Currently there is no accurate objective measure for monitoring pain during the state of drug-induced unconsciousness (such as during surgical anesthesia). Moreover, the absence of an objective measure for detecting pain hampers the physician's ability to provide an optimal dose of analgesics. We have developed a novel method for detecting pain by quantifying skin blood flow dynamics using a miniaturized dynamic light scattering (mDLS) sensor placed on the skin. Healthy awake volunteers were studied with mDLS sensors placed on both index fingers while being subjected to a series of cutaneous painful stimuli (electric shock and heat), randomly applied in a range between the subjects’ pain threshold and tolerance. Power spectrum analysis of the recorded signal was performed with a focus on two frequency bands, representing relative blood flow of non-pulsatile vessels and larger pulsatile arterioles. Relative blood flow of pulsatile vessels decreased while flow of non-pulsatile vessels increased in response to painful stimulation, with a high correlation between the responses obtained on the right and left index fingers. The changes in hemodynamics that occur during painful stimulation suggest a redistribution of blood flow between pulsatile and non-pulsatile vessels, probably related to central activation of the sympathetic system combined with local dynamic autoregulatory responses. Thus, optical parameters of skin blood flow can detect nociceptive stimuli and consequently can serve as objective biomarkers of pain.
Self-measurement of blood pressure (BP) is important for monitoring treatment of hypertension, but current instruments are cumbersome and at times also impractical, especially for the older population. Current optical solutions, such as PPG-based technologies that were developed for improving convenience, provide derived measurements that are often inaccurate, particularly for diastolic values. Alternatively, by using dynamic light scattering (DLS) we are able to measure the direct hemodynamic response. We propose a simple physical model that explains the relation between arterial pressure values and the hemodynamic response which is measured from the finger root following changes in externally applied pressure. Based on this model we have developed a small-scaled, optical, mobile device that measures BP at the finger using dynamic light scattering. The apparatus is positioned at the base of the index finger and contains a ring with an inflatable cuff with two miniaturized dynamic light scattering (mDLS) sensors situated distal to the cuff. The cuff is inflated to above systolic pressure, and changes in blood flow (hemodynamics) are measured during cuff deflation. BP measurement is carried out using specially designed algorithms based on hemodynamic indexes and waveform analysis which capture systolic and diastolic points in real-time. Using this apparatus, we measured BP from 69 patients visiting a hypertension outpatient clinic, and a control group of 15 healthy subjects. BP readings were compared with measurements recorded at the arm location with an Omron device used in the clinic. The mean absolute error (MAE) for systolic and diastolic blood pressure was 7.8 and 9 mmHg, respectively at all ranges of BP measured. In conclusion, using Elfi-Tech's innovative technology, it is possible to measure BP accurately at the finger location using a compact, convenient mDLS-based device with high accuracy.
It is widely recognized that effective stress management could have a dramatic impact on health care and preventive medicine. In order to meet this need, efficient and seamless sensing and analytic tools for the non-invasive stress monitoring during daily life are required. The existing sensors still do not meet the needs in terms of specificity and robustness. We utilized a miniaturized dynamic light scattering sensor (mDLS) which is specially adjusted to measure skin blood flow fluctuations and provides multi- parametric capabilities. Based on the measured dynamic light scattering signal from the red blood cells flowing in skin, a new concept of hemodynamic indexes (HI) and oscillatory hemodynamic indexes (OHI) have been developed. This approach was utilized for stress level assessment for a few usecase scenario. The new stress index was generated through the HI and OHI parameters. In order to validate this new non-invasive stress index, a group of 19 healthy volunteers was studied by measuring the mDLS sensor located on the wrist. Mental stress was induced by using the cognitive dissonance test of Stroop. We found that OHIs indexes have high sensitivity to the mental stress response for most of the tested subjects. In addition, we examined the capability of using this new stress index for the individual monitoring of the diurnal stress level. We found that the new stress index exhibits similar trends as reported for to the well-known diurnal behavior of cortisol levels. Finally, we demonstrated that this new marker provides good sensitivity and specificity to the stress response to sound and musical emotional arousal.
PPG volumetric model is frequently adopted to explain the pulsatile nature of optical response for arterial pulsation. In this article we show that the pulsatile fluctuation of optical response can be explained in terms of the light scattering related changes. According to this assumption, these fluctuations are driven by the modulation the scattering coefficient associated with the blood flow hemodynamic effects. There was shown that the proposed model yields a good correspondence with the pulse-oximetry related parameters. Moreover, it was found that the experimental relationship between the red blood concentration in the blood (hematocrit) and the parameters being derived from the in vivo measured optical signals can be described in terms of this scattering driven model. There was demonstrated that the commonly used volumetric assumption fails to provide a reasonable description of the experimental results. The last fact can be used as a decisive argument in favor of the scattering driven model. This model can be used for better understanding of the pulse oximetry as well as for the guidance for the algorithmic development of the blood hemoglobin/ hematocrit in vivo.
We conducted a study on 861 healthy and sick subjects and demonstrated that some calculated parameters based on measurement of the dynamic light scattering (DLS) signal from the finger correlate highly with chronological age ranging from 1.5 to 85 years old. Measurements of DLS signals were obtained during both occlusion and nonocclusion of blood flow in the finger. For the nonocclusion case we found that the low-frequency component of the DLS signal significantly correlates with the biological age while the high-frequency component of the DLS signal resembles the arterial pulse-wave and does correlate with age. However, the most prominent correlation between the DLS characteristics and age was noted with the stasis stage measurements. We propose that the observed age-related phenomena are caused by alterations in local blood viscosity and interactions of the endothelial cells with erythrocytes. Further, a new noninvasive index based on the age-related optical characteristics was introduced. This noninvasive index may be used as a research and diagnostic tool to examine the endothelial and thrombolytic properties of the vascular system.
Optical spectroscopy approach, using non-coherent light sources, has become an important tool for non-invasive analysis in
vivo. It is based on the assumption that biochemical characteristics of biological system can be determined through the optical
coefficients of blood and tissue particles. Thus, in the framework of this approach, the major concern is to express the obtained
optical signals in terms the optical coefficients of the single particle of blood or tissue. However, since the light propagation in
tissue is dominated by the multiple-scattering component, a direct measurement of single scattering characteristics turns to be
a very difficult task. Practically, only the relative changes of absorption and scattering coefficients are measured. We
suggested to adopt the dynamic light scattering (DLS) or speckle technique for the determination of the light scattering
coefficients of the red blood cells under stasis conditions in vivo. We assumed that under zero flow conditions the RBC
movement is driven mostly by the Brownian motion. It was shown, that under appropriate measurement geometry, the
measured optical signal can be decomposed into a few major components. The most dominant components are ascribed to the
single backscattering and forward scattering coefficients of the red blood cells. In-vitro and in vivo experimental tests have
shown a good correspondence between the theoretically estimated and experientially measured results. The obtained results
indicate that the DLS technique can be adopted for the determination of blood particles scattering characteristics in addition to
the movement and effective viscosity parameters measurement in vivo.
Our analysis of spectral behavior of time-variant optical characteristics caused by RBC aggregation is applied to issues
of non-invasive blood monitoring. Modulations of blood flow cause the change in geometry of RBC aggregates and corresponding variance of light scattering. This changes cause the variation of optical transmission, reflection, and polarization of outcoming light. The last can be translated back in absorption coefficients of various blood constituents, refractive index mismatch, etc. For instance, in case of long occlusion simultaneous measurements of both the azimuthal angle and the ellipticity of outcoming light can provide sufficient data to determine the blood glucose.
Physiological blood coagulation/clotting is an essential biological process that is initiated by vessel injury and includes a cascade of enzymatic reactions finalized by fibrin polymerization and clot formation. We utilize dynamic light scattering (DLS) imaging to monitor in vivo red cell mobility as an indicator of blood coagulation. In the course of the experiments, blood flow is arrested using mechanical occlusion, and then laser injury is applied. We demonstrate that the combination of laser injury with DLS imaging on occluded blood vessels (i.e., under static conditions) is suitable to detect even subtle changes of plasma viscosity in the circulatory system, which reflects the process of clot development. This approach is noninvasive and has a relatively simple and easy-to-use technical design. Thus, the proposed methodology provides a promising tool for investigating blood clotting within the vasculature.
Physiological blood coagulation is an essential biological process. Current tests for plasma coagulation (clotting) need to
be performed ex vivo and require fresh blood sampling for every test. A recently published work describes a new, noninvasive,
in vivo approach to assess blood coagulation status during mechanical occlusion1. For this purpose, we have
tested this approach and applied a controlled laser beam to blood micro-vessels of the mouse ear during mechanical
occlusion. Standard setup for intravital transillumination videomicroscopy and laser based imaging techniques were used
for monitoring the blood clotting process. Temporal mechanical occlusion of blood vessels in the observed area was
applied to ensure blood flow cessation. Subsequently, laser irradiation was used to induce vascular micro-injury. Changes
in the vessel wall, as well as in the pattern of blood flow, predispose the area to vascular thrombosis, according to the
paradigm of Virchow's triad. In our experiments, two elements of Virchow's triad were used to induce the process of
clotting in vivo, and to assess it optically. We identified several parameters that can serve as markers of the blood clotting
process in vivo. These include changes in light absorption in the area of illumination, as well as changes in the pattern of
the red blood cells' micro-movement in the vessels where blood flow is completely arrested. Thus, our results indicate
that blood coagulation status can be characterized by non-invasive, in vivo methodologies.
We present here a bird-eye view of time-dependent optical transmission of blood in red-near infrared spectral range.
This issue is of the key importance both for fundamental understanding and for various applications connected with
non-invasive optical blood analysis. A number of experiments measuring kinetics of blood transmission in the case of
natural heart pulsations and of artificial kinetics following over-systolic occlusion is reviewed. The comprehensive
theoretical approach has to consider scattering-associated mechanism rather than the widely accepted absorption-associated
one. Light scattering occurs on RBC aggregates. The size of aggregates and their shape change in time due
to blood flow variations. It results in the corresponding changes of optical transmission.
The tendency of red blood cells (RBCs) to aggregate is considered to be a critical biological activity, which contributes
to blood viscosity. The ability to assess blood viscosity parameters non-invasively can play an important role in a variety
of fields of medicine. Toward achieving this goal, we have attempted to follow the kinetics of red blood cell's
aggregation process non-invasively. In this work, we have generated the optical signals of RBC aggregation and have
studied them both in vitro and in vivo utilizing a dynamic light scattering (DLS) approach. The system was built and
calibrated, first in vitro by using micro-sphere suspensions of known particle sizes and subsequently in vitro, on a sample
of whole blood. Time dependent behavior of a function expressed in terms of autocorrelation of light intensity
fluctuations was analyzed. The correspondence between in vitro aggregation tests and in vivo results was revealed and is
explained in terms of modified diffusion theory and WKB approximation for light scattering mediated by aggregates.
Therefore, we have demonstrated the applicability of a DLS based technique for the non-invasive measurement of blood
particle sizes and blood viscosity.
The use of small animals in intravital optical microscopy is a well-established experimental model to study blood
microcirculation in vivo. Recent advances in cell biology and optical techniques (e.g., lasers, CCD cameras, software,
etc.) provide the basis for significant improvements with in vivo imaging. This review summarizes the latest
achievements in this specific area focusing on the development of modern optical and biological platforms. This
includes in vivo real time monitoring of individual cells in the context of blood flow, super-sensitive fluorescence
imaging, high-speed cell imaging and light scattering techniques. The capability of these platforms has been
demonstrated in live animal models (e.g., mouse and rat ear, rat mesentery, and others) for real-time monitoring of
individual blood cell properties (e.g., size and shape), cell trafficking, cell-cell interactions (e.g., aggregation in flow or
adhesion to vessel walls), and blood flow viscosity. Future applications are discussed including in vivo early diagnosis of
disease and monitoring cellular responses to environmental and therapeutic interventions.
We prove experimentally that RBC aggregation is among the major factors affecting time evolution of light transmission in both the normal situation of pulsatile blood flow and the situation of over-systolic vessel occlusion. Optical transmissions of tissue in vivo have been measured in red/near-infrared region. Sudden blood flow cessation causes the light transmission rising. For certain wavelengths range this growth becomes non-monotonic. The correspondence between in vivo measurements and the theoretical simulations is reached if we attribute the transmission growth to the change of average size of scatterers. The most important blood parameters such as hemoglobin, glucose, oxygen saturation, etc., influence the transmission growth following over-systolic occlusion and, therefore, may be extracted from the detailed analysis of the time evolution of optical transmission. It forms a basis for new kind of non-invasive measurements, i.e., occlusion spectroscopy. The results of in vivo clinical trials are presented for glucose and hemoglobin.
We develop theoretical models of light transmission through whole blood considering RBC aggregation. RBC aggregates are considered to be the main centers of scattering in red/near- infrared spectral region. In pulsatile blood flow the periodic changes of aggregate geometry cause oscillations of light scattering. Thus scattering-assisted mechanism has to be taken into account in pulse oximeter calibration. In case of over-systolic vessel occlusion the size of aggregates grows, and the light transmission rises. Light diffraction on a single scatterer makes the transmission growth non- monotonic for certain spectral range. For the most typical set of aggregate parameters this range corresponds to wavelengths below 760 nm, and this prediction fits well both in vivo and in vitro experimental results. This spectral range depends on the refraction index mismatch and the geometry of aggregates. Both of them may be affected by the chemistry of blood. For instance, changes of glucose and hemoglobin have different effect on light transmission time response. Consequently, their content may be determined from time evolution of optical transmission.
We consider a number of diffusive and transport models of light transmission through whole blood, targeting better understanding of nature of optical transmission pulsations for blood flow modulated by heartbeats. We claim the existence of scattering- associated mechanism rather than the absorption-associated one. Single erythrocytes and their aggregates are considered to be the main centers of scattering in the red- near infrared spectral region. The shape and size of aggregates change in time due to blood flow changes. The corresponding changes of optical transmission are simulated.
Optical transmission of tissue in-vivo and model red blood cells (RBS) suspensions in vitro have been measured in red and near infrared region targeting better understanding of the nature of in vivo pulsatile signals. It is shown experimentally (both in vitro and in vivo) that the pulsatile signal may result not just from volumetric changes, but also from light scattering fluctuations. Theoretical predictions on time evolution of optical transmission for the case of very long over-systolic occlusion also have been proved experimentally for both in vivo measurements and in vitro model sets. The interconnection of the shape of optical signal and geometry of RBC aggregates is confirmed.