Blood flow measurement system using contrast analysis of adhesion laser speckle

Abstract

The present disclosure relates to a blood flow measurement system using adherent laser speckle contrast analysis. Apparatus, systems and methods for improved laser speckle imaging of samples (such as vascularized tissues) are disclosed herein, wherein the laser speckle imaging is used to determine the movement rate of light scattering particles within the sample. The system includes a structure adjacent to a light source and a photosensitive detector. The structure can be positioned adjacent to the sample (e.g., coupled to the sample) and configured to be oriented toward the light source and the detector relative to the sample so that surface reflections including specular reflections and diffuse reflections are not blocked from entering the detection field of the detector. The separation distance along the structure between the light source and the detector can further enable selective deep penetration into the sample and bias sampling of multiply scattered photons. The system includes an operably coupled processor programmed to derive a contrast metric from the detector and to correlate the contrast metric with the movement rate of the light scattering particles.

Description

[0001] This application is a divisional application of PCT application No. 201780029605.5, which entered the Chinese national phase and whose international application date is April 4, 2017 and invention name is “Blood flow measurement system using adhesion laser speckle contrast analysis”.

[0002] Incorporated herein by reference

[0003] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 318,884, filed on April 6, 2016, which is incorporated herein by reference in its entirety for all purposes. Any and all applications related thereto by or claiming priority from the provisional patent application are incorporated herein by reference in their entirety. Technical Field

[0004] Embodiments of the present disclosure relate to novel methods, devices and systems for optically and non-invasively measuring the rate of movement of light scattering particles within a target sample. In particular, the present disclosure relates to devices, methods and systems for measuring the volume flow and / or movement (e.g., diffusion) of light scattering particles by quantifying the changes in interference patterns produced when the moving particles scatter light. Background Art

[0005] Dynamic light scattering (DLS) techniques for determining particle size and flow rate in solution can be performed in a variety of ways. One DLS method, known as laser speckle imaging (LSI), uses a coherent laser source to illuminate a sample of light-scattering particles and uses a multi-pixel detector (e.g., a silicon-based camera sensor) to image the scattered light. When the scattered coherent light is recombined onto a detection element, the sensor records the so-called "speckle" pattern produced by light interference. If the scattering particles are in motion, the interference pattern will fluctuate over time. The detection element has a finite exposure time, and if the interference pattern fluctuates during exposure, the speckle will "blur" within the detection element or its light intensity will be averaged. Researchers have previously developed a method to quantify the amount of "blurring" during exposure by calculating the standard deviation of a local neighborhood of pixel intensities (which are usually normalized to the mean). This parameter is often referred to as "speckle contrast." A decrease in speckle contrast indicates an increase in motion (e.g., flow or diffusion), and vice versa. LSI is a useful technique in biomedical research for studying blood flow within vascularized tissues. Cells and other structures in the blood scatter coherent light as they flow through the vasculature, and LSI can quantify that flow.

[0006] One disadvantage of conventional LSI is its high susceptibility to motion artifacts. Each imaging component and sample is independently fixed to ensure coaxiality. The sample is often biological and moves independently of the camera and / or light source. When the sample moves independently of the imaging system, the motion from the movement is confused with the motion of scatterers within the sample, leading to erroneous results in the speckle image.

[0007] Another disadvantage of conventional LSI is the susceptibility to surface reflections, shallow depth penetration (usually less than 1mm) and low sampling of dynamic particles in the sample relative to the total detection signal. Ideally, all detected photons would be scattered from dynamic particles (usually located in the sample). However, in conventional LSI, many photons experience specular reflection from the sample surface, or scatter static objects (such as epidermis) at the sample surface, which is called diffuse reflection. For example, specular reflection is the process of reflecting light from a mirror surface, while diffuse reflection is the process of reflecting light from a matte object such as a loose-leaf paper. Shallow penetration and non-dynamic scattering events are largely due to the geometry of the LSI system, in which the imaged sample surface is also directly illuminated by the light source. In this reflective geometry, the light from the light source illuminates the sample surface area, referred to as the "illuminated area" in this article. If the surface is smooth, the light can be reflected off the sample surface in the illuminated area like a mirror, and enter the detector (moving light scatterers such as red blood cells) without interrogating the properties of the target sample. If the surface is matte or rough (i.e., like white paper), the light can experience diffuse reflection on the sample surface in the illuminated area. Light that undergoes specular or diffuse reflection is typically not dynamically scattered by the flowing particles below the surface and is therefore likely to not contain any flow information. Therefore, specular and diffuse reflections result in undesirable signal content being included in LSI measurements. Embodiments disclosed herein are intended to improve these shortcomings and provide more robust dynamic scattering object measurements for medical and industrial applications. Summary of the invention

[0008] The present disclosure describes novel methods, apparatuses and systems for collecting and evaluating interference patterns or speckle patterns produced by the scattering of coherent or partially coherent light to determine the movement rate of scattered particles. In a specific non-limiting case, the disclosed methods, apparatuses and systems can be used in a clinical setting to determine the flow rate of blood cells within vascularized tissue. In a second non-limiting case, the disclosed methods, apparatuses and systems can be used to determine the particle size in a solution of light scattering particles. In a third case, the disclosed methods, apparatuses and systems can be used to determine heart rate by evaluating the periodicity of blood flow during the cardiac cycle.

[0009] The embodiments disclosed herein rely on an innovative concept that replaces the conventional camera and laser source of the LSI that illuminates and records distant images with a sensor and laser source attached to a structure (such as a housing structure) and a known separation that substantially reduces back-reflected light waves (i.e., specularly reflected light or diffusely reflected light) from the surface into the detection field. Some embodiments also disclose adhering the structure to a target sample so that the sample cannot move independently of the light source and detector. Some embodiments also disclose transmitting data to a processing algorithm, where a measure of image contrast is calculated in space and / or time. In a non-limiting case, the light source can be a vertical cavity surface emitting laser (VCSEL), the sensor can be a complementary metal oxide semiconductor (CMOS) image sensor, and the structure can be a wearable band that is attached to a person's wrist or other limb.

[0010] The disclosed embodiments may include any structure adjacent to the light source and the detector that is designed to exclude photons that leave an illuminated area on the surface of the sample from entering the detector. The illuminated area can be defined as the intersection of the light cone described by the half-width intensity of the emitted light and the surface of the sample. In a conventional imaging setup, the light source will be deliberately used to illuminate the surface imaged by the camera. The disclosed embodiments particularly avoid imaging any area illuminated by the light source. The purpose of blocking the detection of photons emitted from the illuminated area is that these photons are more likely to be specularly or diffusely reflected at the surface of the sample. The present technology prefers photons that penetrate deeply and are scattered multiple times within the sample to increase the probability of light scattering interacting with flowing / moving particles.

[0011] In some embodiments, a system for determining the movement rate of multiple light scattering particles in a sample is disclosed. The system includes a light source, a photosensitive detector, a structure of an adjacent light source and a detector for operably positioning the light source and the detector adjacent to the sample, and a processor. The light source is configured to emit at least partially coherent light toward multiple light scattering particles. The detector has one or more pixels and is configured to detect the light scattered by at least some of the multiple light scattering particles. The structure is configured to position the light source and the detector relative to each other and the sample so that the surface reflection from the sample is not detected by the detector and at least some of the emitted light scattered by at least some of the light scattering particles in the multiple light scattering particles is detected by the detector. The processor is operably coupled to the detector and is programmed to derive a contrast metric by comparing the light detected by one or more pixels in time and / or space. The processor is further programmed to associate the contrast metric with the movement rate of the light scattering particles in the sample. The processor may be physically adjacent to the structure, or may not be physically adjacent to the structure. The processor may be configured to receive data wirelessly from the detector.

[0012] The light source and detector can be positioned at approximately the same normal distance (h) from the sample surface, wherein at least partially coherent light is emitted from the light source along a light emission axis substantially perpendicular to the sample surface at a known projection angle (θ). The light source and detector can be separated by a distance greater than 2htan(θ / 2) along the same surface. The structure can be configured to maintain the light source, detector, and sample in a constant spatial relationship during detection.

[0013] The contrast metric may be a standard deviation from a mean, a median, a percentage difference, a potential well fill time difference, a gradient between pixels, and a difference between pixels or pixel sub-regions. The plurality of light scattering particles may include blood cells. The system may be configured to measure blood flow. The processor may be further programmed to determine blood circulation adequacy based on the measured blood flow.

[0014] The structure may include a housing containing a light source and a detector. The housing may contain a processor. The structure may be in the form of a patch configured to be applied to a user's skin surface. The structure may include an adhesive material for adhering the structure to a sample surface. The structure may be configured to couple to the sample by friction. The structure may include a fixing mechanism to fix the structure to an adjacent sample surface during detection. The fixing mechanism may be, for example, a spring-loaded clip, a belt-like member, or a rope-like member. The structure may be configured to adhere to a user's skin area. The structure may be configured to be worn by a user. The structure may be in the form of a wristband.

[0015] The system may be configured to measure the rate of movement at a depth of about 1 mm to about 1 cm in the sample. The detector may be selectively spaced from the light source at a separation distance that allows the detector to target light scattered from a selected depth in the sample for interrogation. The separation distance between the light source and the detector may be adjustable. The detector may be a CMOS or CCD sensor. The light source may be a laser. The light emitted by the light source may be in the near infrared spectrum. The light emitted by the light source may be about 700 nm to about 900 nm. The system may be configured to place the structure in substantially direct contact with the sample surface. The system may include a display for displaying an image of the detected speckle pattern or a digital or graphical representation of speckle contrast, rate of movement, penetration depth, or another metric derived therefrom. The display may be adjacent to the structure. The detector may be configured to receive unfocused light. The detector may be configured to receive a light path that is not altered by an optical element that alters the path or direction of the incident light, including a lens.

[0016] The structure may include an opaque separator configured to limit the numerical aperture of the light source and / or the detector so that the numerical apertures of the light source and the detector do not overlap on the surface of the sample. The opaque separator may be an opaque sheet or block positioned between the light source and the detector. The opaque separator may be an opaque housing operably positioned in front of the detector. The opaque housing may include a hole for limiting the detection angle of the detector.

[0017] The structure may be rigid along a portion between the light source and the detector. One or more pixels of the detector may have a detection region having a center, wherein the structure is configured such that the peak emission axis of the light source is not substantially aligned or substantially aligned with the center of the detection region. The structure may be configured such that the peak emission axis is not substantially aligned or substantially aligned with any portion of the detection region.

[0018] In some embodiments, a method for determining the movement rate of multiple light scattering particles in a sample is disclosed. The method includes positioning a structure adjacent to the sample surface. The structure is adjacent to a light source configured to emit at least partially coherent light and a photosensitive detector having one or more photosensitive pixels. The light source is positioned at a first position adjacent to the sample. The structure is configured to orient the light source relative to the sample at the first position so that at least part of the sample is within the emission numerical aperture of the light source. The light cone emitted by the light source and defined by the half-maximum full width divergent intensity of the emitted light defines an illuminated area on the surface of the sample. The detector is further positioned at a second position adjacent to the sample. The structure is further configured to orient the detector relative to the sample at the second position so that at least part of the sample is within the acceptance numerical aperture of the detector, and light directed from or through the illuminated area is prohibited from entering the detector and reaching the photosensitive pixels. The method also includes starting the light source so that the light is directed to the light scattering particles, and using the detector to detect light emitted from the light source and scattered by at least some of the light scattering particles. The method also includes transmitting a signal related to the detected light from the detector to a processor; comparing the light detected by one or more pixels in time and / or space; deriving a contrast metric based on the comparison; and correlating the contrast metric with a rate of movement of the light scattering particles.

[0019] Positioning the structure may include coupling the structure to the sample. The structure may be coupled to the sample by an adhesive material. Coupling the structure may include applying a patch to the skin of a user. The structure may be frictionally coupled to the sample. The friction coupling structure may include applying a rope, a strap, or a spring-loaded clip to the sample. The structure may be rigid along a portion between the light source and the detector. The structure may be configured to be worn by the user. The method may also include adjusting a separation distance along the structure between the light source and the detector. The structure may be in the form of a wristband. The structure may be coupled adjacently to the skin of the user. The detector may be a CMOS or CCD sensor. The light source may be a laser. The light emitted by the light source may be in the near infrared spectrum. The light emitted by the light source may be about 700 nm to about 900 nm. Positioning the structure may include placing the structure in substantially direct contact with the surface of the sample. Positioning the structure may include placing the light source in substantially direct contact with the surface of the sample and placing the detector in substantially direct contact with the surface of the sample. The method may also include displaying an image of the detected speckle pattern or a digital or graphical representation of speckle contrast, movement rate, penetration depth, or another metric derived therefrom.

[0020] The detector can be configured to receive unfocused light. The detector can be configured to receive an optical path that is not changed by an optical element, which modifies the path or direction of the incident light, including a lens. The method can also include positioning an opaque separator before, after, or simultaneously with the positioning of the detector. The opaque separator can be configured to limit the numerical aperture of the light source and / or the detector so that the numerical apertures of the light source and the detector do not overlap each other on the surface of the sample. The opaque separator can be an opaque sheet or block positioned at a third site between the first site and the second site. The opaque separator can be an opaque shell operably positioned in front of the detector. The opaque shell can include a hole for limiting the detection angle of the detector.

[0021] The method may also include selecting a depth of inquiry within the sample for targeting scattered light and determining a separation distance between a light source and a detector configured to target the selected depth. The first site and the second site may be separated by a determined separation distance. Using a detector to detect light may include detecting light emitted from a light source and scattered by at least some light scattering particles at a first depth within the sample. The method may also include adjusting the separation distance along a structure between the light source and the detector, and using a detector to detect light emitted from a light source and scattered by at least some light scattering particles at a second depth within the sample. The transmission signal may include a wireless transmission signal.

[0022] The light source and detector can be positioned at approximately the same normal distance (h) from the sample surface, wherein at least partially coherent light is emitted from the light source along a light emission axis substantially perpendicular to the sample surface at a known projection angle (θ). The light source and detector can be separated by a separation distance greater than 2htan(θ / 2) along the same surface.

[0023] The light scattering particles may include blood cells. The method may include correlating the rate of movement of the light scattering particles with blood flow. The method may also include determining blood circulation adequacy based on the measured blood flow. The method may also include maintaining the light source, the detector, and the sample in a constant spatial relationship during the detection. The contrast metric may be derived from the standard deviation of the mean, the median, the difference percentage, the potential well filling time difference, the gradient between pixels, or the difference between pixels or pixel sub-regions.

[0024] Detecting light using a detector may include detecting light emitted from a light source and scattered by at least some of the light scattering particles at a depth of about 1 mm to 1 cm within the sample. One or more pixels of the detector may have a detection area having a center, wherein the structure is configured such that the peak emission axis of the light source is not substantially aligned or substantially aligned with the center of the detection area. The structure may be configured such that the peak emission axis is not substantially aligned or substantially aligned with any portion of the detection area. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The embodiments disclosed herein are intended to fall within the scope of the present invention disclosed herein. From the following detailed description with reference to the accompanying drawings, these and other embodiments will be apparent, and the present invention is not limited to any specific disclosed one or more embodiments. The optional and / or preferred features described with reference to some embodiments can be combined with other embodiments and incorporated into other embodiments.

[0026] Figure 1A-Figure 1D A conventional laser speckle imaging system ( Figure 1A ) and built-in laser speckle imaging system ( Figure 1B )Comparison of the launch field and the detection field in . Figure 1A An example of a conventional system is schematically shown. Figure 1B An example of a built-in system is schematically shown. Figure 1C Depicted is an example of using flow index data generated by a conventional system to measure pulsatile blood flow. Figure 1D Depicted is an example of using flow index data generated by an in-house system to measure pulsatile blood flow.

[0027] Figure 2A-2B A conventional laser speckle imaging system ( Figure 2A ) and built-in laser speckle imaging system ( Figure 2B) and the system's ability to detect light reflected from a surface.

[0028] Figure 3 The geometry of the LSI system used to calculate the minimum source-detector separation distance that must be configured to prohibit specular reflections from entering the detector is shown.

[0029] Figure 4 An example of a device configuration is shown in which a structure is coupled to an opaque spacer that is in contact with the sample and serves to prevent light reflected from the sample surface from reaching the image sensor of the detector.

[0030] Figure 5 An example of a device configuration is shown that includes an opaque housing with a restricted aperture coupled to a detector.

[0031] Figure 6 An example of an embodiment of the invention is shown in which the structure housing the light source and detector can be secured to the sample using a wristwatch strap.

[0032] Figure 7A-7B The use of standard PPG ( Fig. 7A ) and an LSI according to the features disclosed herein ( Figure 7B )’s query results. DETAILED DESCRIPTION

[0033] Disclosed herein are novel methods, apparatus, and systems for determining more accurate movement rates (e.g., flow rates, diffusion rates, etc.) of scattering particles within a target sample. In summary, the disclosed embodiments innovatively apply the theory of dynamic light scattering, and in particular, speckle contrast analysis methods. The method of speckle contrast imaging is commonly used to image blood vessels and other vascularized tissues in the field of biomedical engineering. The method utilizes the interference pattern formed when coherent laser light is randomly scattered in a sample medium. The so-called speckle pattern is formed on the image sensor. If the scattering object is in motion, the speckle pattern will fluctuate during the exposure time of the image sensor, which will cause the pattern to blur. For a given camera exposure, faster fluctuations will cause more blur. A measure of "blur" in a speckle image is often called speckle contrast, and is generally defined as:

[0034] K=σ / [1]

[0035] where σ is the standard deviation, and is the average of N pixel intensities (for silicon-based image sensors, pixel intensity is proportional to the voltage output from the detector element). As a non-limiting example of relating a contrast metric to the flow rate of a moving particle, the spatial speckle contrast can be related to the autocorrelation time of the speckle image, which can then be related to the mean square displacement of the moving scattering object (e.g., flow rate or diffusion). Generally, relatively high contrast speckle patterns will produce higher K values, while blurrier patterns will produce lower K values. The flow rate within the sample can then be related to the contrast, which can be calculated analytically or empirically. By calibrating a given system in a particular configuration using samples of known velocity, the movement rate can be determined. In some embodiments, the movement rate can be determined as the velocity or average velocity (e.g., m / s) of the moving light scatterers within the sample. The flow rate can be a measure of the volume of fluid (e.g., blood) transported per unit time (i.e., volumetric flow rate) and can be expressed in any suitable units (e.g., m / s). 3 In some embodiments, flow rate can be determined as a measure of volume flux (e.g., m / s) through, for example, one or more blood vessels. 3 ·s -1 ·m -2 ).

[0036] The disclosed methods, devices and systems are directed to performing improved speckle contrast measurements that increase accuracy, reliability and depth penetration within a target sample. The systems, devices and methods disclosed herein may include a component device including a light source 100, a detector 200 (i.e., a photosensitive detector, such as an image sensor), and one or more processors, which may be operably connected to each other to interrogate a sample. In many embodiments, the sample may be a physiological sample, such as a tissue region of a subject, whose physiological information is to be determined. The subject may be a living animal, such as a human. The component devices may be standard devices used in new configurations, methods and / or systems, or they may be devices specifically designed or adapted to be performed in the systems and methods disclosed herein. The light source 100 may be configured to emit at least partially coherent light. The light source 100 may be a laser, such as a diode laser. In some embodiments, the light source 100 is a VCSEL laser. The detector 200 may include one or more photosensitive elements (e.g., pixels) for detecting light recovered from the light source 100 after interacting with the sample. For example, the detector 200 may be a silicon-based camera sensor. The camera sensor can be any suitable type, including but not limited to CMOS or CCD image sensors. The detector 200 can include or be coupled to an optical element 202, such as a lens. The optical element 202 can include a slit, a hole or other elements for adjusting the angle (i.e., the amount of light) of the detected light, as described below. In some embodiments, the detector 200 can be configured without any optical element 202 and / or can be configured to receive unfocused light, as described below. The detector 200 can be configured to generate one or more signals related to the detected light and transmit these signals to a processor. The signal can include quantitative information about the intensity of the light detected at one or more pixels at a time point or over a period of time. In some embodiments, the signal can include information about one or more wavelengths of the detected light. The signal can be analog or digital. If the signal is analog, they can then be converted into digital signals before or after transmission from the detector 200.

[0037] Advantageously, the image detected by the detector 200 of the present disclosure may be unfocused. The rate of motion (e.g., flow rate) may be determined from a global average of the detected speckle contrast rather than by mapping the detected speckle pattern to focused light scattering particles. Configuring the detector 200 to obtain a focused image may be expensive and spatially limited. A detector 200 configured to receive unfocused light may advantageously be smaller and may be more wearable by a user. Thus, the detector 200 may be configured to receive unfocused (i.e., non-converging) light. For example, the detector 200 may be configured to receive an original, unaltered light path that has not been altered by an optical element (such as a lens) that alters the path or direction of the incident light.

[0038] The disclosed method, system and apparatus may be particularly useful for LSI systems configured with a reflection geometry opposite to a transmission geometry. In the reflection geometry, the light source 100 and the detector 200 are positioned on the same side of the adjacent sample, while in the transmission geometry, they are positioned on the opposite side of the sample. Typically, the detector 200 located in the transmission geometry can detect at least a portion of any light transmitted through the sample rather than scattered. The detector 200 positioned in the reflection geometry can only detect the light reflected and / or scattered by the sample emitted from the light source 100. For large samples (such as certain areas of the body), the reflection geometry may be more suitable, where it is not feasible to position the detector 200 on the opposite side of the sample, for example, because the emitted light is too diffuse or most of it is absorbed to have no important information value. For samples with less clear geometry or with less clear sides (such as arms), if the detector 200 is in the reflection geometry (i.e., theoretically, any non-scattered transmission light from the light source 100 cannot be detected), then it can be considered that the detector 200 is positioned on the same side of the sample. In some cases, detector 200 can be positioned within a broad distribution of emitted light defined by a Gaussian distribution of laser light emitted by light source 100 , but can be positioned outside a narrower measure of the emitted light beam, such as a half-maximum full-width diverging intensity cone of light emitted by light source 100 .

[0039] The disclosed system may include a structure 300 that abuts (e.g., accommodates) a light source 100 and a detector 200 in a fixed (which may be adjustable) orientation that includes a predetermined separation distance. The light source 100, the detector 200, and the structure 300 may include an apparatus 400 for improved sample interrogation. In many embodiments, the apparatus 400 is configured to be coupled to a sample for providing improved interrogation. Other components of the system may also be integrated into the apparatus 400 (e.g., adjacent to the structure 300), including but not limited to processors, circuits, memories, displays, fixing mechanisms, and the like. Figure 1A-Figure 1D Compared with conventional LSI systems ( Figure 1A and Figure 1C ) and built-in LSI system ( Figure 1B and Figure 1D ), which positions the light source 100 and the detector 200 adjacent to the sample and at a fixed separation distance from each other, as described herein. The light source 100 has a numerical aperture that characterizes the angular range (i.e., the stereo projection angle) over which the light source 100 emits light, and the detector 200 has a numerical aperture that characterizes the angular range (i.e., the angle at which photons can enter the detector 200 or the stereo detection angle) over which the detector 200 can receive light. Figure 1A As shown, the numerical apertures of the light source 100 and the detector 200 overlap at the sample surface in a conventional LSI system so that the imaging surface is directly illuminated (i.e., the detector 200 images at least a portion of the illuminated area). Figure 1B As shown, structure 300 configures the light source 100 and the detector 200 of the built-in system so that the numerical apertures do not overlap on the sample surface and a portion of the sample is illuminated outside the imaging field (i.e., the light source 100 is configured to illuminate the illuminated area outside the imaging field of the detector 200). Figure 1C and Figure 1D Depicted are data collected from non-invasive interrogation of vascularized tissue using LSI. The measured waveforms are related to pulsatile blood flow derived from the cardiac cycle. The pulsations reflect changes in volumetric flow rate as the subject's heart pumps blood through the interrogated vasculature. Figure 1C An example of using flow index data generated by a conventional LSI system to interrogate blood flow is depicted, where both reflected light and scattered light are detected by detector 200 . Figure 1D An example of data of flow index generated using a built-in system is depicted, where the light source 100 and the detector 200 are configured to exclude reflected light from the detector 200. Multiple scattered light from within the sample is Figure 1D The more clearly defined signals depicted predominate, which, as described herein, produce a more pulsatile signal with a higher information content related to the flow of light scattering particles (eg, blood cells).

[0040] The structure 300 provides a means for orienting the numerical aperture of the light source 100 and the detector 200 to a desired configuration and maintaining a fixed configuration during detection. In some embodiments, the structure 300 can be coupled to the sample so that the configuration can be maintained relative to the sample even if the sample is in motion during detection. When maintained in a constant spatial orientation, the light source 100, the detector 200, and the sample remain separated by substantially the same distance, and the directions or axes of emission or detection of the light source 100 and the detector 200 remain oriented at substantially the same angle relative to the sample and relative to each other.

[0041] Structure 300 can include any structure that establishes the configuration of light source 100 and detector 200, which eliminates or prohibits specular or diffusely reflected photons (i.e., surface reflection) from entering the detection field of detector 200. Specular reflection refers to mirror-like reflection, which usually occurs on a smooth surface, where the angle of incidence to the surface normal is equal to the angle of reflection to the surface normal. Diffuse reflection refers to randomly oriented surface reflection that occurs on a rough surface (such as matte paint or paper). Photons that undergo diffuse reflection are scattered from the sample surface in random directions but do not penetrate into the sample. Specular reflection and diffuse reflection do not contain information about the amount of mobile light scattering particles in the sample, and therefore, it is desirable to avoid detecting such light so as not to dilute the amount of information of the detected light. Structure 300 that makes light source 100 and detector 200 adjacent and spatially oriented relative to each other and relative to the sample can be used to effectively prohibit the detection of specular reflection by detector 200.

[0042] In some embodiments, such a configuration that eliminates or inhibits detection of specular and / or diffuse reflections can be achieved, at least in part, by controlling the proximity of light source 100 and / or detector 200 to the sample surface, which can be effectively controlled by positioning structure 300 relative to the sample surface, such as Figure 2B shown. Figure 2A and 2B Conventional LSI system ( Figure 2A ) and interior system( Figure 2B ) were compared, in which the light source 100 and detector 200 of the built-in system are positioned closer to the sample surface than in the conventional system. Figure 2A The light source 100 and detector 200 in FIG. 1 are positioned close enough together and far enough from the sample surface that back-reflected light from the emission light of the light source 100, including specular reflections (shown) and diffuse reflections (not shown), can enter the detector 200 (i.e., the reflected light from the emission cone of the light source 100 is within the numerical aperture or detection field of the detector 200). In contrast, Figure 2B The light source 100 and the detector 200 in the structure 300 are positioned with a sufficient separation distance from each other and close enough to the sample surface that the specular reflection (shown) and diffuse reflection (not shown) of the emitted light from the light source 100 do not reach the detector 200 (i.e., the reflection is not within the numerical aperture of the detector 200 and is physically prohibited from entering the detector 200). Since the detector 200 may include a slit or hole (e.g., in the optical element 202) that limits the detection angle, the positioning of the detector 200 can be configured to exclude even diffusely reflected light that can reach the detector 200 structure from the detection angle. When the reflection propagates from the sample surface, the reflection may diverge at a certain angle. The structure 300 can place the detector 200 out of the range of reflected light by positioning the detector 200 closer to the sample surface (if the detector 200 is not positioned above the illuminated area) and / or further away from the light source 100. The detector 200 positioned closer to the sample surface may not need to be positioned as far from the light source 100 as the detector 200 positioned away from the sample surface to avoid detecting reflected light, and vice versa.

[0043] When the structure 300 is coupled to the sample, the structure 300 disclosed herein can be configured to space the light source 100 and the detector 200 apart from each other by a fixed distance and / or position the light source 100 and the detector 200 at a fixed distance away from the sample surface. For example, the structure 300 may include a device for adhering, coupling and / or fixing the light source 100 and the detector 200 to the sample so that each device is positioned at a set distance from the sample surface. For example, the structure 300 may include a wearable device 400, such as a wristband (e.g., a watch), which positions the light source 100 and the detector 200 substantially adjacent to the user's skin. The structure 300 can be configured to be substantially in direct contact with the sample surface when coupled, or can be configured to be retracted from the sample surface by a certain distance when coupled. When the structure 300 is positioned to be substantially in direct contact with the sample, it can also position the light source 100 and / or the detector 200 to be substantially in direct contact, depending on their orientation relative to the structure 300.

[0044] When the light emission axis of the light source 100 is perpendicular to the sample surface, as Figure 3 As shown, the light source 100 is positioned at a distance h from the sample surface and has a divergence angle θ, and the closest point of the detector 200 must be separated from the emission point by more than the following amount

[0045] d>2h tan(θ / 2)[2]

[0046] This is to prevent specular reflections from entering the detector 200 which is positioned at the same distance h from the sample. Figure 3 Schematically shown, the outermost specularly reflected photon will bounce back from the sample surface with a divergence angle θ relative to the incident path of the emitted light. At the normal distance h from the sample surface, the distance of the photon from the emission point of the emitted light is equal to 2htan (θ / 2). Therefore, the nearest point of the detector 200 that can receive photons (at any angle or at the angle of the outermost specularly reflected photons) must be separated from the emission point of the light source 100 by a minimum distance greater than 2htan (θ / 2) to avoid detecting specular reflection. This value can provide useful guiding parameters for configuring the adjacent structure 300 so that the light source 100 and the detector 200 are positioned with appropriate separation distances from each other along the sample surface. For other orientations of the light source 100 and the detector 200, suitable separation distances (such as, deviating from the emission position or positioning at a distance different from the surface) can be similarly calculated by analysis or experience.

[0047] Increasing the distance between the detector 200 and the light source 100 can also impart other advantages to the LSI system. For example, Monte Carlo simulations of the radiation transfer equation have shown that the average number of scattered events and the penetration depth of photons emitted by the light source and detected by the detector positioned in the reflection geometry increase with the increase of the separation distance between the light source 100 and the detector 200. In other words, the farther the light source 100 and the detector 200 are separated, the more likely the detector 200 is to capture photons that have penetrated further into the sample and scattered multiple times within the sample. Increasing the occurrence and deep penetration of multiple scattering within the dynamic region of the sample can provide a more accurate and robust signal, which can contain a higher amount of relevant information. For example, increasing the number of scattering events increases the probability that a photon will be scattered from a moving light scattering particle (rather than just a static light scattering particle), thereby increasing the amount of relevant information of the detected scattered light. Therefore, the disclosed methods, systems and devices can be used to generate a selection bias for photons that are scattered multiple times within a sample. Increasing the penetration depth in a sample such as a vascularized tissue can, for example, better target blood vessels beyond the epidermis (e.g., entering the tissue more than 0.5 mm). Based on these calculations, the separation distance between the light source 100 and the detector 200, as configured by the abutment structure 300, can be used to target a specific penetration depth within the sample. The light source 100 and the detector 200 can be configured with a larger separation distance to target deeper areas of the sample, and vice versa. In some applications, such as determining blood flow, the structure 300 can be configured to target and accurately resolve blood flow at a depth of 0.1 mm to 1 cm within a tissue sample.

[0048] In some embodiments, the structure 300 can be configured so that the separation distance between the light source 100 and the detector 200 is adjustable. For example, the light source 100 and the detector 200 can be movably positioned along a linear axis. The light source 100 and the detector 200 can be closer or farther away by moving one or the other or by moving both. Any suitable mechanical device can be used to displace the light source 100 and / or the detector 200. For example, they can be slidably coupled to the track. In another example, the structure 300 may include one or more threaded connections between the two sides of the structure 300, which can be screwed closer or farther. The separation distance can be adjusted by rotating a screw or a wheel. The movable element may include a locking mechanism for temporarily locking in a position, or they can be frictionally held in place without the force of deliberate adjustment. In some embodiments of the disclosed method, the sample can be interrogated at multiple penetration depths and / or the penetration depth can be adjusted until the desired signal is detected. The processor can be configured to estimate the interrogation depth based on the separation distance, and the separation distance can be based on a previous calibration.

[0049] Additional configurations may also be used to inhibit specular and diffuse reflections, such as placing an opaque separator 500 (e.g., an opaque sheet or block) between the detection and emission elements (i.e., the detector 200 and the light source 100), which blocks reflected photons from entering the detector 200. In such configurations, the light source 100 and the detector 200 may be placed sufficiently close to each other that the numerical apertures of the light source 100 and the detector 200 would normally overlap at the sample surface (i.e., the detector 200 would image the illuminated area), but are prevented from doing so by the opaque separator 500, which may be used to block incident rays of emitted light and / or specular or diffuse reflected light from passing through the opaque separator 500. Figure 4 The use of an opaque spacer 500 is shown, which blocks reflected light from reaching the detector 200. The opaque spacer 500 can be adjacent to the same structure 300 as the light source 100 and the detector 200. It can be configured to be removably / replaceable and / or selectively positioned between the light source 100 and the detector 200. It can have a height that extends substantially to the sample surface, such as Figure 4 In some embodiments, the structure 300 can be configured to couple to a variety of different dividers 500 in different configurations and / or can be configured to receive or accommodate a plurality of dividers 500 .

[0050] In some embodiments, the opaque housing divider 502 can position an aperture 504 in front of the detector 200 as described elsewhere herein or similar to those described elsewhere, where the acceptance angle of the aperture 504 prevents light from the illuminated area 506 from entering the detector 200 . Figure 5 An example of a hole 504 formed in an opaque divider 502 (opaque housing) and positioned below the detector 200 is shown. This construction prevents photons from leaving the illuminated area 506 and entering the detector 200. In this embodiment, photons entering the detector 200 must first pass through a narrow limiting hole 504 positioned in front of the detector 200 by the opaque housing 502. The hole 504 is used to geometrically limit the possible angles of approach from the sample. The hole 504 is configured to limit the detection angle of the detector 200 so that even at the steepest angle reflected from the edge of the illuminated area as shown, no photon reflected from the illuminated area 506 can enter the hole 504 at an angle that geometrically allows it to reach the detector 200. Any photon line originating from the illuminated area 506 and passing through the hole 504 will not be able to enter the detector 200. The opaque housing divider 502 can be an external component coupled to a standard detector. The opaque housing divider 502 may have a different configuration (eg, size) than a standard aperture (eg, lens aperture) found on many standard detectors in order to prevent detection of reflected light from the light source 100 .

[0051] Similar to reflected light, a large amount of ballistic light (i.e., non-scattered light and non-reflected light) is also undesirable for detection by detector 200. In the same way that reflected light does not interact with dynamic light scatterers, ballistic photons can pass directly through the translucent sample without scattering at all. Therefore, ballistic photons interfere with the accuracy of the measurement and dilute the information content of the detected light, thereby reducing the signal-to-noise ratio.

[0052] Various embodiments include a structure 300 configuration that controls the angular orientation and lateral positioning of the emission pattern of the light source 100 relative to the detector 200 and the sample. Some embodiments can avoid aiming a majority of the light source 100 intensity directly at the detector 200 to avoid over-detection of ballistic photons. Deviation of the emission pattern from the detector 200 effectively minimizes the detected ballistic photons. Typically, a laser output beam pattern has a Gaussian shape with a peak emission intensity located at the center of the emitter. Thus, the angle and orientation of the peak emission axis can be configured to avoid direct incidence on the center of a detection surface (e.g., a photosensitive pixel array) of the detector 200. In some embodiments, the peak emission axis can be configured to avoid direct incidence on the detection surface entirely.

[0053] Fixing the light source 100 and detector 200 to the structure 300 can ensure that all three key elements (light source 100, detector 200 and sample) remain rigidly aligned even during movement of the sample. This can subsequently reduce motion artifacts and provide consistent illumination intensity. The light source 100 and detector 200 can be permanently / immovably adhered to the structure. Permanently configuring the light source 100 and detector 200 in the housing allows for consistent interrogation depth between the system and the sample. This concept is as Figure 6 shown. Figure 6 An embodiment of a device 400 as described herein is shown, which includes a light source 100 (e.g., a diode laser) and a detector 200 (e.g., a CMOS image sensor) adhered to a housing structure 300. The components can be miniaturized relative to conventional LSI components so as to be incorporated into a miniaturized device 400. The housing structure 300 can be substantially rigid at least when it is adjacent to the light source 100 and the detector 200 so as to maintain a constant spatial configuration. The housing structure 300 includes or is coupled to a flexible ribbon so that the housing structure takes the form of a wristband in this particular example. When worn by a user, the wristband can be configured to position the light source 100 and the detector 200 substantially adjacent to the user's skin so that the emission numerical aperture of the light source 100 and the detection numerical aperture of the detector 200 are directed toward the user's skin. The ribbon can be adjustable so that it can position the light source 100 and the detector 200 substantially adjacent to the user's skin regardless of size differences between users. In some cases, the wristband can be configured to apply sufficiently tight pressure to place light source 100 and detector 200 in substantially direct contact with the user's skin.

[0054] The structure 300 adjacent to the light source 100 and the detector 200 may include other forms suitable for coupling the light source 100 and the detector 200 to the sample and positioning them relative to the sample surface (such as the skin of the user) in an operating configuration (e.g., a configuration that prohibits detection of specular reflection and / or diffuse reflection). For example, the structure 300 may be coupled to the sample surface via an adhesive. The adhesive may be applied to the sample and / or the structure 300 before operation. In some embodiments, the structure 300 may include an adhesive layer that is configured to fix the structure 300 to the sample surface. The structure may be in the form of a patch (e.g., a relatively flat sheet) having an adhesive layer fixed to the sample surface (e.g., skin). The light source 100 and the detector 200 may be integrated into the patch so that they are spatially configured to be separated at an appropriate distance and their numerical apertures are appropriately directed to the sample. The patch may be particularly suitable for devices configured to be coupled to irregular or curved geometric structures (e.g., on the torso of the user). In some embodiments, structure 300 can be coupled to the sample by a friction engagement device. For example, structure 300 can include a securing mechanism such as a spring-loaded clip (e.g., for clamping to a user's clothing so that structure 300 is positioned adjacent to the skin or clipped to a user's finger), a strap (e.g., for securing the structure adjacent to the user's waist), or a cord (e.g., for securing the structure to an accessory around which the cord is frictionally secured).

[0055] The disclosed embodiments also contemplate transmitting the detector 200 data to a processor, and subsequently processing the data to obtain a spatial and / or temporal contrast measure. The detector 200 signal can be manipulated with advanced digital signal processing circuitry, which can be placed on the same structure 300 as the light source 100 and the detector 200 in a non-limiting manner. Once converted into a digital signal, the signal can be manipulated without signal quality degradation. The digital signal can also be conveniently stored in a memory, and / or sent via a wireless electromagnetic carrier band (such as Bluetooth). The processor can be part of a single device 400 having a light source 100 and a detector 200, and can be adjacent to the structure 300 (such as a housing). In other embodiments, the processor can be outside the device 400, although the processing circuit can be incorporated into the device 400. Some embodiments can incorporate multiple processors, which can all be incorporated into the device 400, all outside the device 400, or distributed between the device 400 and external components. Data can be transmitted between the detector 200 and the processor by any suitable means. For example, the data may be transmitted wirelessly, via a wire or cable (such as a USB cable), downloaded to a portable memory drive, etc. Once the data has been transferred to the processing element, a contrast metric is calculated. A non-limiting example of a contrast metric is specified in Equation 1. Other contrast metrics may also be used, where contrast is generally defined as any measure of the difference, difference, or distinction between the values ​​of multiple pixel elements of a detector, and / or the evolution of a single pixel element over time. Non-limiting examples include statistical properties of spatial or temporal contrast, such as the speckle flow index (defined as 1 / K 2 , where K is speckle contrast as described herein), standard deviation from the mean, median, difference measures such as average percent difference (e.g., between pixels of detector 200), potential well filling time difference, gradient between pixels, measures of comparison (e.g., difference) between sub-regions, magnitude of fluctuations in pixel intensity over time, reduction of pixels to local binary or local ternary patterns, etc. Autocorrelation performed on the signal generated by a single pixel over a period of time can quantify the temporal decorrelation in the detected light intensity due to the motion of mobile light scattering particles.

[0056] In some embodiments, the system may include a display, which may be integrated into the device 400 (e.g., coupled to the structure 300 along with the light source 100 and the detector 200) and / or the processor (e.g., if the processor is external to the device 400, it may be part of a general purpose computer, tablet, smart phone, etc.), or may be a separate component. The display may be used to display, for example, operating parameters and / or data to a user. In some cases, the display may be used to display an image of the speckle pattern detected by the detector 200 and / or may be used to display a numerical or graphical representation of speckle contrast (e.g., a contrast metric), a measured rate of movement (e.g., flow rate), penetration depth (e.g., targeted or average depth), any metric derived therefrom, etc. The display may be coupled to an input mechanism (e.g., a keyboard or mouse on a computer or one or more buttons on the device) that may allow a user to switch between displayed information and / or enter or select input parameters for affecting calculations. The system may include interactive software that allows a user to interact with the processor.

[0057] The features disclosed above can produce more commercialized devices with applications, including but not limited to healthcare and wearable technology. For example, the system can be miniaturized using ultra-compact CMOS sensors and VCSELs. Digital processing circuits can be fixed on the system to perform specific calculations necessary for determining contrast and / or motion (e.g., flow). The system can then be integrated into a wearable wrist monitor to perform blood flow monitoring or heart rate monitoring. In another example, the system can be miniaturized and placed on a medical device designed to monitor vascular health. In this example, the medical device can be adhered to a tissue of interest to a clinician, and the disclosed system and method can be used to measure the flow of red blood cells in the tissue. Specifically, the medical device can be adhered to a patient's foot, for example, to quantify blood flow in the tissue using the disclosed system and method. In such tissues (and other tissues), blood circulation is required to deliver oxygen and remove cell waste. Therefore, a minimum amount of blood flow is required to maintain sustained tissue viability so that nutrient delivery is sufficient to meet metabolic tissue needs. Thus, the disclosed systems and methods can be used to measure blood flow (circulation) in tissue to determine whether the measured amount is consistent with continued tissue viability and, therefore, to assess the adequacy of blood circulation. The processor can be programmed to compare the measured blood flow (circulation) to a predetermined value and determine whether blood circulation is adequate.

[0058] Operation Example

[0059] Fig. 7A and Figure 7B The use of photoplethysmography (PPG), the current standard technology for optical heart rate monitoring, was compared Fig. 7A ) and as measured from a housing structure 300 coupled to a wrist for optical heart rate monitoring according to the disclosed methods, systems, and apparatus (e.g., Figure 2B ) LSI Applications ( Figure 7B ). This example illustrates that flow measurements from the disclosed LSI system are unexpectedly superior to PPG for determining heart rate because the amplitude of the pulsatile signal is several orders of magnitude greater than that of PPG. Fig. 7A As shown, the pulsatile signal originating from the changes in absorption of the emitted light in the artery due to the periodic volume expansion accounts for about 2% of the signal, while about 98% of the signal is non-pulsatile and originates from the absorption of light emitted by the skin, veins and other tissues. Figure 7B As shown, approximately 50% of the signal originates from pulsatile flow, while approximately 50% of the signal originates from non-pulsatile flow. The periodicity of the flow originates from the cardiac cycle, and can be used to determine the heart rate by determining the period between consecutive waveform features, such as systolic contraction peaks.

[0060] Although the present invention has been described in general and detailed form with respect to specific embodiments and applications, these descriptions are not intended to limit the scope thereof in any way to any such embodiments and applications, and it will be understood that many substitutions, variations and changes in the described embodiments, applications and details of the methods and systems shown herein and their operations may be made by those skilled in the art without departing from the spirit of the present invention.

Claims

1. A system for determining a migration rate of a plurality of light scattering particles within a sample, the system comprising: a light source configured to emit at least partially coherent light toward the plurality of light scattering particles; a light-sensitive detector comprising one or more pixels and configured to detect light scattered off of at least some of the plurality of light-scattering particles; a structure adjacent the light source and the detector for operably positioning the light source and the detector adjacent the sample, wherein the structure is configured to position the light source and the detector relative to each other and the sample such that surface reflections from the sample are not detected by the detector and such that at least some of the emitted light scattered off at least some of the plurality of light scattering particles is detected by the detector, wherein the surface reflections include both specular reflections and diffuse reflections from a region of the sample illuminated by the light source; and a processor operably coupled to the detector, the processor being programmed to: deriving a contrast metric by temporally and / or spatially comparing the light detected by the one or more pixels, and relating the contrast metric to a rate of movement of the light scattering particles within the sample, wherein the structure is in the form of a patch configured to be applied to a skin surface of a user; wherein the at least partially coherent light is emitted from the light source at a known projection angle θ along a light emission axis substantially perpendicular to the surface of the sample at a distance h from the surface normal of the sample, wherein h is greater than 0; wherein the light source and the detector are separated along the same surface by a separation distance greater than 2htan(θ / 2); wherein the plurality of light scattering particles include blood cells; and The system is configured to measure blood flow.

2. The system of claim 1, wherein the processor is physically adjacent to the structure.

3. The system of claim 1, wherein the processor is not physically adjacent to the structure.

4. The system of any one of claims 1 to 3, wherein the processor is configured to wirelessly receive data from the detector.

5. The system of any one of claims 1 to 3, wherein the structure is configured to maintain the light source, the detector, and the sample in a constant spatial relationship during detection.

6. The system of any one of claims 1 to 3, wherein the contrast metric is selected from: standard deviation from the mean, median, percentage difference, potential well fill time difference, gradient between pixels, and difference between pixels or pixel sub-regions.

7. The system of claim 1, wherein the processor is further programmed to determine blood circulation adequacy based on the measured blood flow.

8. The system of any one of claims 1 to 3, wherein the structure comprises a housing containing the light source and the detector.

9. The system of claim 8, wherein the housing contains the processor.

10. The system of any one of claims 1 to 3, wherein: The light source and the detector are positioned at substantially the same normal distance h from the surface of the sample, where h is greater than zero.

11. The system of any one of claims 1 to 3, wherein the structure further comprises an adhesive material for adhering the structure to a surface of the sample.

12. The system of any one of claims 1 to 3, wherein the structure is configured to couple to the sample by friction.

13. The system of any one of claims 1 to 3, wherein the structure further comprises a securing mechanism for securing the structure to a surface adjacent to the sample during detection.

14. The system of claim 13, wherein the securing mechanism is selected from the group consisting of: a spring loaded clip, a strap, and a rope.

15. The system of any one of claims 1 to 3, wherein the structure is configured to adhere to an area of ​​skin of a user.

16. The system of any one of claims 1 to 3, wherein the structure is configured to be worn by a user.

17. A system as claimed in any one of claims 1 to 3, wherein the structure is in the form of a wristband.

18. The system of any one of claims 1 to 3, wherein the system is configured to measure the migration rate at a depth of 1 mm to 1 cm in the sample.

19. The system of any one of claims 1 to 3, wherein the detector is selectively spaced apart from the light source by a separation distance that allows the detector to target light scattered from a selected depth in the sample for interrogation.

20. The system of any one of claims 1 to 3, wherein a separation distance between the light source and the detector is adjustable.

21. The system of any one of claims 1 to 3, wherein the detector is a CMOS or CCD sensor.

22. The system of any one of claims 1 to 3, wherein the light source is a laser.

23. The system of any one of claims 1 to 3, wherein the light emitted by the light source is in the near infrared spectrum.

24. The system of claim 23, wherein the light emitted by the light source is between 700 nm and 900 nm.

25. The system of any one of claims 1 to 3, wherein the system is configured to place the structure in substantially direct contact with a surface of the sample.

26. The system of any one of claims 1 to 3, further comprising a display for displaying an image of the detected speckle pattern, or for displaying a numerical or graphical representation of speckle contrast, movement rate, penetration depth, or another metric derived therefrom.

27. The system of claim 26, wherein the display is adjacent to the structure.

28. The system of any one of claims 1 to 3, wherein the detector is configured to receive unfocused light.

29. The system of any one of claims 1 to 3, wherein the detector is configured to receive a light path that is not altered by an optical element that alters the path or direction of incident light.

30. The system of claim 29, wherein the detector is configured to receive a light path that is not altered by a lens.

31. A system as described in any one of claims 1 to 3, wherein the structure further includes an opaque separator, which is configured to limit the numerical aperture of the light source and / or the detector so that the numerical apertures of the light source and the detector do not overlap on the surface of the sample.

32. The system of claim 31, wherein the opaque separator is an opaque sheet or block positioned between the light source and the detector.

33. The system of claim 31, wherein the opaque separator is an opaque housing operably positioned in front of the detector, the opaque housing including an aperture for limiting a detection angle of the detector.

34. The system of any one of claims 1 to 3, wherein the structure is rigid along a portion between the light source and the detector.

35. A system as described in any of claims 1 to 3, wherein the one or more pixels of the detector include a detection area having a center, and wherein the structure is configured such that a peak emission axis of the light source is not substantially aligned or substantially aligned with the center of the detection area.

36. The system of claim 35, wherein the structure is configured such that the peak emission axis is not substantially aligned or substantially aligned with any portion of the detection region.

37. A method for determining a migration rate of a plurality of light scattering particles within a sample, the method comprising: positioning a structure adjacent to a surface of the sample, the structure being adjacent to a light source configured to emit at least partially coherent light and a light-sensitive detector comprising one or more light-sensitive pixels, wherein the positioning places the light source at a first location adjacent to the sample, the structure being configured to orient the light source relative to the sample at the first location such that at least a portion of the sample is within an emission numerical aperture of the light source, wherein a cone of light emitted by the light source and defined by the full width at half maximum divergent intensity of the emitted light defines an illuminated area on the surface of the sample, and wherein the positioning further places the detector at a second location adjacent to the sample, the structure being configured to orient the detector relative to the sample at the second location such that at least a portion of the sample is within an acceptance numerical aperture of the detector and such that light directed from or through the illuminated region is inhibited from entering the detector and reaching the photosensitive pixels, activating the light source so that the light is directed toward the light scattering particles; using the detector to detect light emitted from the light source and scattered by at least some of the light scattering particles; transmitting a signal related to the detected light from the detector to a processor; comparing in time and / or space the light detected by the one or more pixels; Based on the comparison, deriving a contrast metric; and relating the contrast metric to the rate of movement of the light scattering particles, wherein the structure is in the form of a patch, and positioning the structure comprises applying the patch to the skin of a user; wherein the at least partially coherent light is emitted from the light source at a known projection angle θ along a light emission axis substantially perpendicular to the surface of the sample at a distance h from the surface normal of the sample, wherein h is greater than 0; wherein the light source and the detector are separated along the same surface by a separation distance greater than 2htan(θ / 2); wherein the light scattering particles include blood cells; wherein the method further comprises correlating the rate of movement of the light scattering particles to blood flow; and The structure is configured to be worn by a user.

38. The method of claim 37, wherein positioning the structure comprises coupling the structure to the sample.

39. The method of claim 38, wherein the structure is coupled to the sample by an adhesive material.

40. The method of claim 37, wherein: The light source and the detector are positioned at substantially the same normal distance h from the surface of the sample, where h is greater than zero.

41. The method of claim 38, wherein the structure is frictionally coupled to the sample.

42. The method of claim 41, wherein frictionally coupling the structure comprises applying a rope, a strap, or a spring loaded clamp to the sample.

43. A method as claimed in any one of claims 37 to 42, wherein the structure is rigid along a portion between the light source and the detector.

44. The method of any one of claims 37 to 42, further comprising adjusting a separation distance between the light source and the detector along the structure.

45. A method as claimed in any one of claims 37 to 42, wherein the structure is in the form of a wristband.

46. ​​The method of any one of claims 37 to 42, wherein the structure is proximally coupled to the user's skin.

47. The method of any one of claims 37 to 42, wherein the detector is a CMOS or CCD sensor.

48. A method as claimed in any one of claims 37 to 42, wherein the light source is a laser.

49. The method of any one of claims 37 to 42, wherein the light emitted by the light source is in the near infrared spectrum.

50. The method of claim 49, wherein the light emitted by the light source is between 700 nm and 900 nm.

51. The method of any one of claims 37 to 42, wherein positioning the structure comprises placing the structure in substantially direct contact with a surface of the sample.

52. The method of any one of claims 37 to 42, wherein positioning the structure comprises placing the light source in substantially direct contact with a surface of the sample and placing the detector in substantially direct contact with a surface of the sample.

53. A method as claimed in any one of claims 37 to 42, further comprising displaying an image of the detected speckle pattern, or displaying a digital or graphical representation of speckle contrast, movement rate, penetration depth or another metric derived therefrom.

54. The method of any one of claims 37 to 42, wherein the detector is configured to receive unfocused light.

55. The method of any one of claims 37 to 42, wherein the detector is configured to receive a light path that is not altered by an optical element that alters the path or direction of incident light.

56. The method of claim 55, wherein the detector is configured to receive a light path that is not altered by a lens.

57. A method as described in any one of claims 37 to 42, further comprising positioning an opaque separator before, after or simultaneously with the positioning of the detector, wherein the opaque separator is configured to limit the numerical aperture of the light source and / or the detector so that the numerical apertures of the light source and the detector do not overlap each other on the surface of the sample.

58. The method of claim 57, wherein the opaque separator is an opaque sheet or block positioned at a third location between the first location and the second location.

59. The method of claim 57, wherein the opaque separator is an opaque housing operably positioned in front of the detector, the opaque housing including an aperture for limiting a detection angle of the detector.

60. The method of any one of claims 37 to 42, further comprising: selecting a depth within the sample for interrogation of targeted scattered light; and determining a separation distance between the light source and the detector configured to target a selected depth, wherein the first site and the second site are separated by a determined separation distance.

61. The method of any one of claims 37 to 42, wherein detecting light using the detector comprises detecting light emitted from the light source and scattered by at least some light scattering particles at a first depth within the sample, the method further comprising: adjusting a separation distance between the light source and the detector along the structure, and The detector is used to detect light emitted from the light source and scattered by at least some of the light scattering particles at a second depth within the sample.

62. The method of any one of claims 37 to 42, wherein the transmission signal comprises a wireless transmission signal.

63. The method of any one of claims 37 to 42, further comprising maintaining the light source, the detector, and the sample in a constant spatial relationship during detection.

64. A method as described in any of claims 37 to 42, wherein the contrast metric is selected from: standard deviation from the mean, median, percentage difference, potential well filling time difference, gradient between pixels and difference between pixels or pixel sub-regions.

65. The method of any one of claims 37 to 42, wherein detecting light using the detector comprises detecting light emitted from the light source and scattered by at least some light scattering particles at a depth of 1 mm to 1 cm within the sample.

66. A method as described in any one of claims 37 to 42, wherein one or more pixels of the detector include a detection area having a center, and wherein the structure is configured such that the peak emission axis of the light source is not substantially aligned or substantially aligned with the center of the detection area.

67. A method as claimed in claim 66, wherein the structure is configured such that the peak emission axis is not substantially aligned or substantially aligned with any portion of the detection area.

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