assess the effects of light on nerve mitochondrial Cco/NO activity we used cerebrum mitochondria, assayed under hypoxic conditions, using ascorbate/TMPD as described above. A 50 watt Xenon/Halogen Floodlight was used as a source of illumination. In order to deliver variable levels of total light energy the light source was placed at different distances from the sample. For these experiments the effects of light was assayed by determining the instantaneous change in rate of NO synthesis observed in the presence of light, relative the rate prior to light exposure. Figure 14 shows that light stimulates Cco/NO activity in a dose-dependent fashion up to an intensity of 4 mW/cm 2 . Higher intensities than this are less stimulatory.
  • Aim 4 NO synthesis by mouse cerebrum mitochondrial cytochrome c oxidase in a mouse model for Alzheimer's disease.
  • mice [0167] These experiments sought to determine if cerebrum Cco/NO activity is altered in a mouse model for Alzheimer's disease, and 2) to determine if light stimulates cerebrum Cco/NO activity.
  • the mouse model chosen was a Swedish model '5XF AD' transgenic mouse which overexpresses both human APP with 4 Familial Alzheimer's disease point mutations (K670N, M671L, I716V, and V717I) as well as human presenelin I (PSI) with two Familial Alzheimer's disease mutations M146L and L286V).
  • PSI human presenelin I
  • the mice have a high level of APP expression and accelerated accumulation of Abeta-42 (the 42 amino acid peptide processed from the amyloid precursor protein).
  • Abeta-42 accumulation starts at 6 weeks of age, prior to amyloid disposition, which begins at 8 weeks of age. These mice have many of the characteristics that are found in human Alzheimer's disease and are considered to be useful models for Abeta-42 induced neurodegeneration as well as amyloid plaque formation. Black 6 (B6) mice, which do not carry the Alzheimer's mutations, were used as controls.
  • Example 12 Both HNE and H2O2 increase APP processing to Abl-42 which is reversible upon light treatment.
  • Broadband light reverses oxidative stress induced APP processing to A ⁇ l- 42.
  • NT2 cells treated with either HNE or H2O2 showed dramatic increases in APP processing as assed by A ⁇ l-42 production.
  • Broad band light (7.5 Joules total dose) reversed the oxidative stress affects back to control levels, Figure 17.
  • Broadband light reverses oxidative stress induced APP processing to A ⁇ l- 40.
  • NT2 cells treated with either HNE showed dramatic increases in APP processing as assed by A ⁇ l-40 production.
  • Broad band light (7.5 Joules total dose) reversed the oxidative stress affects back to control levels, Figure 18.
  • Mitochondrial cytochrome oxidase produces nitric oxide under hypoxic conditions: implications for oxygen sensing and hypoxic signaling in eukaryotes. CellMetab. 3:277-87.
  • Oxygen- regulated isoforms of cytochrome c oxidase have differential effects on its nitric oxide production and on hypoxic signaling. Proc Natl Acad Sci U S A. 105:8203-8.
  • NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA. 103:12867-72.
  • Tachtsidis L, Tisdall, M., Leung, T. S., Cooper, CE., Delpy, D. T., Smith, M., and Elwell, CE. 2007. Physiol. Meas. 28, 199-211.

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Abstract

La présente invention porte sur des procédés d'utilisation d'un rayonnement électromagnétique dans la partie visible du spectre pour moduler une fonction mitochondriale dans le traitement de diverses affections, incluant la maladie d'Alzheimer, d'autres démences, une hypoxie et une neuropathie périphérique diabétique, et des troubles sensoriels des extrémités.
PCT/US2009/059104 2008-09-30 2009-09-30 Procédés et dispositifs de modulation de lumière visible d'une fonction mitochondriale dans une hypoxie et une maladie WO2010039886A1 (fr)

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WO2013056110A1 (fr) * 2011-10-14 2013-04-18 Nitto Denko Corporation Dispositifs émetteurs de lumière pour la cicatrisation de plaies
WO2013086457A1 (fr) * 2011-12-07 2013-06-13 California Institute Of Technology Administration d'un composé cagé et compositions, procédés et systèmes associés
EP2613849A1 (fr) * 2010-09-10 2013-07-17 Alvaro Martinez Radiothérapie pour traiter la maladie d'alzheimer
EP2854945A1 (fr) * 2012-05-31 2015-04-08 Photopharmics Inc. Appareils pour le traitement et le diagnostic d'affections neurologiques associées aux neurones moteurs
EP3243902A4 (fr) * 2015-01-06 2018-05-30 Luterion Co., Ltd. Luterion et procédés de séparation et de culture associés
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* Cited by examiner, † Cited by third party
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EP2613849A1 (fr) * 2010-09-10 2013-07-17 Alvaro Martinez Radiothérapie pour traiter la maladie d'alzheimer
EP2613849A4 (fr) * 2010-09-10 2014-04-02 Beaumont Hospital William Radiothérapie pour traiter la maladie d'alzheimer
ITMI20102223A1 (it) * 2010-12-01 2012-06-02 Touch Life Rehab S R L Metodo per la gestione di protocolli di terapie laser
WO2013056110A1 (fr) * 2011-10-14 2013-04-18 Nitto Denko Corporation Dispositifs émetteurs de lumière pour la cicatrisation de plaies
TWI670098B (zh) * 2011-10-14 2019-09-01 日商日東電工股份有限公司 用於創傷癒合之發光裝置、光療系統及發光裝置與光療系統之用途
US10786683B2 (en) 2011-10-14 2020-09-29 Nitto Denko Corporation Light-emitting devices for wound healing
WO2013086457A1 (fr) * 2011-12-07 2013-06-13 California Institute Of Technology Administration d'un composé cagé et compositions, procédés et systèmes associés
US9636656B2 (en) 2011-12-07 2017-05-02 California Institute Of Technology Caged compound delivery and related compositions, methods and systems
EP2854945A1 (fr) * 2012-05-31 2015-04-08 Photopharmics Inc. Appareils pour le traitement et le diagnostic d'affections neurologiques associées aux neurones moteurs
EP2854945A4 (fr) * 2012-05-31 2016-05-18 Photopharmics Inc Appareils pour le traitement et le diagnostic d'affections neurologiques associées aux neurones moteurs
EP3243902A4 (fr) * 2015-01-06 2018-05-30 Luterion Co., Ltd. Luterion et procédés de séparation et de culture associés
US10569194B2 (en) 2015-01-06 2020-02-25 Luterion Co., Ltd. Luterion and separating and culturing methods for same

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