The growing interest in the development of new wearable electronic devices for mobile healthcare provides great opportunities for the development of methods for assessing blood perfusion in this direction. Laser Doppler flowmetry (LDF) is one of the promising methods. A fine analysis of capillary blood ow structure and rhythm in the time and frequency domains, coupled with a new possibility of round-the-clock monitoring can provide valuable diagnostic information about the state of microvascular blood ow. In this study, wearable implementation of laser Doppler flowmetry was utilised for microcirculatory function assessment in patients with diabetes and healthy controls of two distinct age groups. Four wearable laser Doppler flowmetry monitors were used for the analysis of blood microcirculation. Thirty-seven healthy volunteers and 18 patients with type 2 diabetes mellitus participated in the study. The results of the studies have shown that the average perfusion differs between healthy volunteers of distinct age groups and between healthy volunteers of the younger age group and patients with diabetes mellitus. It was noted that the average level of perfusion measured on the wrist in the two groups of healthy volunteers has no statistically significant differences found in similar measurements on the fingertips. The wearable implementation of LDF can become a truly new diagnostic interface to monitor cardiovascular parameters, which could be of interest for diagnostics of conditions associated with microvascular disorders

Dunaev, Andrey V.

Kozlov, Igor O.

Loktionova, Yulia I.

Rafailov, Edik U.

Rafailov, Ilya E.

Sidorov, Victor V.

Sokolovski, Sergei G.

Zharkikh, Elena V.

Zherebtsov, Evgeny A.

Zherebtsova, Angelina I.

English

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PROCEEDINGS OF SPIESPIEDigitalLibrary.org/conference-proceedings-of-spieWearable sensor system formultipoint measurements of bloodperfusion: pilot studies in patientswith diabetes mellitusEvgeny A. Zherebtsov, Elena V. Zharkikh, Igor O. Kozlov,Yulia I. Loktionova, Angelina I. Zherebtsova, et al.Evgeny A. Zherebtsov, Elena V. Zharkikh, Igor O. Kozlov, Yulia I. Loktionova,Angelina I. Zherebtsova, Ilya E. Rafailov, Sergei G. Sokolovski, Victor V.Sidorov, Andrey V. Dunaev, Edik U. Rafailov, "Wearable sensor system formultipoint measurements of blood perfusion: pilot studies in patients withdiabetes mellitus," Proc. SPIE 11079, Medical Laser Applications and Laser-Tissue Interactions IX, 110791O (22 July 2019); doi: 10.1117/12.2526966Event: European Conferences on Biomedical Optics, 2019, Munich, GermanyDownloaded From: https://www.spiedigitallibrary.org/conference-proceedings-of-spie on 31 Jul 2019  Terms of Use: https://www.spiedigitallibrary.org/terms-of-useWearable sensor system for multipoint measurements of bloodperfusion: pilot studies in patients with diabetes mellitusEvgeny A. Zherebtsov*a,b, Elena V. Zharkikhb, Igor O. Kozlovb, Yulia I. Loktionovab,Angelina I. Zherebtsovab, Ilya E. Rafailovc, Sergei G. Sokolovskid, Victor V. Sidorove,Andrey V. Dunaevb, and Edik U. RafailovdaOptoelectronics and Measurement Techniques, University of Oulu, Oulu, FI-90014, FinlandbResearch and Development Center of Biomedical Photonics, Orel State University namedafter I.S. Turgenev, Orel, RussiacAston Medical Technology Ltd., Birmingham, UKdAston Institute of Photonic Technologies, Aston University, Birmingham, UKeSPE ”LAZMA” Ltd, Moscow, RussiaABSTRACTThe growing interest in the development of new wearable electronic devices for mobile healthcare provides greatopportunities for the development of methods for assessing blood perfusion in this direction. Laser Dopplerflowmetry (LDF) is one of the promising methods. A fine analysis of capillary blood flow structure and rhythmin the time and frequency domains, coupled with a new possibility of round-the-clock monitoring can providevaluable diagnostic information about the state of microvascular blood flow. In this study, wearable implemen-tation of laser Doppler flowmetry was utilised for microcirculatory function assessment in patients with diabetesand healthy controls of two distinct age groups. Four wearable laser Doppler flowmetry monitors were used forthe analysis of blood microcirculation. Thirty seven healthy volunteers and 18 patients with type 2 diabetes mel-litus participated in the study. The results of the studies have shown that the average perfusion differs betweenhealthy volunteers of distinct age groups and between healthy volunteers of the younger age group and patientswith diabetes mellitus. It was noted that the average level of perfusion measured on the wrist in the two groupsof healthy volunteers has no statistically significant differences found in similar measurements on the fingertips.The wearable implementation of LDF can become a truly new diagnostic interface to monitor cardiovascularparameters, which could be of interest for diagnostics of conditions associated with microvascular disorders.Keywords: laser Doppler flowmetry, blood flow, wearable blood perfusion sensor, diabetes mellitus, ageing1. INTRODUCTIONSince the early 1990s, Dynamic Light Scattering (DLS) and Laser Doppler Flowmetry (LDF) measurementshave become an object of wide research and industrial interest in the field of life sciences. That methods arebased on optical non-invasive sensing of tissue using laser light and further analysis of the scattered radiationpartially reflected by the moving red blood cells. A great advantage of the LDF technique is its ability to measureblood flow in a local area of tissue with an excellent temporal resolution.1 At present, there is a surge of interestin wearable, electronic diagnostic devices. The main reason of such interest is due to the possibility of dailymonitoring promising a new quality of diagnosis. Round-the-clock monitoring, even such a simple indicatorlike heart rate, allows for the acquisition of new information about the whole body state. Blood perfusionmeasurements promise a great improvement in such kind of diagnostics. The additional synergistic effect may beobtained by annotation of physiological data by location data as well as information about the current physicalactivity (accelerometer data).In recent years, diagnosis, care and treatment of patients with diabetes mellitus (DM) have been the highesthealthcare priorities. In 2017, over 425 million people worldwide were diagnosed with diabetes (estimates from*Send correspondence to Evgeny ZherebtsovE-mail: evgenii.zherebtsov@oulu.fiMedical Laser Applications and Laser-Tissue Interactions IX, edited by Lothar D. Lilge, Carsten M. Philipp, Proc. of SPIE Vol. 11079, 110791O · © 2019 SPIE · CCC code: 1605-7422/19/$21 · doi: 10.1117/12.2526966Proc. of SPIE Vol. 11079  110791O-1Downloaded From: https://www.spiedigitallibrary.org/conference-proceedings-of-spie on 31 Jul 2019Terms of Use: https://www.spiedigitallibrary.org/terms-of-usethe International Diabetes Federation).2 This number is expected to increase to 629 million people by 2045.Clinical observations demonstrate that persistently high blood sugar can damage blood vessels and nerves andthat microvascular abnormalities may already appear in the preclinical phases of diabetes.34Microcirculation disorders manifest themselves in all parts of the body and affect the functioning of vari-ous organs, including kidneys, eyes, cardiovascular system and skin . This significantly reduces the life qualityof patients and may lead to their full disability. Chronic hyperglycaemia and insulin resistance in DM causeincreased vascular permeability, disruption of vascular tone, causing structural and functional changes in cap-illaries and arterioles.567 The earliest, usually reversible, manifestation of these diseases is the development ofmicrocirculatory dysfunction due to endothelial damage, excessive expression of certain adhesion molecules andother factors.Assessment of the microcirculation may conveniently be performed in the skin because of its ease of ac-cessibility. The cutaneous blood flow can be evaluated using various optical diagnostic methods,8 of whichlaser speckle, videocapillaroscopy, optical coherence tomography, and laser Doppler flowmetry (LDF) are mostfrequently used.91011 On the theoretical basis of the LDF method, novel wearable VCSEL-based sensors formultipoint measurements of blood perfusion have recently been proposed.12 The extensive tests of the systemas part of pre-clinical studies are needed to justify the range of its applications for clinical practice. Thus, thiswork aimed to investigate changes in microcirculatory blood flow of healthy volunteers and patients with type 2diabetes mellitus using the novel wearable blood perfusion sensor system.2. THE METHOD OF RESEARCHExperimental studies were conducted using wearable laser Doppler flowmetry monitors “AMT-LAZMA 1”(Aston Medical Technology Ltd., UK) for the analysis of blood microcirculation. The system comprises one ormore wearable devices with an integrated LDF sensor and skin thermometer, and a wireless data acquisitionmodule. Every wearable sensor in the system uses a VCSEL chip as a single mode laser source to implement fibre-free direct illumination of tissue. The devices implement identical channels for recording blood perfusion andallow simultaneous measurements at several points of the body. The fibre-free solution and direct illuminationof tissue by the laser diode make it possible to avoid fibre coupling losses as well as to decrease the movementartefacts which are common in fibre-based LDF monitors (Figure 1).Figure 1. Wearable sensor system for multipoint measurements of blood perfusionThe accurate synchronisation of the time during recordings from different parts of the body makes possiblethe study of the synchronisation of the skin blood flow under different conditions. Figure 2 shows changes in theLDF signal, recorded in a test measurement on the fingertips and wrists, during the breath holding test. Theblack line on the graphs corresponds to the average value of perfusion in 2 symmetrical measurement areas, andthe red area is the range of signal variations.As can be seen from the graphs presented, blood tissue perfusion is higher and more synchronous whenmeasured on fingertips compared to measurements performed on the wrists. The breath holding test causes aProc. of SPIE Vol. 11079  110791O-2Downloaded From: https://www.spiedigitallibrary.org/conference-proceedings-of-spie on 31 Jul 2019Terms of Use: https://www.spiedigitallibrary.org/terms-of-useFigure 2. Test measurements with series of breath holding tests: (a) represents measurements from fingers, (b) representsmeasurements from wrists.short-term vasoconstriction, which is observed as a drop in perfusion in both fingers and wrists. As could beobserved from the graphs, despite the more extensive range of perfusion measurements in the wrists, under theprovocative stimuli the microcirculatory blood flow in symmetrical areas of the body shows a rather synchronousresponse.These studies were conducted in accordance with the principles set out in the Helsinki Declaration of 2013by the world medical Association and were approved by the Ethics committee of Orel State University. Thestudy involved 37 healthy volunteers and 18 patients with type 2 diabetes. Volunteers with cardiovascular andother serious chronic diseases that affect the blood circulation system, alcohol or drug dependence were excludedfrom the studies. Before starting the measurements, each volunteer gave a voluntary informed written consentto participate in the experiment and passed a questionnaire to identify possible health problems. The healthyparticipants were divided into two groups according to their age: 16 volunteers with the age of 19.6± 0.6 (group1) and 21 volunteers with age 53.2 ± 11.4 (group 2). The LDF signal was recorded using the blood perfusionmeasurement system on wrists and the fingertips of middle fingers of both hands.Studies were conducted in a sitting position, in a state of physical and mental rest, not earlier than 2 hoursafter eating. The volunteer’s hands were placed on the table at the heart’s level. The blood perfusion wasrecorded for 10 minutes, while the sensors were attached to the palmar surface of the distal phalanx of 3rdfingers and both wrists.3. RESULTS (AND DISCUSSION)The figure 3 shows the scatterplots of parameters for the studied groups.Studies have shown that the average perfusion differs between healthy volunteers of different age groupsand between healthy volunteers of the younger age group and patients with diabetes mellitus. There was nostatistically significant difference between parameters of the older aged control group and patients. On thefingertips, the highest level of perfusion is observed in the second group of healthy volunteers, and the lowestvalues are recorded for the first group. This result might be due to structural changes in microcirculation duringProc. of SPIE Vol. 11079  110791O-3Downloaded From: https://www.spiedigitallibrary.org/conference-proceedings-of-spie on 31 Jul 2019Terms of Use: https://www.spiedigitallibrary.org/terms-of-useFigure 3. Measurements of mean blood perfusion in patients with type 2 diabetes: (a) - separate analysis for left andright sides of body and (b) data from symmetrical points combined together. Red young healthy volunteers (age of19.6± 0.6); green middle-age healthy volunteers (age of 52.6± 10.2); blue middle-age patients with type 2 diabetes (ageof 53.2± 11.4).ageing, including an increase in the total parallel vascular length.13 When measuring on the wrists, patients withdiabetes have the highest level of perfusion, and the smallest are the first group of volunteers. An increase inperfusion in patients with diabetes under basal conditions has been described in previous works by other authorsin connection with the effect of diabetic neuropathy on the blood flow.14 It is interesting to note that whenmeasuring on the wrists, the average level of perfusion in the two distinct groups of healthy volunteers has nostatistically significant differences found in similar measurements on the fingertips. This result may be due tothe lower amplitude of the signal recorded on the wrists compared to records made on the fingers. It should benoted that when comparing the parameters of individual limbs, the difference between the level of perfusion inhealthy volunteers of the younger age group and patients ceases to be statistically significant.4. CONCLUSIONSThe novel wearable sensor system for multipoint recordings of blood perfusion applied for measurements inhealthy volunteers and patients with type 2 diabetes has demonstrated a good quality of recorded blood perfusionsignals from areas of skin with different levels of microvascular bed density. The conducted experiments haveshowed that the implementation of the blood perfusion sensor as a fibre-free wireless wearable device is a veryconvenient solution to be applied as a point-of-care testing. The measurements in the groups of different ageallowed for registration of age specific changes in the blood perfusion as well as changes which can be associatedwith the development of diabetes. The wearable implementation of LDF can become a truly new diagnosticinterface to monitor cardiovascular parameters, which could be of interest for diagnostics of conditions associatedwith microvascular disorders.ACKNOWLEDGMENTSThis study was funded by the Russian Science Foundation (the research project 18-79-00237). Evgeny Zherebtsovkindly acknowledges for personal support from grant of Academy of Finland No.318281 (data processing).REFERENCES[1] Johnson, J. M., Minson, C. T., and Kellogg Jr., D. L., “Cutaneous vasodilator and vasoconstrictor mecha-nisms in temperature regulation,” Comprehensive Physiology 4, 33–89 (2014).[2] IDF, “Diabetes atlas. 8th edition.” http://www.diabetesatlas.org (2017).[3] Caballero, A. E., Arora, S., Saouaf, R., Lim, S. C., Smakowski, P., Park, J. Y., King, G. L., LoGerfo, F. W.,Horton, E. S., and Veves, A., “Microvascular and macrovascular reactivity is reduced in subjects at risk fortype 2 diabetes,” Diabetes 48(9), 1856–1862 (1999).Proc. of SPIE Vol. 11079  110791O-4Downloaded From: https://www.spiedigitallibrary.org/conference-proceedings-of-spie on 31 Jul 2019Terms of Use: https://www.spiedigitallibrary.org/terms-of-use[4] Smirnova, E., Podtaev, S., Mizeva, I., and Loran, E., “Assessment of endothelial dysfunction in patientswith impaired glucose tolerance during a cold pressor test,” Diabetes and Vascular Disease Research 10(6),489–497 (2013).[5] Dremin, V. V., Sidorov, V. V., Krupatkin, A. I., Galstyan, G. R., Novikova, I. N., Zherebtsova, A. I.,Zherebtsov, E. A., Dunaev, A. V., Abdulvapova, Z. N., Litvinova, K. S., Rafailov, I. E., Sokolovski, S. G.,and Rafailov, E. U., “The blood perfusion and nadh/fad content combined analysis in patients with diabetesfoot,” Proc. SPIE 9698, 969810 (2016).[6] Filina, M. A., Potapova, E. V., Makovik, I. N., Zharkih, E. V., Dremin, V. V., Zherebtsov, E. A., Dunaev,A. V., Sidorov, V. V., Krupatkin, A. I., Alimicheva, E. A., Masalygina, G. I., and Muradyan, V. F.,“Functional changes in blood microcirculation in the skin of the foot during heating tests in patients withdiabetes mellitus,” Human Physiology 43(6), 693–699 (2017).[7] Mizeva, I., Zharkikh, E., Dremin, V., Zherebtsov, E., Makovik, I., Potapova, E., and Dunaev, A., “Spectralanalysis of the blood flow in the foot microvascular bed during thermal testing in patients with diabetesmellitus,” Microvascular Research 120, 13–20 (2018).[8] Daly, S. M. and Leahy, M. J., “Go with the flow: A review of methods and advancements in blood flowimaging,” Journal of Biophotonics 6(3), 217–255 (2013).[9] Volkov, M. V., Kostrova, D. A., Margaryants, N. B., Gurov, I. P., Erofeev, N. P., Dremin, V. V., Zharkikh,E. V., Zherebtsov, E. A., Kozlov, I. O., and Dunaev, A. V., “Evaluation of blood microcirculation parametersby combined use of laser doppler flowmetry and videocapillaroscopy methods,” Proc. SPIE 10336, 1033607(2017).[10] Dremin, V. V., Zherebtsov, E. A., Makovik, I. N., Kozlov, I. O., Sidorov, V. V., Krupatkin, A. I., Dunaev,A. V., Rafailov, I. E., Litvinova, K. S., Sokolovski, S. G., and Rafailov, E. U., “Laser doppler flowmetry inblood and lymph monitoring, technical aspects and analysis,” Proc. SPIE 10063, 1006303 (2017).[11] Potapova, E. V., Dremin, V. V., Zherebtsov, E. A., Makovik, I. N., Zharkikh, E. V., Dunaev, A. V.,Pilipenko, O. V., Sidorov, V. V., and Krupatkin, A. I., “A complex approach to noninvasive estimation ofmicrocirculatory tissue impairments in feet of patients with diabetes mellitus using spectroscopy,” Opticsand Spectroscopy 123(6), 955–964 (2017).[12] Zherebtsov, E., Sokolovski, S., Sidorov, V., Rafailov, I., Dunaev, A., and Rafailov, E., “Novel wearablevcsel-based blood perfusion sensor,” 2018 International Conference Laser Optics (ICLO) , 564–564 (2018).[13] Li, L., Mac-Mary, S., Sainthillier, J.-M., Nouveau, S., de Lacharriere, O., and Humbert, P., “Age-relatedchanges of the cutaneous microcirculation in vivo,” Gerontology 52, 142–153 (2006).[14] Schramm, J., Dinh, T., and Veves, A., “Microvascular changes in the diabetic foot,” International Journalof Lower Extremity Wounds 5(3), 149–159 (2006).Proc. of SPIE Vol. 11079  110791O-5Downloaded From: https://www.spiedigitallibrary.org/conference-proceedings-of-spie on 31 Jul 2019Terms of Use: https://www.spiedigitallibrary.org/terms-of-use

Wearable sensor system for multipoint measurements of blood perfusion: pilot studies in patients with diabetes mellitus

Dremin

Volkov

Zherebtsov

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Wearable sensor system for multipoint measurements of blood perfusion: pilot studies in patients with diabetes mellitus

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