Patent Application
20230364442
The present application claims priorities to the earlier European application N°2199710.3 filed on Oct. 1, 2020, and international application PCT/EP2021059842 filed on Apr. 15, 2021, the content of those earlier applications being incorporated by reference in their entirety in the present application.
The present invention generally relates to photobiomodulation (PBM) and more precisely to devices and methods for applying photobiomodulation therapy (PBMT).
The following definitions apply to the present document.
Photobiomodulation, named PBM in the present document, refers to the treatment of biological objects, such as a tissue or an organ, with certain wavelength(s) of light. This treatment may facilitate tissue or nerve regeneration and remodeling, resolve inflammation, reduce edema, relieve pain, modulate the immune system and the metabolism. It positively acts on age related macular degeneration, blood treatment, wound healing, immunomodulation, and possibly even viral and bacterial infections.
Many conditions are associated with perturbations of the metabolism, including deficiencies of the mitochondrial respiration. These conditions include neurodegenerative diseases (Parkinson’s, Alzheimer’s and Huntington’s diseases), atherosclerosis, certain forms of diabetes, autoimmune diseases, cancer, chronic wounds, damages resulting from ischemia-reperfusions and chronic or acute inflammation like the acute respiratory distress syndrome (ARDS). It is also well known that the metabolism is significantly altered in the cases of stroke, heart attack, grafts or ischemic wounds, among other. As an example, it has been shown that the mitochondrial respiration plays an important role in the heart remodeling [Kindo, 2016], and that the cardiac metabolism reacts to a parietal stress by a mitochondrial dysfunction [Kindo, 2012].
Therefore, strategies to normalize, restore and/or increase the metabolism are of high interest to treat and characterize numerous conditions. PBM therapy is one of these strategies [Hamblin 2017; Hamblin 2018].
PBM therapy is based on the administration of light at low (sub-thermal) irradiance, mostly at wavelengths ranging between 600 and 900 nm, a spectral window corresponding to the maximal light penetration depth in most soft tissues. PBM has a broad range of molecular, cellular, and tissular effects [Hamblin 2017; Hamblin 2018].
However, its mechanisms are not yet fully understood. Moreover, PBM treatment parameters are very rarely optimized and/or mastered. Based on the studies conducted by several groups [Hamblin 2017; Hamblin 2018] and, most importantly, in vitro and in vivo observations carried out by the inventors, one can conclude that PBM generates several positive effects, in particular:
These observations probably result from a stimulation of the metabolic activities and are of high interest for numerous medical applications, including those mentioned above [Hamblin 2017; Hamblin 2018].
PBM is, in particular, of interest for the treatment of myocardial infarction (MI) [Liebert, 2017], which is one the most common acute pathologies. It represents a major cause of death worldwide. At present, the treatments of choice for patients suffering from MI to limit its size and reduce acute myocardial ischemic injury are time consuming, have side effects and limited efficacies. They consist of either primary percutaneous coronary intervention or thrombolytic therapy. Moreover, the treatment itself (process of reperfusion) can be the cause of death of cardiomyocytes until days after the treatment, a process also known as myocardial reperfusion injury, for which, up to this date, there is still no effective treatment [Chouchani, 2016; Ferrari, 2017; Kalogeris, 2017]. PBMT is also of interest for the treatment of systemic inflammation as it is the case for fibromyalgia, rheumatology-related arthritis or auto immune disease, in particular when the circulating blood is directly illuminated. PBMT can also help to avoid consequences of SARS-Cov2 in acute phase where a strong immune response through a cytokinic storm induces acute respiratory distress syndrome (ARDS) or during chronic phases resulting from long SARS-Cov2 effect. US 2007/219604 A1 discloses a method for applying PBM on a biological object wherein light is delivered with an adequate temporal evolution of the optical power, the power being determined on the basis of the biological object optical coefficients and the light delivery geometry on/in the biological object. In this patent application US 2007/219604 A1, the PBM effects are induced by the generation of a fluence rate, successively in each parts of the volume of the biological object. It should be noted that specific values of the fluence rates and illumination times are not mentioned in this application.
Existing methods for applying PBM are however not efficient enough, in particular because of the bimodal effects of PBM, as explained below.
The limited use of PBMT can also be explained by the absence of methods to monitor the metabolic activity of biological tissues. This statement is supported by another discovery of the inventors demonstrating that the importance of the PBM effects depends on the time at which light is applied relative the metabolic activity, as determined, for example, by the oxygen consumption. There is therefore a need to improve the use of PBM for the treatment of biological objects.
The “step-based” evolution of the fluence rate can be fitted by the analytical expression presented as insert in
The inventors have shown that the control of the light dosimetry (fluence rate [mW/cm2]; light dose [J/cm2]) and spectroscopy (wavelength(s)) as well as the illumination duration and the time of illumination are crucial to induce optimal PBM effects. This observation is very important since the PBM effects are known to be bimodal (sometimes qualified as biphasic), i.e. too high or too low fluence rates and/or light doses significantly reduce the PBM effects and are therefore frequently associated to the Arndt-Schultz rule observed in pharmacology. This bimodal response has been reported by numerous groups looking at various “standard” effects (mitochondria membrane potential; ATP production; etc) [Huang 2009; Hamblin 2017; Hamblin 2018].
Looking at the PBM effects on the endogenous production of PpIX in different cell lines, including glioma cells and human cardiomyocytes (HCM), the inventors found that both the fluence rate and the illumination time must be applied in a controlled manner. These two parameters must be applied with specific values, for a given illumination in each parts of the volume of the biological object to optimize PBM effects. In contradiction to what is reported in this field, the inventors have discovered that the bimodal effects of PBM are only observed for a specific set of these parameters. These sets of parameters are defined as “hot spots” (
It is also established that the optical properties of biological tissues, described mostly by their absorption and scattering coefficients, have an important impact on the propagation of the light around a light source [Tuchin, 2015; Hamblin 2017; Hamblin 2018]. In general, the fluence rate (and the light dose) decreases with the distance from the light source due to the absorption and scattering of the light in the tissue (see
An object of the present invention is to provide an improved PBM for the treatment of biological objects, such as tissues, circulating blood and/or the lymph.
Another object of the present invention is to provide an efficient treatment of ischemia reperfusion injuries, such as myocardial infarction (MI), by PBM applied with the conditions and methods mentioned above and below.
Another object of the present invention is to provide an efficient treatment of fibrillations, including atrial fibrillations, by PBM applied with the conditions and methods mentioned above and below.
Another object of the present invention is to provide an efficient PBM-based treatment of metabolic disorders such as type 2 diabetes, hepatic diseases or hormones secretion with the conditions and methods mentioned above and below.
Another object of the present invention is to provide an efficient treatment of systemic inflammation or exacerbated systemic immune response by PBM applied with the conditions and methods mentioned above and below.
Another object of the present invention is to provide an efficient PBM-based treatment to maintain systemic homeostasis during hypoxemia and or hypoxia with the conditions and methods mentioned above and below.
Another object of the present invention is to provide efficient methods in cells-based therapy notably to increase the proliferation rate of stem cells as well as to trig cells differentiation.
Another object of the present invention is to provide an efficient treatment/diagnosis of PpIX-based methods, for instance in photodynamic therapy or in cancer detection by imaging the PpIX fluorescence. Embodiments of this invention involves: the use of a helmet, integrating light emitting diodes, which induce a PBM illumination through the skull on a specific area of the brain before the PhotoDynamic Detection (PDD) or PhotoDynamic Therapy (PDT)procedures used to manage cancers.
Another object of the present invention is to increasing and homogenizing the endogenous production of PpIX in plants and larvae. One embodiment of this approach is to increase the efficacy of the phototoxic effects induced in weed/larvae.
Another object of the present invention is to provide an efficient treatment of conditions by PBMT based on the monitoring of the metabolic activity. This monitoring, based on a frequency analysis of parameters reflecting the metabolic activity, enables to adjust the radiometric (fluence rate, illumination time, light dose, ...) and spectral (wavelength(s)) parameters in such a way that the PBM effects are maximized. This monitoring can also be used to assess the status of the metabolic activity to determine the optimal light application moment. Embodiments of the present invention involve the use of standard probes to measure physiological of biochemical parameters reflecting the metabolic activity. As mentioned below, such probes include, thermocouple, Clark’s pO2 probes or optical fiber-based probes to measure these parameters. The signals delivered by these probes are then processed by a dedicated unit to perform the frequency analysis enabling to extract parameters providing information on the PBM effects and metabolic activity.
The above objects are achieved with the device and methods of the invention as defined in the claims.
Advantageously the device and method according to the invention are characterized by the fact that the PBM effects are induced by the generation of a specific fluence rate during a specific time corresponding to specific “hot spots” as selection conditions (see below), successively in each parts of the volume of the biological object.
An illustrative embodiment of the present invention consists to use one or several light source(s) coupled to one or several light distributor(s) applying a specific fluence rate during a specific time corresponding to one or several “hot spots” presented in
The invention optionally also encompasses devices and methods predicting the time for applying PBM on a biological object, based on a frequency analysis (Differential analysis of temporal signal (integration of the past or derivation of the present)) of fluctuations of parameters reflecting the metabolic activity or predictive methods based on artificial intelligence of one or several parameters reflecting the PBM effects or the metabolic activity of the biological object. Optionally, the light power delivered by the device, the illumination time and the moment of PBM application relative to variations of the metabolic activity is adapted on the basis of feedback observables (see the list given below) to optimize the PBM effects.
As can be seen on
Oxidation is the main process producing the necessary energy in cells. It can occur in aerobic or anaerobic conditions. In many situations, biological oxidation starts with substrate dehydrogenation, i.e. the displacement of two hydrogen atoms, whereas coenzymes such as NAD+, NADP+ and FAD serve as acceptors of these atoms. Since the cellular concentration of these coenzymes is low, they must be recycled by re-oxidization. Therefore, these coenzymes serve as primary donor and acceptor in the process of oxidative phosphorylation (OXPHOS) [Ferraresi, 2012]. Since NADH and FAD are bound to many enzymes involved in metabolic pathways [Alberts, 2002], the relative ratio between the NADH and FAD binding sites changes as well when the cells are switching their metabolism [Banerjee, 1989]. Hence, cell responses to changes of the O2 level (change of metabolic activity) resulting from PBM can be monitored looking at their effects on FAD and NADH.
These coenzymes can be studied non-destructively looking at their autofluorescence, i.e. without the addition of exogenous probes [Ramanujam, 2001]. One of the most common optical techniques giving information about the metabolic state of cells is based on the determination of the redox ratio of FAD and NADH by fluorescence spectroscopy [Chance, 1979; Walsh, 2012; Blacker, 2016], in particular time-resolved fluorescence spectroscopy [Skala, 2007; Skala, 2010; Kalinina, 2016; Walsh, 2013], a field corresponding to the expertise of the inventors since more than two decades [Wagnières, 1998]. For instance, in cancer cells, an increase of cellular metabolism is usually indicated by a decrease of the redox ratio [Chance, 1989].
Therefore, steady-state and/or time-resolved fluorescence spectroscopy (or imaging) of the tissue autofluorescence is an interesting feedback observable to monitor or adapt the light dose used for PBM. Interestingly, the combined use of this approach with direct O2 sensing based on the time-resolved luminescence spectroscopy of molecular probes (PPIX or exogenous pO2 probes as proposed by Kalinina et al. [Kalinina, 2016]) or interstitial Clark’s probes, provide unique information on the PBM effects. Monitoring these parameters is minimally invasive and fast.
In normal conditions, the body maintains a stable level of oxygen saturation for the most part by chemical processes of aerobic metabolism associated with breathing. However, it is well known that the hemoglobin saturation can change for different metabolic activities.
Since many methods are well established to measure the hemoglobin saturation, notably the peripheral or central venous saturation which is known to reflect the cardiac output excepting in sepsis shocks, applying this approach to monitor the changes of metabolic activities induced by PBM is of high interest.
In addition, since several gazes can be endogenously produced and diffused within the tissue and the circulating blood, and can bind to various metalloproteins, which present strong optical absorption bands, for instance, NO or H2S can bind deoxyhemoglobin to create nitrosyl hemoglobin or sulfhemoglobin or carboxyhemoglobin which decrease the level of available deoxyhemoglobin, and since PBM can induce photodissociation (Photolysis) of metalloproteins as hemoglobin, especially nitrosyl [Lohr, 2009] with a simultaneous formation of methemoglobin, and since the changes of these different forms of “hemoglobin” can be measured (via optical absorption measurement [Van leeuwen, 2017] ), monitoring the changes of the metabolic activities induced by PBM through the assessment of these various metalloproteins complexes is of high interest.
It is well known that glycolysis, which is the metabolic pathway that converts glucose into pyruvate, leads to an acidification of the extracellular surrounding media. This acidification frequently results from the excretion of lactic acid after its conversion from pyruvate [Wu, 2007]. Since many methods are well established to measure the pH or the level of bicarbonate in tissues or in the circulating blood, applying this approach to monitor the changes of metabolic activities induced by PBM is of high interest.
As tissular (or saliva) lactate concentration can be constantly assess with minimally invasive device such subcutaneous microneedle [Tsurukoa, 2016] or in mouth, this approach can be used to monitor the changes of metabolic activities induced by PBM.
Reactive oxygen species (ROS) are chemically reactive chemical species containing oxygen. Examples include peroxides, superoxide, hydroxyl radical, singlet oxygen, [Hayyan, 2016] and alpha-oxygen. In a biological context, ROS are formed as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis [Devasagayam, 2004]. ROS are produced during a variety of biochemical reactions within the cell and within organelles such as mitochondria, peroxisomes, and endoplasmic reticulum.
Effects of ROS on cell metabolism are well documented in a variety of species [Nachiappan, 2010]. These include not only roles in apoptosis (programmed cell death) but also positive effects such as the induction of host defense genes and mobilization of ion transport systems. This implicates them in control of cellular function. In particular, platelets involved in wound repair and blood homeostasis release ROS to recruit additional platelets to sites of injury. These also provide a link to the adaptive immune system via the recruitment of leukocytes.
Abnormal levels of ROS are implicated in numerous pathologies through a strong modulation of various biological cascades [Sies, 2020]. Interestingly ROS level are also primordial for cell reprograming [Bigarella, 2014; Zhou, 2016] and tissular remodeling. For instance, their production kinetics depend on a broad spectrum of extrinsic or intrinsic repetitive stimulus such as hormones secretion or mechanical forces (like vascular shear stress), which influence directly the tissular behavior and properties [Hwang, 2003; Brandes, 2014], and finally phenotypic aspects.
Since many methods are well established to measure the ROS in tissues, applying this approach to monitor the changes of metabolic activities induced by PBM is of high interest.
As ROS and reactive nitrogen species (RNS) are intricate by nature [Moldogazieva, 2018] and since many methods to assess to RNS are well established [Griendling, 2016], the termed of reactive oxygen and nitrogen species RONS should be used here. Actually, in a full extends, the term should be reactive oxygen and nitrogen and sulfur species (RONSS).
Hydrogen sulfide (H2S) exert a wide range of actions on the whole organism. It is an epigenetic modulator inducing histone modification particularly via DNA demethylation, a process which permit cell differentiation [Yang, 2015]. It is fundamental in aging process of aerobic living organism by maintaining a high level of copy number of mitochondrial DNA [Li, 2015], as well in senescence process through sirtuin 1 activation. Interestingly, H2S is the only species which is both substrate and inhibitor of the OXPHOS inside the mitochondria depending of its concentration [Szabo, 2014], which may to be in parallel to the famous observation that exogenous H2S inhalation induce a suspended animation-like state in small mammals, known as artificial hibernation, or hypometabolism [Blackstone, 2005]. H2S is known to protects against many cardiac conditions, including pressure overload-induced heart failure [Snijder, 2015]. This supports the hypothesis that endogenous H2S is a regulator of energy production in mammalian cells particularly during stress conditions, which enables cells to cope with energy demand when oxygen supply is insufficient [Fu, 2012].
Moreover, we observed in fertilized chick’s eggs an in-ovo anoxia reoxygenation. This study was performed by gently placing an H2S microprobe above the ventricle of the chicken or the dorsal aorta. We observed that the H2S level increased significatively within the anoxic (transient) cardioplegia (or when the heart beat extremely slowly) and decrease when it beat again. Therefore, it appears that the blood flow plays a role by removing endogenous production of H2S which could bind deoxyhemoglobin to form sulfhemoglobin and propagate it.
Since many methods are well established to measure H2S in tissues [Olson, 2012], applying this approach to monitor the changes of metabolic activities induced by PBM is of high interest.
Alongside oxygen and sulfur, selenium, the constitutive element of H2Se belongs to the chalcogens group and have similar excretory and metabolic pathways. Analog to H2S, H2Se, is an endogenous small gaseous molecule which can induce a suspended animation like state and show reperfusion injury protection [Iwata, 2015]. It reversibly binds COX, which inhibits the mitochondrial respiration and argued to be the fourth gasotransmitors with H2S, NO and carbon monoxide (CO) [Kuganesan, 2019]. Moreover, incorporated into numerous selenoprotein oxidoreductase enzymes as glutathione peroxidase, it is essential for maintaining redox-status homeostasis in health and diseases, and its deficiency induces a substantial increase of ROS, which is suspected to be one important cause of cancer and CVD [Bleys, 2008].
Since many methods are well established to measure H2Se in tissues or Selenium in serum, applying this approach to monitor the changes of metabolic activities induced by PBM is of high interest.
Ions play an important role in the metabolism of all organisms as reflected by the wide variety of chemical reactions in which they take part [van Vliet, 2001]. Ions are cofactors of enzymes, catalyzing basic functions such as electron transport, redox reactions, and energy metabolism; and they also are essential for maintaining the osmotic pressure of cells. Because both ions limitation and ions overload delay growth and can cause cell death, ion homeostasis is of critical importance to all living organisms.
Since many methods are well established to measure ions in tissues (in particular calcium, potassium, chloric and/or hydrosulfide ions), applying this approach to monitor the changes of metabolic activities induced by PBM is of high interest.
It is well established that broadband Near InfraRed Spectroscopy (NIRS) can be used to monitor concentration changes of the oxidation state of cytochromes as cytochrome-c-oxidase (ΔoxCCO) which plays a key role in the mitochondrial respiration [Roever, 2017].
Since different methods are well established to measure ΔoxCCO in tissues (or other cytochromes involved in the metabolism), applying these methods, including NIRS to monitor the changes of metabolic activities induced by PBM is of high interest.
Metabolic imaging focuses and targets changes in metabolic pathways for the characterization of various clinical conditions. Most molecular imaging techniques are based on PET and MRS, including conventional 1H and 13C MRS at thermal equilibrium and hyperpolarized magnetic resonance imaging (HP MRI). The metabolic pathways that are altered in many pathological conditions and the corresponding probes and techniques used to study those alterations have been reviewed by Di Gialleonardo et al. [Di Gialleonardo, 2016]. In addition, Fuss et al. [Fuss, 2016] described the use of medical imaging to address various conditions in humans.
Since many metabolic imaging-based methods are well established to assess the metabolism, applying these methods, including functional metabolic imaging, to monitor the changes of metabolic activities induced by PBM is of high interest.
Vascular tone refers to the degree of constriction experienced by a blood vessel relative to its maximally dilated state. All arterial and venous vessels under basal conditions present some degree of smooth muscle contraction between balance of constrictor and dilatator influences that determines the diameter of the vessel, e g the vascular resistance to adapt / regulate blood flow and pressure. Basal vascular tone differs among macro and micro-circulation and organs. Certain organs have a large vasodilatory capacity (e.g., myocardium, skeletal muscle, skin, splanchnic circulation) hence a high vascular tone, whereas others organs have relatively low vasodilatory capacity (e.g., cerebral and renal circulations), hence a low vascular tone.
The vascular tone regulation differs among the macro (arteries, veins) and the micro (arterioles, venules, capillaries). Notably, even if the tone can be modulated via extrinsic factor (nerves, circulating metabolites), blood vessel can exhibit spontaneous oscillations (vasomotion) which give rise to flow motion [Aalkaejer, 2011]. Therefore, through the dependence of the vascular tone in a multiplicity of actuator from local to systemic, the analysis of this tone, give insight on the metabolic activity, and can reflect the degree of aging [Bentov, 2015] and many pathophysiological conditions, as ulcer risk, type 2 diabetes [Smirnova,2013], endothelial dysfunction or hypertension [Ticcinelli, 2017], renal diseases [Loutzenhiser, 2002] [Carlstrom, 2015] or metabolic syndrome [Walther, 2015]. Moreover, the assessment of the skin microvascular endothelial function is used as diagnosis as well as prognostic of CVD [Hellman, 2015].
Since many methods are well established to assess to the vascular tone and the vasomotion, such as videocapillaroscopy, plethysmography [Tamura, 2019], laser doppler flowmetry, pressures measurement via cutaneous vascular conductance (CVC) or time frequency analysis as example, and since all the cardiovascular system is argued to be a single entity of coupled oscillators in a dynamic point of view [Shiogai, 2010], any methods which enable to assess to the change of metabolic activities induced by PBM (including heart rate variability (HRV) which give information on the autonomic nervous system via ECG or heart sound measurement [Alvarez, 2018] via phonocardiogram (PCG) [Patidar, 2014] are of high interest. As observe by the inventors along surgical procedure respiratory frequency variability (RFI) [stevanovska,2007] or ballistocardiography to monitor the changes of metabolic activities induced by PBM is of high interest.
Electrocardiogram (ECG), electroencephalogram (EEG) and electromyogram (EMG) are standard measurements of electrical activity of the metabolism of the heart, the brain and the muscle respectively. Novel ECG analysis based on signal computational classification [Patidar, 2015] are promised tools in heart diagnosis notably giving insight in coronary artery disease [Kumar, 2017] [Acharia, 2017], arrhythmia and ischemia disorders [Bhoi, 2017]. Same kind of analysis have been performed on EEG which show interesting outcomes in epileptic seizures, the most common brain disorders [Bhattacharyya, 2018].
Since many methods are well established to monitor these electromagnetic endogenous signals, methods which enable to assess to the change of metabolic activities induced by PBM are of high interest.
It can be used in the clinic for measuring various physiologic parameters [Petterson, 2016]. This approach is used for pacemakers as Ensite from St Jude Medical, OptiVol from Medtronic and closed loop stimulation from biotronik.
Since many methods are well established to measure electrical bioimpedance in tissue or directly on the skin, any these methods which enable to assess to the change of metabolic activities induced by PBM is oh high interest.
A long list of circulating markers of interest to monitor the light dose during PBM includes metabolites (succinate, pyruvate, etc.), coagulation factors, apoptotic factors, (pro and anti) inflammatory factors, as well as hepatic factors, mitokines, or level of isolated mitochondria for instance. It should be noted that only a few of them is enumerated here.
Glucose level: Many pathologies are associated with a dysregulation of circulating glucose level, which directly induces systemic metabolic disorders, as it is the case for diabetes. Hence, monitoring the change of the metabolic activities through the assessment of the glycaemia is of high interest.
Succinate: Succinate is a key intermediate of the tricarboxylic acid cycle (TCA) cycle which plays an essential role in anabolic and catabolic pathways. Moreover, it is notably associated with reperfusion injuries [Chouchani 2014]. Mitochondria are the physiological source of succinate, however accumulated succinate can be transported into the cytosol and then in the circulating blood. This TCA cycle intermediate connects intracellular metabolic status and intercellular signaling [Tretter, 2016]. Level of succinate in blood can vary from 2 to 20 µM, where this concentration can increase, with hypoxic stress, pro-inflammatory stimuli, exercise, or with pathological conditions such as type 2 diabetes, obesity or ischemia reperfusion injury [Grimolizzi, 2018]. Since circulating level of succinate can be monitored via bioluminescent assay, or Raman spectroscopy the assessment of the change of metabolic activities induced by PBM via the circulating level of succinate is of high interest.
Lactate and lactate dehydrogenase (LDH): LDH is a common marker of cell damage and cell death. In addition, LDH produced during anaerobic exercise can be reduced by PBM [Park, 2017].
Hence, using these markers to assess the change of metabolic activities induced by PBM is of high interest. Moreover, combination of LDH level with aspartate aminotransferase (AST) level serves as a potent indicator of the damage to the body’s tissues. It should be noted that lactate levels can be assessed with new aerometric method directly on the saliva [Tamura, 2018].
Since the high level of metabolism activites in inflammatory or immune response, notably by the capacity of immune cells to change their phenotype, serum/plasma level of immune/inflammatory markers, such as: mtDNA copies, number of leucocytes, total antioxidant capacity, bicarbonate, malondialdehyde (MDA), uric acid, bilirubin, level of cytokines or chemokine markers such as interleukins IL2, IL6, IL7, IL10, IL18 or TNFα for instance, as well as macrophage inflammatory protein 1-α, IP10, MCP1, as well as activation of lymphocytes T and / or monocytes M2 through flux cytometryare are also of high interest.
Serum/plasma levels of thioredoxin: The level of this enzyme is elevated in infection, ischemia-reperfusion, and other oxidative stresses. Therefore, they are good markers for monitoring of the oxidative stresses. Plasma levels of thioredoxin are also elevated in patients with coronary spastic angina and other cardiovascular diseases [Nakamura, 2004].
Cardiac markers: Several established markers (myoglobin, creatine kinase isoenzyme, troponin I and T, B-type natriuretic peptide, transaminase) are clinically used for cardiac infarction diagnosis and also for other organs injuries. To a lesser extent, LDH, glycogen phosphorylase and recently ischemia-modified albumin can be used in diagnosis within 30-minute assay [Dasgupta, 2014]. This is also the case for thioredoxin level [Jekell, 2004].
Level of circulating eNOS as well NO or nitrite or nitrate: The levels of these compounds are essential, notably for the regulation of systemic blood pressure and systemic homeostasis [Wood, 2013]. By extension, also levels of circulating H2S or sulfite or sulfate level can be assessed to monitor the change of the metabolic activities induced by PBM.
Circulating mitochondria: It has been recently shown that cell free functional mitochondria are present in the circulating blood. Moreover, mitokynes are important in the metabolic remodeling, especially in the heart failure [Duan, 2019]. Therefore, monitoring of the change of the metabolic activities through the assessment of the circulating mitochondria level or mitokynes level is of high interest.
Although, the optical imaging of cardiac electrical signals using voltage-sensitive fluorochromes (VSF) has only been performed in experimental studies because these VSFs are not yet approved for clinical use, FDA approved dyes, such as Indo Cyanine Green (ICG) [Martisiene, 2016], exhibits voltage sensitivity in various tissues, thus raising hopes that electrical activity of cardiac tissues could be optically mapped in the clinic. Therefore, methods based on the use of voltage-sensitive dyes to map (or to assess locally with a “point measurement” system) the cardiac electrical signal to monitor/adapt the light dose during PBM is of high interest.
p) The use of redox sensors to assess of the status of various tissular redox states. Since metabolic and redox reactions are intricated and since many methods are based on the measurement of redox sensors proteins to asses to metabolic activities, monitoring changes of metabolic activities induced by PBM with redox indicators probes is of high interest.
Ultrasonography is a well-established method to investigate cardiac tissue. Many parameters characterizing the heart tissues as well as the blood flow are routinely obtained during ultrasonography.
Therefore, methods based on the use of ultrasonography to monitor the light dose during PBM are of high interest.
pO2 can be easily measured within exogenous or endogenous probes in different compartment (tissular or organ) or different organelles within the cell. For instance, such probes can be optically detected. Other techniques, such as EPR oximetry, polarographic electrodes or BOLD imaging are of high interest to assess changes of metabolic activities induced by PBM.
In the clinic, real time assessment of these variables is a must to monitor the metabolic activity, especially in case of cardiovascular injuries. Such measurements notably involve, arterial and venous gases pressures, cardiac output, stroke volumes, capillary pressure, as well as systemic and pulmonary resistance. Therefore, the use of these methods to assess changes of metabolic activities induced by PBM are of high interest.
It is well known that Krebs cycle enzymes kinetics are good markers of metabolism notably to assess to the level of mitochondrial proteins. Since, for instance, acotinase or succinate dehydrogenase activities are commonly measured in clinics, the use of these methods to assess changes of metabolic activities induced by PBM are of high interest.
Protoporphyrin IX, is a precursor of numerous organometallic proteins, such as hemoglobin and chlorophyll. The inventors have shown that cells treated by PBM tend to increase their endogenous production of PpIX. Therefore, the Δuse of methods based on the detection of the PpIX level to assess changes of metabolic activities induced by PBM are of high interest. Since the heme concentration is a feedback parameter in the PpIX endogenous production pathway, by extension, measuring the level of circulating hematocrits to assess changes of the metabolic activities induced by PBM is of high of interest.
Oxylipines are bioactive metabolites derived from the oxygenation of polyunsaturated fatty acids. Furthermore, they play a key role in the progression of cardiovascular disease thrombosis and risk factors. Hence, their monitoring is of high interest.
It is well known that glycoproteins, comprising of protein and carbohydrate chains, are involved in many physiological functions, including immunity. They possess receptors signaling domains that recruit signaling molecules.
Glycerol can serve as a marker of apoptosis. One of the function of glycerol is that is serves as a chemical chaperone. In particular, it possesses an ability to enhance the expression of apoptotic regulators (bax).
aa) The assessment of the immunomodulatory effects induced by PBM can be monitored by pro-inflammatory circulating monocytes like CD14, CD16 which can differentiate to the dendritic cells. It can be also assessed by the cytokines profiles of macrophages.
ab) Monitoring of the basis of the level of oxytocin. For the latter, it has been shown that monitoring of the oxytocin levels in the intensive care unit in the premature infants serves as a relevant marker of pain.
Optionally, the light power the illumination duration and the application time of PBM define by this device, is to be combined with the administration of exogenous stimulus wherein the stimulus could be an agents (see the list given below) to increase the PBM effects. It should be note that the time between the administration of exogenous agents and the PBM illumination may take into account the assimilation duration as well as activation kinetics of the agent.
As already shown by the inventors, an administration of ALA combined with PBM increases the PpIX build up and, consequently, the level of endogenous PpIX. Therefore, the coadministration of ALA and light is of high interest to increase PBM effects. It should be noted that other exogenous agents can be combined within PBM to increase its effects, as indicated below.
As presented in
The assessments of these PBM effects on angiogenesis were performed using an approach based on fluorescence angiographies performed on the CAM several days after PBM.
Interestingly, in parallel, the inventors observed in-ovo, through the monitoring of the H2S and NO level on the chicken embryo, that a topical application of STS induced a significant increase of NO after a long time (6 at 12 hours), whereas, when performing a PBM irradiation 1 - 2 hours after the STS application, the time when NO was produced was significantly reduces, typically down to one hour.
Since STS is a clinically approved H2S donor [Snijder, 2015] to protects against many cardiac conditions, as also already reported for H2S [Yu, 2014], including pressure overload-induced heart failure via upregulation of endothelial nitric oxide (NO) synthase [Kondo, 2013] as well as renal ischemia / reperfusion injury [Bos, 2009], the combined use of PBM, applied with the device/protocol mentioned above, with the administration of H2S donors (such as STS or methylsulfonylmethane (MSM), or dithiolthiones for instance, or other donors presenting different H2S kinetics release) and/or NO donor substances, as for instance arginine, including NO itself, is of high interest.
Since Cysteine is an important source of sulfide in the human metabolism, combining the administration of this proteinogenic amino acid, or derivatives thereof, such as selenocysteine, or synthetic form as N-acetylcysteine is of high interest to potentiate the effects of PBM. MSM, a naturally occurring organosulfur compound, is utilized as an alternative source of biologically active sulfur. It is mostly used for anti-inflammatory treatments. It has been investigated in animal models, as well as in many human clinical trials [Butawan, 2017]. MSM is also recognized for its antioxidant capacity and it was proposed that the antioxidant mechanism acts indirectly via the mitochondria rather than directly at the chemical level [Beilke, 1987]. As an FDA approved substance, MSM, is well-tolerated by most individuals at dosages of up to four grams daily, with very few side effects [Butawan, 2017]. Results from in vivo and in vitro studies indicate that MSM actions are at the crosstalk of oxidative stress and inflammation at the transcription and sub-cellular levels [Butawan, 2017]. Interestingly, Kim et al. [Kim, 2009] demonstrated that MSM can also diminish the expression of inducible nitric oxide (NO) synthase (iNOS) and cyclooxygenase-2 (COX-2) through suppression of the nuclear factor-kappa B (NF-κB), a transcription factor involved in the immune and cellular responses to stress. This observation is highly interesting since NO is a powerful vasodilator involved in many metabolic functions. As some other gas transmitters, called gasotransmitors [Donald, 2016], NO can have differential effects depending on its local concentration and microenvironment [Thomas, 2015] which can impact many different processes [Rapozzi, 2013; Reeves, 2009]. It has also been suggested that PBM causes NO photodissociation from COX [Karu, 2005; Lane, 2006]. Concomitantly, NO photodissociation from other intracellular “reservoirs” such as nitrosylated forms of myoglobin and hemoglobin have also been hypothesized [Lohr, 2009]. It is well established that cell respiration is down regulated by the NO production by mitochondrial NO synthase. The O2 displacement from COX by NO inhibits cellular respiration, and ATP production [Antunes, 2004; Cooper, 2008]. Therefore, it is believed that PBM increases ATP production. An alternative and, possibly, parallel mechanism to explain the release and/or increase of NO bioavailability by PBM could be linked to an action of COX as a nitrite reductase enzyme (a one-electron reduction of nitrite gives NO), in particular when the O2 partial pressure is low [Ball, 2011].
All together, these observations indicate that MSM has an indirect effect on the mitochondrial electron transport chain (ETC) through its NO modulation. In addition, this analysis of the literature indicates that the combined use of PBM with NO donors, such as S-Nitrosothiols or alkyl nitrites, including NO itself, induces a potent synergetic effect.
Moreover, since interaction between H2S and NO can produce nitroxyl (HNO), which plays an effective role within the cardiovascular system about oxidative stress and cardioprotection, heart contractility, vascular tone as well as angiogenesis [Nagpure, 2016; Wu 2018], the coadministration of (H)NO as well as nitroxyl donor, cimlanod or 1-Nitrosocyclo Hexyl Acetate for instance, is of high interest to increase PBM effects.
Ebselen, an FDA approved H2Se donor is of high interest to increases PBM effects as already discuss by the inventor (page 13, point g).
As already mention, NAD+ is required for redox reactions and control hundreds of key process of energy metabolism to cell survival, rising and falling depending on food uptake, exercise, and time of the days. Therefore, administration of NAD+ donor, as vitamin B3 within PBM is of high of interest to increase PBM effect.
Other exogenous agents of interest for their combined use with PBM are:
By extension, any exogenous agents which are known to modulate the metabolism, especially within the mitochondria through the modulation of the ETC or ROS modulator for instance, are of high interest to increase PBM effects. It is the case for adenosine diphosphate (ADP) which is known to increase the OCR, or for vitamin K, ketamine suxamethonium, acetylcholine and atropine, as well as bradykinin. Additional agents include, catecholamines like adrenaline noradrenaline or dopamine, opioids which activate various G proteins, or various kinases modulator or various anti-oxidant and/or anti-inflammatory donor such as resveratrol. Finally, targets of the rapamycin or sirtuin modulators are of high of interest to increase PBM effects.
By extension, since temperature, exogenous or endogenous mechanical pressure [Li, 2005; Hwang 2003], physical exercise as well as electrostimulation, hyperoxia, hemostasis (remote preconditioning) are known to modulate the metabolism, any exogenous stimulus, or combination of, like environmental/physical /electrical or electromagnetic stimulus applied on the biological object is of high interest to increase PBM effect. For instance, it is known that the level of endogenous H2S is inversely correlated within the temperature. An increase of the temperature in situ can be viewed as an indirect endogenous H2S donor and, reciprocally, an increase of the in situ temperature can be viewed as an endogenous H2S inhibitor.
As observed by the inventors, the potency of PBM not only depends on the light dose [J/m2] and spectroscopy (wavelengths) but, surprisingly, also on the fluence rate for specific illumination times. For example, the inventors have observed for a specific case, as indicated in
This is an illustration of a more complex PBM response compare to the well-known bimodal effects of PBM, i.e. too high or too low fluence rates and/or light doses significantly reduce the PBM effects. The inventors have also demonstrated, in certain conditions, the absence of “neutralization” of the PBM effects by an over-dose/irradiance before and/or after PBM applied with optimal conditions.
The inventors have also observed surprising results when performing PBM with a combination of wavelengths, one of them being ineffective when used alone. This is the case for 730 nm which is not potent when used alone, as it can be seen in the
Indeed, it is well established that the optical properties of biological tissues, described mostly by their absorption µa and reduced scattering µs’ coefficients, have an important impact on the propagation of the light around a light distributor. In general, the fluence rate (and the light dose) decreases with the distance from the light source due to the absorption and scattering of the light in the tissue for a given power (and illumination time).
It should be noted that the geometry of the light distributor (illumination geometry) is adapted to the specific organs to be treated. For example, frontal (broad field), balloon-based, or interstitial illuminations, with one or several fibers, are considered, in particular (see the products commercialized by Medlight SA “http://www.medlight.com/#” as illustrative examples).
The inventors have also established an innovation to adjust the radiometric and spectral conditions used in PBMT based on frequency analysis (in particular using the wavelet theory) of parameters reflecting the metabolic activity. More precisely, they have conducted a time frequency analysis of the partial pressure of oxygen (pO2) of the chick’s embryo chorioallantoic membrane (CAM) during PBM.
It is well known that arterioles, particularly in the peripheral microcirculation, strongly respond to the surrounding tissue pO2 [Jackson, 2016] through complex metabolic regulation mechanisms [Reglin, 2014] where low frequency oscillations of the blood perfusion exist [Kvandal, 2006].
Based on local measurements of the pO2 performed in the CAM during a “long” (several hours) time using commercially available Clark’s probes (Unisense®, OX-needle, OX100-Fast) we calculated frequency spectra resulting from a wavelet-based analysis of the pO2. Wavelet analysis is a well-known mathematical transform which enables to characterize nonstationary frequencies during the measurement time.
H2S is a potent regulator of the vascular tone [Köhn, 2012] which can be induced by the administration of NaSH. We measured with our Clark’s probe that a H2S stimulation of a CAM arteriole induced by the topical application of NaSH (10 µl, 1 µM in physiologic serum) generates a strong modulation of the pO2 around 60 mmHg. This modulation is observed at least for the myogenic (0.05 Hz - 0.15 Hz), the endothelial nitric oxide synthase dependent (0.01 Hz - 0.02 Hz) and the endothelial nitric oxide synthase independent (0.005 Hz - 0.01 Hz) bands. Other lower frequencies bands are also activated where it was notably suggesting that some of them are correlated within prostaglandin or prostacyclin release from the endothelium.
Our innovation results from PBM irradiations of the CAM we have performed with a frontal light distributor (850 nm, 7 mW.cm-2, 30 s) at t=80 min and t = 105 min (see
It appears, in particular, that the bands 3, 5 and 6, as well as those corresponding to undefined lower frequencies, are fully or partially inhibited by PBM (see
Therefore, adapting the radiometric and spectral conditions used in PBM therapy based on the frequency analysis of parameters reflecting the metabolic activity is of high interest.
This specific type of monitoring can be performed for two main purposes: i) to apply the PBM light at an optimal time relative to the metabolic “oscillations” or, ii) to assess the level of change of the metabolism induced by PBM in such a way that it is optimal (to adapt the radiometry).
The pO2, as presented just above, is not the only parameter to be analyzed using the wavelets, or frequency-based analysis to monitor the light dosimetry during PBM. The list presented above (List of feedback observables) describes other parameters of interest:
The inventors have also shown that application(s) time of light irradiation within the biological object is crucial to induce significant PBM effects. These observations are very important since biological objects are dynamic within a wide frequency scale of metabolic activity triggered from transient or regular endogenous or exogenous factors. Notably, the inventors have shown that, when light is applied at a specific time during the metabolic activity of glioma cells or HCM, the metabolic response of cells is significatively modulate differently which modulate accordingly phenotypical long-time response. Inventors have also shown, using the in-ovo chicken embryo heart models during anoxia / reoxygenation studies, that the survival rate is significantly higher when the PBM irradiations start just before the reoxygenation, compare to when PBM is performed during ischemia long time before or long time after the reoxygenation. Interestingly, it is observed in this condition, that reoxygenation induces an arrest of the heart beating during a time ranging between one second and several minutes. PBM conditioning prior to reoxygenation significatively avoid this arrest. Therefore, the inventors have shown that PBM restarts or modulates the heart beat following an anoxic cardioplegia or presenting bradychardia or tachycardia, whereas no influence is observed on healthy beating hearts. These in oνo observations have been confirmed in νiνo by the inventors during ischemia/reperfusion events induced by the ligation of swine hearts coronary.
One aspect of the present invention is the application of the device or method to treat ischemia reperfusion injury, in particular those affecting the myocardium to reduce the infarction size following acute myocardium infarction (MI).
Based on the chicken embryo heart the inventors developed an anoxia reoxygenation experiment in ovo where eggs were placed in a thermoregulated gas chamber with a continuous monitoring of the environmental and embryonic temperature and pO2. For some experiments, small H2S, NO and pH probes were also positioned around the embryonic heart or at different location of the embryonic tissue. This chamber was placed under a microscope for image recording. After a stabilization time (temperature stabilization), an anoxic environment was created by flushing nitrogen all around the egg during tens of minutes without any change of the environmental temperature, followed by a reoxygenation of the egg as depicted on the
At Embryonic Development Day (EDD) 3, flushing pure N2 during 45 min before a reoxygenating of the embryos induced a mortality rate larger than 50% 48 h after the end of the experiment. This experiment supports one aspect of the “reperfusion injury” mentioned as the “oxygen paradox” in the article published by Latham et al. (Latham, 1951), i.e. that reperfusions could be, in certain cases, lethal (Piper, 2000). In our case, as well for isolated chicken heart embryo (Raddatz, 2010), reoxygenation induce a burst of Reactive Oxygen Species (ROS) and a permanent or transient cardioplegia followed by irregular heartbeat (bradycardia, tachycardia). In our experiment, when embryo at EDD3 undergo a 45 min anoxia, we observed that a photoconditioning (671 or 808 nm, 5 mW.cm2, 30 s) of the embryo just before the reperfusion significantly avoid cardioplegia and, importantly, increase the survival rate at 48 h. Interestingly, this positive effect of PBM is not observed if light is applied too early or too late after the reoxygenation. This last observation clearly suggests that the time at which the light is applied relative to the reoxygenation is critical to produce a beneficial outcome.
Therefore, one application of high interest for the invention consists to use PBM delivered by our original medical device and method to treat damages resulting from hypoxia reoxygenation events and by extension for ischemia reperfusion events.
The inventors have also shown that the heart beat can be stimulated by PBM after an anoxic non-permanent cardioplegia of the chicken embryo heart.
Before Embryonic Development Day (EDD) 7, oxygen supply of the chick’s embryo was mainly performed by diffusion across the shell, then through the embryo. Heart beat and blood flow, which are observable from EDD 2, mainly act as stimulus for cardiovascular development. Embryo, up to day 5 are flattened on the “surface” located just below an albumin layer. Therefore, it is easily accessible after removing a part of the shell. This is why, in parallel to the chicken embryo ontogeny, embryo from EDD 2 up to EDD 5 are used since decades as excellent models for developmental biology and, in particular, in cardiogenesis and rythmogenesis. This model is also used for anoxia-reoxygenation studies [Sedmera, 2002] where their behaviors are studied during and following hypoxia or anoxia, but also during hypoxic induced tachycardia, bradycardia or for fibrillation studies.
One interesting PBM effects observed by the inventors during an anoxic in ovo experiment is in relation with the positive effect(s) of light which enable to restart the heard after a cardioplegia. Indeed, a prolonged anoxia leads to a stop of the heart beat which, sometimes, restarts to beat again transiently until an irreversible and total cardioplegia takes place. The inventors observed, in most cases, that a PBM irradiation often restart the beating heart (
This surprising positive effect of PBM strongly suggests that it triggers the metabolic activities involved in the heart beat, including after an anoxic cardioplegia. Since PBM is known to reduce inflammations and to boost the metabolic activity, PBM is of high interest to treat conditions such as fibrillations, including atrial fibrillations, for instance
By extension, since the metabolism is subject to autonomous (i.e. independent of the cell cycle [Papagiannakis, 2017]) and non-autonomous rhythms of various frequencies, as it is the case, for instance, for the circadian rhythm [Bailey, 2014], applying PBM light at specific times and/or frequencies to lock, trig and/or (re)synchronize metabolic oscillations is of high of interest, in particular to treat various metabolic disorders, such as type 2 diabetes [Petrenko, 2020], metabolic switch as aerobic glycolysis (Warbugg effect) in cancer cells [Gatenby, 2018], or within hepatic disorders and diseases [Zhong, 2018].
The inventors have also shown that PBM light delivered directly in the blood perfusing large vessels (pulmonary artery, vena cava of pigs), or in the right atrium, which contain deoxygenated blood, can be used to modulate systemic hemodynamics and oxygen tension, generate anti-inflammatory, immunomodulatory, anti-aggregation, endothelial and epithelial cells protection. Surprisingly, such illuminations of deoxygenated blood during long hypoxia event in swine maintain homeostasis according to gas measurements performed in arterial and venous blood (using cobas b 123 POC System Roche diagnostics®). In addition, these illuminations maintained and stabilized functional hemodynamic variables, such as the cardiac output, concomitantly to an increase and a stabilization of the systemic labile NO level, as measured within a heparinated NO probe (NO-NP Unisense® placed into pulmonary arteries or the atrium during tens of minutes after the PBM Illumination. This effect is unexpected since it is usually well accepted that the lifetime of labile NO in blood is ten to hundred times shorter. Interestingly, without a concomitant increase of methhemoglobin assess in venous or arterial gas during the experiment. In addition, the inventors have shown that PBM light delivered directly in the blood perfusing large vessels (pulmonary artery), or in the right atrium, which contain deoxygenated blood, can be used to control hypoxemia, hemoglobin saturation, arterial and venous oxygen partial pressure associated to a hypoxia. In addition, this approach can be used to maintain the glycaemia level (
According to the results presented in
Let’s consider the specific situation corresponding to the geometry and the optical coefficients mentioned in
the only way to maintain F constant, called F′ thereafter, for increasing values of z is to increase E. This statement derives from the inversion of the previous expression which writes:
Since each HCM cell must be illuminated during 3 minutes with F′ = 3 mW/cm2, another concept of important has to do with the tolerance affecting this fluence rate. If cells must be irradiated with exactly 3 mW/cm2 the total treatment of the whole sample would take an infinite time since the volume corresponding to these cells is equal to 0 mm3 (they are confined in a plane located at depth “z” which has a volume equal to 0 mm3). However, looking at
Since E = (F′/k). eµeff z, we have
Therefore, Δz only depends on F′, ΔF’ and µeff.
If the tissue volume to be treated ranges between z1(proximal position) and z2 (distal position), the number “n” of different irradiances to apply during 180 s (thereafter called T) is equal to: z2 - z1 /Δz.
Consequently, the spatial evolution of the irradiance E is as presented in
The temporal evolution of the irradiance E(t) is (see
where E will be equal (providing that the diffusion approximation equation is valid) to F′/k.eΔF′/2F′ when 0<t<T, F′/k.e3ΔF′/2F′ when T<t<2T, F′/k.e5ΔF′/2F′ when 2T<t<3T, F′/k.e(2n+1)ΔF′/2F′ when nT<t<(n+1)T, with n = µeff.F′.(z2 - z1)/ ΔF′(see equation 6 below).
Therefore, the total time “ttot” it takes to treat a volume of tissue ranging between z1 and z2 is: T.(z2 - z1)/ Δz. With the explicit expression of Δz (Equation 4) we have:
Finally, it should be noted that, similarly to F′, T can be applied with a certain tolerance due to the FWHM of the PBM peak along the illumination time axis (see
In summary, in this example the device according to the invention applies an irradiance E(t), during a time which ranges between 0 and ttot, given by: E(t) = (F′/k). eΔF′.t/F′.T.
Since the device illuminates a certain area of surface S [m2] with a certain power P [W], we have that E(t) = P(t)/S.
Therefore, the device delivers an optical power P(t), during a time which ranges between 0 and ttot, given by: P(t) = (S.F′/k). eΔF′.t/F′.T. Equation 7)
All parameters involved in the expressions of E(t) and ttot are determined for a specific organ (of known thickness z2 - z1) and illumination geometry (of surface S): Indeed, F′, ΔF’ and T are derived from the
This detailed description, for an optimal PBM effect on the whole volume addressing a specific hot spot of
In the description given above, the tissue is considered to be static while the power of the light source is changed with time to generate optimal fluence rate during an optimal time in the targeted tissues. However, there are situations, for example in fluids, including the blood, where the geometry is dynamic, due to the blood flow for example. In such situations, the power delivered by the light distributor can be stable (no time evolution), but the light pattern produced by the light distributor, combined with the fluid optical properties, can be such that the fluence rate is optimal in some volume elements due to the fluid flow. Therefore, longitudinal variation of the emittance in such a way that the light dose and/or fluence rate is optimal to induce PBM effects at different locations of a moving fluid, such as blood must be introducing. An illustrative example is presented in
Based on the surprising results obtained by the inventors indicating that the effects resulting from the use of PBM-potent wavelengths applied in sub-optimal radiometric conditions can be optimize by the combined application of a non-potent wavelength, another PBMT protocol can be defined. An illustrative example (
A detailed example of the device according to the invention is presented in this example.
This treatment of ischemia-reperfusion of heart muscle can be performed:
The optical distribution routes considered are:
This involves implanting light distributors, preferably cylindrical and based on one or more optical fibers, through the heart (
These light distributors are placed in the suffering cardiac area (ischemic area for example) at the end of the surgical procedure before or during reperfusing the coronary arteries.
These light distributors are placed according to the procedure described below:
Optical delivery in such a way that the time evolution of the light power of the light source is done according to the determination described in the previous step. It can be modulated by monitoring methods based on various instrumental or biological data previously described. A simplified diagram illustrating an example of a part of the device supplying an optical distributor is presented in
In the case of a single irradiation:
In the case of multiple irradiations:
This involves the placement of one or more light distributors percutaneously into the left ventricle by an interventional cardiologist under fluoroscopy during myocardial revascularization in the acute phase of a MI in pre, per or post conditioning.
These light distributors are placed at the start of the procedure before revascularizing the occluded coronary artery(ies).
These light distributors are implanted according to the procedure described below:
This involves the placement of one or more light distributors percutaneously in the arteries, whatever they may be, under fluoroscopy during a revascularization process after an ischemic phenomenon in interventional radiology, in pre, per or post conditioning, during a MI, a lung or other organ transplantations submitted to ischemia reperfusion phenomena.
These light distributors are placed at the beginning or at the end of the procedure before reperfusion.
These light distributors, in the case of the coronary arteries, are implanted according to the procedure described below:
Translation of these procedures can be performed to heart transplant since it is known that ischemic reperfusion injuries is a major issue during organ transplant, this issue being the main cause of graft rejections.
By extension, the procedures described above can also be applied to other organs subject to ischemia reperfusion injury, as it is the case for kidney, liver, spleen, or brain for instance. These procedures can be combined with other procedures in order to illuminate simultaneously different part of the body, the thyroid for instance, to control a possible negative systemic response induce by the organ subject to I/R.
Since ΔF’, defined in the detailed description, is larger than zero, the temporal evolution of the irradiance (or power) delivered by the light source can be continuous instead of incremental (as presented by the dotted lines fitting the histograms in
The different tissue layers of thickness Δz can be illuminated with the appropriated fluence rate while increasing or decreasing (incrementally and/or continuously) the irradiance (or the power).
In this case, ttot is the same, but the temporal evolution of the irradiance (or the power), are given by the expression E(t) = (F′/k).eΔF′.(ttot-t)/F′.T or P(t) = (S.F′/k).eΔF′.(ttot-t)/F′.T, respectively (0<t<ttot).
Solutions of the diffusion approximation exist for many of these geometries to determine the fluence rate. Therefore, a general expression of equations 5 for other illuminations, organs and/or light delivery geometries can be written as: E(t) = FE (µa, µs, g, next, ntissue, F′, ΔF’, S, T, t), where FE is a function which depends on the tissue optical parameters, the organ and illumination geometries, the fluence rate, as well as its FWHM, and the illumination time(s) generating local maxima of the PBM effects. Numerous different approaches are known to determine FE, as described below in example 6.
Similarly, a general expression of equations 7 for other illuminations, organs and/or light delivery geometries can be written as: P(t) = FP (µa, µs, g, next, ntissue, F′, ΔF’, S, T, t), where FP is a function which depends on the tissue optical parameters, the organ and illumination geometries, the fluence rate, as well as its FWHM, and the illumination time(s) generating local maxima of the PBM effects. Numerous different approaches are known to determine FP, as described below in example 6.
A combination of the light delivery geometries presented in
Finally, heterogeneous tissues, in particular layered tissues structures, must also be envisaged.
Since different types of tissues have different optical properties, the formalism described above is valid for different values of µa, µs, g, next, ntissue, in particular if these optical properties are subject to changes for a given tissue during the illumination.
Different approaches are well established to model the propagation of light in biological tissues [Martelli, 2009]. Therefore, these approaches can be used instead of, or in combination with, the formalism presented above, which is based on the diffusion approximation of the light transport equation, to determine the temporal evolution of the light source to generate optimal PBM effects.
These approaches, which have been mostly developed in photomedicine to master the dosimetry of light in tissues, are classified in two categories:
The specific values given above for F′(3 mW/cm2), ΔF′(1.6 mW/cm2) and T (180 s) result from our experimental observations obtained in specific conditions in terms of sample (human cardiomyocytes: HCM), environment (medium, temperatures, pO2, ...) and spectral design (only one illumination performed at 689 nm). However, changing one, or a combination, of these conditions would lead to different values for F′, ΔF’ and T, in particular. This is, in particular, the case if the chronogram of the application(s) of light is changed.
Therefore, the concepts presented above may be generalized for different conditions and cell types.
It should be underlined that
This is important, in particular to minimize the total treatment time.
Indeed, since “high” irradiances cannot be applied without damaging the tissues, only tissues located “close” to the illumination surface can be treated with the “high” irradiance of 15 mW/cm2.
Otherwise, cells close to the light source would experience thermal damages when distant cells receive a relatively high fluence rate.
It is well accepted by the scientific community of this field that thermal effects start to be significant if an irradiance of several hundreds of mW/cm2 of red (or NIR) light is applied during more than several seconds over a broad (diameter larger than µeff-1) spot.
In this case, the treatment algorithm looks as follows:
As long as E < 100 mW/cm2, the temporal evolution of this irradiance (or power) is given by the equations 5 (or 7) with: F′ = 15 mW/cm2; ΔF’ = 4 mW/cm2 and T = 40 s. Otherwise, the values of F′ = 3 mW/cm2; ΔF’ = 1.6 mW/cm2 and T = 180 s must be used.
This example can be enlarged by the use of the combination of wavelength(s) within their own hot spot(s).
Numerous light sources are commercially available nowadays to treat tissues by PBM. Needless to mention that none of them generate an irradiance (or power) according to equations 5 (or 7).
However, since many of these commercially available light sources emit CW light and generate an irradiance larger than 0.62 mW/cm2 (3 mW/cm2 divided by k = 4.87 in our specific conditions), they may be combined with an attenuator which would change its transmission with time in such a way that the irradiance would correspond to the value given by equation 5.
More precisely, if E′ is the irradiance produced at 689 nm by such a source without attenuator, the temporal evolution of the attenuator transmission (Tr) would be given by: Tr(t) = E(t)/E′, where E(t) would be given by equation 5.
In summary, a particular design of the device according to the invention must integrate CW light sources combined with one or several attenuators to end up with an irradiance corresponding to that given in equation 5.
The generalizations mentioned above in Examples 1 to 8 also apply to this example.
Since biological objects have dynamic optical absorption and responses to light, in part due to dynamic changes of their redox states, wavelength or multiplexed wavelengths used for PBM can be synchronized/modulated at higher frequencies than the temporal variation defining in equation 5 taking into account the kinetics/dynamic of the oxidative metabolic redox states.
As already mention in example 10, light can be modulated at higher frequency than that used for the variations of the irradiance (or power or fluence rate) according to equations 5 and 7. Since the average power P(t) is the time average of pulsed optical power p(t):
The temporal evolution of P(t) can be changed by the modulation of the duty cycle of p(t), for a given frequency and peak power.
As observed by the inventors under total blood volume illumination performed in the central venous line, transient or middle but significative modulations of the paO2 and other arterial gas such as chloric ion, took place in arterial blood only. Indeed, these modulations were not observed in the central venous blood (See
For instance, in order to overpass negative outcomes of the SARS-CoV-2 and, more generally, in the case of ARDS, optimizing the immune response, the hemoglobin oxygen affinity, the thrombogenesis processes and to promote the tissue regeneration using notably the bystander effects of PBM by inserting one or several light distributors in blood vessels, such as lung arteries, has shown impressive positive effects, as demonstrated by the inventors.
In particular, an example of a clinical procedure (“Seldinger method”) to position light distributors in the right and left pulmonary arteries is described below:
The PBM effects result from the absorption of light by different primary photoacceptors leading, in particular, to changes of numerous signaling and transcription factors. PBM light is also known to photodissociate NO from nitroso-hemoglobin and to influence the nitrate reductase activity (NRA) involving certain metalloproteins, which also release labile NO at low oxygen tension and the presence of nitrite. Since NO is preconize within mild or deep hypoxemia, therefore different illuminations scheme must be considered to activate different mechanisms For instance, in circulating blood, the first illumination scheme can consist in the delivery of a constant or pulsed irradiance/fluence rate (higher power as possible while avoiding thermal effects, i.e. typically hundreds of mW.cm-2) applied during an optimal time, ranging between seconds and minutes, at an appropriate wavelength to target the photodissociation of, for instance, nitrosyl-hemoglobin or sulfhemoglobin. This first illumination scheme must be combined with a second scheme based on the concept of hot spots mentioned above.
As shown in
As shown in
It consists of one or more optical fibers. These fibers are put in a catheter sheath that can be attached to the skin. The distal ends of the fibers are hermetically connected to the catheter via an SMA connector which will be connected to the source. The proximal end is adjustable (between 2 and 8 cm) by retracting the catheter sheath, allowing the optical fibers to deploy, which are reinforced by a rigid material introduced into the spinal cord.
Embodiments of this surprising effect consists to:
Spatial synchronization of metabolic activities is a must to sustains local or systemic homeostasis as well as to enable blood flow in arterial or venous capillaries. Notably, synchronized local contraction of a vessel from place to place induce vasomotion. These contractions can be seen as a spatial wavefront which move all along the vessel. A disruption of these synchronized contractions from a injured myogenic conduction for instance can be the cause of many vascular pathologies. Since it has been shown that different parts of the biological object can be targeted sequentially or successively by the selection of particular hotspots and since PBM can modulate or trig specific metabolic activities notably in the myogenic frequency range, illumination of a injured vessel at specific distance for instance, equal to the length define by the spatial period of the contraction wave can sustain the synchronization of the contraction from place to place in case of myogenic desynchronization or trig contractions from place to place to restore the blood flow.
Aalkjær, C., Boedtkjer, D. & Matchkov, V., 2011. Vasomotion - what is currently thought? Acta Physiologica, 202(3), pp.253-269.
Acharya, U.R. et al., 2017. Application of higher-order spectra for the characterization of Coronary artery disease using electrocardiogram signals. Biomedical Signal Processing and Control, 31, pp.31-43. Available at: http://dx.doi.org/10.1016/j.bspc.2016.07.003
B. Alberts, A. Johnson, J. Lewis, M. Raff, K. Roberts, and P. Walter, Molecular Biology of the Cell, 4th ed. Garland Science, 2002.
Álvarez, R.C. et al., 2018. Cardiac Hemodynamic Monitoring in the Subcutaneous Space: A pre-clinical proof-of-concept. MeMeA 2018 - 2018 IEEE International Symposium on Medical Measurements and Applications, Proceedings.
F. Antunes, A. Boveris, and E. Cadenas, “On the mechanism and biology of cytochrome oxidase inhibition by nitric oxide,” Proc. Natl. Acad. Sci. U. S. A., vol. 101, no. 48, pp. 16774-16779, November 2004.
Bailey, S.M., Udoh, U.S. & Young, M.E., 2014. Circadian regulation of metabolism. Journal of Endocrinology, 222(2). DOI: https://doi.org/10.1530/JOE-14-0200.
K. A. Ball, P. R. Castello, and R. O. Poyton, “Low intensity light stimulates nitrite-dependent nitric oxide synthesis but not oxygen consumption by cytochrome c oxidase: Implications for phototherapy,” J. Photochem. Photobiol. B, vol. 102, no. 3, pp. 182-191, March 2011.
S. Banerjee and D. K. Bhatt, “Histochemical studies on the distribution of certain dehydrogenases in squamous cell carcinoma of cheek,” Indian J. Cancer, vol. 26, no. 1, pp. 21-30, March 1989.
M. A. Beilke, C. Collins-Lech, and P. G. Sohnle, “Effects of dimethyl sulfoxide on the oxidative function of human neutrophils,” J. Lab. Clin. Med., vol. 110, no. 1, pp. 91-96, July 1987.
I. Bentov and M. J. Reed, “The effect of aging on the cutaneous microvasculature,” Microvasc. Res., vol. 100, pp. 25-31, 2015
Bhattacharyya, A. et al., 2018. A novel approach for automated detection of focal EEG signals using empirical wavelet transform. Neural Computing and Applications, 29(8), pp.47-57.
Bhoi, A.K., Sherpa, K.S. & Khandelwal, B., 2017. Arrhythmia and ischemia classification and clustering using QRS-ST-T (QT) analysis of electrocardiogram. Cluster Computing, 21(1), pp.1033-1044.
Bigarella, C.L., Liang, R. & Ghaffari, S., 2014. Stem cells and the impact of ROS signaling. Development (Cambridge), 141(22), pp.4206-4218.
T. S. Blacker and M. R. Duchen, “Investigating mitochondrial redox state using NADH and NADPH autofluorescence,” Free Radic. Biol. Med., vol. 100, no. Supplement C, pp. 53-65, November 2016.
Blackstone, E., Morrison, M. & Roth, M.B., 2005. H2S induces a suspended animation-like state in mice. Science, 308(5721), p.518.
Bleys, J., Navas-Acien, A. & Guallar, E., 2008. Serum selenium levels and all-cause, cancer, and cardiovascular mortality among US adults. Archives of Internal Medicine, 168(4), pp.404-410.
Brandes, R.P., Weissmann, N. & Schröder, K., 2014. Nox family NADPH oxidases in mechano-transduction: Mechanisms and consequences. Antioxidants and Redox Signaling, 20(6), pp.887-898.
M. Butawan, R. L. Benjamin, and R. J. Bloomer, “Methylsulfonylmethane: Applications and Safety of a Novel Dietary Supplement,” Nutrients, vol. 9, no. 3, March 2017.
Bos, E.M. et al., 2009. Hydrogen sulfide-induced hypometabolism prevents renal ischemia/reperfusion injury. Journal of the American Society of Nephrology, 20(9), pp.1901-1905.
Carlström, M., Wilcox, C.S. & Arendshorst, W.J., 2015. Renal autoregulation in health and disease. Physiological Reviews, 95(2), pp.405-511.
B. Chance, B. Schoener, R. Oshino, F. Itshak, and Y. Nakase, “Oxidation-reduction ratio studies of mitochondria in freeze-trapped samples. NADH and flavoprotein fluorescence signals,” J. Biol. Chem., vol. 254, no. 11, pp. 4764-4771, June 1979.
B. Chance, “Metabolic Heterogeneities in Rapidly Metabolizing Tissues,” J. Appl. Cardiol., vol. 4, no. 4, pp. 207-221, 1989.
Chouchani E. T.,1,2 Victoria R. Pell,3 Andrew M. James,4 Lorraine M. Work,5 Kourosh Saeb-Parsy,6 Christian Frezza,7 Thomas Krieg,3 and Michael P. Murphy4, “A Unifying Mechanism for Mitochondrial Superoxide Production during Ischemia-Reperfusion Injury”, Cell Metabolism 23, Feb. 9, 2016.
Chouchani, E.T. et al., 2014. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature, 515(7527), pp.431-435.
Chung H, Dai T, Sharma S, Huang Y, Carroll J, Hamblin M. The Nuts and Bolts of Low-level Laser (Light) Therapy. Ann Biomed Eng. 2012;40(2):516-533. doi:10.1007/s10439-011-0454-7.
C. E. Cooper and G. C. Brown, “The inhibition of mitochondrial cytochrome oxidase by the gases carbon monoxide, nitric oxide, hydrogen cyanide and hydrogen sulfide: chemical mechanism and physiological significance,” J. Bioenerg. Biomembr., vol. 40, no. 5, pp. 533-539, October 2008.
Dasgupta, A., 2014. Cardiac Markers. Clinical Chemistry, Immunology and Laboratory Quality Control, pp.127-144. https://doi.org/10.1016/B978-0-12-407821-5.00008-5.
Devasagayam TP, Tilak JC, Boloor KK, Sane KS, Ghaskadbi SS, Lele RD, “Free radicals and antioxidants in human health: current status and future prospects”. The Journal of the Association of Physicians of India. 52: 794-804, 2004.
Di Gialleonardo V., David M. Wilson, and Kayvan R. Keshari, “The Potential of Metabolic Imaging”, Semin. Nucl. Med., 46(1): 28-39, 2016.
Donald JA. Gasotransmitter Family. In: Handbook of Hormones. Elsevier; 2016:601. doi:doi.org/10.1016/B978-0-12-801028-0.00103-3.
Duan, J. et al.. Metabolic remodeling induced by mitokines in heart failure. Aging (Albany NY). 2019 Sep 15; 11(17): 7307-7327.
Ferraresi C., M. R. Hamblin, and N. A. Parizotto, “Low-level laser (light) therapy (LLLT) on muscle tissue: performance, fatigue and repair benefited by the power of light,” Photonics Lasers Med., vol. 1, no. 4, pp. 267-286, November 2012.
Ferrari R., MD, PhD; Cristina Balla, MD; Michele Malagù, MD; Gabriele Guardigli, MD; Giampaolo Morciano, MD, PhD; Matteo Bertini, MD; Simone Biscaglia, MD; Gianluca Campo, MD, “Reperfusion Damage - A Story of Success, Failure, and Hope”, Circ J, 81: 131-141, 2017.
Fu M, Zhang W, Wu L, Yang G, Li H, Wang R., “Hydrogen sulfide (H2S) metabolism in mitochondria and its regulatory role in energy production”, Proc Natl Acad Sci U S A., 109(8):2943-8, 2012.
Fuss T. L., B.A. and Leo L. Cheng, “Metabolic Imaging in Humans”, Top Magn Reson Imaging, 25(5): 223-235, 2016.
R. A. Gatenby and R. J. Gillies, “Why do cancers have high aerobic glycolysis?,” Nat. Rev. Cancer, vol. 4, no. 11, pp. 891-899, November 2004.
Grimolizzi, F. & Arranz, L., 2018. Multiple faces of succinate beyond metabolism in blood. Haematologica, 103(10), pp.1586-1592.
Griendling, K.K. et al., 2016. Measurement of Reactive Oxygen Species, Reactive Nitrogen Species, and Redox-Dependent Signaling in the Cardiovascular System: A Scientific Statement from the American Heart Association, Circulation journal, 119,5,39-65.
Hamblin M., M. Victor Pires de Sousa and T. Agrawal, “Handbook of Low-Level Laser Therapy”, Pan Stanford Publishing Pte. Ltd., Singapore, 2017.
Hamblin M., C. Ferraresi, Y.-Y. Huang, L. F. de Freitas, and J. Carroll, “Low-level light therapy: photobiomodulation”, Editor: SPIE Press, Bellingham, Washington, USA, 2018.
Hayyan M, Hashim MA, AlNashef IM (March 2016). “Superoxide Ion: Generation and Chemical Implications”. Chemical Reviews. 116 (5): 3029-85.
Hellmann, M., Roustit, M. & Cracowski, J.L., 2015. Skin microvascular endothelial function as a biomarker in cardiovascular diseases? Pharmacological Reports, 67(4), pp.803-810.
Huang, Ying-Ying, Carroll JD, H.M., 2009. Biphasic dose response. Dose response, pp.358-383. http:// dx.doi.org/10.2203/dose-response.09-027.Hamblin
Hwang, J. et al., 2003. Pulsatile Versus Oscillatory Shear Stress Regulates NADPH Oxidase Subunit Expression: Implication for Native LDL Oxidation. Circulation Research, 93(12), pp.1225-1232.
Iwata, A. et al., 2015. Selenide Targets to Reperfusing Tissue and Protects It From Injury∗. Read Online: Critical Care Medicine | Society of Critical Care Medicine, 43(7).
Jacques S., “How tissue optics affect dosimetry of photodynamic therapy”, Journal of Biomedical Optics 15(5), 051608, 2010.
Jekell, A. et al., 2004. Elevated circulating levels of thioredoxin and stress in chronic heart failure. The european Journal of Heart failure, 6, pp.883-890.
Jackson, W.F., 2016. Arteriolar oxygen reactivity: where is the sensor and what is the mechanism of action? Journal of Physiology, 594(18), pp.5055-5077.
S. Kalinina et al., “Correlative NAD(P)H-FLIM and oxygen sensing-PLIM for metabolic mapping,” J. Biophotonics, vol. 9, no. 8, pp. 800-811, August 2016.
Kalogeris T., Christopher P. Baines1,2,3, Maike Krenz1,2, and Ronald J. Korthuis Ischemia/Reperfusion, Compr Physiol. ; 7(1): 113-170, 2017.
T. I. Karu, L. V. Pyatibrat, and N. I. Afanasyeva, “Cellular effects of low power laser therapy can be mediated by nitric oxide,” Lasers Surg. Med., vol. 36, no. 4, pp. 307-314, April 2005.
Kennedy R. T., et al., « Metabolic oscillations in □-cells », Diabetes, 51(S1), 2002.
Y. H. Kim, D. H. Kim, H. Lim, D.-Y. Baek, H.-K. Shin, and J.-K. Kim, “The anti-inflammatory effects of methylsulfonylmethane on lipopolysaccharide-induced inflammatory responses in murine macrophages,” Biol. Pharm. Bull., vol. 32, no. 4, pp. 651-656, April 2009.
Kindo, M. et al., 2016. Left Ventricular Transmural Gradient in Mitochondrial Respiration Is Associated with Increased Sub-Endocardium Nitric Oxide and Reactive Oxygen Species Productions. Frontiers in physiology, 7(August), pp.1-8.
Kindo, M. et al., 2012. Pressure overload-induced mild cardiac hypertrophy reduces left ventricular transmural differences in mitochondrial respiratory chain activity and increases oxidative stress. Frontier in physiology, 3(August), pp.1-14.
Kondo K, Bhushan S, King AL, Prabhu SD, Hamid T, Koenig S, et al. “H2S protects against pressure overload-induced heart failure via upregulation of endothelial nitric oxide synthase”, Circulation, 127:1116-1127, 2013.
Köhn, C. et al., 2012. Hydrogen sulfide: Potent regulator of vascular tone and stimulator of angiogenesis. International Journal of Biomedical Science, 8(2), pp.81-86.
Kuganesan, M. et al., 2019. Selenium and hydrogen selenide: essential micronutrient and the fourth gasotransmitter? Intensive Care Medicine Experimental, 7(1). http://dx.doi.org/10.1186/s40635-019-0281-y.
Kumar, M., Pachori, R.B. & Acharya, U.R., 2017. Characterization of coronary artery disease using flexible analytic wavelet transform applied on ECG signals. Biomedical Signal Processing and Control, 31, pp.301-308.
Kvandal, P. et al., 2006. Low-frequency oscillations of the laser Doppler perfusion signal in human skin. Microvascular Research, 72(3), pp.120-127.
N. Lane, “Cell biology: power games,” Nature, vol. 443, no. 7114, pp. 901-903, October 2006.
Latham, F., 1951. THE OXYGEN PARADOX EXPERIMENTS ON THE EFFECTS OF OXYGEN IN HUMAN ANOXIA. The Lancet, 257(6646), pp.77-81
Li, S. & Yang, G., 2015. Hydrogen Sulfide Maintains Mitochondrial DNA Replication via Demethylation of TFAM. Antioxidants and Redox Signaling, 23(7), pp.630-642.
Li, Y.S.J., Haga, J.H. & Chien, S., 2005. Molecular basis of the effects of shear stress on vascular endothelial cells. Journal of Biomechanics, 38(10), pp.1949-1971.
Li, Y and Patrick J. Pagano, 2017. Microvascular NADPH oxidase in health and disease. Free Radic Biol Med., 109(1), pp.33-47.
Liebert, A. et al., 2017. A Role for Photobiomodulation in the Prevention of Myocardial Ischemic Reperfusion Injury: A Systematic Review and Potential Molecular Mechanisms. Scientific Reports, 7(February), pp.1-13. Available at: http://dx.doi.org/10.1038/srep42386.
N. L. Lohr, A. Keszler, P. Pratt, M. Bienengraber, D. C. Warltier, and N. Hogg, “Enhancement of nitric oxide release from nitrosyl hemoglobin and nitrosyl myoglobin by red/near infrared radiation: potential role in cardioprotection,” J. Mol. Cell. Cardiol., vol. 47, no. 2, pp. 256-263, August 2009.
Loutzenhiser, R., Bidani, A. & Chilton, L., 2002. Renal myogenic response: Kinetic attributes and physiological role. Circulation Research, 90(12), pp.1316-1324.
Martelli F., Del Bianco S., Ismaelli A., “Light propagation through biological tissue and other diffusive media: theory, solutions, and software”, Bellingham: Society of Photo-Optical Instrumentation Engineers, 2009.
Irma Martišienė, Regina Mačianskienė, Voltage-Sensitive Fluorescence of Indocyanine Green in the Heart, Biophysical Journal, Volume 110, Issue 3, 2016, Pages 723-732, ISSN 0006-3495.
Moldogazieva, N.T. et al., 2018. ROS and RNS signalling: adaptive redox switches through oxidative/nitrosative protein modifications. Fpp.507-543. Available at: https://doi.org/10.1080/10715762.2018.1457217.
Moss, N.G., Gentle, T.K. & Arendshorst, W.J., 2016. Modulation of the myogenic mechanism: Concordant effects of NO synthesis inhibition and O-2 dismutation on renal autoregulation in the time and frequency domains. American Journal of Physiology - Renal Physiology, 310(9), pp.F832-F845.
Nachiappan, Vasanthi; Muthukumar, Kannan, “Cadmium-induced oxidative stress in Saccharomyces cerevisiae”. Indian Journal of Biochemistry and Biophysics. 47 (6), 2010.
Nagpure, B. V. & Bian, J.S., 2016. Interaction of Hydrogen Sulfide with Nitric Oxide in the Cardiovascular System. Oxidative Medicine and Cellular Longevity, 2016.
Nakamura, H., 2004. Thioredoxin as a Key Molecule in Redox Signaling. Antioxidants and Redox Signaling, 6(1), pp.15-17.
Nowak-Sliwinska P., J.-P. Ballini, G. Wagnières, and H. van den Bergh, “Processing of fluorescence angiograms for the quantification of vascular effects induced by anti-angiogenic agents in the CAM model,” Microvasc. Res., vol. 79, no. 1, pp. 21-28, January 2010.
P.T. Nowicki, S. Flavahan, H. Hassanain, S. Mitra, S. Holland, P.J. Goldschmidt-Clermont, N.A.F., 2001. Redox Signaling of the Arteriolar Myogenic Response. Circulation research, 89, pp.114-116.
Olson, K.R., 2012. A practical look at the chemistry and biology of hydrogen sulfide. Antioxidants and Redox Signaling, 17(1), pp.32-44.
Papagiannakis A, Niebel B, Wit E, Heinemann M, Autonomous Metabolic Oscillations Robustly Gate the Early and Late Cell Cycle. Molecular Cell, Volume, 65, Issue 2, 19 Jan. 2017, Pages 285-295, https://doi.org/10.1016/j.molcel.2016.11.018.
Park, H.C. et al., 2017. Effect of LED phototherapy on blood lactate level in Taekwondo contest. Mechanisms of Photobiomodulation Therapy XII, 10048(February 2017), p.100480I.
Patidar, S. & Pachori, R.B., 2014. Classification of cardiac sound signals using constrained tunable-Q wavelet transform. Expert Systems with Applications, 41(16), pp.7161-7170. Available at: http://dx.doi.org/10.1016/j.eswa.2014.05.052.
Patidar, S., Pachori, R.B. & Rajendra Acharya, U., 2015. Automated diagnosis of coronary artery disease using tunable-Q wavelet transform applied on heart rate signals. Knowledge-Based Systems, 82, pp.1-10. Available at: http://dx.doi.org/10.1016/j.knosys.2015.02.011.
Pettersen, F.J. et al., 2016. Bioimpedance measurements of temporal changes in beating hearts. Biomedical Physics and Engineering Express, 2(6).
Petrenko, V. et al., 2020. In pancreatic islets from type 2 diabetes patients, the dampened circadian oscillators lead to reduced insulin and glucagon exocytosis. Proceedings of the National Academy of Sciences of the United States of America, 117(5), pp.2484-2495
Piper, H.M., 2000. The calcium paradox revisited: An artefact of great heuristic value. Cardiovascular Research, 45(1), pp.123-127
N. Ramanujam, R. Richards-Kortum, S. Thomsen, A. Mahadevan-Jansen, M. Follen, and B. Chance, “Low Temperature Fluorescence Imaging of Freeze-trapped Human Cervical Tissues,” Opt. Express, vol. 8, no. 6, pp. 335-343, March 2001.
V. Rapozzi, E. Della Pietra, S. Zorzet, M. Zacchigna, B. Bonavida, and L. E. Xodo, “Nitric oxide-mediated activity in anti-cancer photodynamic therapy,” Nitric Oxide Biol. Chem., vol. 30, pp. 26-35, April 2013.
Raddatz E, Thomas AC and al. Differential contribution of mitochondria, NADPH oxidases, and glycolysis to region-specific oxidant stress in the anoxic-reoxygenated embryonic heart. Am J Physiol Heart Circ Physiol 300: H820-H835, 2011.
K. J. Reeves, M. W. R. Reed, and N. J. Brown, “Is nitric oxide important in photodynamic therapy?,” J. Photochem. Photobiol. B, vol. 95, no. 3, pp. 141-147, June 2009.
Reglin, B. & Pries, A.R., 2014. Metabolic control of microvascular networks: Oxygen sensing and beyond. Journal of Vascular Research, 51(5), pp.376-392.
De Roever I, Bale G, Cooper RJ, Tachtsidis I.” Functional NIRS Measurement of Cytochrome-C-Oxidase Demonstrates a More Brain-Specific Marker of Frontal Lobe Activation Compared to the Haemoglobins”, Adv Exp Med Biol. 2017;977:141-147, 2017.
Sachar M. et al. “Protoporphyrin IX: the Good, the Bad, and the Ugly.” The Journal of pharmacology and experimental therapeutics vol. 356,2 (2016): 267-75. doi:10.1124/jpet.115.228130.
Sedmera, D., Kucera, P. & Raddatz, E., 2002. Developmental changes in cardiac recovery from anoxia-reoxygenation. American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 283(2 52-2), pp.379-388.
Shiogai, Y., Stefanovska, A. & McClintock, P.V.E., 2010. Nonlinear dynamics of cardiovascular ageing. Physics Reports, 488(2-3), pp.51-110.
Sies, H. & Jones, D.P., Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nature Reviews Molecular Cell Biology. 2020 Available at: http://dx.doi.org/10.1038/s41580-020-0230-3.
M. C. Skala et al., “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci., vol. 104, no. 49, pp. 19494-19499, December 2007.
M. Skala and N. Ramanujam, “Multiphoton Redox Ratio Imaging for Metabolic Monitoring in vivo,” Methods Mol. Biol. Clifton NJ, vol. 594, pp. 155-162, 2010.
Smirnova, E. et al., 2013. Assessment of endothelial dysfunction in patients with impaired glucose tolerance during a cold pressor test. Diabetes and Vascular Disease Research, 10(6), pp.489-497.
Snijder P. M., A R Frenay, R A de Boer, A Pasch, J L Hillebrands, H G D Leuvenink and H van Goor, “Exogenous administration of thiosulfate, a donor of hydrogen sulfide, attenuates angiotensin II-induced hypertensive heart disease in rats”, Br J Pharmacol. 2015 Mar; 172(6): 1494-1504.
Stefanovska, A., 2006. Coupled oscillators: Complex but not complicated cardiovascular and brain interactions. Annual International Conference of the IEEE Engineering in Medicine and Biology - Proceedings, pp.437-440
Szabo, C. et al., 2014. Regulation of mitochondrial bioenergetic function by hydrogen sulfide. Part I. Biochemical and physiological mechanisms. British Journal of Pharmacology, 171(8), pp.2099-2122.
Tamura, T., 2019. Current progress of photoplethysmography and SPO2 for health monitoring. Biomedical Engineering Letters, 9(1), pp.21-36. Available at: https://doi.org/10.1007/s13534-019-00097-w.
Tamura, T., 2018. Seamless Healthcare Monitoring, https://doi.org/10.1007/978-3-319-69362-0
Thomas DD. Breathing new life into nitric oxide signaling: A brief overview of the interplay between oxygen and nitric oxide. Redox Biol. 2015;5:225-233. doi:10.1016/j.redox.2015.05.002.
Ticcinelli, V. et al., 2017. Coherence and coupling functions reveal microvascular impairment in treated hypertension. Frontiers in Physiology, 8(OCT), pp.1-20.
Tretter, L., Patocs, A. & Chinopoulos, C., 2016. Succinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis. Biochimica et Biophysica Acta - Bioenergetics, 1857(8), pp.1086-1101. Available at: http://dx.doi.org/10.1016/j.bbabio.2016.03.012.
Tsuruoka, N. et al., 2016. Lactate and glucose measurement in subepidermal tissue using minimally invasive microperfusion needle. Biomedical microdevices, (18:19), pp.2-9. http://dx.doi.org/10.1007/s10544-016-0049-z.
Tuchin V., “Tissue Optics and Photonics: Light-Tissue Interaction”, J of Biomedical Photonics & Eng 1(2), pp 98 - 134, 2015.
Van Leeuwen, S.R., Baranoski, G.V.G. & Kimmel, B.W., 2017. Three-wavelength method for the optical differentiation of methemoglobin and sulfhemoglobin in oxygenated blood. Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS, pp.4570-4573.
Arnoud H. M. van Vliet, Stefan Bereswill, and Johannes G. Kusters, “Ion Metabolism and Transport”, in: Helicobacter pylori: Physiology and Genetics, Mobley HLT, Mendz GL, Hazell SL, editors, Washington (DC): ASM Press; 2001.
Wagnières G. et al., “In Vivo Fluorescence Spectroscopy and Imaging for Oncological Applications”, Photochemistry and Photobiology, 68(5): 603-632, 1998.
A. Walsh, R. S. Cook, B. Rexer, C. L. Arteaga, and M. C. Skala, “Optical imaging of metabolism in HER2 overexpressing breast cancer cells,” Biomed. Opt. Express, vol. 3, no. 1, pp. 75-85, January 2012.
A. J. Walsh et al., “Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer,” Cancer Res., vol. 73, no. 20, pp. 6164-6174, October 2013.
G. Walther et al., “Metabolic syndrome individuals with and without type 2 diabetes mellitus present generalized vascular dysfunction: Cross-sectional study,” Arterioscler. Thromb. Vasc. Biol., vol. 35, no. 4, pp. 1022-1029, 2015.
Wilson B., Patterson M., “The physics of photodynamic therapy”, Phys. Med. Biol., (31)4, pp 327-360, 1986.
Wood K, Cortese-Krott M and al. Circulating Blood Endothelial Nitric Oxide Synthase Contributes to the Regulation of Systemic Blood Pressure and Nitrite Homeostasis. Arterioscler Thromb Vasc Biol. 2013;33:1861-1871.
Wu, M., Neilson, A., Swift, A.L., Moran, R., Tamagnine, J., Parslow, D., Armistead S., Lemire, K., Orrell, J., Teich, J., Chomicz, S., Ferrick, D.A., Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells. Am J Physiol Cell Physiol. 292, C125-C136, 2007.
Wu, D., Hu, Q. & Zhu, D., 2018. An update on hydrogen sulfide and nitric oxide interactions in the cardiovascular system. Oxidative Medicine and Cellular Longevity, 2018.
Yang, G., 2015. H2S epigenetic regulation of vascular cell functions. Cardiovascular Regenerative Medicine, pp.2-5.
Yu XH, Cui LB, Wu K, et al. Hydrogen sulfide as a potent cardiovascular protective agent. Clin Chim Acta. 2014;437:78-87. doi:10.1016/j.cca.2014.07.012.
Zhong, X. et al., 2018. Circadian Clock Regulation of Hepatic Lipid Metabolism by Modulation of m6A mRNA Methylation. Cell Reports, 25(7), p.1816-1828.e4.
Zhou, G. et al., 2016. Optimal ROS Signaling Is Critical for Nuclear Reprogramming. Cell Reports, 15(5), pp.919-925. Available at: http://dx.doi.org/10.1016/j.celrep.2016.03.084.
| Number | Date | Country | Kind |
|---|---|---|---|
| 20199710.3 | Oct 2020 | EP | regional |
| PCT/EP2021/059842 | Apr 2021 | WO | international |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2021/077205 | 10/1/2021 | WO |
