Noninvasive device and method for detecting blood cells

Abstract

A method for detecting and counting RBCs in the bloodstream noninvasively is disclosed. The noninvasive method of detecting blood cells comprises: illuminating a tissue containing a superficial blood vessel, at one or more discrete locations, with at least one intensity modulated optical beam focused into the superficial blood vessel in the tissue having a focal width of equal to or less than 30 pm; receiving at least one ultrasound signal from at least one ultrasound detector, positioned at a lateral offset from a focal point of the intensity modulated optical beam focused into the superficial blood vessel; and detecting acoustic emission patterns related to blood cells in the at least one received ultrasound signal.

Description

NONINVASIVE DEVICE AND METHOD FOR DETECTING BLOOD CELLSFIELD OF THE INVENTION

[0001] The present invention relates generally to methods of detecting blood cells. More specifically, the present invention relates to a noninvasive device and method of detecting blood cells using an ultrasound detector.BACKGROUND OF THE INVENTION

[0002] Detecting and counting red blood cells (RBCs) is one of the most common tests conducted blood testing. Usually, the detection and counting of RBCs is the laboratory done to blood samples, using known methods such as imaging techniques, automated hematology analyzer (e.g., using electrical impedance and light scattering) and the like.

[0003] Some method for noninvasive racking of single RBCs in the blood stream, relied on a coaxial configuration in which an optical beam and an acoustic detector, based on piezoelectric technology, were focused on the same small area to maximize sensitivity, allowing for the detection of a single RBC during the short time it passes through the optical beam, but resulting in a bulky setup and the need to scan the transducer (or at least the acoustic path) together with the illumination to maintain the co-axial operation. This method requires expensive scanning equipment.

[0004] Therefore, there is no simple method for detecting and counting RBCs in the bloodstream noninvasively.SUMMARY OF THE INVENTION

[0005] Some aspects of the invention are aimed at providing a reliable method for detecting and counting RBCs in the bloodstream noninvasively. A miniature ultrasound (US) detector may be attached to the surface of an accessible organ (skin, oral mucosa, etc.) of the examinee, in the vicinity of a blood vessel. The blood vessel may be illuminated with an intensity modulated optical beam having a focal width of equal to or less than 50 pm. In some embodiments, RBCs passing through the beam may create an acoustic wave via the optoacoustic effect that is sufficiently strong to be detected by the ultrasound detector.

[0006] Embodiment of the invention may be directed to a noninvasive method of detecting blood cells, comprising: illuminating a tissue containing a superficial blood vessel, at one or more discrete locations on the superficial blood vessel, with at least one intensity modulatedoptical beam focused into the superficial blood vessel in the tissue having a focal width of equal to or less than 50 pm; receiving at least one ultrasound signal from at least one ultrasound detector, positioned at a lateral offset from a focal point of the intensity modulated optical beam focused into the superficial blood vessel; and detecting acoustic emission patterns related to blood cells in the at least one received ultrasound signal.

[0007] In some embodiments, the number of discrete locations on the same superficial blood vessel is less than 10. In some embodiments, the at least one ultrasound detector has, in one dimension, an acceptance angle larger than or equal to 20 degrees. In some embodiments, the one dimension is selected from, a width of an optical mode guided in the waveguide, and a width of the waveguide core of the at least one ultrasound detector. In some embodiments, the width of the optical mode, or the waveguide core is smaller or equal to 50 pm.

[0008] In some embodiments, the at least one ultrasound detector has at least one other dimension larger than 0.5 mm. In some embodiments, the at least one other dimension is selected from, a length of the localized resonance mode, a length of the waveguide core, a distance between two adjacent folding of a folded waveguide core, and a distance between two distant folding of the folded waveguide core.

[0009] In some embodiments, the lateral offset from the intensity modulated optical beam is between 0.005-30 mm. In some embodiments, the superficial blood vessel is located at most 2 mm below a surface of the tissue. In some embodiments, the focal width of the intensity modulated optical beam is less than 10 pm, optionally less than 5 pm. In some embodiments, the acceptance angle is smaller than or equal to 180 degrees.

[0010] In some embodiments, the method may further comprise counting acoustic pulse generated by blood cells passing through the focal point of the intensity modulated optical beam.

[0011] In some embodiments, the blood cells are red blood cells. In some embodiments, the ultrasound detector is placed on the tissue.

[0012] In some embodiments, the method may further comprise scanning the tissue with the intensity modulated optical beam to detect the blood vessel, and wherein illuminating the tissue is from a stationary position above the blood vessel.

[0013] In some embodiments, the ultrasound detector comprises a waveguide having a core with a large refractive index (>1.7). In some embodiments, the waveguide has a dimension at least one of: a width of the an optical mode guided in the waveguide, a length of thelocalized resonance mode, a width and a length of the waveguide is equal to or smaller than 50 |im. In some embodiments, illuminating the tissue comprises illuminating using a plurality of optical beams each being focused on a different location at the tissue.

[0014] In some embodiments, receiving at least one ultrasound signal, comprises receiving a plurality of ultrasound signals from a plurality of ultrasound detectors, each positioned at a lateral offset from the at least one beam. In some embodiments, each ultrasound detector of the plurality is positioned at a lateral offset from a corresponding beam.

[0015] In some embodiments, illuminating the tissue comprises placing a transparent plate on the tissue, wherein the plate is transparent in the wavelength of the at least one optical beam. In some embodiments, the at least one ultrasound detector is attached to the transparent plate. In some embodiments, the intensity modulated optical beam is pulsed. In some embodiments, each pulse is equal to or shorter than 100 ns. In some embodiments, a Rayleigh length of the intensity modulated optical beam is equal to or shorter than 50 pm, optionally shorter than 30 pm, optionally shorter than 10 pm.

[0016] Some additional aspect of the invention may be directed to a system for detecting blood cells, comprising: at least one light source configured to emit at least one intensity modulated optical beam; an optical unit configured to focus the optical beam, at one or more discrete locations on the superficial blood vessel, to a focal width of less than 50 pm; at least one ultrasound detector, positioned a focal point of the intensity modulated optical beam focused into the superficial blood vessel; and a controller configured to: control the at least one light source to emit the at least one intensity modulated optical beam; receive at least one ultrasound signal from the at least one ultrasound detector; and detect acoustic emission patterns related to blood cells in the received at least one ultrasound signal.

[0017] In some embodiments, the number of discrete locations on the same superficial blood vessel is less than 10. In some embodiments, the at least one ultrasound detector has, in one dimension, an acceptance angle larger than or equal to 20 degrees. In some embodiments, the one dimension is selected from, a width of the an optical mode guided in the waveguide, and a width of the waveguide core of the at least one ultrasound detector. In some embodiments, the width of the optical mode guided in the waveguide or the waveguide core is smaller or equal to 50 pm.

[0018] In some embodiments, the at least one ultrasound detector has at least one other dimension larger than 0.5 mm. In some embodiments, the at least one other dimension isselected from, a length of the localized resonance mode, a length of the waveguide core, a distance between two adjacent folding of a folded waveguide core, and a distance between two distant folding of the folded waveguide core.

[0019] In some embodiments, the lateral offset from the intensity modulated optical beam is between 0.005-30 mm.

[0020] In some embodiments, the focal width of the at least one intensity modulated optical beam is less than 10 pm, optionally less than 5 pm. In some embodiments, the ultrasound detector comprises a waveguide having a core with a large refractive index (>1.7). In some embodiments, the waveguide has at least one of the length and a width equal to or smaller than 50 pm.

[0021] In some embodiments, the system may include a plurality of light sources configured to generate a plurality of intensity modulated optical beams each being focused in a different location. In some embodiments, the system may include a plurality of ultrasound detectors, each positioned at a lateral offset from the at least one intensity modulated optical beam, the system may include each ultrasound detector of the plurality is positioned at a lateral offset from a corresponding intensity modulated optical beam.

[0022] In some embodiments, the system may further include a transparent plate and wherein the plate is transparent in the wavelength of the intensity modulated optical beam. In some embodiments, the ultrasound detector is attached to the transparent plate, the system may include.

[0023] In some embodiments, the intensity modulated optical beam is pulsed. In some embodiments, each pulse is equal to or shorter than 100 ns. In some embodiments, a Rayleigh length of the intensity modulated optical beam is equal to or shorter than 50 pm, optionally shorter than 30 pm, optionally shorter than 10 pm.BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which:

[0025] Figs. 1A-1E are a cross section and 3 top views of a waveguide for an ultrasound detector according to some embodiments of the invention;

[0026] Figs. 2A-2B are illustrations of a cross section of system for detecting blood cells attached to a tissue and an enlargement of the ultrasound detector section in the system according to some embodiments of the invention;

[0027] Fig. 2C is an illustration of a cross section of another system for detecting blood cells attached to a tissue according to some embodiments of the invention;

[0028] Fig. 2D is an illustration of a top view of the system of Figs. 2A-2B according to some embodiments of the invention;

[0029] Fig. 2E is an illustration of a top view of the system of Fig. 2C according to some embodiments of the invention;

[0030] Fig. 2F is a block diagram of a system for detecting blood cells according to some embodiments of the invention;

[0031] Fig. 3 is a flowchart of a method of detecting blood cells according to some embodiments of the invention; and

[0032] Fig. 4 is a block diagram, depicting a computing device which may be included in a system for detecting blood cells according to some embodiments of the invention.

[0033] It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements.DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0034] One skilled in the art will realize the invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting of the invention described herein. Scope of the invention is thus indicated by the appended claims, rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

[0035] Unless explicitly stated, the method embodiments described herein are not constrained to a particular order or sequence. Additionally, some of the described method embodiments or elements thereof can occur or be performed simultaneously, at the same point in time, or concurrently.

[0036] Embodiments of the invention may be directed to a method and a system for noninvasive detecting a counting blood cells (e.g., RBC) inside the blood stream. In some embodiments, the method may include illuminating a tissue containing a superficial blood vessel (e.g., capillary, arterioles and venules) in the tissue (e.g., at a depth < 2 mm) with an intensity-modulated optical beam (pulsed, chirped, etc.). The intensity-modulated optical beam may be tightly focused into the superficial blood vessel causing each cell passing through the beam to create an acoustic wave via the optoacoustic effect. The acoustic wave may be detected by a miniaturized ultrasound detector with a large acceptance angle positioned at a lateral offset from the beam.

[0037] Reference is now made to Figs. 1A-1D which are a cross section and 3 top views of a waveguide for an ultrasound detector according to some embodiments of the invention. In some embodiments, an optical acoustic sensor 50 may include a waveguide 20. In some embodiments, in order to achieve semi-isotropic sensing with sufficient sensitivity to detect RBCs off-axis in short durations, (as discussed herein below) detector 50 may be based on a waveguide produced in a core with a large refractive index (>1.7), such as silicon nitride or silicon, that enables miniaturizing the detector to small dimensions (<50 pm, <30 pm, <20 pm) to enable semi-isotropic sensitivity of high-frequency ultrasound (>20 MHz). In some embodiments, the dimension is selected from, a width of the an optical mode guided in the waveguide, and a width of the waveguide core of the at least one ultrasound detector.

[0038] In some embodiments, the strength of the optoacoustic signal may be proportional to the square of the acoustic bandwidth, and the size of the detector (e.g., width and length, as discussed herein below) is inversely proportional to the maximum frequency that may be detected at a given angle. Thus in a nonlimiting example, a 30 pm waveguide may detect a signal 4 times stronger than a 60 pm waveguide, facilitating the ability to detect a single RBC in a short time. To further increase the sensitivity of the detector, the core may be coated with a transparent polymer top cladding with a high photo-elastic coefficient that is higher than that of the core. In most cases, this will also mean that the bulk and young modulus of the polymer cladding are lower than that of the core.

[0039] Waveguide 20 is shown as having a silicon or SiN waveguide core 202 that is embedded in an over-cladding 204 comprising a transparent polymer, in accordance with some applications of the present invention.

[0040] In some nonlimiting examples, waveguide 20 comprises a waveguide core 202 comprising silicon or SiN and an over-cladding 204 comprising Benzocyclobutene (BCB) or Poly dimethylsiloxane (PDMS). It is noted that the silicon or SiN waveguide core and / or the BCB / PDMS over-cladding are shown by way of illustration and not limitation. Waveguide core 202 may comprise any other optical material characterized by a relatively high refractive index and a relatively low photo-elastic coefficient. Similarly, over-cladding 204 may comprise any other suitable transparent polymer. Optionally but not necessarily, waveguide 20 additionally comprises a silica under-cladding 206 which is typically a substrate on which the waveguide core is fabricated. Optionally but not necessarily, waveguide 20 comprises an additional silicon substrate 208.

[0041] Waveguide core 202 of waveguide 20 is typically characterized by a high refractive index and a low photo-elastic coefficient, and over-cladding 204 is typically characterized by a low refractive index, a high photo-elastic coefficient, and a Young Modulus of under 10 (E) GPa, e.g., under 5 GPa.

[0042] In particular, the refractive index of waveguide core 202 is greater than the refractive index of over-cladding 204, and the photo-elastic coefficient of over-cladding 204 is greater (e.g., 4 times greater) than the photo-elastic coefficient of waveguide core 202. The following Table 1 shows optical, mechanical, acoustical, and photo-elastic properties of Silicon (Si), Silica (SiO2), and Benzocyclobutene (BCB):

[0043]

[0044] In some embodiments, ultrasound detector 50 may further include a light source (not illustrated), e.g., a laser, is coupled to optical waveguide 20 and a reference optical signal (not illustrated) from the laser interferes with the signal emanating from the waveguide.

[0045] Some nonlimiting examples for optional geometries of waveguide core 202 are given in Figs. 1B-1D. In some embodiments, waveguides 20a, 20b and 20c may include a waveguide having a core 202 with a large refractive index (> 1.7), for example, Si or SiN. In some embodiments, the waveguide has a dimension at least one of : a width of an optical mode guided in the waveguide, a length of the localized resonance mode, a width and a length of the waveguide is equal to or smaller than 30 pm. For example, waveguide 20a may include an optical micro-ring waveguide core 202a. Core 202a may include Si or SiN and may be coated with over-cladding 204, discussed herein above. The micro- ring waveguide may include a set of waveguide cores 202a in which at least one is a closed loop coupled to some sort of light input and output. In some embodiments, the closed loop can be a circle, an ellipsoid and the like. Therefore, the dimension that is smaller than 50 pm may be the radial length al or the radial length a2 illustrated.

[0046] In additional examples, waveguides 20b and 20c, may include 2 Bragg gratings with a spacer in between, leading to an optical resonance. The spacer may correspond to a pi shift in the phase in a configuration known a pi-phase- shifted Bragg grating or larger phase shift in a Fabry-Perot configuration. In both cases, the detector width w is approximately equal to the physical width of the core, whereas the detector length corresponds to the localization length of the resonance mode, over which 50% of its energy is located.

[0047] Reference is now made to Fig. IE which is an illustration of a top view of another waveguide for an ultrasound detector according to some embodiments of the invention. In addition to the waveguide types discussed above that include micro-rings, Fabry-Perots, or pi-phase- shifted Bragg grating, the waveguide may include bends. If no waveguide is used, the waveguide may include bends to increase the sensing length while maintaining a short physical length. Fig. IE that shows an example of a waveguide bent in an Archimedean- spiral increase the sensing length. Waveguide 25 may included a folded core, having an external dimension D, that may be larger than 0.5 mm. For example, D may be 1 mm, 5, mm, 10 mm, 50 mm, 100 mm and any value or range in between.

[0048] If a resonator is used, the refractive-index modulation may be detected by monitoring the wavelength shifts of the resonance by tuning a continuous-wave (CW) laser to the regionof the resonance wavelength and monitoring the intensity or phase modulation at the output of the resonator. If no resonator is used, the phase modulation at the output of the sensing arm may be detected by interfering it with a reference beam from the same CW laser.

[0049] In some embodiments, ultrasound detector 50 may have, in one dimension, an acceptance angle a (illustrated in Fig. 2A) larger than or equal to 20 degrees, for example, 30 degrees, 40 degrees, 60 degrees and 80 degrees, 90 degrees, 100 degrees, 120 degrees, 140 degrees, 160 degrees and 180 degrees and any value or range in between. In some embodiments, this dimension may be: the width ‘w’ of an optical mode guided in the waveguide, a width of a waveguide core ‘w’ shown in Figs. 1C, ID and 2B. In some embodiments, the width of the waveguide core is smaller or equal to 50 pm, for example, 45 pm, 40 pm, 35 pm, 30 pm, 25 pm, 20 pm, 15 pm, 10 pm, 5 pm, 1 pm, 0.5 pm, or any value or range in-between.

[0050] Reference is now made to Figs. 2A-2E with are illustration of cross sections (Figs, 2A-2C), and top views (Figs 2D-2E)of systems for detecting blood cells attached to a tissue and an enlargement of the ultrasound detector section in the system and to Fig. 2F which is a block diagram of the system according to some embodiments of the invention. A system 100 for detecting blood cells may include at least one light source 30 configured to emit at least one intensity modulated optical beam 35. In some embodiments, system 100 may include a plurality of light sources 30. In a nonlimiting example, at least one light source 30 may be configured to emit light at a wavelength of 490 to 570 nm (e.g., in the green range), for example, for interacting and creating an acoustic wave via the optoacoustic effect in RBCs 17 flowing in superficial blood vessel 16. In another nonlimiting example, least one light source 30 may be configured to emit light at a wavelength of 1400 to 1500 nm or 1850 to 2200 nm (e.g., in the near-infrared range), for example, for interacting and creating an acoustic wave via the optoacoustic effect in water.

[0051] In some embodiments, at least one light source 30 may be configured to emit light in pulses, for example, in pulses equal to or shorter than 100 ns, 90 ns, 75 ns, 60 ns, 50 ns, 40 ns, 20 ns, 10 ns, 5 ns, 2 ns, 1 ns, 0.5 ns, 0.1 ns and any value or range in between.

[0052] In some embodiments, a Rayleigh length (or depth of field) of the intensity modulated optical beam 35 is equal to or shorter than 30 pm, 20 pm, 10 pm, 5 pm, 2 pm, 1 pm and any value or range in between.

[0053] In some embodiments, system 100 may include an optical unit 40 configured to focus the optical beam 35 to a focal width ‘fw’ at the focal point 36, of less than 50 pm. In some embodiments, the beam may illuminate, one or more discrete locations on the superficial blood vessel. As used herein, illuminate one or more discrete locations is defined as directing a single beam 35, at less than 10 different locations, towards tissue 15, without the need of any scanning.

[0054] In some embodiments, the focal width of at least one intensity modulated optical beam 35 is less than 10 pm, optionally less than 5 pm. In some embodiments, the optical width is selected to avoid simultaneously illuminating different blood vessels 16 at different depths. In some embodiments, optical unit 40 may be configured to focus at least one intensity modulated optical beam 35 at a depth ‘d’ below atissue 15 surface, equal or smaller than 2 mm. In some embodiments, when a plurality of light sources 30 are used, optical unit 40 is configured to focus each light beam 35 to a different location in tissue 15.

[0055] In some embodiments, optical unit 40 may include any number of lenses, mirrors, or other optical devices in a setup that allows focusing at least one intensity modulated optical beam 35.

[0056] In some embodiments, system 100 may include at least one ultrasound detector 50, positioned at a lateral offset ‘Loffset’ from focal point 36 of the intensity modulated optical beam 35 focused into the superficial blood vessel 16. In some embodiments, the lateral offset may be between 0.005 to 20 mm. In some embodiments, ultrasound detector 50 may have in one dimension, an acceptance angle larger than 20 degrees. In some embodiments, the lateral offset may be between 0.005 to 0.01 mm, 0.01 to 0.5 mm, 0.5 to 1 mm, 1 to 5 mm, 3 to 8 mm, 7 to 10 mm, 9 to 13 mm, 12 to 16 mm, 15 to 20 mm, 20 mm to 30 mm and any value or range in between. In some embodiments, one dimension is, a width ‘w’ of an optical mode guided in the waveguide, a width ‘ w’ of a waveguide core to the at least one ultrasound detector 50.

[0057] In some embodiments, ultrasound detector 50 may include a waveguide 20, 20a, 20b 20c, and 25, discussed above with respect to Figs. 1A-1D. Wave guides, 20a, 20b 20c may be straight waveguides and wave guide 25 a folded waveguide. Fig. 2C shows a cross section of system 100 comprising ultrasound detector 50 having folded waveguide 25. As shown in the cross section crosses several folding of waveguide 25. In some embodiments, each of the folding may, when stand alone) have an acceptance angle a larger than or equal to 20degrees. However, when folded the total acceptance / detection area, is the area below the folding of waveguide 25. A top view of this system is shown in Fig. IE, when light source 36 is located at an area which includes transparent portions, allowing bean 35 to illuminate tissue 15.

[0058] In some embodiments, at least one ultrasound detector 50 may have at least one other dimension larger than 0.5 mm. For example, the other dimension may be the length L of waveguide 20 as shown in Fig. 2D or the length of NxA segment illustrated in Figs. 1C and ID. In another example, the other dimension may be a distance al or a2 between two adjacent folding of a folded waveguide core, shown in Fig. IB. In yet another example, the other dimension may be a distance D between two distant folding of the folded waveguide core, shown in Fig. 2E.

[0059] In some embodiments, this specific arrangement may allow an off-axis detection of acoustic waves. The off-axis detection may have one disadvantage in the case of imaging in compared to a co-axial configuration. A coaxial configuration has an advantage in the case of 3D imaging since it provides depth-resolved information from the acoustic signal. In such a case, the illumination depth of field is chosen to be relatively large, > 100 pm, to illuminate several blood vessels (16 at different depths at once, where distinguishing between capillaries 16 is possible since different depths correspond to different arrival times for the acoustic pulses. In contrast, in off-axis detection RBCs 17 if a long depth of field is used, signals from different depths will reach the detector at similar times since the delay is determined mostly by the lateral distance, which is the same for all the depth positions in beam 35. In such case, depth information is lost, and the imaging is turned into 2D. Therefore, accoridng to some embodiments of the invention, a tightly focused beam 35, having a focal width of less than 50 pm (optionally less than 30 pm) at focal pint 36, is used, thereby ensuring that only a single blood vessel (16 (as illustrated) is illuminated. Accordingly, the disadvantages in using off-axis detection is eliminated, as there is no need to separate between signals from different blood vessels).

[0060] In some embodiments, system 100 may further include a plurality of ultrasound detectors 50, each positioned at a lateral offset from at least one intensity modulated optical beam 35.

[0061] In some embodiments, system 100 may further include a transparent plate 60, transparent in the wavelength of the intensity modulated optical beam (e.g., 490 to 570 nm).In some embodiments, ultrasound detector 50 may attached to the transparent plate, such that a full contact is formed between ultrasound detector 50 and the surface of tissue 15.

[0062] In some embodiments, system 100 may include a computing device 10, discussed in detail in Fig. 4. Computing device 10 may be configured to execute method accoridng to embodiments of the invention, for example, the method of Fig. 3.

[0063] Reference is now made to Fig. 3 which is a flowchart of a noninvasive method of detecting blood cells according to some embodiments of the invention.

[0064] In step 310, the method may include illuminating a tissue containing a superficial blood vessel, at one or more discrete locations, with at least one intensity modulated optical beam focused into superficial blood vessel in the tissue having a focal width of equal to or less than 50 pm (optionally less than 30 pm). For example, controller 2 of computing device 10 (illustrated in Fig. 4) may control at least one light source 30 to emit at least one intensity modulated optical beam 35, focused into superficial blood vessel (16 in tissue 15, at a depth ‘d’ of at most 2 mm, as illustrated and discussed with respect to Figs. 2A-2B. In some embodiments, the number of discrete locations on the same superficial blood vessel is less than 10.

[0065] In some embodiments, the illumination may be performed directly on tissue 15 with no materials in between. In other embodiments, transparent plate 60, which is transparent in the illumination wavelength may be used, to flatten the surface of tissue 15. In some embodiments, waveguide 20 of detector 50 may be mounted on the surface of plate 60, or integrated on its surface, as illustrated in Fig. 2B. In order to further increase the detection’s total field of view, several waveguides 20 may be fabricated at different positions, thus enabling to count RBCs 17 over larger regions. In some embodiments, the total thickness of cladding 204 of waveguide 20 may be small (< 50 pm, < 30 pm or less), the protrusion of acoustic detector 50 may be minimal, allowing for good contact with tissue 15.

[0066] In some embodiments, illuminating RBCs 17 with beam 35 may cause RBCs 17 to vibrate and emit acoustic waves having high frequency (>20 MHz).

[0067] In step 320, the method may include receiving at least one ultrasound signal from at least one ultrasound detector, positioned at a lateral offset from focal point 36 of the intensity modulated optical beam 35 focused into the superficial blood. For example, controller 2 may receive at least one ultrasound signal from the at least one ultrasound detector.

[0068] In some embodiments, detecting the acoustic emission pattern of RBCs 17, it was found that RBCs do not emit ultrasound only in the (vertical) direction of the illumination, where co-axial detection is used, but rather in all directions, where the exact emission pattern depends on their orientation and acoustic wavelength. Since the orientation of RBCs in the blood stream is random, ultrasound emission is expected to be isotropic on average, enabling, in principle, off-axis detection. Therefore, for off-axis detection, the detector may be stationary, and only scanning of the optical beam may be required. In some embodiments, waveguide 20 of detector 50 may be manually positioned at an arbitrary position on tissue 15 and optical beam 35 may scan the surface of tissue 15 to find blood vessel 16 in the vicinity of waveguide 20, and then remain in the position during the measurement, while detector 50 records the acoustic signals generated when RBCs 17 pass through beam 35.

[0069] In step 330, the method may include detecting acoustic emission patterns related to blood cells in the at least one received ultrasound signal. For example, controller 2 may detect acoustic emission patterns related to RBCs 17 in the received at least one ultrasound signal. In some embodiments, typical acoustic emission patterns related to RBCs may be stored in a storage system 6 of computing device 10, to be used for identifying the acoustic emission pattern of each RBC 17 passing through beam 35. The patterns may be collected and counted in order to count the number of RBCs 17 passing through beam 35 during a predetermined amount of time.

[0070] In some embodiments, multi-beam illumination may be performed using a plurality of beams 35. In some embodiments, a structured illumination of a plurality of beams 35 may be performed, in which the same blood vessel 16 is illuminated at several lateral positions. In some embodiments, the off-axis configuration of system 100 may enable a simultaneous detection and separation of the signals from different beam positions using acoustic delays. The acoustic delays may be indicative of the lateral distance from the detector. For example, by comparing the waveforms obtained for the different illumination positions, which should be identical up to a delay, the flow speed of RBCs 17 may be calculated, without any need of scanning beam 35 or waveguide 20 during the measurement. Such capabilities are not possible in the co-axial configuration since it does not allow the simultaneous detection of signals from different lateral positions.

[0071] Reference is now made to Fig. 4, which is a block diagram depicting a computing device, which may be included within an embodiment of a system for a noninvasive detection of blood cells.

[0072] Computing device 10 may include a processor or controller 2 that may be, for example, a central processing unit (CPU) processor, a chip or any suitable computing or computational device, an operating system 3, a memory 4, executable code 5, a storage system 6, input devices 7 and output devices 8. Processor 2 (or one or more controllers or processors, possibly across multiple units or devices) may be configured to carry out methods described herein, and / or to execute or act as the various modules, units, etc. More than one computing device 1 may be included in, and one or more computing devices 10 may act as the components of, a system according to embodiments of the invention.

[0073] Operating system 3 may be or may include any code segment (e.g., one similar to executable code 5 described herein) designed and / or configured to perform tasks involving coordination, scheduling, arbitration, supervising, controlling or otherwise managing operation of computing device 10, for example, scheduling execution of software programs or tasks or enabling software programs or other modules or units to communicate. Operating system 3 may be a commercial operating system. It will be noted that an operating system 3 may be an optional component, e.g., in some embodiments, a system may include a computing device that does not require or include an operating system 3.

[0074] Memory 4 may be or may include, for example, a Random Access Memory (RAM), a read only memory (ROM), a Dynamic RAM (DRAM), a Synchronous DRAM (SDRAM), a double data rate (DDR) memory chip, a Flash memory, a volatile memory, a nonvolatile memory, a cache memory, a buffer, a short term memory unit, a long term memory unit, or other suitable memory units or storage units. Memory 4 may be or may include a plurality of possibly different memory units. Memory 4 may be a computer or processor non-transitory readable medium, or a computer non-transitory storage medium, e.g., a RAM. In one embodiment, a non-transitory storage medium such as memory 4, a hard disk drive, another storage device, etc. may store instructions or code which when executed by a processor may cause the processor to carry out methods as described herein.

[0075] Executable code 5 may be any executable code, e.g., an application, a program, a process, task or script. Executable code 5 may be executed by processor or controller 2 possibly under control of operating system 3. For example, executable code 5 may be anapplication that may include a noninvasive method of detecting blood cells as further described herein above. Although, for the sake of clarity, a single item of executable code 5 is shown in Fig. 1, a system according to some embodiments of the invention may include a plurality of executable code segments similar to executable code 5 that may be loaded into memory 4 and cause processor 2 to carry out methods described herein.

[0076] Storage system 6 may be or may include, for example, a flash memory as known in the art, a memory that is internal to, or embedded in, a micro controller or chip as known in the art, a hard disk drive, a CD-Recordable (CD-R) drive, a Blu-ray disk (BD), a universal serial bus (USB) device or other suitable removable and / or fixed storage unit. Data related to blood cells may be stored in storage system 6 and may be loaded from storage system 6 into memory 4 where it may be processed by processor or controller 2. In some embodiments, some of the components shown in Fig. 4 may be omitted. For example, memory 4 may be a non-volatile memory having the storage capacity of storage system 6. Accordingly, although shown as a separate component, storage system 6 may be embedded or included in memory 4.

[0077] Input devices 7 may be or may include any suitable input devices, components or systems, e.g., a detachable keyboard or keypad, a mouse and the like. Output devices 8 may include one or more (possibly detachable) displays or monitors, speakers and / or any other suitable output devices. Any applicable input / output (RO) devices may be connected to Computing device 1 as shown by blocks 7 and 8. For example, a wired or wireless network interface card (NIC), a universal serial bus (USB) device or external hard drive may be included in input devices 7 and / or output devices 8. It will be recognized that any suitable number of input devices 7 and output device 8 may be operatively connected to Computing device 10 as shown by blocks 7 and 8.

[0078] A system according to some embodiments of the invention may include components such as, but not limited to, a plurality of central processing units (CPU) or any other suitable multi-purpose or specific processors or controllers (e.g., similar to element 2), a plurality of input units, a plurality of output units, a plurality of memory units, and a plurality of storage units.

[0079] Unless explicitly stated, the method embodiments described herein are not constrained to a particular order or sequence. Furthermore, all formulas described herein are intended as examples only and other or different formulas may be used. Additionally, someof the described method embodiments or elements thereof may occur or be performed at the same point in time.

[0080] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents may occur to those skilled in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

[0081] Various embodiments have been presented. Each of these embodiments may of course include features from other embodiments presented, and embodiments not specifically described may include various features described herein.

Claims

CLAIMS1. A noninvasive method of detecting blood cells, comprising: illuminating a tissue containing a superficial blood vessel, at one or more discrete locations, with at least one intensity modulated optical beam focused into the superficial blood vessel in the tissue having a focal width of equal to or less than 30 pm; receiving at least one ultrasound signal from at least one ultrasound detector, positioned at a lateral offset from a focal point of the intensity modulated optical beam focused into the superficial blood vessel; and detecting acoustic emission patterns related to blood cells in the at least one received ultrasound signal.

2. The method of claim 1, wherein the at least one ultrasound detector has, in one dimension, an acceptance angle larger than or equal to 20 degrees.

3. The method of claim 2, wherein the one dimension is selected from, a width of an optical mode guided in the waveguide, and a width of a waveguide core to the at least one ultrasound detector.

4. The method of claim 2, wherein the width of the waveguide core is smaller or equal to 50 pm.

5. The method of any one of claims 1 to 4, wherein the at least one ultrasound detector has at least one other dimension larger than 0.5 mm.

6. The method of claim 5, wherein the at least one other dimension is selected from, a length of the localized resonance mode, a length of the waveguide core, a distance between two adjacent folding of a folded waveguide core, and a distance between two distant folding of the folded waveguide core.

7. The method of any one of claims 1 to 6, wherein the lateral offset is between 0.005-30 mm.

8. The method of any one of claims 1 to 7, wherein the superficial blood vessel is located at most 2 mm below a surface of the tissue.

9. The method of any one of claims 1 to 8, wherein the focal width of the intensity modulated optical beam is less than 10 pm, optionally less than 5 pm.

10. The method of any one of claims 1 to 9, wherein the acceptance angle is smaller than or equal to 180 degrees.

11. The method of any one of claims 1 to 10, further comprising: counting acoustic pulse generated by blood cells passing through the focal point of the intensity modulated optical beam.

12. The method of any one of claims 1 to 11, wherein the blood cells are red blood cells.

13. The method of any one of claims 1 to 12, wherein the ultrasound detector is placed on the tissue.

14. The method of any one of claims 1 to 13, further comprising: scanning the tissue with the intensity modulated optical beam to detect the blood vessel, and wherein illuminating the tissue is from a stationary position above the blood vessel.

15. The method of any one of claims 1 to 14, wherein the ultrasound detector comprises a waveguide having a core with a large refractive index (>1.7).

16. The method of any one of claims 1 to 15, wherein illuminating the tissue comprises illuminating using a plurality of optical beams each being focused on a different location at the tissue.

17. The method accoridng to any one of claims 1 to 16, wherein receiving at least one ultrasound signal, comprises receiving a plurality of ultrasound signals from a plurality of ultrasound detectors, each positioned at a lateral offset from the at least one beam.

18. The method of claim 17, wherein each ultrasound detector of the plurality is positioned at a lateral offset from a corresponding beam.

19. The method of any one of claims 1 to 18, wherein illuminating the tissue comprises placing a transparent plate on the tissue, wherein the plate is transparent in the wavelength of the at least one optical beam.

20. The method of claim 19, wherein the at least one ultrasound detector is attached to the transparent plate.

21. The method of any one of claims 1 to 16, wherein the intensity modulated optical beam is pulsed.

22. The method of claim 17, wherein each pulse is equal to or shorter than 100 ns.

23. The method of any one of claims 1 to 18, wherein a Rayleigh length of the intensity modulated optical beam is equal to or shorter than 50 pm, optionally shorter than 10 pm.

24. The method of any one of claims 1 to 23, wherein the number of discrete locations on the same superficial blood vessel is less than 10.

25. A system for detecting blood cells, comprising: at least one light source configured to emit at least one intensity modulated optical beam; an optical unit configured to focus the optical beam, at one or more discrete locations, to a focal width of less than 30 pm; at least one ultrasound detector, positioned at a lateral offset a focal point of the intensity modulated optical beam focused ; and a controller configured to: control the at least one light source to emit,] the at least one intensity modulated optical beam; receive at least one ultrasound signal from the at least one ultrasound detector; and detect acoustic emission patterns related to blood cells in the received at least one ultrasound signal.

26. The system of claim 25, wherein the focal width of the at least one intensity modulated optical beam is less than 10 pm, optionally less than 5 pm.

27. The system of claim 25 or 24, wherein the lateral offset is between 0.005-30 mm.

28. The system of any one of claims 25 to 27, wherein the at least one ultrasound detector has, in one dimension, an acceptance angle larger than or equal to 20 degrees.

29. The system of claim 28, wherein the one dimension is selected from, a width of an optical mode guided in the waveguide, a width of a waveguide core to the at least one ultrasound detector.

30. The system of claim 29, wherein the width of the waveguide core is smaller or equal to 50 pm.

31. The system of any one of claims 25 to 28, wherein the at least one ultrasound detector has at least one other dimension larger than 0.5 mm.

32. The system of claim 31, wherein the at least one other dimension is selected from, a length of the localized resonance mode, a length of the waveguide core, a distance between two adjacent folding of a folded waveguide core, and a distance between two distant folding of the folded waveguide core.

33. The system of any one of claims 25 to 32, wherein the ultrasound detector comprises a waveguide having a core with a large refractive index (>1.7).

34. The system of claim 33, wherein the waveguide has at least one of the length and a width equal to or smaller than 50 pm.

35. The system of any one of claims 25 to 34, comprising a plurality of light sources configured to generate a plurality of intensity modulated optical beams each being focused in a different location.

36. The system of any one of claims 25 to 35 comprising a plurality of ultrasound detectors, each positioned at a lateral offset from the at least one intensity modulated optical beam.

37. The system of claim 36, wherein each ultrasound detector of the plurality is positioned at a lateral offset from a corresponding intensity modulated optical beam.

38. The system of any one of claims 25 to 37, comprising a transparent plate and wherein the plate is transparent in the wavelength of the intensity modulated optical beam.

39. The system of claim 38, wherein the ultrasound detector is attached to the transparent plate.

40. The system of any one of claims 25 to 39, wherein the intensity modulated optical beam is pulsed.

41. The system of claim 40, wherein each pulse is equal to or shorter than 100 ns.

42. The system of any one of claims 25 to 41, wherein a Rayleigh length of the intensity modulated optical beam is equal to or shorter than 30 pm, optionally shorter than 10 pm.

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