Innovative Medical Device for Non-Invasive Evaluation of Microcirculation and Metabolic Regulation Using FMSF
(Flow Mediated Skin Fluorescence)
What is measured?
- Flow Mediated Skin Fluorescence (FMSF) is a technique based on the measurement of NADH fluorescence from skin tissue cells.
- Nicotinamide adenine dinucleotide (NADH) and its oxidized form (NAD+) play a crucial role in biological systems as redox coenzymes.
- The NADH/NAD+ pair is the carrier of electrons in the respiratory chain of each living cell.
- Although NADH emits significant fluorescence, this is not the case with NAD+.
- The fluorescence from NADH is the strongest component of the overall fluorescence emitted from human skin.
- The penetration depth of excitation light for NADH (340 nm) in skin tissue is low (about 0.5 mm), therefore a substantial fraction is absorbed by the epidermis and papillary dermis.
- In these skin regions, the density of blood microvessels is low and the changes in NADH fluorescence depend on the supply of oxygen diffused from deeper layers.
How is it measured?
- The FMSF technique measures changes in the intensity of NADH fluorescence from the skin on the forearm as a function of time, in response to blocking and releasing blood flow in the forearm.
- Blood flow in the forearm is blocked using a typical occlusion cuff, as used to measure blood pressure.
Advantages of FMSF method
- useful for assessing circulatory status by comparing the vascular response to reactive hyperemia (PORH) to the resting state (before occlusion),
- suitable for assessing the degree of ischemia and reperfusion in skin cells depending on blood flow in the vessels,
- useful for assessing the progress and remission of microcirculation disorders, metabolic regulation and vascular complications,
- optimal for the observation of microcirculation oscillations, the amplitude and frequency of which may signal irregularities in the microcirculation,
- helpful for monitoring vascular circulation disorders and selecting individualized forms of therapy.
The FMSF method enables disorders to be detected at an early stage of development and monitoring of the treatment process. It helps to identify patients in possible need of preventive or therapeutic interventions, who may be referred for further diagnosis.The FMSF method has intellectual property protection, including in the following countries: EU, USA, Canada, China, Japan, Australia, Russia.
The FMSF-PORH (Flow Mediated Skin Fluorescence-Post Occlusive Reactive Hyperemia) test is based on analysis of ischemic and hyperemic responses and microcirculatory oscillations.
The test enables non-invasive assessment of vascular circulation and/or metabolic regulation. It measures stimulation of the circulation in response to reactive hyperemia. An occlusion cuff, commonly used to measure blood pressure, is used to induce reactive hyperemia (PORH). The test enables assessment of both vasoconstriction and vasodilation. The kinetics of changes in response to reactive hyperemia can also be monitored. The FMSF-PORH test can be used to monitor the treatment process, observe the effects of drugs on vascular health, and track the effects of training and exercise on overall health.
Main parts of a typical trace recorded for an individual patient using AngioExpert
- Baseline – collected for 3 min (or 4 min if unstable).
- Ischemic response (IR) – 3 min occlusion with cuff inflated to 60 mmHg above systolic blood pressure, resulting in an increase of NADH fluorescence.
- Hyperemic response (HR) caused by releasing pressure in the occlusion cuff – NADH fluorescence decreases below the baseline, reaching a minimum followed by a return to the baseline.
- Hyperemic response (HR) with two distinct phases:
- hyperemia – related to a sharp drop in NADH fluorescence for 20–30 s;
- reperfusion – a much slower return to the baseline.
- Microvascular oscillations on the baseline and the hyperemic response line express the efficacy of vascular-metabolic regulation related to microvascular dermal flow. A weakening of their amplitude and changes in frequency may indicate the presence of microvascular dysfunction.
Definition of measured parameters
- Hyperemic response parameters HRmax and HRindex express changes in NADH fluorescence (mainly from the keratinocytes in the epidermis) and determine the metabolic reaction of the skin cells to hyperemia and reperfusion.
- Ischemic response parameters IRmax and IR index express changes in NADH fluorescence (mainly from keratinocytes in the epidermis) and determine the sensitivity of skin cells to hypoxia caused by blocking blood flow in the forearm. This sensitivity is determined primarily by the efficiency of oxygen transport to the epidermal cells just before occlusion.
- The RHR (Reactive Hyperemia Response) parameter characterizes the ischemic and hyperemic responses. It reflects vascular endothelial function related to nitric oxide (NO) production in blood vessels, due to occlusion-induced hyperemia. The RHR parameter is the sum of the IRmax + HRmax parameters.
Interpretation of the measured parameters
- The key parameter for analysis of the ischemic and hyperemic responses is the RHR. The RHR parameter characterizes vascular status based on NO bioavailability mainly in large and medium-sized arteries as a result of transient ischemia. It enables sensitive assessment of the state of vascular circulation.
The following ranges in the RHR parameter are distinguished:
RHR > 35% high 25% < RHR < 35% moderate RHR < 25% low
The RHR parameter is used to assess dysfunction of the vascular circulation, especially the macrocirculation, and to predict the risk of developing cardiovascular diseases which are often comorbid with diabetes mellitus.
Analysis of the NADH fluorescence signal shape and interpretation of the determined parameters are unique and sensitive markers for cardiovascular risk assessment.
The higher the values of the parameters, the better the prognosis for the patient. The FMSF technique enables the diagnosis of microcirculation disorders, metabolic regulation and the risk of vascular complications at an early stage of their development.
The FMSF technique is an innovative way of monitoring and analyzing microcirculatory oscillations and diagnosing early-stage dysfunction in microvascular flow.
Oscillations in the microcirculation, known as flowmotion, are a well-recognized characteristic of cutaneous blood flow. Their amplitude and frequency reflect the efficiency and regularity of the cutaneous microvascular flow. A weaker amplitude and changes in their frequency may indicate the presence of microvascular dysfunction.
Skin flowmotion can be monitored accurately and precisely using the FMSF technique, as there is very low noise in the recorded FMSF traces. Since NADH fluorescence is sensitive to the supply of oxygen to the epidermis via skin microcirculation, the use of the FMSF technique to monitor flowmotion appears a unique tool for the characterization of microcirculatory status.Two different periods of oscillations can be distinguished in the FMSF signal:
- basal oscillations at rest
- flowmotion during the reperfusion stage, induced by reactive hyperemia (PORH)
Microcirculatory oscillations in the FMSF signal are analyzed in three major frequency intervals: ≤ 0.021 Hz, 0.021–0.052 Hz, and 0.052–0.15 Hz. These correspond to endothelial (endo), neurogenic (neuro), and myogenic (myo) activity, respectively. The mean squared error of the deviation in the fluorescence signal (increased 106 times) from the baseline at rest (FM parameter) and during reperfusion (FM(R) parameter) is used as a measure of oscillation strength. FM and FM(R) remain unitless values, because the changes in fluorescence are normalized. Another measure of oscillation strength is the Power Spectral Density (PSD) parameter. PSD is strongly correlated with the values for FM and FM(R) and can be used to determine the contribution of each component of the oscillations to the total value.
Oscillations at other frequencies (e.g. oscillations related to the heart rate) are also visible in the FMSF signal, confirming the high sensitivity of the method.
It has been observed that microvascular flow, during the resting (FM) and post-occlusion (FM(R)) periods, have been found to be impaired among patients with various diseases and disorders, including diabetes, cardiovascular disease, and hypertension, as well as among patients in a state of physical exhaustion caused by various factors.
Analysis of microcirculatory oscillations at the baseline
The following parameters have been defined as quantitative measures of microcirculatory oscillations recorded at the baseline:
- FM (FlowMotion at baseline) – characterizes basal flowmotion at rest.
NOI (Normoxia Oscillatory Index) – characterizes microcirculatory oscillations recorded at the baseline. It represents the proportion of endothelial (< 0.021 Hz) and neurogenic (0.021–0.052 Hz) oscillations with respect to all oscillations detected in the low-frequency range (< 0.15 Hz).
The limit value for the NOI parameter indicating the occurrence of a stress factor (emotional, physical, or post-infection stress) is NOI < 60%
Chronically low NOI, indicating a disturbance in the resting microvascular flow, can lead to the development of vascular circulatory disorders.
The NOI parameter is used to assess fatigue due to stress from various sources as well as to monitor microcirculation in the recovery and rehabilitation process.
Analysis of microcirculatory oscillations at the reperfusion line
Microcirculatory oscillations at the reperfusion line are produced by stimulation through transient ischemia. This involves closing off blood flow in the brachial artery with an occlusion cuff.
The following parameters have been defined as quantitative measures of microcirculatory oscillations recorded at the reperfusion line:
- FM(R) – represents flowmotion during the reperfusion phase, reflecting the strong effect of hypoxia on flowmotion, mainly due to increased vessel activity. This parameter enables the assessment of vascular wall stiffness.
log(HS) (HS, Hypoxia Sensitivity) – a direct measure of the intensity of flowmotion related to myogenic oscillations (0.052–0.15 Hz) recorded during reperfusion. This parameter characterizes sensitivity to hypoxia by measuring myogenic microcirculatory oscillations with frequencies in the range of 0.052–0.15 Hz stimulated by hypoxia. Four ranges of log(HS) values have been distinguished, characterizing different levels of microcirculatory response to hypoxia:
HS ⩾ 100 high log(HS) ⩾ 2 30 ≤ HS < 100 moderate 1,5 ≤ log(HS) < 2 10 ≤ HS < 30 low 1 ≤ log(HS) < 1,5 HS < 10 very low log(HS) < 1
The log(HS) parameter depends on blood pressure and is highest at very low pressure values.
The log(HS) parameter is used to assess microcirculatory dysfunction in diabetes, cardiovascular disease, peripheral arterial disease, and hypertension. It is useful for predicting healing in difficult-to-heal wounds (including diabetic foot ulcers). The log(HS) parameter is also used to assess microcirculatory status for determining exercise tolerance in healthy and non-healthy people.
Three-parameter evaluation of the test results
Assessment of the vascular state using the FMSF technique is based on three parameters: RHR, log(HS), and NOI. It is an optimal diagnostic tool for characterizing the macro- and microcirculation status, which is the body’s individual response to transient hypoxia.
The RHR (Reactive Hyperemia Response) parameter characterizes the condition of blood vessels on the basis of NO bioavailability, mainly in large and medium-sized arteries as a result of transient ischemia. It enables sensitive assessment of the state of vascular circulation.
The log(HS) (Hypoxia Sensitivity) parameter determines the degree of sensitivity of the body to hypoxia by measuring myogenic oscillations stimulated by transient hypoxia.
The NOI (Normoxia Oscillatory Index) parameter characterizes microcirculation based on the percentage of endothelial and neurogenic components of microcirculation oscillations at the baseline. It is a marker of peripheral vasoconstriction at rest, which may be reversible. NOI effectively assesses the state of microcirculation disturbed by a stress factor, such as emotional stress, physical exhaustion, or post-infection stress.
The clinical data show that the risk of vascular complications is limited among people whose RHR and log(HS) parameters are not significantly below the mean values determined by the FMSF technique, especially if they simultaneously meet the following condition: RHR > 30% and log(HS) > 1,5 (HS > 30)
According to current medical knowledge, vascular circulation disorders accompany many diseases and dysfunctions. Based on the clinical condition of the patient, as well as the latest literature data, the FMSF technique can be included in the diagnosis and monitoring of any disease state with etiology related to micro- and/or macrovascular disorders.
The FMSF technique is suitable for monitoring patients at pre-determined intervals, depending on the needs of the individual patient and subject to medical advice. Unless otherwise advised by a doctor, it is recommended to repeat the test annually or more frequently when significant changes in the RHR and/or log(HS) parameters are observed. The NOI parameter is an auxiliary parameter for the assessment of microcirculatory disorders caused by fatigue induced by various sources of stress.
Test results example
is a medical device which uses the FMSF-PORH method to evaluate microvascular circulation.
is intended for non-invasive monitoring of microcirculation, metabolic regulation and vascular complications in diabetes.
Angionica Ltd. is a spin-off company whose main goal is the implementation of the innovative Flow Mediated Skin Fluorescence (FMSF) method developed by Lodz University of Technology (TUL) and the Jagiellonian University (UJ).
FMSF is a new diagnostic method based on photodiode technology, protected by international patents in the world’s major markets.
Award Winner of Competition Polish Product of the FutureIn 2021, Angionica won first prize in the 23 rd Polish Product of the Future Competition for "AngioExpert: innovative device for non-invasive evaluation of vascular circulation using the FMSF method" (Awards Catalogue)
Angionica Ltd. has implemented and maintains Quality management system in accordance with PN-EN ISO 13485:2016-04 – Medical devices – Quality management systems – Requirements for regulatory purposes.
CERTIFICATE ISO 13485:2016-04 (PL)
CERTIFICATE ISO 13485:2016-04 (EN)
CERTIFICATE ISO 13485:2016-04 (DE)
Angionica Ltd. applies a quality management system for design, manufacture, final inspection and post-market surveillance that complies with the requirements of MDR 2017/745 Regulation.
They write about us
- eFEekty - Biuletyn Funduszy Europejskich w Polsce, 10/59, June 2023 "Krążenie pod kontrolą"
- Blog of Lodz University of Technology 09/27/2022 "See the state of microcirculation in UV/VIS light"
- Blog HealthRising 26/09/2022 "Feel Like You’ve Run a Marathon? A Long COVID Study Suggests Why"
- „Życie Uczelni” information bulletin of the TUL 07/14/2022 "An innovative method of diagnosing vascular circulatory disorders"
- Puls Medycyny 29/06/2022 "Polacy odkryli, jak diagnozować zaburzenia mikrokrążenia. Metoda wejdzie do gabinetów POZ?"
- Gazeta Wyborcza – Zdrowie 28/10/2021 "Wyprzedzić poważne problemy krążeniowe. FMSF - nowa, obiecująca metoda diagnostyczna"