Method and system for predicting the response of the microvascular circulation to hypoxia by assesing oscillatory function of microcirculation
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- Filing Date
- 2025-02-07
- Publication Date
- 2026-08-13
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Abstract
Description
P32230PC00 / WAW 07-02-2025METHOD AND SYSTEM FOR PREDICTING THE RESPONSE OF THE MICROVASCULAR CIRCULATION TO HYPOXIA BY ASSESING OSCILLATORY FUNCTION OF MICROCIRCULATIONDESCRIPTION FIELD OF THE INVENTION
[0001] The invention relates to the field of medicine, especially to a method for predicting the response of the microvascular circulation to hypoxia. The methods for predicting the response of the microvascular circulation to hypoxia might have broad utility, for example, in identifying disfunctions and disorders, in particular directly relating to hypoxia, touching the whole population regardless of sex or age distribution. The invention also relates to a device for predicting the response of the microvascular circulation to hypoxia.BACKGROUND
[0002] Microcirculatory oscillations, known as flowmotion, are a well-recognized characteristic of blood flow. The mechanistic aspects of this phenomenon have been the subject of extensive research: Nilsson, H.; Aalkjaer, C. Vasomotion: Mechanisms and Physiological Importance. Mol. Interv. 2003, 3, 79-89; Rossi, M.; Carpi, A.; Galetta, F.; Franzoni, F.; Santoro, G. The Investigation of Skin Blood Flowmotion: a New Approach to Study the Microcirculatory Impairment in Vascular Diseases? Biomed. Pharmacother. 2006, 60, 437-442; Aalkjaer, C.; Boedtkjer, D.; Matchkov, V. Vasomotion — What Is Currently Thought? Acta Physiol. 2011, 202, 253-269; Kim, D.H.; Choi, J.Y.; Kim, S.M.; Son, S.-M.; Choi, S.-Y.; Koo, B.; Rah, C.-S.; Nam, J.H.; Ju, M.J.; Lee, J.S.; et al. Vasomotion in Human Arteries and Their Regulations Based on Ion Channel Regulations: 10 Years Study. J. Cell. Physiol. 2023, 238, 2076-2089.
[0003] The major physiological function of flowmotion is to secure the proper perfusion of tissues. Impaired flowmotion can result in vascular resistance and is observed in many diseases and disorders, see Schmidt-Lucke C., Borgstrbm P., Schmidt-Lucke J.A. Low Frequency Flowmotion / (Vasomotion) during Patho-Physiological Conditions. Life Sci. 2002;71 :2713-2728; Bari F., Toth-Szuki V., Domoki F., Kalman J. Flow Motion Pattern Differences in the Forehead and Forearm Skin: Age-Dependent Alterations Are Not Specific for Alzheimer’s Disease. Microvasc. Res. 2005;70:121-128; Rossi M., Matteucci E., Pesce M., Consani C., Galetta F., Giampietro O., Santoro G. Study of Skin Vasomotion in Type 1 Diabetic Patients and of Its Possible Relationship with Clinical and Laboratory Variables. Clin. Hemorheol. Microcirc. 2013;53:357-367; Bruning R.S., Kenney W.L., Alexander L.M. Altered Skin Flowmotion in Hypertensive Humans. Microvasc. Res. 2015;97:81-87; Tikhonova I.V., Kosyakova N.I., Tankanag A.V., Chemeris N.K. Oscillations of Skin Microvascular Blood Flow in Patients with Asthma. Microcirculation. 2016;23:33-43; Mizeva I., Makovik I., Dunaev A., Krupatkin A., Meglinski I. Analysis of Skin Blood Microflow Oscillations in Patients with Rheumatic Diseases. J. Biomed. Opt.2017;22:070501 ; Pedanekar T., Kedare R., Sengupta A. Monitoring Tumor Progression by Mapping Skin Microcirculation with Laser Doppler Flowmetry. Lasers Med. Sci. 2019;34:61-77.P32230PC00 / WAW 07-02-2025
[0004] Microcirculation is mostly studied in humans at the level of skin, i.e. as a skin microcirculation. Although rhythmic motions of vessel wall and triggered by them changes of blood flow are seen in the whole vascular bed, their visualization and recording are especially easy in the vasculature of the skin. Skin microcirculation vasomotion is the rhythmic variation of the skin microvessel diameter and is responsible for the skin microcirculatory blood flow oscillations, i.e. the skin blood flowmotion. Functional impairment (dysfunction) of the microcirculatory function of many regions, tissues and organs, including impairment of natural and spontaneous blood flow oscillations plays very important role in pathophysiology of many diseases, especially such as vascular diseases and hypertension. As skin microcirculation impairment mirrors impairments in other regions, the analysis of microcirculatory blood flow oscillations or the skin blood flowmotion has a diagnostic value.
[0005] Several methods and apparatuses for non-invasive evaluation of the health of vascular endothelium in vivo have been developed. In particular, methods are known that are based on monitoring the physiological conditions or characteristics of the arteries in the patient's limb after reactive hyperemia which is one of several well-established perturbation systems. It involves the characterization of hyperemic flow following a period of flow occlusion (post-occlusive reactive hyperemia; PORH). In this PORH assessment hyperemic blood flow to tissue that had been temporarily deprived of flow is significantly increased in subjects with normal vascular functioning, compared to patients having impaired vascular flow. In particular, this is important for understanding the function of the vascular circulation in diseases associated with ischemia (hypoxia).
[0006] Reactive hyperemia is a physiological phenomenon that occurs in a patient after blocking (or occlusion) of a major artery. Such blocking or occlusion of artery in the limb, such as brachial artery, is typically done by inflating a blood pressure cuff slightly above systolic pressure for a period of about 5 minutes. Anoxia or severe hypoxia in the limb downstream from the occluded artery is usually a result of such blocking. Sudden release of the blocking causes endothelial cells to react by generating NO and vascular dilating. The phenomenon of reactive hyperemia lasts up to 10 minutes before return to pretest blood volume values.
[0007] So far, the major technique applied for the characterization of flowmotion using PORH test has been Laser Doppler Flowmetry (LDF), see: Stefanovska A., Bracic M., Kvernmo H.D. Wavelet Analysis of Oscillations in the Peripheral Blood Circulation Measured by Laser Doppler Technique. IEEE Trans. Biomed. Eng. 1999;46:1230-1239; Kvandal P., Landsverk S.A., Bernjak A., Stefanovska A., Kvernmo H.D., Kirkeb0en K.A. Low-Frequency Oscillations of the Laser Doppler Perfusion Signal in Human Skin. Microvasc. Res. 2006;72:120-127. LDF is predominantly applied for the assessment of skin microcirculation. Cutaneous vascular function can also be considered an indicator of general vascular function, see: Holowatz L.A., Thompson-Torgerson C.S., Kenney W.L. The Human Cutaneous Circulation as a Model of Generalized Microvascular Function. J. Appl. Physiol. 2008;105:370-372;Hellmann M., Roustit M., Cracowski J.L. Skin Microvascular Endothelial Function as a Biomarker in Cardiovascular Diseases? Pharmacol. Rep. 2015;67:803-810. However, due to the significant noise associated with LDF measurement, quantitative analysis of the changes in flowmotion associated with different diseases and pathologies is not always possible.P32230PC00 / WAW 07-02-2025
[0008] Another non-invasive method of flowmotion evaluation is known from EP2713860 B1. The FMSF (Flow Mediated Skin Fluorescence) technique is based on the measurement of nicotinamide adenine dinucleotide (NADH) fluorescence from human skin, predominantly from the epidermis. The epidermis is not vascularized, and the red blood cells do not interfere with the measured NADH fluorescence. The FMSF technique combined with the post-occlusive reactive hyperemia (PORH) test enables the measurement of the reaction of microcirculatory oscillations to hypoxia.
[0009] EP3454731 A1 discloses another flowmotion evaluation method and system useful for at least observing the hypoxia during the PORH test. The invention relates to multi-sensor imaging systems for generating a pulsatile blood perfusion map, comprising a high accuracy blood flow sensor (702; 802) configured to generate a reference blood volume waveform at a reference site of a patient's body (706; 806), one or more low accuracy blood flow sensors (704; 804) configured to simultaneously generate a second blood volume waveform at any region of interest of the patient's body (708; 808), and a controller. The high accuracy blood flow sensor (702; 802) is a pulse oximeter and the one or more low accuracy blood flow sensors (704; 804) are one or more camera sensors each equipped with an optical filter.
[0010] Moreover, US11382525 BB discloses another flowmotion evaluation method and system useful for at least observing the hypoxia during the PORH test. The invention relates to devices and methods of use thereof for real time blood flow measurements of skin. In one embodiment, the device is a compact laser speckle imaging, or LSI, system that is integrated with a dermatoscope. In another embodiment, the device allows the user to diagnose a disease or condition in an individual, or as part of an overall treatment regimen.
[0011] Also, US2024241239 discloses flowmotion evaluation method and system useful for performing the PORH test. According to the invention, systems and methods of imaging using photoacoustic computed tomography through an ergodic relay having an integrated single-element ultrasonic transducer have been provided.
[0012] However, all those known method and systems used for PORH test are very inconvenient for the patient. All those measurement methods require the patient to tackle very unpleasant feeling, including pain during occlusion period. This is why such measurements pertaining to evaluation of reaction to hypoxia cannot be performed in disabled persons or children.
[0013] On the other hand, it is known that flowmotion is regulated by the rhythmic oscillations of blood vessel diameter, known as vasomotion, which is a constriction and dilation of microvessels, namely the spontaneous change in microvessels diameters. The link between vasomotion and cardiovascular diseases is acknowledged in many research studies (Fonseca et al., 2018; Smith, 2020). However, the mechanism responsible for vasomotion has not been thoroughly understood (see Front Bioeng Biotechnol. 2022 Mar 2;10:819716. doi: 10.3389 / fbioe.2022.819716; The Origin of Vasomotion and Stochastic Resonance in Vasomotion).
[0014] Many studies (Miick-Weymann et al., 1996; Bracic and Stefanovska, 1998; Stefanovska et al., 1999; Sbderstrbm et al., 2003; Cracowski et al., 2006) analyzed characteristic frequencies of blood flow oscillation signals, and these frequencies components correspond to several types of activities. The oscillations in the region around ~1 Hz are related to the cardiac activity, the oscillations in the regionP32230PC00 / WAW 07-02-2025around ~0.3 Hz are related to the respiratory activity, and the oscillations ranging from 0.001 to 0.2 Hz are related to endothelial, neurogenic and myogenic activities (Stefanovska et al., 1999; Soderstrom et al., 2003). Other studies differentiate five frequency subranges, namely endothelial (0.01-0.02 Hz), neurogenic (0.02-0.06 Hz), myogenic (0.06-0.15 Hz), respiratory (0.15-0.4 Hz), and cardiac activity (0.4-1.6 Hz), (see X Zhao et al. DOI:10.1111 / micc.12882, August 2024, Different Measures of Hyperglycemia Are Negatively Associated With Skin Microvascular Flowmotion: The Maastricht Study).
[0015] The term “vasomotion” is sometimes used to name the oscillations related to endothelial, neurogenic and myogenic activities whose frequency interval is from 0.001 to 0.2 Hz. However, the term vasomotion is also used more specifically to characterize only one particular vascular tone, caused by oscillations of vascular smooth muscle, and is used to describe only myogenic microcirculatory oscillations. This second meaning is used by the inventors throughout the present disclosure if not mentioned to the contrary.
[0016] All discussed methods useful for performing PORH test are suitable to monitor characteristic frequencies of blood flow oscillation signals under normoxia conditions. For example, a specific parameter called NOI (the normoxia oscillatory index) can be measured under normoxia condition using FMSF technique as disclosed in EP3784115 B1.
[0017] Using some of these known measurement techniques, recently, researchers have investigated the role of vasomotion (endothelial, neurogenic or myogenic tone) in diabetes and other types of disfunction, including erectile disfunction. For example, experimental results show significant differences in vasomotion between diabetic patients, prediabetic patients, and nondiabetic people (Hsiu et al., 2018). Low-frequency pulsations of the blood flow associated with endothelial activities are lower in diabetic patients (Mizeva et al., 2018). Diabetic patients were found to have endothelial dysfunction in some arteries (De Ciuceis, 2020). Detecting microvascular dysfunction before diabetic complications could play an important role in the pre-diagnosis of diabetes (Fredriksson et al., 2021). Additionally, it has been confirmed by Slowikowska-Hilczer, J., Walczak-Jedrzejowska, R., Adamczewska, D., Byczkiewicz P., Marchlewska K., Katarzynska J., Gebicki J. a New Approach to the Assessment of Erectile Dysfunction Based on Vasomotion Monitored by the Flow-Mediated Skin Fluorescence (FMSF) Technique — a Preliminary Study. J. Clin. Med. 2024, 13, 3210 that the use of the FMSF technique for the observation of microcirculatory oscillations allows for a clear differentiation of psychological stress and stress caused by androgen deficiency. Psychological stress seems to be compensated by an increase in myogenic tone (vasomotion) in healthy individuals, whereas in individuals with androgen deficiency, this compensatory mechanism may be impaired due to lower myogenic activity. This compensatory effect is particularly important as chronic psychological stress can result in the development of serious vascular circulatory disorders.
[0018] However, although methods and systems for evaluation of microcirculation parameters both under normoxia and under hypoxia conditions are known, none of them are suitable for predicting the response of the microvascular circulation to hypoxia in an accurate manner without causing anxiety, discomfort or even pain in the patient.OBJECT OF THE INVENTIONP32230PC00 / WAW 07-02-2025
[0019] The object of the invention is to propose an alternative method to a known problem which is predicting the response of the microvascular circulation to hypoxia. Moreover, the object of the invention is to propose a method for predicting the response of the microvascular circulation to hypoxia which would be less harmful for the patient and more convenient for children and disabled persons. Finally, the object of the invention is to propose a method and a system for predicting the response of the microvascular circulation to hypoxia that could be easily and correctly used in practice for predicting the response of the microvascular circulation to hypoxia even in primary care physicians' offices.SUMMARY OF THE INVENTION
[0020] According to a first aspect, the invention provides a device for predicting the response of the microvascular circulation to hypoxia by assessing oscillatory function of microcirculation, the device comprisingmeans for measuring a signal indicative of oscillatory function of microcirculation in time under normoxic conditions without any blockage or stimulation of the blood flowa processing unit which is configured to receive and record time course of said signal indicative of oscillatory function of microcirculation in time and to calculate at least one parameter of oscillatory function of microcirculation based on said signaloutputting means configured to output said calculated parametersaid at least one parameter of oscillatory function of microcirculation being a vasomotion parameter VM defined as a power spectra density in frequency domain from 0.052 Hz to 0.15 Hzcharacterized in that said processing unit is further configured tocompare said calculated VM parameter with a first value range and / or a second value range and / or a third value range, said first value range being defined as optimal VM value range indicative of a not impaired response of the microvascular circulation to hypoxia, said second value range being defined as acceptable VM value range indicative of a risk of impaired response of the microvascular circulation to hypoxia, said third value range being defined as impaired VM value range indicative of an impaired response of the microvascular circulation to hypoxia,wherein the lower limit and the upper limit value of the acceptable range of the VM parameter is correlated, accordingly, with the lower limit and the upper limit value of a corresponding acceptable range of the HS parameter, the correlation being defined by a general formula log(HS)=A*log(VM)+B, wherein the HS parameter is defined as a power spectra density in frequency domain from 0.052 Hz to 0.15 Hz measured under hypoxia conditions,send to said outputting means said calculated VM parameter along with a result of comparison so as to output information on the range in which the calculated VM parameter is comprised, which is indicative of the response of the microvascular circulation to hypoxia.
[0021] Advantageously, the correlation function is log(HS)=(0.62±0.03)*log(VM)+(0.81±0.02).
[0022] Advantageously, the second value range being defined as acceptable VM value range indicative of a risk of impaired response of the microvascular circulation to hypoxia is defined as: 2± 25% <VM < 12± 25%, most preferably 2<VM<12;P32230PC00 / WAW 07-02-2025
[0023] According to a second aspect, the invention provides a method for predicting the response of the microvascular circulation to hypoxia by assessing blood microcirculation of a subject, based on at least one parameter of oscillatory function of microcirculation, the method comprisinga step of measuring a signal indicative of oscillatory function of microcirculation in time under normoxic conditions without any blockage or stimulation of the blood flowand computer implemented steps ofreceiving and recording a time course of said signal indicative of oscillatory function of microcirculation in time andcalculating at least one parameter of oscillatory function of microcirculation based on said signal anda step of outputting said calculated parameter by outputting meanssaid at least one parameter of oscillatory function of microcirculation being a vasomotion parameter VM defined as a power spectra density in frequency domain from 0.052 Hz to 0.15 Hzcharacterized in that said computer implemented steps further comprisecomparing said calculated VM parameter with a first value range and / or a second value range and / or a third value range, said first value range being defined as optimal VM value range indicative of a not impaired response of the microvascular circulation to hypoxia, said second value range being defined as acceptable VM value range indicative of a risk of impaired response of the microvascular circulation to hypoxia, said third value range being defined as impaired VM value range indicative of an impaired response of the microvascular circulation to hypoxia,wherein the lower limit and the upper limit value of the acceptable range of the VM parameter is correlated, accordingly, with the lower limit and the upper limit value of a corresponding acceptable range of the HS parameter, the correlation being defined by a general formula log(HS)=A*log(VM)+B, wherein the HS parameter is defined as a power spectra density in frequency domain from 0.052 Hz to 0.15 Hz measured under hypoxia conditionssending to said outputting means said calculated VM parameter along with a result of comparison so as to output information on the range in which the calculated VM parameter is comprised, which is indicative of the response of the microvascular circulation to hypoxia.
[0024] Yet, according to another aspect, the invention provides a method of identifying patients with a risk of impaired response of the microvascular circulation to hypoxia, based on the VM parameter obtained by the method according to the present invention.
[0025] Yet, according to another aspect, the invention provides a method of screening patients with a risk of impaired response of the microvascular circulation to hypoxia based on the VM parameter obtained by the method according to the invention for further diagnosis of diseases selected from a group consisting of Alzheimer's disease, diabetes, hypertension, asthma, rheumatic diseases, tumor progression, erectile dysfunction, cardiovascular diseases, peripheral artery disease and chronic wounds.P32230PC00 / WAW 07-02-2025
[0026] Yet, according to another aspect, the invention provides a use of the VM parameter obtained by the method according to the invention, for predicting a response of the microvascular circulation to hypoxia without inducing hypoxia.ADVANTAGES OF THE INVENTION
[0027] The present invention provides simple approach that facilitates accurate prediction and assessment of the response of the microvascular circulation to hypoxia, and is free from the drawbacks that are known from the state of the art. Some of the advantages of the invention will be further characterized.
[0028] The invention provides an easier, more convenient, less time-consuming for the patient and the medical staff, method for predicting the response of the microvascular circulation to hypoxia. The authors of the invention proposed the parameter VM to be unexpectedly indicative of the response of the microvascular circulation to hypoxia. Said one numerical value of the parameter VM can be easily interpreted by comparing with specific three ranges that have been proven to be indicative of three different conditions of the microvascular circulation, possessing diagnostic importance.
[0029] Computer implemented analysis of the VM parameter carried out by comparing it with predetermined VM ranges, allows to determine in a simple manner the current condition of the microvascular circulation. Outputting information about the type of condition that has been determined, allows the medical staff to easily interpret the result of the prediction of the response of the microvascular circulation to hypoxia, even if the medical staff is not well-trained in this type of measurements. The method and the device according to the invention allow to reduce the time required for measurements of the response of the microvascular circulation to hypoxia while completely eliminating discomfort or even pain in the patient typically observed while carrying out the tests employing occlusion of blood flow known from the prior art.
[0030] Elimination of the inflatable cuff required for PORH test allows to simplify the construction of the device and as a consequence to reduce costs of the device according to the invention.
[0031] The method and the device according to the invention allow for significant reduction of the cost of this type of measurements and make the method more accessible for patients in primary care doctor's offices.
[0032] A better understanding of the nature and advantages of embodiments of the present invention may be gained with reference to the following detailed description and the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWING
[0033] The enclosed drawings should illustrate embodiments of the present invention and convey a further understanding thereof. In connection with the description, they serve as explanation of concepts and principles of the invention. Other embodiments and many of the stated advantages can be derived in relation to the drawings. The elements of the drawings are not necessarily to scale towards each other. Identical, functionally equivalent and acting equal features and components are denoted in the figures of the drawings with the same reference numbers, unless noted otherwise.Fig. 1 shows an exemplary signal course during a PORH test.Fig.2 shows an exemplary printout of the basic parameters determined forthe microcirculation oscillation signal under hyperemia conditions with the FMFS technique.P32230PC00 / WAW 07-02-2025Fig.3 shows an exemplary printout of the basic parameters determined forthe microcirculation oscillation signal under normoxia conditions with the FMFS technique.Fig.4 shows a correlation function between vasomotion (myogenic) component at the baseline and at the reperfusion line.Fig.5 shows a schematic view of the device according to the invention.Fig.6 shows an exemplary housing design of the device according to the invention.Fig7 shows a flow diagram of the method according to the invention.DETAILED DESCRIPTION OF THE INVENTION
[0034] The present invention will now be described in detail. First, appropriate definitions are provided. Next, background studies are presented. Finally, a detailed description of all components of the way of industrial application of the present invention is provided. Only exemplary implementations of the present application are shown and described in the detailed description below. As will be appreciated by those skilled in the art, the contents of this disclosure enable those skilled in the art to make changes to the disclosed detailed embodiments without departing from the spirit and scope of the inventions to which this application relates. Accordingly, the description in the drawings and detailed description is merely exemplary and not limiting.DEFINITIONS
[0035] The present technology is described herein using several definitions, as set forth throughout the specification. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, unless otherwise stated, the singular forms “a,” “an,” and “the” include plural reference. Thus, for example, a reference to “a means” is a reference to one or more means.
[0036] As used herein, the term “microcirculation oscillation signal ” is intended to be a signal that can be measured with the use of different techniques, advantageously non-invasive techniques, more advantageously at the skin level, by measuring different physical parameters like , for example, power spectra density of blood flow oscillations at frequencies below 2Hz, especially at five frequency subranges, namely endothelial (0.01-0.02 Hz), neurogenic (0.02-0.052 Hz), myogenic (0.052-0.15 Hz), respiratory (0.15-0.4 Hz), and cardiac activity (0.4-1.6 Hz) and via measuring different physical phenomenon like measuring nicotinamide adenine dinucleotide (NADH) fluorescence from human skin or blood flow by laser Doppler flowmetry (LDF), laser speckle contrast imaging (LSCI), pulse oximetry, blood flow sensors, photoacoustic tomography.KEY FINDINGS RELATING TO MEASURED MYOGENIC COMPONENT OF THE MICROCIRCULATION OSCILLATIONS
[0037] As already mentioned in the description of the state of the art, it has been found that in humans, microvessels contract and dilate to allow the flow of single blood cell. This phenomena can be observed as a measurable oscillating signal with the use of different techniques.
[0038] Fig.1 shows a typical time course of the signal representing skin microcirculations during the PORH test performed with the device implementing Flow Mediated Skin Fluorescence (FMSF) which is a technique that measures the changes in NADH fluorescence intensity in the skin, for example in the forearm skin. FMSF-PORH diagnostic test (Flow Mediated Skin Fluorescence-Post Occlusive ReactiveP32230PC00 / WAW 07-02-2025Hyperemia) is based on the analysis of the ischemic and hyperemic response and on the analysis of microcirculation oscillations.
[0039] Key parts of the PORH run are: 1) baseline - collected over 3 minutes (or 4 minutes if unstable), 2) Ischemic response (IR) - induced by 3 minutes of occlusion of blood flow in the brachial artery with an occlusive band inflated to 60 mmHg above systolic blood pressure, resulting in an increase in NADH fluorescence; 3) Hyperemic response (HR) - as a result of the release of the artery from the compression of the occlusive band - during this time, a decrease in fluorescence below the baseline is observed until a minimum is reached, after which a return to the baseline occurs.
[0040] It can be observed that the hyperemic response (HR) consists of two distinct phases:a) hyperemia - associated with a sharp decrease in NADH fluorescence within 20-30 s;b) reperfusion - a much slower process during which a return to the initial state occurs.
[0041] The observed microvascular oscillations at the baseline and hyperemic course line reflect the efficiency and regularity of the cutaneous microvascular flow. The similar microcirculation signal course during the PORH test can be obtained with any known measurement technique, for example with laser Doppler flowmetry.
[0042] NADH fluorescence signal oscillates under normoxia conditions (baseline) as well as under hyperemia conditions (reperfusion line). This is why this type of signal can be analyzed in frequency domain using Fourier transformation or wavelets algorithms.
[0043] As already mentioned, there are characteristic frequencies of blood flow oscillation signals, and these frequencies components correspond to several types of activities. The oscillations in the region around -1 Hz are related to the cardiac activity, the oscillations in the region around ~0.3 Hz are related to the respiratory activity, and the oscillations ranging from 0.001 to 0.2 Hz are related to endothelial, neurogenic and myogenic activities. The authors of the invention focused only on the myogenic component which is 0.052-0.15 Hz, called here “vasomotion”.
[0044] The inventors decided to analyze widely the diagnostic meaning of some selected parameters that can be retrieved from the PORH test both under normoxia conditions as well as under hyperemia / reperfusion conditions. Those parameters were at least:
[0045] VM (Vasomotion) - power spectra density (PSD), calculated as a mean squared amplitude of myogenic oscillations under normoxia conditions (intensity of myogenic microcirculation oscillations under normoxia) multiplied by a factor 106
[0046] FM (Flowmotion) - mean squared amplitude of oscillations of the NADH fluorescence signal under normoxia conditions multiplied by a factor 106; the size is the same as power spectra density of all oscillations under normoxia conditions
[0047] HS (Hypoxia Sensitivity) - power spectra density (PSD), calculated as a mean squared amplitude of myogenic oscillations under hyperemia / reperfusion conditions (intensity of myogenic microcirculation oscillations during hyperemia and reperfusion period) multiplied by a factor 106.
[0048] A person skilled in the art will appreciate that said parameters are named in an arbitrary manner and can be named differently in different measurement techniques. FM or VM parameters are in the range of approx. 1-100. The precision of FMSF measurement technique allows to observe such small changes.P32230PC00 / WAW 07-02-2025
[0049] Since the calculated values of VM and HS do not have the upper limit and do not follow the normal distribution, a log transformation of each power spectra density value can be considered in statistical analysis of the obtained results for different populations of studied patients.
[0050] The response of the body, especially the vascular system, to hypoxia (lack of oxygen) is crucial in assessing health. Log(HS) (HS, Hypoxia Sensitivity (sensitivity to hypoxia)) - a parameter that is a direct measure of the intensity of myogenic oscillations of the microcirculation recorded during reperfusion, with frequencies in the range of 0.052-0.15 Hz. Log(HS) parameter characterizes the organism's sensitivity to hypoxia by measuring myogenic microcirculation oscillations with frequencies in the range of 0.052-0.15 Hz , stimulated by hypoxia. Four ranges of log(HS) parameter values have been distinguished in the state of the art, characterizing different levels of microcirculation response to hypoxia (very low, low, medium and high, high level range being the range introduced only for persons with extreme response like sportsman):HS > 100 high log(HS) > 230 < HS < 100 moderate 1.5 < log(HS) < 210 < HS < 30 low 1 < log(HS) < 1.5HS < 10 very low log(HS) < 1
[0051] Log(HS) parameter depends on the blood pressure and reaches its highest values at very low pressure values. Log(HS) parameter is used to assess microcirculation disorders in diabetes, cardiovascular diseases, peripheral artery disease and hypertension, to predict the healing process of chronic wounds, including diabetic foot, as well as to assess the state of microcirculation in order to determine the tolerance of physical exercise in healthy and sick individuals.
[0052] It has been shown in a large group of study participants that many diseases and pathologies are accompanied by a reduced value of the HS parameter. Details regarding the interpretation of the HS parameter can be found in the following publications:
[0053] Marcinek A., Katarzynska J., Gebicki J. a New Approach to Vascular Screening: Identification of Impaired Vascular Function Using the FMSF Technique Sensors 2024, 24, 1721 ; Marcinek A., Katarzynska J., Cypryk K., Los-Stegienta A., Slowikowska-Hilczer J., Walczak-Jedrzejowska R., Zielinski J., Gebicki J. Assessment of Microvascular Function Based on Flowmotion Monitored by the FMSF Technique. Biosensors 2024, 14, 45
[0054] Recent studies carried out by the inventors using the Flow Mediated Skin Fluorescence (FMSF) have shown that the VM (Vasomotion) parameter, reflecting the intensity of myogenic microcirculation oscillations under normoxia conditions (without compression of the brachial artery), correlates perfectly with the HS parameter reflecting the intensity of myogenic microcirculation oscillations following hypoxia induced by compression of the brachial artery. Fig.4 shows unexpectedly observed correlation as well as characteristics of the group used to create the correlation chart.
[0055] The correlation function determined by the inventors can be defined as follows: log(HS)=A*log(VM)+B,
[0056] Preferably, the correlation function has been found to be log(HS)=(0.62±0.03)*log(VM)+(0.81±0.02).P32230PC00 / WAW 07-02-2025
[0057] By measuring the VM parameter under normoxia conditions (i.e. without compression of the brachial artery) it is possible to predict the body's response to hypoxia (lack of oxygen) routinely illustrated by the HS parameter.
[0058] The inventors have additionally mapped specific threshold HS values to VM values, as shown in Table 1.Table 1
[0059] The person skilled in the art will appreciate that HS limit values are those which are commonly found as having diagnostic meaning based on current knowledge in this area and can change slightly over the years.
[0060] As shown in the Table 1 , based on this correlation, it can be assumed that a very weak response to hypoxia (HS < 10), e.g. the value of HS = 10 corresponds to the value of VM = 2.03, and a weak response to hypoxia (10 < HS < 30), e.g. the value of HS= 30 corresponds to the value of VM = 11.91. Therefore, it can be concluded that the body's response to hypoxia can be predicted based on the measurement of the VM parameter alone. This feature of the measurement method allows to implement said method into a wearable device for example.
[0061] The conclusion about existing correlation between HS parameter and VM parameter was based on studies involving 910 persons. As it can be seen from the Table 2, studies were conducted for female and male patients in the age 20-95 years, women: 21-94 years, men: 20-95 years, although statistically mostly persons over 55 years old took part in the background studies. Such age distribution in the studied group has been selected because of the fact that elderly patients with cardiovascular disease and / or diabetes better reflect the VM vs HS relationship than if measurements were done for a healthy control group. In the cases as analyzed, the impaired response may play an important role in the treatment process.Table 2P32230PC00 / WAW 07-02-2025Note: Continuous variables, mean ± SD; dichotomous variables, n (%).Abbreviations: BMI, Body Mass Index; DBP, diastolic blood pressure; SBP, systolic blood pressure, AH - arterial hypertension; CVD, cardiovascular disease; DM, diabetes mellitus; log(FM), flowmotion (logarithm); log(VM), vasomotion (logarithm); log(HS), hypoxia sensitivity (logarithm)Detailed results of studies for chosen patients with comorbidities are presented in Table 3 and Table 4 below. Anthropometric measurements including weight, height, body mass index (BMI), were taken and comorbidities were noted.Table 3 Vascular diseases group - selected casesTable 4 Vascular diseases group - selected cases with age distributionP32230PC00 / WAW 07-02-2025
[0063] Detailed results of studies for a control group, namely chosen patients without comorbidities are presented in Table 5 below.Table 5 Control group - selected cases
[0064] As a result of above-described studies, the inventors have surprisingly found that the parameter VM is strictly correlated with known HS parameter, the latter one possible to be measured only under hypoxia conditions.
[0065] The inventors proposed a new and inventive way of using the parameter VM to predict the response ofthe microcirculation circulation to hypoxia. For910 patients with cardiovascular disease and diabetes, a strong correlation between VM and HS values has been observed. In more than 60%, theP32230PC00 / WAW 07-02-2025strong post-occlusion response log( HS) is due to strong myogenic oscillations visible before the application of occlusion log(VM) (i.e. with a non-occlusive device ). In a screening examination of patients or at the general practitioner’s office, this should allow for the detection of people with VM <2 (log( VM ) < 0.3), who should undergo more detailed examination
[0066] A severely disturbed VM parameter (VM < 2) may indicate a serious dysfunction of microvascular regulation, which may accompany many diseases, in particular: neurodegenerative diseases (Alzheimer's, Parkinson's, dementia), depression, autism, migraine, cancer, microvascular complications in diabetes and erectile dysfunction. Too high a value of the VM parameter, associated with a value of the NOI parameter < 60%, may indicate the presence of stress of various origins (emotional, post-exercise or post-infectious stress).
[0067] Moreover the background studies have shown that the VM parameter (log(VM) and the parameter HS (log(HS) show a statistically significant dependence on age, and in both cases it is very similar. The correlation functions found for both parameters are:log(VM) = (-0.0123±0.0015) Age + (1.363±0.102); r= -0.264 log(HS) = (-0.0127±0.0014) Age + (1.999±0.099); r = -0.280As it can be seen both functions share almost the same slope and Pearson's correlation coefficient (r). In the case of the remaining parameters tested (BMI, blood pressure), this relationship is extremely weak or non-existent. Statistical analysis for chosen parameters for different age ranges in the study group mentioned-above are presented in the Table 6 below:Table 6 Statistical analysis with age distributionP32230PC00 / WAW 07-02-2025
[0068] This unexpectedly found correlation between the VM and HS parameters and their similar dependence on the age can be used to predict the circulatory response to hypoxia without the use of brachial artery occlusion.
[0069] Moreover, during the background studies the inventors found also that:a) the VM parameter correlates with the IRmax parameter determining mitochondrial function, the correlation being defined as: IRmax vs. log(VM): r = 0.183, p < 0.0001.b) the VM parameter correlates with the HRmax parameter determining the macrocirculatory function, the correlation being defined as: HRmax vs. log(VM): r = 0.304, p < 0.0001.c) the VM parameter correlates with the hybrid RHR parameter defining jointly mitochondrial and macrocirculatory function, the correlation being defined as: RHR vs. log(VM): r = 0.316, p < 0.0001. The knowledge about those correlation might be important for additional assessment of the response of the circulatory system to hypoxia based on the VM parameter without brachial artery occlusion, as the IRmax, HRmax, RHR parameters measured with brachial artery occlusion are a direct mitochondrial and circulatory response to hypoxia.OVERALL PROCESS OF INDUSTRIAL APPLICATION
[0070] An exemplary overview of the device according to the invention with a novel functionality is illustrated in Fig. 5. The device 100 for predicting the response of the microvascular circulation to hypoxia by assessing blood microcirculation of a subject, based on at least one parameter of oscillatory function of microcirculation, comprises several units which are hardware and / or hardware / software implemented.
[0071] The device 100 according to the invention comprises means 101 for measuring a signal indicative of oscillatory function of microcirculation, in particular skin microcirculation, in time under normoxic conditions, without any blockage (occlusion) of the blood flow or blood reperfusion. In case of FMFS technique, said measuring means 101 can for example comprises means 101 a for illumination of a skin of a subject with exciting light capable to induce NADH fluorescence and means 101 b for detecting and measuring NADH fluorescence signal emitted from the skin; Said illumination means 101 a can be a source 101a of excitation light capable of emitting UV light in the range absorbed by NADH, i.e. at the wavelength range of 300 to 400 nm, preferably 340 nm. Said means 101b for detecting can be a detector of fluorescence signal at least in the range emitted by NADH, i.e. at the wavelength range of 400 to 600 nm, preferably 420 nm to 480 nm, especially about 460 nm. Said illumination and detecting means (101a, 101b) are preferably combined in a single measuring head 101 to be placed at the selected location close to the skin of the subject. Such a measuring head 101 will also have measurement window and can also comprise interference filters (not shown). Preferably, the device 100 according to the invention is void of occlusive cuff. In another embodiment the device 100 according to the invention comprises an occlusive cuff.
[0072] Generally, there is a certain flexibility in configuration of the device 100 for predicting the response of the microvascular circulation to hypoxia with the use of any known technique, including theP32230PC00 / WAW 07-02-2025FMFS technique. However, the person skilled in the art will appreciate that depending on the measurement technique measuring means 101 can comprise components different from those listed above.
[0073] In case of FMFS technique, conventional light sources 101 a of excitation light known in the art can be used, including filtered spectral lamp such as mercury or xenon lamp, light emitting diode LED, laser diode or pulsed laser. Advantageous light source is the light emitting diode LED 101 a. Regarding detecting means 101b, conventional detectors 101b can be used, such as photodiode detector, fast photodiode detector, photon multiplier tube, etc.
[0074] The exciting light can be carried out to the skin through the window of the measuring head 101 placed close to the skin, either in direct contact with the skin or in close vicinity to the skin. The emitted skin fluorescence can be collected through the same window of the measuring head 101.
[0075] The measuring head 101 can be connected to the light source 101 a and detector 101 b through the light guide (not shown) or it can comprise of both light source and detector in one arrangement. Any conventional light guide can be used for carrying excitation light and for collecting fluorescence light, such as optical fibers, optionally in a flexible housing. The interference filter system ensures the selection of the appropriate wavelength of both the exciting and measured light, and the lens system (not shown) ensures optimal use of this radiation.
[0076] The selection of electronic components of the device 100, including selection of the operating parameters of diodes 101a, influences the sampling rate (i.e. the time resolution of the measurement). For example, the sampling rate can be 25 Hz.
[0077] Moreover, the device 100 according to the invention comprises a processing unit 102 with associated memory means 103, which is configured to receive and record time course of said signal indicative of oscillatory function of microcirculation, in particular of skin microcirculation, in time and to calculate at least one parameter of oscillatory function of skin microcirculation based on said signal.
[0078] Said processing unit 102 can comprise a module 102a for pre-processing of the received signal and a module 102b for calculating at least one parameter of oscillatory function. Said at least one parameter of oscillatory function of microcirculation can be a vasomotion parameter (myogenic component) VM defined as a power spectra density in frequency domain from 0.052 Hz to 0.15 Hz.
[0079] The measured fluorescence signal and its changes, resulting from oscillations, are subjected to mathematical processing by the pre-processing module 102a. First, the signal is normalized, i.e. divided by the mean fluorescence value. After this stage, the average signal value is equal to 1 and the relative changes, e.g. oscillations, are of the order of 105. Therefore, the oscillation parameters are given with a multiplier of 106, so that the oscillations take place relative to the baseline, which is not always a straight horizontal line, more often it is observed to decline and stabilize after some time, sometimes it is an increase, or a decrease / increase. The inventors have found that it is best to approximate this baseline with a 2nd degree polynomial, see the solid line in the Fig.1.
[0080] The person skilled in the art will appreciate that each design of the device 100 according to the invention will give a different value of measured fluorescence for the same reference system, due to the fact that fluorescence is measured in arbitrary units. Therefore, appropriate calibration of the measurement method is required. It can be done in two ways. Firstly, calibration can be relative toP32230PC00 / WAW 07-02-2025a specific reference system chosen as a standard. Secondly, calibration can be performed by observing changes to the baseline fluorescence, i.e. measuring them as relative. The second method has been chosen because it not only makes the measurement technique independent of technical modifications, but also of physical differences in the patient’s skin (tan, complexion, hair, skin lesions, etc.). This means that regardless of the solution, the application of the NADH fluorescence observation method should give the same result (for all measured parameters) if normalization and the same calculation methods are used, e.g. VM as Fourier transform of the signal in the range 0.052-0.15Hz.
[0081] This is why all results are normalized to the mean signal value preferably in the between 1 and 2 minutes of measurement (central measurement period) by the pre-processing module 102a. The mean value of the results from this interval is computed and then fluorescence signals in the whole measurement range is divided by this mean value. In this manner normalized presentation of results is obtained (about the value 1), independently of an individual level of the fluorescence from the skin of a given subject. Then the baseline signal is subtracted from the normalized signal, the baseline being approximated by a second-degree polynomial.
[0082] The calculating module 102b calculates the VM parameter using Fourier analysis. Without the step of preprocessing, performed by the pre-processing module 102a, the Fourier analysis would show the existence of a low-frequency oscillation component corresponding to this unstable baseline. After correcting the signal with respect to the baseline (subtracting a second-degree polynomial fitted to the baseline changes from the signal line), an analysis of the observed changes can be for example performed over a period of 2-2.5 min after discarding the initial 30s of measurement. The calculating module 102b analyzes the signal, i.e. by changing the dependence of the signal oscillations (oscillation amplitude averaged over the number of measurement points) on time into the dependence of the signal oscillations on the frequency of vibrations that make up these oscillations. In the case of a fast Fourier transform (FFT) with a rectangular window, the calculated total power spectral density (PSD) (density, oscillation power) corresponding to the mean squared amplitude will be very strongly correlated with the FM (Flowmotion) value (r = 1).
[0083] When analyzing the FFT of a signal collected e.g. during 2 min = 120 s, with a sampling rate of 25 Hz (3000 points), a frequency resolution of 1 / 120 s = 0.00833 Hz is obtained, which gives 1500 points from 0 to 1 / 225Hz = 12.5 Hz. It is obvious that extending the observation time of the oscillations will increase the frequency resolution (more points in the spectrum).
[0084] It is possible to use different methods of Fourier analysis and wavelet analysis to obtain the frequency image, but the results will be partially different from the method which is typically used in the FMSF technique.
[0085] The calculating module 102b divides the entire frequency range 0-12.5Hz into appropriate intervals, e.g.: <0.021 Hz (endothelial oscillations), 0.021-0.052 Hz (neurogenic oscillations), 0.052-0.15 Hz (myogenic oscillations = VM) and the contribution of oscillations with frequencies from individual intervals to the total signal fluctuation can be determined. The summed PSD 106values in the range 0.052-0.15 Hz (myogenic component) is the calculated VM parameter.
[0086] Said processing unit 102 further comprises a module 102c for interpretating the diagnostic meaning of said at least one calculated parameter by comparing the calculated VM parameter with threeP32230PC00 / WAW 07-02-2025predetermined ranges. Namely said module 102c is configured to compare said calculated VM parameter with a first value range and / or a second value range and / or a third value range, said first value range being defined as optimal VM value range indicative of a not impaired response of the microvascular circulation to hypoxia, said second value range being defined as acceptable VM value range indicative of a risk of impaired response of the microvascular circulation to hypoxia, said third value range being defined as impaired VM value range indicative of an impaired response of the microvascular circulation to hypoxia. The interpretation module 102c (diagnostic comparison module 102c) can analyze these VM values after taking the logarithm, because the calculated values follow then a normal distribution.
[0087] In one embodiment the optimal VM value range can be: VM>9, preferably VM >12 ± 25%, most preferably VM >12;
[0088] In one embodiment the acceptable VM value range can be: 1 ,5<VM<9 or2.5<VM<15; preferably 2± 25% <VM < 12± 25%, most preferably 2<VM<12;
[0089] In one embodiment the impaired VM value range can be: VM < 1.5, preferably VM < 2± 25% most preferably VM < 2;
[0090] Based on the data received for the group of patients involved in the basic studies, said indicated ranges seem to guarantee same diagnostic utility as shown in the Table 7.Table 7< << >< << >< << >
[0091] The person skilled in the art will appreciate that exemplary ranges mentioned above might differ slightly in the future if further appropriate percentage of the population is evaluated and appropriate results are taken into account, although the assumption is that the correlation function is of the general form log(HS)=A*log(VM)+B, wherein a is equal to 0.62 ± 0.03 and B is equal to 0.81 ± 0.02
[0092] The device 100 according to the invention further comprises outputting means 104 configured to output said calculated parameter VM and a result of comparison so as to output information on the range in which the calculated VM parameter is comprised, which is indicative of the response of the microvascular circulation to hypoxia.
[0093] Said outputting means 104 can be a display 104 for displaying at least one calculated parameter, namely VM parameter as well as the information to which of three ranges the calculated VM parameter value belongs. The information about ranges can be of different graphic design, includingP32230PC00 / WAW 07-02-2025color bars or simple text messages, easy to understand by the medical staff. An exemplary housing design of the device according to the invention, including outputting means 104 being a touch display, is presented in Figure 6. As already mentioned, measuring VM parameter instead of HS parameter for the same diagnostic purpose allows to enter a new era with small, even wearable, devices that could be commonly used in in primary care physicians' offices. The device according to the invention can be also designed as a mobile measuring head (stethoscope type).
[0094] In another embodiment said outputting means 104 can be a printer for printing at least said calculated parameter VM as well as the information to which of three ranges the calculated VM parameter value belongs. Yet in another embodiment said outputting means 104 can be a loudspeaker 104 for outputting said at least said calculated parameter VM in the form of a string of sounds as well as the information to which of three ranges the calculated VM parameter value belongs.
[0095] According to another aspect, the invention provides a method for predicting the response of the microvascular circulation to hypoxia by assessing blood microcirculation of a subject, based on at least one parameter of oscillatory function of skin microcirculation.
[0096] The method according to the invention comprises a step of measuring a signal indicative of oscillatory function of skin microcirculation in time under normoxic conditions without any blockage or stimulation of the blood flow.
[0097] This step can involve any measurement technique in which microcirculation oscillations can be measured. Among others it can be the FMSF technique. As already mentioned, in said technique NADH fluorescence (460 nm) is measured, excited by 340 nm ultraviolet light at a sampling rate of 25 Hz. The penetration of the excitation light into skin tissue is low (approximately 0.3-0.5 mm) and a significant part is absorbed by the epidermis. The wavelength of the excitation light in the step of measuring a signal indicative of oscillatory function of skin microcirculation in time must be in the UV range absorbed by NADH, i.e. 300 to 400 nm. The wavelength of fluorescent light may be in the range emitted by NADH after absorption of excitation light, i.e. 420 to 480 nm.
[0098] As shown in Fig. 6, the method according to the invention comprises a step of measuring a signal indicative of oscillatory function of microcirculation in time. In particular the signal can be a signal indicative of oscillatory function of skin microcirculation This step can be realized by measuring means 101.
[0099] The method according to the invention further comprises a step of receiving and recording a time course of said signal indicative of oscillatory function of skin microcirculation in time. This step can be realized by a processing unit 102 and associated memory 103.
[0100] The method according to the invention further comprises a step of calculating a myogenic component, namely VM (Vasmotion) parameter of oscillatory function of skin microcirculation, defined as a power spectra density in a frequency domain from 0.052 Hz to 0.15 Hz, based on said recorded signal. This step comprises for example Fourier analysis and deriving the power spectra density value for specific frequency range relating to myogenic component.
[0101] In the next step, said calculated VM parameter is compared with a first value range and / or a second value range and / or a third value range, said first value range being defined as optimal VM value range indicative of a not impaired response of the microvascular circulation to hypoxia, saidP32230PC00 / WAW 07-02-2025second value range being defined as acceptable VM value range indicative of a risk of impaired response of the microvascular circulation to hypoxia, said third value range being defined as impaired VM value range indicative of an impaired response of the microvascular circulation to hypoxia. In this step of comparing VM parameter, comparison of these VM values can be done after taking the logarithm, because the calculated values follow then a normal distribution.
[0102] The method according to the invention further comprises a step of sending to outputting means 104 said calculated VM parameter along with a result of comparison so as to output information on the range in which the calculated VM parameter is comprised, which is indicative of the response of the microvascular circulation to hypoxia. In one embodiment the course of microcirculation oscillation signal in time can be plotted against time by said outputting means 104.
[0103] The step of measuring a signal indicative of oscillatory function of microcirculation in time under normoxic conditions is performed without any blockage or stimulation of the blood flow, and in one embodiment, said step can comprise a step of illuminating a skin of a subject with exciting light capable to induce NADH fluorescence and detecting and measuring NADH fluorescence signal emitted from the skin.
[0104] In one embodiment, the measurement will be performed on a forearm or the palmar side of a hand and the measuring head will be attached to the support for placing hand or to the band fixed on the hand. In another embodiment, the measurement will be performed on the dorsal side of a hand placed on a support, such as tripod, and the measuring head will be fixed above the hand. In another embodiment, the measurement will be performed on a finger, by means of a cup, a hoop or a cuff at the end of the measuring head, said cup, hoop or cuff being tightened around the finger depending on the size of the latter. In yet another embodiment the measurement will be performed in a multi-point manner. For example, several light-guides can be carried to the band mounted around a forearm or a finger.
[0105] Resigning from occlusion not only facilitates and shortens the measurement and increases patient comfort. It makes possible to measure microcirculation oscillation signal, with an appropriate design of the measuring head, e.g. similar to a medical stethoscope, anywhere in the body, for example measurements can be performed on lower limbs, torso (chest, back), neck, head or tongue.
Claims
1. P32230PC00 / WAW 07-02-2025CLAIMS1. A device for predicting the response of the microvascular circulation to hypoxia by assessing oscillatory function of microcirculation, the device comprising- means for measuring a signal indicative of oscillatory function of microcirculation in time under normoxic conditions without any blockage or stimulation of the blood flow- a processing unit which is configured to receive and record time course of said signal indicative of oscillatory function of microcirculation in time and to calculate at least one parameter of oscillatory function of microcirculation based on said signal-outputting means configured to output said calculated parametersaid at least one parameter of oscillatory function of microcirculation being a vasomotion parameter VM defined as a power spectra density in frequency domain from 0.052 Hz to 0.15 Hzcharacterized in thatsaid processing unit is further configured to- compare said calculated VM parameter with a first value range and / or a second value range and / or a third value range, said first value range being defined as optimal VM value range indicative of a not impaired response of the microvascular circulation to hypoxia, said second value range being defined as acceptable VM value range indicative of a risk of impaired response of the microvascular circulation to hypoxia, said third value range being defined as impaired VM value range indicative of an impaired response of the microvascular circulation to hypoxia,wherein the lower limit and the upper limit value of the acceptable range of the VM parameter is correlated, accordingly, with the lower limit and the upper limit value of a corresponding acceptable range of the HS parameter, the correlation being defined by a general formula log(HS)=A*log(VM)+B, wherein the HS parameter is defined as a power spectra density in frequency domain from 0.052 Hz to 0.15 Hz measured under hypoxia conditions,- send to said outputting means said calculated VM parameter along with a result of comparison so as to output information on the range in which the calculated VM parameter is comprised, which is indicative of the response of the microvascular circulation to hypoxia.2.The device according to claim 1 , wherein the correlation function is log(HS)=(0.62±0.03)*log(VM)+(0.81±0.02).3.The device according to claim 1 or claim 2, wherein the second value range being defined as acceptable VM value range indicative of a risk of impaired response of the microvascular circulation to hypoxia is defined as: 2± 25% <VM < 12± 25%, most preferably 2<VM<12;4. The device according to any of preceding claims, wherein means for measuring a signal indicative of oscillatory function of microcirculation in time under normoxic conditions without any blockage or stimulation of the blood flow comprises- means for illumination of a skin of said subject with exciting light capable to induce NADH fluorescenceP32230PC00 / WAW 07-02-2025- means for detecting and measuring NADH fluorescence signal emitted from the skin;5. The device according to any of preceding claims, wherein the device (100) is a wearable device.
6. The device according to claim 1 , wherein the device (100) further comprises an occlusion cuff.
7. A method for predicting the response of the microvascular circulation to hypoxia by assessing blood microcirculation of a subject, based on at least one parameter of oscillatory function of microcirculation, the method comprising- a step of measuring a signal indicative of oscillatory function of microcirculation in time under normoxic conditions without any blockage or stimulation of the blood flowand computer implemented steps of- receiving and recording a time course of said signal indicative of oscillatory function of microcirculation in time and- calculating at least one parameter of oscillatory function of microcirculation based on said signal and -a step of outputting said calculated parameter by outputting meanssaid at least one parameter of oscillatory function of microcirculation being a vasomotion parameter VM defined as a power spectra density in frequency domain from 0.052 Hz to 0.15 Hzcharacterized in thatsaid computer implemented steps further comprise- comparing said calculated VM parameter with a first value range and / or a second value range and / or a third value range, said first value range being defined as optimal VM value range indicative of a not impaired response of the microvascular circulation to hypoxia, said second value range being defined as acceptable VM value range indicative of a risk of impaired response of the microvascular circulation to hypoxia, said third value range being defined as impaired VM value range indicative of an impaired response of the microvascular circulation to hypoxia,wherein the lower limit and the upper limit value of the acceptable range of the VM parameter is correlated, accordingly, with the lower limit and the upper limit value of a corresponding acceptable range of the HS parameter, the correlation being defined by a general formula log(HS)=A*log(VM)+B, wherein the HS parameter is defined as a power spectra density in frequency domain from 0.052 Hz to 0.15 Hz measured under hypoxia conditions- sending to said outputting means said calculated VM parameter along with a result of comparison so as to output information on the range in which the calculated VM parameter is comprised, which is indicative of the response of the microvascular circulation to hypoxia.8.The method according to claim 7, wherein the correlation function is log(HS)=(0.62±0.03)*log(VM)+(0.81±0.02).9.The method according to claim 7 or claim 8, wherein the second value range being defined as acceptable VM value range indicative of a risk of impaired response of the microvascular circulation to hypoxia is defined as: 2± 25% <VM < 12± 25%, most preferably 2<VM<12;P32230PC00 / WAW 07-02-202510. The method according to claim 7, wherein the step of measuring a signal indicative of oscillatory function of microcirculation in time under normoxic conditions without any blockage or stimulation of the blood flow comprises- means for illumination of a skin of said subject with exciting light capable to induce NADH fluorescence - means for detecting and measuring NADH fluorescence signal emitted from the skin.
11. The method according to any of preceding claims, wherein before calculating at least one parameter of oscillatory function the method comprises a pre-processing step in which the recorded signal, indicative of oscillatory function of microcirculation, is normalized by dividing the signal value by the mean fluorescence value and multiplied by 106.
12. The method according to any of preceding claims, wherein the pre-processing step further comprises calculating a baseline by approximating the baseline with a 2nd degree polynomial and subtracting said baseline from the normalized signal.
13. A method of identifying patients with a risk of impaired response of the microvascular circulation to hypoxia, based on the VM parameter obtained by the method according to any of claims 7 to 12.
14. A method of screening patients with a risk of impaired response of the microvascular circulation to hypoxia based on the VM parameter obtained by the method according to any of claims 7 to 12 for further diagnosis of diseases selected from a group consisting of Alzheimer's disease, diabetes, hypertension, asthma, rheumatic diseases, tumor progression, erectile dysfunction, cardiovascular diseases, peripheral artery disease and chronic wounds.
15. Use of the VM parameter obtained by the method of any of claims 7 to 12 for predicting a response of the microvascular circulation to hypoxia without inducing hypoxia.
16. Use according to claim 15, wherein the VM parameter is obtained by measurement made using the device according to any of claims 1 to 6.