Particle detection system and method for on-axis particle detection and / or differential detection

Abstract

To provide a novel system for detecting particles in a fluid.SOLUTION: Provided herein are optical systems and methods for detecting and characterizing particles. Systems and methods are provided which increase the sensitivity of an optical particle counter and allow detection of smaller particles while analyzing a larger fluid volume. The described systems and methods allow sensitive and accurate detection and size characterization of nanoscale particles (e.g., less than 50 nm, optionally less than 20 nm, optionally less than 10 nm) for large volumes of analyzed fluids.SELECTED DRAWING: Figure 1A

Description

Cross - Reference to Related Applications

[0001]

[0001] This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 838,835, filed on April 25, 2019, which is hereby incorporated by reference in its entirety.

Background Art

[0002]

[0002] Advances in technologies that require cleanroom conditions have led to an ever - increasing need for the detection and characterization of ever - smaller particles. For example, microelectronics foundries pursue the detection of particles smaller than 20 nm, and in some cases smaller than 10 nm. This is because particles can potentially affect manufacturing processes and products that are becoming increasingly sensitive. Similarly, the need for aseptic processing conditions in the manufacture of pharmaceuticals and biomaterials requires accurate characterization of viable and non - viable particles in order to meet compliance standards related to health and human safety.

[0003]

[0003] Typically, these industries rely on optical particle counters for the detection and characterization of small particles. The ability to detect smaller particles requires new approaches to optical particle counting, such as systems that employ more complex techniques such as increased laser output, shorter excitation wavelengths, and condensation nucleus counting. This can dramatically increase the cost and overall complexity of devices for detecting particles on the nanometer scale. In these new approaches, more frequent calibration and maintenance may be required to provide the necessary reliability and reproducibility.

[0004]

[0004] Various optical particle counters are known in the art. For example, a scattered light optical particle counter is provided in U.S. Patent No. 7,916,293, and transmission / extinction particle counters that utilize structured beams and / or interferometric spectroscopy are provided in U.S. Patent Nos. 7,746,469, 9,983,113, 10,416,069, U.S. Patent Application Publication No. 2019 / 0277745, U.S. Patent Application Publication No. 2017 / 0176312, and PCT International Publication No. 2019 / 082186. Each of these references is incorporated herein by reference in its entirety, and in particular, is incorporated to describe the components and configurations of particle counter systems useful for the detection and characterization of small particles.

[0005]

[0005] From the foregoing, it can be seen that there is a need in the art for systems and methods that provide enhanced optically sensed particles having small size dimensions.

SUMMARY OF THE INVENTION

[0006]

[0006] Provided herein are optical particle counter and / or analyzer systems and methods that improve the sensitivity, accuracy, and throughput of an optical particle counter to enable the detection and characterization of smaller particles over a large volume of sampled fluid, for example, using on-axis detection of transmitted and / or forward scattered light, using a probe beam that optionally includes a structured beam such as a dark beam, and optionally using a differential detection system. In some embodiments, the system and method incorporate detector configurations and signal analysis techniques that enable improved optical shaping, improved amount of sample fluid analyzed as a function of time, improved overall particle detection sensitivity for small particles (e.g., having an effective lateral dimension (e.g., diameter) of 10 microns or less, or optionally 1 micron or less, or optionally 500 nanometers or less), and / or suppression of false positive indications, and provide for the detection and characterization of particles in a fluid using a structured beam such as a dark beam.

[0007]

[0007] This system and method are particularly well-suited for particle measurements (e.g., detection and / or sizing characterization) using on-axis particle measurements by detection and / or differential detection configurations and methods of transmitted and forward-scattered light. This system and method are very versatile and can be implemented using a series of particle measurement techniques including, (i) particle detection using interference detection of particles, (ii) particle detection using Gaussian and non-Gaussian beams such as structured beams, dark beams, (iii) particle detection using differential detection, (iv) particle detection using multi-pass techniques (e.g., dual-pass), and / or (v) particle detection using polarization control.

[0008]

[0008] In some embodiments, for example, the systems and methods of the present invention use structured beams such as, for example, dark beams, and optionally a differential detection configuration, to perform on-axis particle measurements by detecting transmitted and forward-scattered light, along the transverse direction (e.g., along an axis orthogonal to the beam axis) and / or along the z-axis (e.g., along an axis along the beam axis between the light source and the detector), to achieve a rapid conversion of the flow cell (e.g., faster than the average velocity of the particles as they pass through the beam), and in combination with optical and / or flow cell elements (e.g., transducers, oscillators, piezoelectric elements, etc.) to achieve a greater sampling volume of the fluid per unit time compared to systems that do not use the conversion. In one embodiment, for example, the laser source or the flow cell is converted via, for example, a transducer or an oscillator, to increase the amount of sample fluid analyzed per unit time via particle detection using a structured beam such as a dark beam. In one embodiment, for example, the flow cell is converted at an average conversion rate that is at least twice as fast as the average particle velocity as it moves through the beam, and optionally, in some applications, the flow cell is converted at an average conversion rate that is 5 to 100 times as fast as the average particle velocity as it moves through the beam. In some embodiments, for example, the flow rate of the fluid containing the particles is selected over a range of 5 to 300 cm / second. In some embodiments, for example, the flow cell is converted at an average conversion rate of 25 cm / second or greater. In one embodiment, the transducer achieves conversion of the flow cell along a distance selected from the range of 10 to 1000 microns. In some embodiments, the transducer undergoes periodic conversion at a frequency selected from the range of 100 kHz to 100 MHz. The conversion can be a periodic conversion in one or more directions including vibration, and / or can be a linear or non-linear conversion. In some embodiments, for example, the oscillator vibrates at a frequency high enough such that the flow cell completes its displacement in a time shorter than that required for the particles to pass through a region of high radiation density. In some embodiments, the transducer is an oscillator that vibrates at a frequency selected from the range of 100 kHz to 100 MHz.

[0009]

[0009] In some embodiments, for example, the systems and methods of the present invention use structured beams such as, for example, dark beams, and optionally a differential detection configuration, to perform on-axis particle measurements by detecting transmitted and forward-scattered light, in combination with the use of pixelated light detector(s) having pixel regions corresponding to the spatial extent of the particle-beam interaction signal within the beam (e.g., within 1.5 times and optionally within 1.2 times), enhancing the detection of more particle transitions and leading to an improvement in the amount of sample analyzed per unit time. In some embodiments, such pixelated detection configurations enable the segmentation of the particle signal image from the surrounding "larger" beam image. In some embodiments, the systems and methods incorporate a pixelated light detector having one or more columns of elements to achieve efficient differential detection between at least two elements. Pixel widths independently selected from the range of 10 to 500 microns are useful in certain embodiments and, optionally, are useful for some applications where each is independently selected from the range of 50 to 100 microns.

[0010]

[0010] In some embodiments, the systems and methods of the present invention optionally use a differential detection configuration and / or use a structured beam such as a dark beam, and combine the on-axis particle measurement by detecting transmitted and forward-scattered light with additional off-axis detection of scattered light or fluorescence to distinguish biological particles (e.g., microbial particles) from non-biological particles. Since biological particles such as microorganisms are mainly composed of water, the refractive index contrast with water is very low, so there is almost no scattering. Therefore, biological particles either generate a small side-scattered signal or are not detected using side scattering. Biological particles generate a strong response signal in the present methods and systems that use on-axis detection of transmitted and forward-scattered light, for example, using a structured beam and / or differential detection techniques. In some methods and systems of the present invention, the observation (or comparison) of a large on-axis signal compared to the side-scattered signal, or the observation of a signal at the on-axis detector with no corresponding signal at the side-scattered detector, is used to characterize the particle as a biological particle such as a microbial particle. Alternatively, in some methods and systems of the present invention, the observation (or comparison) of equivalent on-axis and side-scattered signals, or the observation of signals at both the on-axis and side-scattered detectors, is used to characterize the particle as a non-biological particle.

[0011]

[0011] In some embodiments, the systems and methods of the present invention use on-axis particle detection by detecting transmitted and forward-scattered light using a structured beam such as a dark beam to characterize the refractive index of the particle, for example, with respect to the refractive index (e.g., the composition of the fluid flow) of the medium in which the particle is present (e.g., larger or smaller). This aspect enables determining attributes of the particle composition, such as providing a means for distinguishing metal particles from non-metal particles based on refractive index. In systems incorporating a differential detection configuration, for example, the "classical" particle signal can be accurately inverted with high reliability and reproducibility to distinguish metal particles from non-metal particles. In some embodiments, for example, the difference in the refractive index of the particle with respect to the refractive index of the carrier fluid results in a signal that can be used to characterize the optical properties and composition of the particle.

[0012]

[0012] When the analyzed particles have a refractive index higher than that of the carrier fluid, such as in the case of polystyrene latex (PSL) particles in an aqueous medium, bright fringes are observed above the beam and dark fringes are observed below the beam under the condition that the particles enter the beam in the flow cell. For example, when the particles enter the beam from below. On the other hand, when the analyzed particles have a refractive index lower than that of the carrier fluid, such as in the case of gold nanoparticles in an aqueous medium, dark fringes are observed above the beam and bright fringes are observed below the beam, so that the fringe pattern is reversed under the condition that the particles enter the beam in the flow cell, such as when the particles enter the beam from below. Therefore, by observing and characterizing the sequence, order, and / or arrangement of bright and dark fringes during the interaction between the particles and the beam, the refractive index of the particles with respect to the carrier (e.g., larger or smaller) can be characterized, and thus information related to the composition of the particles can also be inferred. Differential detection provides an efficient and accurate means of characterizing the sequence, order, and / or position of dark and bright fringes in the present system and technique as a function of time along the trajectory of the particles passing through the beam, for example, (i) when the particles first enter the beam (e.g., from below), (ii) when the particles pass through the beam waist, and (iii) when the particles exit the beam.

[0013]

[0013] In some embodiments, for example, the systems and methods of the present invention use, optionally, a differential detection configuration and / or use a structured beam such as a dark beam to perform on-axis particle measurements by detecting transmitted and forward-scattered light, for example, by moving a detector using a positioner and / or by operating a mirror before the detector balances the signals between a first and a second detector region corresponding to the upper pixel or upper subset of pixels and the lower pixel or lower subset of pixels of the pixel, across the entire beam, such as a differential detector. In embodiments of this differential detection mode, the adjustment of the detector and / or the beam position on the detector using an adjuster achieves enhanced noise cancellation, particularly for situations where the position of the beam is susceptible to the effects of vibrations and acoustic inputs, for example, when the system is not isolated from the sources of such vibrations and acoustic inputs. In embodiments of this differential detection mode, a portion of the beam is provided to an imager or a plurality of detectors (e.g., a quad detector) to provide feedback on the beam output density and the spot size within the flow cell. In some embodiments, the adjuster operates via closed-loop control, for example, by periodically measuring the noise amplitude of the differential signal, when there are no particles present and actively adjusts the position of the differential detector and / or the beam position of the differential detector with respect to the noise amplitude of the differential signal.

[0014]

[0014] In some embodiments, the system and method include one or more regulators to ensure, for example, that the laser beam intensity is balanced between the upper and lower halves of the differential detector in order to reduce noise and enhance the signal. In one embodiment, for example, a closed-loop system is used to determine and analyze the noise amplitude of the differential signal when no particles are present. In one embodiment, a steering mirror is used to adjust the beam position on the detector to minimize the noise level of the differential signal. This state occurs when the beam output is evenly divided between the upper and lower elements. For example, within 20% of uniform, optionally within 10% of uniform, etc. Similarly, such control can also be achieved by transforming the position of the detector and rotating the detector to align the beam and the detector axis.

[0015]

[0015] In some embodiments, for example, the system and method of the present invention combine axial particle measurements by detecting transmitted and forward-scattered light in connection with a cooled detector for an improved signal-to-noise ratio, using a structured beam such as a dark beam, in combination with an optical modulator equipped with a lock-in amplifier.

[0016]

[0016] In some embodiments, the system and method of the present invention combine axial particle measurements by detecting transmitted and forward-scattered light, using a structured beam such as a dark beam and optionally a differential detection configuration, in combination with collimating or imaging the beam onto an optical detector.

[0017]

[0017] In some embodiments, for example, the system and method of the present invention combine axial particle measurements by detecting transmitted and forward-scattered light, using a structured beam such as a dark beam and optionally a differential detection configuration, in combination with a knife-edge prism for splitting the beam into separate optical detectors.

[0018]

[0018] In one aspect, a particle detection system includes a flow cell for flowing a fluid containing particles, a light source for generating one or more coherent beams of electromagnetic radiation, a beam shaping system for passing the one or more coherent beams of electromagnetic radiation through the flow cell to generate electromagnetic radiation scattered by the particles, and at least one photodetector array for receiving the electromagnetic radiation from the flow cell, wherein the light source, the beam shaping system, and the photodetector array are configured to enable detection of the particles. In one embodiment, the light source, the beam shaping system, and the photodetector array are configured to implement interference detection of the particles. In one embodiment, the light source, the beam shaping system, and the photodetector array are configured to implement structured beam detection of the particles by passing a structured probe beam of coherent electromagnetic radiation through the flow cell. In one embodiment, the light source and the photodetector array are configured to implement structured dark beam detection of the particles, such as a structured dark beam characterized by a spatial intensity profile having a region of attenuated intensity, such as a central line decrease in intensity.

[0019]

[0019] In one embodiment, the photodetector array is arranged to be in optical communication with the flow cell to receive the incident electromagnetic radiation transmitted through the flow cell and the electromagnetic radiation scattered by the particles. For example, the electromagnetic radiation scattered by the particles includes forward-scattered electromagnetic radiation. In one embodiment, the incident electromagnetic radiation transmitted through the flow cell and the electromagnetic radiation scattered by the particles undergo, for example, constructive and / or destructive optical interference to generate one or more diffraction patterns. In one embodiment, the photodetector array is provided at a scattering angle within 0 to 5 degrees with respect to the optical axis of the incident beam, optionally, in some applications, at a scattering angle within 0 to 1 degree with respect to the optical axis of the incident beam, optionally, in some applications, at a scattering angle within 0 to 0.5 degree with respect to the optical axis of the incident beam, optionally, in some applications, at a scattering angle within 0 to 0.1 degree with respect to the optical axis of the incident beam. In one embodiment, the photodetector array is provided in optical communication with the flow cell to detect the interaction between the particles, the electromagnetic radiation scattered by the particles, and the illumination wavefront.

[0020]

[0020] In one embodiment, the light source provides a coherent incident beam, such as a Gaussian incident beam, to the flow cell. The systems and methods of the present invention are also well adapted for structured beam detection using structured beams such as dark beams. In one embodiment, the light source includes one or more shaping and / or combining optical elements for generating one or more coherent beams of electromagnetic radiation. In one embodiment, the one or more shaping and / or combining optical elements are diffractive elements, polarization elements, intensity modulation elements, phase modulation elements, or any combination thereof. In one embodiment, the one or more coherent beams of electromagnetic radiation include structured non-Gaussian beams. In one embodiment, the one or more coherent beams of electromagnetic radiation include dark beams. In one embodiment, the one or more coherent beams of electromagnetic radiation include beams characterized by one or more line singularities. In one embodiment, the one or more coherent beams of electromagnetic radiation include anamorphic beams. In one embodiment, the one or more coherent beams of electromagnetic radiation include anamorphic beams in a top hat configuration.

[0021]

[0021] The systems and methods are compatible with a wide range of detectors and detector configurations. In one embodiment, a forward looking on-axis detector pair(s) is provided at a scattering angle, for example, within 0 degrees to 20 degrees, optionally within 0 degrees to 5 degrees, optionally within 0 degrees to 1 degree, optionally within 0 degrees to 0.5 degrees, optionally within 0 degrees to 0.1 degrees with respect to the optical axis of the incident beam, for some applications, with respect to the optical axis of the incident beam. Differential detection can be used in the present systems and methods to achieve significant noise reduction, for example, by using a detector configuration having first and second active regions aligned to receive a portion of the incident beam, and optionally, the beam output is evenly divided between the first active region and the second active region.

[0022]

[0022] The system and method of the present invention achieve the detection of particles in a flowing fluid, including the detection, counting, and sizing of a single particle in the fluid flow. In one embodiment, the fluid is a liquid or a gas. In one embodiment, the system is for detecting particles in a liquid chemical. In one embodiment, the system is for detecting particles in ultrapure water. In one embodiment, the system is for detecting particles in a high-pressure gas. In one embodiment, the system is for detecting particles in air. In one embodiment, the system is for detecting particles on a surface.

[0023]

[0023] In some embodiments, the present system and method are for analyzing a large number of samples per unit time in the following ways: (i) adjusting the depth of focus of a beam of electromagnetic radiation, (ii) increasing the effective scanning area of the beam, and / or (iii) increasing the signal-to-noise ratio generated by the detector element of a particle counter. The described system and method may enable the detection of nanoscale particles (e.g., less than 50 nm, optionally less than 20 nm, optionally less than 10 nm) using lower laser power requirements than conventional optical particle counters, for example.

[0024]

[0024] One way to increase the effective scanning area of the beam or laser of an optical particle counter is to rapidly deflect the beam through a target flow cell so that the beam effectively scans a larger cross-sectional area or volume of the fluid being analyzed. The beam can be deflected by various methods including vibrating the flow cell, the optical focusing system, or the electromagnetic source. The vibration can be at a frequency higher than the transit time of the particles in the fluid (based on the flow rate of the fluid in the flow cell), reducing or eliminating the possibility that particles can be lost by movement through the beam. The vibration can be in the x direction (lateral with respect to a beam propagating in the z direction), the y direction (perpendicular to a beam propagating in the z direction), and / or the z direction (along the beam path). The oscillator can be various acoustic, electrical, or mechanical devices known in the art, such as a piezoelectric device.

[0025]

[0025] In one aspect, a system for detecting particles in a fluid is provided, the system comprising: i) a flow cell for flowing a fluid containing particles along a flow direction through a beam of electromagnetic radiation; ii) a light source in optical communication with the flow cell for providing a beam of electromagnetic radiation, optionally a structured beam such as a dark beam; iii) a focusing system in optical communication with the light source for focusing the beam of electromagnetic radiation to generate a region of high radiation density such as a focused beam region within the flow cell; iv) a transducer, such as an oscillator, operably connected to the flow cell to translate the flow cell closer to or farther from the focusing system so that the region of high radiation density changes position within the flow cell (i.e., in the z - direction); and v) an optical collection system for collecting at least a portion of the electromagnetic radiation and directing it towards a photodetector. Optionally, the photodetector is arranged to be in optical communication with the flow cell for receiving the incident electromagnetic radiation transmitted through the flow cell and the electromagnetic radiation forward - scattered by the particles, the photodetector generating an electrical signal characteristic of the number and / or size of the detected particles, and the change in position of the region of high radiation density enables the characterization of particles in a larger cross - sectional area of the flow cell and / or a larger volume of the fluid. In some embodiments, for example, the photodetector array is provided at a scattering angle within 0 to 5 degrees, optionally within 0 to 0.5 degrees, with respect to the optical axis of the incident beam.

[0026]

[0026] In one aspect, a system for detecting particles in a fluid is provided, the system comprising: i) a flow cell for flowing a fluid containing particles along a flow direction through a beam of electromagnetic radiation; ii) a light source in optical communication with the flow cell for providing a beam of electromagnetic radiation, optionally a structured beam such as a dark beam; iii) a focusing system in optical communication with the light source for focusing the beam of electromagnetic radiation to generate a region of high radiation density such as a focused beam region within the flow cell; iv) a transducer, such as an oscillator, operably connected to the flow cell for laterally translating the flow cell (e.g., in a direction orthogonal to the probe beam axis) across the beam of electromagnetic radiation so that the region of high radiation density changes position within the flow cell; v) an optical collection system for collecting at least a portion of the electromagnetic radiation and directing it towards a photodetector, optionally the photodetector is arranged to be in optical communication with the flow cell for receiving the incident electromagnetic radiation transmitted through the flow cell and the electromagnetic radiation forward scattered by the particles, the photodetector generating an electrical signal characteristic of the number and / or size of the detected particles, and the change in position of the region of high radiation density enables the characterization of particles over a larger cross-sectional area of the flow cell and / or a larger volume of the fluid. In some embodiments, for example, the photodetector array is provided at a scattering angle within 0 to 5 degrees, optionally within 0 to 0.5 degrees, with respect to the optical axis of the incident beam, and optionally, in some applications, the photodetector is a differential detection system.

[0027]

[0027] In one aspect, a system for detecting particles in a fluid is provided, the system comprising: i) a flow cell for flowing a fluid containing particles along a flow direction through a beam of electromagnetic radiation; ii) a light source in optical communication with the flow cell for providing a beam of electromagnetic radiation, optionally a structured beam such as a dark beam; iii) a focusing system in optical communication with the light source for focusing the beam of electromagnetic radiation to generate a region of high radiation density such as a focused beam region within the flow cell; iv) a first transducer, such as an oscillator, operably connected to the flow cell for converting the flow cell to move it closer to or farther from the focusing system so that the region of high radiation density varies the depth of the flow cell; v) a second transducer, such as an oscillator, operably connected to the flow cell for laterally translating the flow cell across the beam of electromagnetic radiation so that the region of high radiation density varies the lateral position within the flow cell; vi) an optical collection system for collecting at least a portion of the electromagnetic radiation and directing it towards a photodetector. Optionally, the photodetector is arranged to be in optical communication with the flow cell for receiving the incident electromagnetic radiation transmitted through the flow cell and the electromagnetic radiation forward scattered by the particles, and the photodetector generates an electrical signal characteristic of the number and / or size of the detected particles. The first transducer and the second transducer operate independently, and the variation of the depth and the lateral position of the region of high radiation density enables the characterization of particles within a larger volume of the flow cell. In some embodiments, for example, the photodetector array is provided at a scattering angle within 0 to 5 degrees, optionally within 0 to 0.5 degrees, with respect to the optical axis of the incident beam. Optionally, in some applications, the photodetector is a differential detection system.

[0028]

[0028] A transducer such as an oscillator can convert the flow cell along a periodic displacement or vibrate at a frequency higher than the time required for the particles to pass through the region of high radiation density.

[0029] Adjusting the beam profile at the waist (the narrowest point of the propagating beam and thus the point of highest energy density) can also be used to increase the cross-sectional area of the flow cell being analyzed. For example, by expanding the beam waist in the lateral (x) direction, a higher cross-sectional area or volume can pass through the waist, which typically provides the energy density necessary to detect particles in the fluid. Although the energy density and laser output decrease as the area increases, a high energy density can be maintained by reducing the beam waist in the vertical (y) direction.

[0030]

[0030] In one aspect, a system for detecting particles in a fluid is provided, the system comprising: i) a flow cell for flowing a fluid containing particles along a flow direction through a beam of electromagnetic radiation; ii) a light source in optical communication with the flow cell for providing a beam of electromagnetic radiation, optionally a structured beam such as a dark beam; iii) a focusing system in optical communication with the light source for focusing the beam of electromagnetic radiation onto the flow cell, the focusing system generating a double waist of the electromagnetic beam in both the x and y directions on a cross-section within the flow cell, the double waist having a longer length in the x direction than in the y direction; iv) an optical collection system for collecting at least a portion of the electromagnetic radiation and directing it towards a photodetector, optionally the photodetector being arranged in optical communication with the flow cell to receive the incident electromagnetic radiation transmitted through the flow cell and the electromagnetic radiation forward-scattered by the particles, the photodetector generating an electrical signal characteristic of the number and / or size of the detected particles. The length of the double waist in the x direction is 2 times, 10 times, 20 times, 50 times, or optionally 100 times or more the length in the y direction. In some embodiments, for example, the photodetector array is provided at a scattering angle within 0 to 5 degrees, optionally within 0 to 0.5 degrees, with respect to the optical axis of the incident beam. Optionally, in some applications, the photodetector is a differential detection system.

[0031]

[0031] In one aspect, a system for detecting particles in a fluid is provided, the system comprising: i) a flow cell for flowing a fluid containing particles along a flow direction through a beam of electromagnetic radiation; ii) a light source in optical communication with the flow cell for providing a beam of electromagnetic radiation, optionally a structured beam such as a dark beam; iii) a focusing system in optical communication with the light source for focusing the beam of electromagnetic radiation to generate a region of high radiation density, such as a focused beam region, within the flow cell; iv) an optical collection system for collecting at least a portion of the electromagnetic radiation and directing it towards a pixelated photodetector. Optionally, the pixelated photodetector is arranged to be in optical communication with the flow cell for receiving the incident electromagnetic radiation transmitted through the flow cell and the electromagnetic radiation forward-scattered by the particles, and each pixel of the pixelated photodetector has a region corresponding to the spatial extent of the particle-beam interaction signal within the beam. The pixelated photodetector generates an electrical signal characteristic of the number and / or size of the detected particles. In some embodiments, the region corresponding to the spatial extent of the particle-beam interaction signal within the beam refers to a region that coincides with 75% of the spatial extent of the particle-beam interaction signal. Optionally, in some applications, it is a region that coincides with 90% of the spatial extent of the particle-beam interaction signal, and optionally, in some applications, it is a region that coincides with 95% of the spatial extent of the particle-beam interaction signal. In some embodiments, for example, the photodetector array is provided at a scattering angle within 0 to 5 degrees with respect to the optical axis of the incident beam, and optionally, within 0 to 0.5 degrees with respect to the optical axis of the incident beam. Optionally, in some applications, the photodetector is a differential detection system.

[0032]

[0032] In one aspect, a system for detecting particles in a fluid is provided, the system comprising: i) a flow cell for flowing a fluid containing particles along a flow direction through a beam of electromagnetic radiation; ii) a light source in optical communication with the flow cell for providing a beam of electromagnetic radiation, optionally a structured beam such as a dark beam; iii) a focusing system in optical communication with the light source for focusing the beam of electromagnetic radiation to generate a region of high radiation density such as a focused beam region within the flow cell; iv) and an optical collection system for collecting at least a portion of the electromagnetic radiation and directing it towards a pixelated photodetector. Optionally, the photodetector is arranged to be in optical communication with the flow cell for receiving the incident electromagnetic radiation transmitted through the flow cell and the electromagnetic radiation forward scattered by the particles. The optical collection system collimates or focuses the beam of electromagnetic radiation, and each pixel of the pixelated photodetector has a region corresponding to the spatial extent of the particle-beam interaction signal within the beam. The photodetector generates an electrical signal characteristic of the number and / or size of the detected particles. In some embodiments, for example, the photodetector array is provided at a scattering angle within 0 to 5 degrees, optionally within 0 to 0.5 degrees, with respect to the optical axis of the incident beam.

[0033]

[0033] The image of the particle-beam interaction signal is important at the slow axis (major axis) of the beam at the detector. The vertical extent of the signal within the beam is not as important in some methods and applications. As the particle passes through the beam, the signal transitions across the upper and lower detector elements. To maximize the signal-to-noise ratio, the spatial extent of the particle-beam interaction signal at the slow axis can be mainly arranged on a single pair of detector elements. Spreading the particle-beam interaction signal across multiple pairs of detectors reduces the signal-to-noise ratio of the measurement.

[0034]

[0034] In some embodiments, the pixelated photodetector characterizes (e.g., differentiates actual particles from noise) particles based on one or more horizontal columns of pixels, e.g., a horizontal column having a height of 100 pixels, 20 pixels, 10 pixels, 5 pixels, 3 pixels, 2 pixels, or optionally 1 pixel. In the case of differential detection, two or more horizontal pixel columns can be used.

[0035]

[0035] The systems and methods described herein can also be used, for example, to determine or estimate the refractive index of a particle relative to the refractive index of a fluid medium. The system can use a lateral scatter detector to distinguish biological particles, such as cells and microbial particles, from non-biological particles. Since cells and cell fragments contain a relatively large amount of water, the refractive index of biological particles tends to be relatively similar to the fluid being analyzed. Thus, by including a lateral scatter detector, detection events that trigger both the primary photodetector and the lateral scatter detector correspond to non-biological particles because the radiation is refracted or scattered into the lateral scatter detector. However, detection events that trigger the primary detector but not the lateral scatter correspond to biological particles because the radiation is not refracted to the extent necessary to direct it into the lateral scatter detector.

[0036]

[0036] In one aspect, a system for detecting particles in a fluid is provided, the system comprising: i) a flow cell for flowing a fluid containing particles along a flow direction through a beam of electromagnetic radiation; ii) a light source in optical communication with the flow cell for providing a beam of electromagnetic radiation, optionally a structured beam such as a dark beam; iii) a focusing system in optical communication with the light source for focusing the beam of electromagnetic radiation onto the flow cell; iii) an optical collection system for collecting at least a portion of the electromagnetic radiation and directing it towards a photodetector, optionally, the photodetector being arranged in optical communication with the flow cell to receive the incident electromagnetic radiation transmitted through the flow cell and the electromagnetic radiation forward scattered by the particles; iv) a side-scattering detector in optical communication with the flow cell, the photodetector generating an electrical signal characteristic of the number and / or size of the detected particles, the side-scattering detector enabling the system to characterize the particles biologically or non-biologically due to the difference in refractive index between the fluid and the particles. In some embodiments, for example, the photodetector array is provided at a scattering angle within 0 to 5 degrees, optionally within 0 to 0.5 degrees, with respect to the optical axis of the incident beam.

[0037]

[0037] Systems using differential detection as described herein can also characterize the refractive index of the particles as higher or lower than that of the fluid. This is important because metal particles typically have a lower refractive index than common fluids, while non-metals have a higher refractive index than fluids. Most metals are conductive, and conductive materials are more detrimental at many stages of semiconductor manufacturing processes, so identifying more dangerous particles by distinguishing metals is possible.

[0038]

[0038] In one aspect, a system for detecting particles in a fluid is provided, the system comprising: i) a flow cell for flowing a liquid containing particles along a flow direction through a beam of electromagnetic radiation; ii) a light source in optical communication with the flow cell for providing a beam of electromagnetic radiation, optionally a structured beam such as a dark beam; iii) a focusing system in optical communication with the light source for focusing the beam of electromagnetic radiation on the flow cell; iv) an optical collection system for collecting at least a portion of the electromagnetic radiation and directing it towards a photodetector comprising at least two detector elements. Optionally, the photodetector is arranged in optical communication with the flow cell to receive the incident electromagnetic radiation transmitted through the flow cell and the electromagnetic radiation forward-scattered by the particles. Each detector element generates an electrical signal characteristic of the number and / or size of the detected particles. The photodetector characterizes the particles based on a differential signal generated from each detector element signal. The detector characterizes the particles as having a refractive index lower or higher than that of the fluid. The detector can characterize the particles as metallic or non-metallic. In some embodiments, for example, the photodetector array is provided at a scattering angle within 0 to 5 degrees, optionally within 0 to 0.5 degrees, with respect to the optical axis of the incident beam.

[0039]

[0039] In one aspect, a system for detecting particles in a fluid is provided, the system comprising: i) a flow cell for flowing a fluid containing particles along a flow direction through a beam of electromagnetic radiation; ii) a light source in optical communication with the flow cell for providing a beam of electromagnetic radiation, optionally a structured beam such as a dark beam; iii) a focusing system in optical communication with the light source for focusing the beam of electromagnetic radiation onto the flow cell; iv) an optical collection system for collecting at least a portion of the electromagnetic radiation and directing it towards a photodetector, the photodetector comprising at least two detection elements, and optionally, the photodetector being arranged in optical communication with the flow cell for receiving the incident electromagnetic radiation transmitted through the flow cell and the electromagnetic radiation forward scattered by the particles; v) an adjuster operably connected to the photodetector or the focusing system, the adjuster moving the photodetector or changing the focusing system such that the intensity of the electromagnetic beam is evenly distributed in one direction across each detection element of the photodetector, the photodetector generating an electrical signal characteristic of the number and / or size of the detected particles. The beam can be distributed vertically, horizontally, or both. In some embodiments, for example, the photodetector array is provided at a scattering angle within 0 to 5 degrees, optionally within 0 to 0.5 degrees, with respect to the optical axis of the incident beam.

[0040]

[0040] In one aspect, a system for detecting particles in a fluid is provided. The system includes: (i) a flow cell for flowing a fluid containing particles along a flow direction through a beam of electromagnetic radiation; (ii) a light source in optical communication with the flow cell for providing the beam of electromagnetic radiation; (iii) a focusing system in optical communication with the light source for focusing the beam of electromagnetic radiation to generate a region of high radiation density within the flow cell; (iv) an optical collection system for collecting at least a portion of the electromagnetic radiation and directing it towards a pixelated photodetector, wherein for at least some of the pixels of the pixelated photodetector, each pixel has an area sufficient to collect a majority of the energy of the particle-beam interaction signal; and (v) the pixelated photodetector generates an electrical signal characteristic of the number and / or size of the detected particles.

[0041]

[0041] In one aspect, a system for detecting particles in a fluid is provided. The system includes: (i) a flow chamber for flowing a fluid containing particles along a flow direction through a beam of electromagnetic radiation; (ii) a light source in optical communication with the flow chamber for providing the beam of electromagnetic radiation; (iii) a focusing system in optical communication with the light source for focusing the beam of electromagnetic radiation to generate a region of high radiation density within the flow chamber; (iv) an optical collection system for collecting at least a portion of the electromagnetic radiation and directing it towards a pixelated photodetector, wherein for at least some of the pixels of the pixelated photodetector, each pixel has an area corresponding to the spatial extent of the particle-beam interaction signal within the beam; and the pixelated photodetector generates an electrical signal characteristic of the number and / or size of the detected particles.

[0042]

[0042] In one aspect, a system for detecting particles in a fluid is provided, the system comprising: (i) a flow cell for flowing a fluid containing particles along a flow direction through a beam of electromagnetic radiation; (ii) a light source in optical communication with the flow cell for providing the beam of electromagnetic radiation; (iii) a focusing system in optical communication with the light source for focusing the beam of electromagnetic radiation to generate a region of high radiation density within the flow cell; (iv) an optical collection system for collecting at least a portion of the electromagnetic radiation and directing it towards a pixelated photodetector, the optical collection system comprising means for recollimating or focusing the beam of electromagnetic radiation, and for at least some of the pixels of the pixelated photodetector, each pixel having a region corresponding to the spatial extent of the particle-beam interaction signal within the beam, the photodetector generating an electrical signal characteristic of the number and / or size of the detected particles xx.

[0043]

[0043] A regulator may be operably connected to the photodetector to translate, move, rotate, or tilt the photodetector. The regulator may be a mirror or lens operably connected to the focusing system to adjust the path of the beam of electromagnetic radiation. The regulator may also be configured to provide an optical beam output density to the flow cell or the photodetector, to adjust the beam spot size, and to adjust the region of high radiation density within the flow cell or any combination thereof. The system described herein may further include an imager, the beam of electromagnetic radiation may be directed towards the imager, and the imager may provide feedback to the regulator in a closed loop for an optimal optical beam output density, an optimal beam spot size, an optimal region of high radiation density within the flow cell, or any combination thereof.

[0044]

[0044] The beam of electromagnetic radiation may be a Gaussian beam, a structured non-Gaussian beam, a structured dark beam, or an anamorphic beam in a top-hat configuration.

[0045]

[0045] The system of the present invention includes an optical particle counter, an optical particle analyzer, and an optical particle sizer.

[0046]

[0046] The photodetector can include at least two detector elements and characterizes the particles based on a differential signal from the individual signals from each detector element indicating the particles. The described system can include an analyzer for generating and / or analyzing the differential signal. The focusing system can direct a beam of electromagnetic radiation through the flow cell at least twice, and the particles in the flow cell interact with different portions of each individual beam passing through the flow cell. The analyzer can analyze the differential signal in the time domain. The focusing system can include a half-wave plate, a quarter-wave plate, or both for changing the polarization state of the beam.

[0047]

[0047] The described system can further include a modulator that optically communicates with a light source for modulating a beam of electromagnetic radiation, such as a modulator like a chopper. The modulator can have a modulation frequency of 50 kHz, 100 kHz, 200 kHz, or optionally 500 kHz or more. The photodetector can have a cooling system for reducing the dark current and increasing the signal-to-noise ratio. The described system can further include a lock-in amplifier, and the lock-in amplifier is bandwidth-adjusted to the frequency of the modulator.

[0048]

[0048] The focusing system can include one or more diffractive optical elements. The diffractive optical element can extend the depth of focus of a beam of electromagnetic radiation and generate a longer beam waist and a larger region of high radiation density within the flow cell.

[0049]

[0049] The focusing system can include a variable-focus lens, such as an ultra-fast variable-focus lens, for changing the depth of focus or the region of high radiation density within the flow cell.

[0050]

[0050] The various aspects described herein can also be used in combination with each other, and various possible combinations are specifically disclosed herein.

[0051]

[0051] Various methods of using the described system for detecting particles in a fluid are also specifically disclosed herein.

[0052]

[0052] The present invention also provides a method for detecting, counting, and / or characterizing the size of particles in a fluid using a probe beam of electromagnetic radiation, such as a structured beam including a dark beam. In some embodiments, the method includes detecting transmitted and forward scattered light from a flow cell having a fluid containing particles. In some embodiments, the method uses a segmented detector including one or more pixel pairs, and / or a differential detection configuration such as differential detection using a structured beam such as a dark beam, to detect transmitted and forward scattered light from a flow cell. In some embodiments, the method includes detecting transmitted and forward scattered light from a flow cell having a fluid containing particles, and optionally includes additional off-axis detection of scattered light, for example using a scattered light collection option and a scattered light detector. The present invention also provides a method for detecting, counting, and / or characterizing the size of particles in a fluid by detecting transmitted and forward scattered light, and optionally achieving a rapid (e.g., faster than the average velocity of the particles as they pass through the beam) transformation along the lateral direction and / or the z-axis line of the flow cell (e.g., along the beam axis between the light source and the detector), to achieve a greater sampling volume of the fluid per unit time compared to a system that does not use the transformation. The present invention also optionally uses a pixelated light detector(s) having a pixel region corresponding to the spatial extent (e.g., within 1.5 times, optionally within 1.2 times) of the particle-beam interaction signal in the beam to detect transmitted and forward scattered light, to provide a method for detecting, counting, and / or characterizing the size of particles in a fluid, with enhanced detection of more particle transitions and improved sample volume analyzed per unit time. The present invention also provides a method for detecting, counting, and / or characterizing the size of particles in a fluid by detecting transmitted and forward scattered light, optionally including additional off-axis detection of scattered light or fluorescence to distinguish biological particles from non-biological particles, for example using a scattered light collection option and a scattered light detector.

[0053]

[0053] In one embodiment, a method for detecting, counting, and / or characterizing particles in a fluid includes: (i) providing a flow of fluid containing particles, for example, within a flow cell; (ii) generating a beam of electromagnetic radiation using a light source and optionally one or more beam steering and / or shaping components such as a structured beam or a dark beam; (iii) passing the beam of electromagnetic radiation through the flow cell using a shaping optical system such as a beam steering and / or focusing system to generate electromagnetic radiation transmitted by the flow cell and electromagnetic radiation forward scattered by the particle(s) within the flow cell; (iv) directing at least a portion of the electromagnetic radiation transmitted by the flow cell and the electromagnetic radiation forward scattered by the particle(s) from the flow cell towards an array of photodetectors, for example, a segmented array of photodetectors including one or more pixel pairs; (v) detecting the electromagnetic radiation transmitted by the flow cell and a portion of the electromagnetic radiation forward scattered by the particle(s) to generate one or more signals; and (vi) analyzing the one or more signals using hardware or a processor, for example, by generating and analyzing a differential signal, to detect and / or analyze the particles. In one embodiment of the method, the array of photodetectors is arranged to be in optical communication with the flow cell for receiving the incident electromagnetic radiation passing through the flow cell and the electromagnetic radiation scattered by the particles, and for example, the electromagnetic radiation scattered by the particles includes the forward scattered electromagnetic radiation. In one embodiment of the method, the incident electromagnetic radiation passing through the flow cell and the electromagnetic radiation scattered by the particles undergo constructive and / or destructive optical interference. In one embodiment of the method, the array of photodetectors is provided at a scattering angle within 0 degrees to 5 degrees with respect to the optical axis of the incident beam, and optionally, for some applications, at a scattering angle within 0 degrees to 1 degree with respect to the optical axis of the incident beam, and optionally, for some applications, at a scattering angle within 0 degrees to 0.5 degrees with respect to the optical axis of the incident beam, and optionally, for some applications, at a scattering angle within 0 degrees to 0.1 degrees with respect to the optical axis of the incident beam. In one embodiment of the method, the array of photodetectors is provided to be in optical communication with the flow cell for detecting the interaction of the particles with the electromagnetic radiation scattered by the particles and the illumination wavefront.

[0054]

[0054] Although not wishing to be bound by a particular theory, there may be an explanation herein of the beliefs or understanding of the underlying principles related to the apparatus and methods disclosed herein. Regardless of the ultimate correctness of the mechanical explanations or hypotheses, it is recognized that embodiments of the present invention can be functional and useful.

Brief Description of the Drawings

[0055]

Figure 1A

Figure 1B

Figure 2

Figure 3

Figure 4

Figure 5

Modes for Carrying Out the Invention

[0056]

[0060] In the following description, numerous specific details of the apparatus, apparatus components, and methods of the present invention are set forth in order to provide a complete description of the exact nature of the invention. However, it will be apparent to those skilled in the art that the present invention may be practiced without these specific details.

[0057]

[0061] In general, the terms and phrases used herein have their technically recognized meanings, which can be found by reference to standard texts, periodical references, and contexts known to those skilled in the art. The following definitions are provided to clarify their specific use in the context of the present invention.

[0058]

[0062] "Particle" refers to a small object that is often regarded as a contaminant. A particle can be any material created by the action of friction, for example, when two surfaces come into mechanical contact and there is mechanical movement. Particles can consist of dust, dirt, smoke, ash, water, soot, metal, oxide, ceramic, mineral, or any combination thereof or an aggregate of materials such as other materials or contaminants. "Particle" may also refer to biological particles, such as viruses, spores, and microorganisms including bacteria, fungi, archaea, protists, and other single-celled microorganisms. In some embodiments, for example, biological particles are characterized by a size dimension (e.g., effective diameter) in the range of 0.1 - 15 μm, and optionally, for some applications, in the range of 0.5 - 5 μm. A particle may refer to a small object that absorbs, emits, or scatters light and is thus detectable by an optical particle counter. As used herein, "particle" is intended to exclude individual atoms or molecules of a carrier fluid, such as water, air, process liquid chemicals, process gases, etc. In some embodiments, particles initially exist on a surface, such as the tool surface of a microfabrication facility, are released from the surface, and can then be analyzed in a fluid. Some systems and methods detect particles that include an aggregate of materials having a size dimension such as an effective diameter, where the size dimension is 5 nm, 10 nm, 20 nm, 30 nm, 50 nm, 100 nm, greater than 500 nm, 1 μm or greater, or 10 μm or greater. Some embodiments of the present invention detect particles having a size dimension such as an effective diameter selected from the range of 10 nm - 150 μm, optionally 10 nm - 10 μm for some applications, optionally 10 nm - 1 μm for some applications, and optionally, 10 nm - 0.5 μm for some applications.

[0059]

[0063] The expression "detecting a particle" broadly refers to sensing, identifying, counting, and / or characterizing the presence of a particle, such as characterizing the particle in terms of size dimensions such as effective diameter. In some embodiments, detecting a particle refers to counting the particle. In some embodiments, detecting a particle refers to characterizing and / or measuring the physical properties of the particle, such as effective diameter, cross-sectional dimensions, shape, size, aerodynamic size, or any combination thereof. In some embodiments, the detection of the particle is performed in a flowing fluid such as a gas having a volumetric flow rate selected over a range of 0.05 CFM to 10 CFM, optionally 0.1 CFM to 5 CFM for some applications, and optionally 0.5 CFM to 2 CFM for some applications. In some embodiments, the detection of the particle is performed in a flowing fluid such as a liquid having a volumetric flow rate selected over a range of 1 to 1000 mL / min.

[0060]

[0064] "Optical particle counter" or "particle counter" is used interchangeably and generally refers to a particle detection system that uses optical detection to detect particles by analyzing particles in a fluid flow. Optical particle counters include, for example, liquid particle counters and aerosol particle counters, including systems for detecting individual single particles in a fluid flow. An optical particle counter provides a probe beam of electromagnetic radiation (e.g., a laser) to an analysis region or volume where the beam interacts with any particles and detects the particles based on scattered (forward and / or side scatter), emitted, and / or transmitted light from the flow cell. Detection can focus on electromagnetic radiation scattered, absorbed, obscured, and / or emitted by the particle(s). Various detectors for optical particle counters include, for example, detector arrays including a single detection element (e.g., a photodiode, a photomultiplier tube, etc.), segmented detectors, cameras, various detector orientations, etc., and are known in the art. Optical particle counters include condensation particle counters, condensation nucleus counters, split beam differential systems, etc. When used in the context of a condensation particle counter, the particle counter portion generally refers to the detection system or its components (e.g., an electromagnetic radiation source, an optical system, a filter, optical collection, a detector, a processor, etc.). In one embodiment, for example, an optical particle counter includes a light source for generating a beam of electromagnetic radiation, a beam steering and / or shaping optical system for directing and focusing the beam onto a fluid sample, e.g., a region through which a liquid or gas is flowing, such as a flow cell. A typical optical particle counter consists of a photodetector, such as a photodetector array in optical communication with the flow cell, and collection optics for collecting and imaging electromagnetic radiation scattered, transmitted, or emitted by particles passing through the beam. The particle counter may further include electronics and / or processor components for reading, signal processing, and analysis of the electrical signals generated by the photodetector, including a current-to-voltage converter, a pulse height analyzer, and signal filtering and / or amplification electronics.An optical particle counter may also include a fluid actuation system such as a pump, fan, or blower to generate a flow for transporting a fluid sample containing particles through the detection region of the flow cell, and can generate a flow characterized, for example, by a volumetric flow rate. Useful flow rates for a sample containing one or more gases include flow rates selected in the range of 0.05 CFM to 10 CFM, optionally 0.1 CFM to 5 CFM for some applications, and optionally 0.5 CFM to 2 CFM for some applications. Useful flow rates for a sample containing one or more liquids include flow rates selected in the range of 1 to 1000 mL / min.

[0061]

[0065] The expression "interference detection of particles" refers to systems and methods that use optical interference to detect one or more particles. In some embodiments, coherent beams of electromagnetic radiation are superimposed to cause optical interference for sensing, counting, and / or determining the size characteristics of particles that interact with at least a portion of the electromagnetic radiation.

[0062]

[0066] "Structured beam detection" refers to systems and methods in which a structured beam of electromagnetic radiation having a non-Gaussian intensity distribution passes through a flow cell containing particles and is detected using a photodetector array to sense, count, and / or characterize the particles.

[0063]

[0067] "Dark beam detection" refers to systems and methods in which a dark beam of electromagnetic radiation having a spatial intensity profile with a region of attenuated intensity, such as a central line decrease in intensity, passes through a flow cell containing particles and is detected using a photodetector array to sense, count, and / or characterize the particles.

[0064]

[0068] In a method of providing statistically significant data, to detect and count small particles (e.g., having an effective diameter of less than 100 nm) in clean and ultra-clean fluids, a high signal-to-noise ratio (abbreviated as S / N or SNR) is required. Due to the high S / N ratio, nanoparticles can be clearly detected above the noise floor. As used herein, "statistically significant data" refers to the detection of particles per unit time sufficient to accurately evaluate the contamination level in the fluid. In some embodiments, the high S / N is not directly related to sizing accuracy. For example, in some optical particle counters, since the beam waist occupies only a small part of the flow cell channel, in this approach, a subset of the entire flow is monitored so that particles can pass through the edge of the beam where the irradiance is smaller than the center. When a 50 nm particle passes through the outer edge of the beam, it can generate a signal similar to that of a 10 nm particle passing through the center of the beam. Thus, in some optical particle counters, the S / N is high and it may be possible to detect 2 nm particles, but the sizing accuracy is not very high. In some of the current optical particle counters and methods, the goal is to be able to count enough particles to achieve a quantitative and statistically sound assessment of the contamination level of ultra-high purity fluids in the shortest possible time. For example, current state-of-the-art particle counters may take up to 40 minutes to count enough particles to achieve a statistically appropriate concentration (acceptable relative standard deviation) measurement when monitoring the state of an ultra-pure water system. By improving and maintaining a high S / N through this system and method, the time interval required to measure this statistically acceptable minimum number of particles can be shortened by more than one-tenth. This provides value as the user can more quickly identify deviations from process control limits.

[0065]

[0069] The expression "high signal-to-noise ratio" refers to the signal-to-noise ratio of an optical particle detection system sufficient for accurate and sensitive detection of particles in a fluid flow, including particles characterized by small physical dimensions (e.g., an effective diameter of 200 nm or less, optionally, in some embodiments, 100 nm or less, and optionally, in some embodiments, 50 nm or less). In one embodiment, "high signal-to-noise ratio" refers to a signal-to-noise ratio high enough to sense particles characterized by small physical dimensions, such as particles having a small effective diameter of 20 nm, optionally, in some applications, a small diameter of 10 nm, and optionally, in some applications, a small diameter of 1 nm. In one embodiment, "high signal-to-noise ratio" refers to a signal-to-noise ratio high enough to accurately detect and count particles with a false detection rate of 50 counts / L or less, such as the detection of particles having an effective diameter selected in the range of 1 to 1000 nm. In one embodiment, "high signal-to-noise ratio" refers to a signal-to-noise ratio high enough to provide a statistically acceptable minimum number of particles in a time frame at least 10 times less than that of a conventional optical particle counter.

[0066]

[0070] The expression "differential detection" refers to, for example, a technique and system that uses a differential signal from a forward optical axis detector pair(s) at a scattering angle within 0 degrees to 0.5 degrees with respect to the optical axis of the incident beam, and optionally, in some applications, at a scattering angle within 0 degrees to 0.1 degrees with respect to the optical axis of the incident beam, and optionally at or near 0 degrees. Using at least 2 pixels, a differential signal (e.g., one upper (or top) and one lower (or bottom)) can be generated to form a single pixel pair for differential detection. Alternatively, multiple pixels can be used in a segmented differential detector that includes, for example, one or more pixel pairs in each active detector region of the differential detector (e.g., an upper active region and a lower active region), using multiple pixel pairs. For example, one pixel of each pixel pair corresponds to the upper active detector region, and the other pixel of each pixel pair corresponds to the lower active region. The number of pixel pairs can be in the range of, for example, 1 to 500 pixels, and optionally, in some applications, in the range of 50 to 100 pixels. In some embodiments, the differential signal is generated by differentially adding signals from pixel pairs corresponding to different active regions of a segmented detector array, such as the upper half and the lower half. Differential detection can be used in this system and method to reduce noise and thus improve the signal-to-noise ratio. In some embodiments, for example, differential detection is used for detecting a combination of incident electromagnetic radiation passing through the flow cell and electromagnetic radiation forward-scattered by one or more particles in the fluid flow within the flow cell. In some embodiments, for example, the distribution of the incident light has an output distribution that is balanced between the first and second active detection regions (e.g., the upper half and the lower half) of the differential detector such that the first and second active detection regions are characterized by an incident radiation output within 10%, optionally, in some applications, within 5%, and optionally, in some applications, within 1%. Differential detection includes, for example, techniques and systems with closed-loop control based on an evaluation of the noise amplitude of the differential signal when no particles are present (i.e., when there is no scattering from particles).In some embodiments, a steering mirror is used to adjust the incident beam position of the detector to reduce or minimize the noise level of the differential signal, which may occur when the beam output is evenly divided between first and second active detector elements (e.g., the upper and lower elements of the detector). Closed-loop control can also be achieved by transforming the position of the detector, rotating the detector to align the beam axis and the detector axis, and reducing or minimizing the noise level of the differential signal.

[0067]

[0071] "Structured beam" refers to a coherent beam of electromagnetic radiation (e.g., a laser) having a non-Gaussian spatial intensity distribution. Structured beams include beams characterized by attenuation regions such as dark beams, beams with line foci with dark line singularities, beams characterized by two or more discrete intensity lobes, etc. In one embodiment, the structured beam corresponds to a transverse mode such as TEM01. Structured beams include focused, combined, and laser beams. Structured beams and dark beams can be generated by techniques known in the art, including the use of optical masks, modification of laser cavities, combination of multiple beams, spatial and / or polarization filters, and other operations such as interference or polarization modification schemes.

[0068]

[0072] "Beam propagation axis" refers to an axis parallel to the direction of travel of a beam of electromagnetic radiation.

[0069]

[0073] "Optical communication" refers to components arranged to allow light to move between components. Optical communication includes configurations where two components communicate directly optically and light moves directly between the components, and configurations where two components communicate indirectly optically and light moves between the components via one or more additional optical elements such as lenses, mirrors, windows, filters.

[0070]

[0074] "Optical axis" refers to the direction in which electromagnetic radiation propagates through the system.

[0071]

[0075] "Photodetector array" refers to a photodetector for spatially resolving an input signal (e.g., electromagnetic radiation) two-dimensionally across the entire active area of the detector. A photodetector array can generate an image corresponding to an intensity pattern on the active area of the detector, for example. In one embodiment, the photodetector array includes an array of individual detector elements, also referred to herein as pixels, and is, for example, a two-dimensional array of photodetectors, a charge-coupled device (CCD) detector, a complementary metal-oxide-semiconductor (CMOS) detector, a metal-oxide-semiconductor (MOS) detector, an active pixel sensor, a microchannel plate detector, or a two-dimensional array of photodiodes.

[0072]

[0076] "Light source" refers to a device or device component for delivering electromagnetic radiation to a sample. This term is not limited to visible radiation such as visible light, but is used in a broad sense to include any electromagnetic radiation, including visible radiation, ultraviolet radiation, and / or infrared radiation. The light source can be embodied as a laser or laser array such as a diode laser, a diode laser array, a diode laser-pumped solid-state laser, an LED, an LED array, a gas-phase laser, a solid-state laser, etc. In some embodiments, the light source is for generating one or more coherent beams of electromagnetic radiation, for example, for generating a probe beam with an optical particle counter. In one embodiment, the light source can include one or more components such as a beam shaping system, a phase mask, a beam combiner, a polarization controller, a wave plate, or other components for generating a structured beam such as a dark beam, and supplies a probe beam to an optical particle counter.

[0073]

[0077] The terms "electromagnetic radiation" and "light" are used synonymously in this description and refer to waves of electric and magnetic fields. The electromagnetic radiation useful in the methods of the present invention includes, but is not limited to, ultraviolet light, visible light, infrared light, or any combination thereof having wavelengths between about 100 nanometers and about 15 micrometers.

[0074]

[0078] A "high aspect ratio" beam refers to an optical beam such as a structured beam or a dark beam, having an aspect ratio selected from the range of 10:1 to 200:1.

[0075]

[0079] The present system and method integrate active and / or passive components, such as structured beams, e.g., dark beams, and optionally using a differential detection configuration, to enhance on-axis particle measurements by detecting transmitted and forward-scattered light, providing important performance advantages including: (i) achieving a high signal-to-noise ratio and increased sensitivity for detecting and sizing small particles (e.g., having an effective lateral dimension (e.g., diameter) of 10 microns or less, or optionally 1 micron or less or optionally 500 nanometers or less), (ii) increasing the amount of sample fluid analyzed as a function of time, and / or (iii) suppressing false positive indications.

[0076]

[0080] FIG. 1 provides a schematic diagram of a system for detecting particles via on-axis particle measurement by detecting transmitted and forward-scattered light, using a structured beam such as, for example, a dark beam and a differential detection configuration. As shown in FIG. 1, a particle detection system (200) includes a flow cell (210) for transporting a flow of fluid (150) containing particles schematically depicted as a circle within the flow cell (210), such as a flow of gas or liquid having particles. A light source (220), such as a laser source, generates electromagnetic radiation provided to a beam steering and shaping system (221) to generate a probe beam (222), such as a structured beam including a dark beam, provided to the flow cell (210). The probe beam passes through the flow cell (210) and is detected via an on-axis photodetector array (240), such as segmented 1D (one-dimensional) or 2D (two-dimensional) photodetectors (240A and 240B) including one or more pixel pairs, which operatively communicate with a processor (101) to provide output signal(s) to the processor (101). The photodetector array (240) and / or the processor (101) may provide differential detection, for example, in a configuration where individual segmented detector regions are each disposed on different intensity lobes of a structured beam such as a dark beam.

[0077]

[0081] The processor (101) receives and analyzes the output signal from the photodetector array (240) through the generation and analysis of a differential signal (e.g., differential addition, subtraction, etc.) that combines signals from segmented 1D or 2D photodetectors (240A and 240B), and realizes the detection of particles by means of counting and / or size characterization. In some embodiments, one or more transducers (205), such as an oscillator, a displacer, a piezoelectric element, etc., are operably coupled to the flow cell (210) to achieve rapid (e.g., at an average conversion speed at least twice as fast as the average speed of particles passing through the beam) conversion in the lateral direction of the flow cell (e.g., the direction perpendicular to the axis of the incident probe beam) and / or along the z-axis (e.g., along the beam axis between the light source and the detector and / or along the axis of the incident probe beam), and achieve a larger sampling volume of the fluid per unit time. In some embodiments, for example, the photodetector array (240) is provided at a scattering angle within 0 degrees to 5 degrees with respect to the optical axis of the incident beam, optionally at a scattering angle within 0 degrees to 0.5 degrees with respect to the optical axis of the incident beam, and optionally at a scattering angle within 0 degrees to 0.1 degrees with respect to the optical axis of the incident beam.

[0078]

[0082] Also, FIG. 1A shows an optional optical off-axis scattered light detector (268) and a side scattered light collection optical system (267) disposed off-axis with respect to the beam propagation axis of the probe beam (222) and the detector axis of the photodetector array (240). The side scattered light collection optical system (267), such as one or more lenses and / or mirrors, is arranged to receive off-axis scattered light resulting from the interaction of the particles in the flow cell (210) with the probe beam. The side scattered light collection optical system (267) directs at least a portion of the collected scattered light towards a side scattered light detector (268) that is operatively communicating to provide an output signal(s) to the processor (101) for analysis, optionally imaging, detecting and / or characterizing the particle(s). Embodiments incorporating a combination of on-axis differential detection and off-axis side scattered light detection are particularly useful for characterizing particles as biological or non-biological particles. In some embodiments, for example, the processor (101) compares signals from the on-axis photodetector array (240) and the side scattered light detector (268) to determine whether the particle is a biological particle or a non-biological particle. In some embodiments, for example, a small output signal from the side scattered light detector (268) or the absence of a measurable signal from the side scattered light detector (268), accompanied by a measurable signal from the on-axis photodetector array (240), indicates a biological particle such as a microbial particle.

[0079]

[0083] FIG. 1B provides a schematic diagram of an alternative system for detecting particles for on-axis particle measurement by detecting transmitted and forward-scattered light using, for example, a structured beam such as a dark beam and a differential detection configuration, and the optical shape is set to provide a dual-path optical shape. As shown in FIG. 1B, the system (200) includes a light source (220), a beam steering and shaping system (221), a flow cell (210), and a light detector array (240) including a pair of detector arrays and a transducer (205). Further, a beam splitter (265) and a mirror (275) are included to provide a dual-path optical shape. Optionally, the beam steering and shaping system (221) realizes a high aspect ratio beam such as a beam characterized by an aspect ratio selected from the range of 10:1 to 200:1 provided to the flow cell (210). The light detector array (240) is configured as a pair of detector arrays including a pair of detector arrays (240A and 240B, schematically shown separately below the particle detection schematic adjacent to the exemplary signals corresponding to particle detection events and extended from their positions within the detector (240) for clarity). The light detector array (240) can be configured to realize differential detection. Optionally, the pair of detector arrays (240A and 240B) are arranged on the intensity lobe of a structured beam such as a dark beam. In some embodiments, one or more transducers (205) such as an oscillator, a displacer, a piezoelectric element, etc. are operably coupled to the flow cell (210) to effect rapid (e.g., at an average conversion rate greater than twice the average velocity of the particles passing through the beam) conversion in the lateral direction and / or the z-axis of the flow cell (e.g., along the beam axis between the light source and the detector and / or along the axis of the incident probe beam) to achieve a greater sampling volume of the fluid per unit time. In some embodiments, for example, the light detector array is provided at a scattering angle within 0 degrees to 5 degrees with respect to the optical axis of the incident beam. Optionally, it is provided at a scattering angle within 0 degrees to 0.5 degrees with respect to the optical axis of the incident beam.

[0080]

[0084] FIG. 1B also shows a representative signal of the photodetector array (240) from the individual pair of detector arrays (240A and 240B) as a function of time of particles passing through the beam in the flow cell (or the trajectory of particles passing through the beam), where the solid line is the signal from detector array 240A and the dotted line is the signal from detector array 240B. As shown in FIG. 1B, the signals from the individual pair of detector arrays (240A and 240B) are each characterized by a minimum and a maximum value and are inverted with respect to each other. The signals from the individual pair of detector arrays (240A and 240B) can be combined, for example, via differential addition, subtraction, multiplication, etc. to provide a signal such as a differential signal, which can be analyzed to provide accurate information regarding the size, optical properties (e.g., refractive index), and composition of the particles.

[0081]

[0085] The depicted optical configuration allows for constructive and destructive interference of the beam that aids sensitivity, including, for example, a combination of light transmitted from the flow cell and forward light scattered from particles within the flow cell. Using a dual-path optical configuration and differential detection improves the sensitivity and accuracy for detecting small particles (e.g., having an effective dimension of less than 100 nm, optionally less than 50 nm, optionally less than 20 nm). Using a high aspect ratio beam increases the amount of sample that can be detected and the amount of sample that can be monitored per unit time.

[0082]

[0086] FIG. 2 shows a perspective view of the components of a particle measurement system including a vibration transducer operably connected to a sample cell that optically communicates with an objective lens. As shown in FIG. 2, the objective lens (300) focuses an optical beam (320), such as a structured beam, from a light source (220) toward the flow cell (210), which is operably coupled to a transducer comprising a vibration transducer (310) for converting the flow cell (210) along the lateral direction (330). The lateral direction (330) is optionally orthogonal to the z-axis line (331) corresponding to the propagation axis of the incident beam, such that a region of high radiation density changes the position within the flow cell, enabling an increase in the amount of fluid analyzed per unit time. In some embodiments, the transducer (310) effects conversion of the flow cell (210) along the z-axis line (331), such that a region of high radiation density changes the position within the flow cell, enabling an increase in the amount of fluid analyzed per unit time. The electromagnetic radiation transmitted by the flow cell and the electromagnetic radiation forward scattered by the particles within the flow cell are detected by an array of photodetectors (240), such as segmented 1D or 2D photodetectors (240A and 240B), using, for example, an on-axis differential detection system.

[0083]

[0087] FIG. 3 provides a schematic view showing an exemplary imaging detector using a pixelated differential detector configuration. Section 1 of FIG. 3 provides a schematic view of a beam imaged on a pixelated detector having an upper active region (“upper half”) and a lower active region (“lower half”) in which the energy of the beam is uniformly distributed (50% each) within ±1% to 5% between the upper and lower halves of the detector. Since the beam energy is balanced between the two active regions, correlated laser noise is at least partially canceled using differential detection. Further, sizing matching of the pixels to the signal (i.e., the spatial extent of the signal) optimizes the signal-to-noise ratio, for example, to achieve a high signal-to-noise ratio.

[0084]

[0088] Section 2 of FIG. 3 provides a schematic diagram of the beam imaged on a pixelated detector corresponding to the condition where particles enter the beam in the flow cell, for example, enter the beam from below. As shown in Section 2 of FIG. 3, bright fringes are observed in one or a subset of the pixels in the upper half of the pixelated detector, and dark fringes are observed in one or a subset of the pixels in the lower half of the pixelated detector. Section 3 of FIG. 3 provides a schematic diagram of the beam imaged on a pixelated detector corresponding to the condition where particles are being converted while passing through the upper part of the beam waist in the flow cell. As shown in Section 3 of FIG. 3, dark fringes are observed in one or a subset of the pixels in the upper half of the pixelated detector, and bright fringes are observed in one or a subset of the pixels in the lower half of the pixelated detector. In this configuration, the differential signal is driven by slight variations in the output at the detector. As the pixel size increases, the slight variations when the particle crosses the beam decrease. If the pixel becomes too small, even with the same slight variations, the output of the detector decreases and the amplitude of the signal decreases. Therefore, there is an optimal value in the middle to reflect this trade-off.

[0085]

[0089] FIG. 4 provides a schematic diagram showing an exemplary signal as a function of time achieved using differential detection of particles including a differential signal (500), an upper signal (510) from one or a subset of pixels from the upper half of the differential detector, and a lower signal (520) from one or a subset of pixels from the lower half of the differential detector. As shown in FIG. 4, the differential signal (500) is generated by differentially adding the lower signal (520) and the upper signal (510). By thus deriving the differential signal (500) from the upper signal (510) and the lower signal (520), simultaneous reduction of noise is achieved by correlated differential noise cancellation, and the overall signal-to-noise ratio is improved.

[0086]

[0090] Analyze the differential signal (500) to provide information regarding the effective size dimension(s) and optical properties (e.g., refractive index) of the particles, distinguish different particle optical properties such as refractive index, and thus be able to provide information about the particle composition. To illustrate this concept, the detection of particles with different refractive indices and compositions is compared, namely, (i) polystyrene latex (PSL) and (ii) gold nanoparticles. The refractive index of PSL particles is 1.59, which is greater than the refractive index of water, 1.33. Thus, when entering the beam (e.g., the situation corresponding to section 2 of FIG. 4), bright fringes are observed in the upper half of the differential detector, and dark fringes are observed in the lower half of the differential detector. Then, when converting through the beam waist (e.g., the situation corresponding to section 3 of FIG. 4), dark fringes are observed in the upper half of the differential detector, and bright fringes are observed in the lower half of the differential detector. On the other hand, when gold nanoparticles with a refractive index smaller than that of water at the wavelength of the probe beam are analyzed using some embodiments of the differential detection method of the present invention, a signal inverted with respect to the PSL particles is observed. When entering the beam (e.g., the situation corresponding to section 2 of FIG. 4), dark fringes are observed in the upper half of the differential detector, and bright fringes are observed in the lower half of the differential detector. Then, when converting through the beam waist (e.g., the situation corresponding to section 3 of FIG. 4), bright fringes are observed in the upper half of the differential detector, and dark fringes are observed in the lower half of the differential detector. In this way, the refractive index (and composition) of the particles analyzed by this method can be characterized using the sequence and position of bright and dark fringes as observed in the differential signal.

[0087]

[0091] 1D and 2D detectors including segmented detectors are useful for differential detection in certain embodiments. In a 1D segmented detector, two options are useful for some applications. (i) Orient the detector segments perpendicular or parallel to the particles passing through the beam so that two adjacent pixels can be used as a single pair of top and bottom pixels. Alternatively, mount two 1D detectors at 90 degrees to the beam and use a knife-edge prism to send the upper half of the beam to one 1D detector and the lower half of the beam to a second 1D detector. The number of pixel pairs can be in the range of, for example, 1 to 500 pixels, and optionally, in some applications, in the range of 50 to 100 pixels. A pixel width selected from the range of 10 to 500 microns is useful for certain embodiments and, optionally, for some applications selected from the range of 50 to 100 microns.

[0088]

[0092] FIG. 5 provides a schematic diagram showing an optical configuration and detector arrangement for providing closed-loop feedback control of differential detector alignment to balance beam energy across, for example, two active regions (e.g., upper and lower halves) of a detector. Thus, laser noise is at least partially cancelled using differential detection. The use of closed-loop feedback control in certain embodiments is useful for correcting alignment drift and / or for dealing with external acoustic or vibration interference. As shown in FIG. 5, a light source (600), such as a laser, provides a structured beam that passes through a flow cell (620) via an optical beam (605a), e.g., steering and / or focusing optics (610a). The optical beam (605a) interacts with particles in the fluid flowing through the flow cell (620) to generate transmitted electromagnetic radiation and forward-scattered electromagnetic radiation (collectively 605b), which is collected via collection optics (610b). The transmitted electromagnetic radiation and forward-scattered electromagnetic radiation (605b) are directed towards a mirror (630), optionally a steering mirror, which directs at least a portion of the transmitted electromagnetic radiation and forward-scattered electromagnetic radiation (605b) towards a differential detector (640), e.g., a segmented detector having a first active region and a second active region (e.g., upper and lower halves). A positioner (650) is operably coupled to the differential detector (640) to adjust the position of the differential detector (640), such as by moving the detector laterally and / or vertically or rotating the detector. In one embodiment, a processor (660) operably communicates with the mirror (630) and / or the positioner (650) to control the relative alignment of the transmitted electromagnetic radiation and forward-scattered electromagnetic radiation (605b) on the first and second active regions of the differential detector (640), such as the upper and lower halves of the differential detector (640). In one embodiment, the processor (660) receives and analyzes signals corresponding to the first active region and the second active region (e.g., upper and lower halves) and determines a differential signal.

[0089]

[0093] To minimize noise and maximize the signal, the output transmitted electromagnetic radiation and the forward scattered electromagnetic radiation (605b) can be balanced between the first active region and the second active region (e.g., the upper half and the lower half) of the differential detector (640). In some embodiments, this is accomplished by a closed loop system where the processor analyzes the differential signal when no particles are present and minimizes the noise amplitude of the differential signal via control of the positioner (650) and the mirror (630). In some embodiments, for example, the mirror (630) is used to adjust the beam position on the detector (640) to minimize the noise level of the differential signal. This condition occurs when the beam output is most evenly divided between the upper and lower elements of the differential detector. Minimizing the noise level of the differential signal can also be achieved, for example, by translating the position of the detector, rotating the detector (640), and aligning the beam and detector axes using the positioner (650).

[0090]

[0094] The present invention can be further understood by the following non - limiting examples.

[0091]

[0095] Example 1 - Particle Measurement Using Structured Beams and / or Differential Detection

[0096] This example describes optical shapes, detector configurations, and signal analysis techniques that enable enhanced particle detection and size characterization corresponding to specific embodiments aimed at exemplifying certain features of the present invention.

[0092]

[0097] Scanning Modulated Focus: In some embodiments, for example, the system is designed to create a region of high laser beam optical output density at the measurement point. In conventional systems, this illumination region is typically restricted by the focal angle of the objective lens, limiting the cross-sectional area within the sample cell where the smallest particles can be identified and characterized. A high-speed mechanical oscillator, such as a piezoelectric or similar device, can be used to physically move or translate the sample cell closer to or farther from the objective lens. This mechanical translation causes the point of highest optical density within the sample cell to move. When performed at a sufficiently high frequency and faster than the particle transit time of the laser beam, a larger cross-sectional area of the sample cell can be characterized for the particles. This approach results in an increase in the sample volume of the fluid per unit time without the need for an increase in laser output.

[0093]

[0098] Scanning Modulated Cross Axis : In some embodiments, for example, the system is designed to create a region of high laser beam optical output density at the measurement point. In conventional systems, this region is typically restricted by the focal angle of the objective lens, limiting the cross-sectional area within the sample cell where the smallest particles can be identified and characterized. A high-speed mechanical oscillator, such as a piezoelectric or similar device, can be used to physically move or translate the sample across the entire laser beam. This mechanical translation causes the point of highest optical density within the sample cell to move laterally. When performed at a sufficiently high frequency and faster than the particle transit time of the laser beam, a larger cross-sectional area of the sample cell can be characterized for the particles. This essentially results in an increase in the sample volume of the fluid per unit time without the need for an increase in laser output.

[0094]

[0099] Two - Dimensional Scanning Modulation : In some embodiments, for example, the scanning modulation focus and the scanning modulation cross-axis can be used individually or in combination to increase the cumulative effect.

[0095]

[0100] Imaging of Sample Amount on Detector: In some embodiments, for example, this feature results from the relationship that the signal-to-noise ratio (SNR or S / R) is maximized when at least a portion of the pixels of the photodetector each have a width sufficient to collect most of the energy of the particle beam interaction signal. The image of the particle beam interaction signal is important along the slow axis (major axis) of the beam at the detector. The vertical extent of the signal within the beam is not as important. As the particle passes through the beam, the signal transitions across the upper and lower detector elements. To maximize the signal-to-noise ratio, the spatial extent of the particle beam interaction signal along the slow axis can be mainly disposed on a single pair of detector elements. Dispensing the particle beam interaction signal across multiple pairs of detectors reduces the measured signal-to-noise ratio. Considering that the sample volume may be illuminated with a high aspect ratio beam (in the beam waist orthogonal to the position of the sample volume), the image of this position created along the beam axis will be of a similar shape and needs to have a magnification sufficient to disperse the image across an appropriate number of pixel detector elements.

[0096]

[0101] Alternative detector shapes may include the following features. After the focused beam passes through the sample volume, the horizontal and vertical beam waists are in the same cross-section within the sample volume, and the beam is collected and re-collimated by the downstream optical system. In this region of the beam, the signal of particle events occurring at or near the beam waist is dispersed across the entire lateral span of the collimated beam. To optimize the signal-to-noise ratio, the beam is focused onto a pixelated detector. Here, the pixel size is the same as or smaller than the RMS spot size of the focusing optics. In this way, spatial discrimination of particle events throughout the sample volume is achieved. The smallest detector area (area of the pixel) is used to capture the particle events.

[0097]

[0102] Partial Attenuation Imaging: In some embodiments, for example, wide (horizontal) and narrow (vertical) images of the sample volume beam cross-section, created by focusing the beam onto a pixelated detector after passing through the sample volume, serve a role in this system and method. This image at the detector can be an enlarged reproduction of the beam profile at the sample volume. When particles pass through the beam at or near the waist, their image at the detector forms a vertical track across the image footprint. To maximize the signal-to-noise ratio as described above, a horizontal slice (possibly a single pixel width in the vertical direction) of the image footprint can be a means to achieve an optimal signal-to-noise ratio.

[0098]

[0103] High Aspect Ratio Beam : In some embodiments, for example, when the beam is presented to the flow of the sample fluid, it is shaped and focused by appropriate optical elements. It focuses tightly in the direction of the fluid flow. When the fluid flows along the y-axis line, the beam is tightly focused in the y-direction. The point of the tightest focus identifies the position of the y-axis beam waist. If the z-axis line is along the axis of the beam, along the x-axis line, the beam becomes much wider than in the y-direction, but the beam also needs to have a minimum x-axis width in the xy plane transverse to the y-axis waist. The beam shaping optics are arranged such that the waists of the x-axis and y-axis occur in the same xy plane. In this case, the beam profiles of both the x-axis and y-axis converge to their respective waists in the same xy plane and diverge from there in the propagation direction. This constitutes a high aspect ratio beam. The co-location of the waists in the same xy plane is necessary for downstream imaging considerations.

[0099]

[0104] Differential Signal : In some embodiments, for example, using the differential signal from a forward-looking on-axis detector pair(s) at a scattering angle of 0 degrees results in significant noise reduction.

[0100]

[0105] Microbial Detection: In some embodiments, for example, the use of structured beams or dark beams with axial differential detection is very effective for detecting microorganisms in water, even if they have a very small refractive index contrast. Microorganisms often go undetected by conventional light scattering particle counters because of their low refractive index contrast (most contain water). The particle counters of some embodiments use a dark beam with axial differential detection combined with lateral scattering detection. If both detectors produce signals of appropriate size, the particle is not a microorganism. If the axial differential detector provides a large signal and the lateral scattering does not provide a response, it is a microorganism.

[0101]

[0106] RI Difference between Particle and Medium : In some embodiments, for example, the shape of the differential signal over time depends on the refractive index of the particle with respect to the medium. The differential detection signal is either an increasing signal above zero followed by a decreasing signal below zero (a bump followed by a dip), or vice versa, a signal below zero followed by an increasing signal above zero (a dip followed by a bump). This signal changes based on the direction of flow and whether the upper detector is subtracted from the lower or vice versa. As an example: In a given configuration, if the refractive index of the particle is greater than the refractive index of the medium, the detection signal will be a bump followed by a dip, but if the refractive index of the particle is less than the medium, the signal will be a dip followed by a bump. Types of materials with a refractive index lower than water or fluid chemicals are gases and many metals. Materials with a refractive index less than that of a gas include certain metals (in the visible part of the spectrum).

[0102]

[0107] Closed - Loop Focus System: In some embodiments, for example, adjusting the optical elements along all three axes achieves a useful and / or optimal beam output density and / or beam size. A small portion of the beam directed towards the photodetector is diverted to the imager, and the size, shape, and / or output density are used to achieve useful and / or optimal particle detection conditions. The laser beam can be accurately and evenly / equally balanced between the upper and lower elements of the differential detector such that laser noise is canceled out in the differential signal. In other words, the detected output can beneficially and / or optimally be the same for the upper and lower detectors. This can be achieved, in some embodiments, by vertically translating the detector (also, the tilt function of a 2D array to align with a high aspect ratio beam), or by steering the laser beam with a mirror or lens to maximize noise cancellation. In some embodiments, a closed-loop system is implemented and the detector and laser are automatically aligned in an arrangement that minimizes background noise by optimizing the "balance" of the laser output across the differential detector elements. Additionally, a closed-loop focus system can be used to adjust a five-axis optical translation stage to achieve an optimal beam output density and / or beam spot size. For example, a small portion of the beam can be redirected to the imager and the acquired image can be used to determine the adjustments necessary to obtain the optimal beam size, shape, and output density.

[0103]

[0108] As the operating temperature of the detector decreases, the dark current of the detector decreases. This decrease in dark current improves the SNR (signal-to-noise ratio) of the detector, reduces the NEP (noise equivalent power) of the detector, and makes it more sensitive to lower incident light levels. There is a theoretical limit to this response to thermal changes, and it may be adopted to design a thermal system to cool to the required level with the required stability.

[0104]

[0109] Use of Chopper: In some embodiments, for example, further improvements in the extraction of low-level optical signals embedded in the noise floor can be achieved by considering how the problems inherent in DC technology and the use of AC methods and modulated light, or a chopper approach, can reduce it. In some embodiments, a chopper is used to turn the incident light on and off at the detector, changing it from DC illumination to AC illumination, typically in the range of kHz. In some embodiments, a lock-in amplifier is used to create synchronous signal detection with a narrow bandwidth tuned to the chopper frequency. In most physical systems, including the electro-optical detection and amplification related to particle detection, noise increases as the frequency approaches DC. For example, a common operational amplifier used in particle detection has 1 / f noise. By shifting the detection measurement from a low-frequency or DC noise source to a measurement at the AC chopper frequency, a higher signal-to-noise ratio and the detection of much weaker signals, usually associated with smaller particles, can be achieved.

[0105]

[0110] Signal Processing Techniques in Particle Signal Detection : In some embodiments, the paths and velocities of various particles of different sizes and material types passing through the collision light source in the time domain are useful considerations for the design and signal analysis in this system and method. For example, the sampling of these discrete and complex time-domain signals can be converted to the frequency domain by Fourier transform or FFT (Fast Fourier Transform). By decomposing the complex periodic signal trace of the particles, an equation for the frequency-domain signal composed of a series of sine waves with various amplitudes, frequencies, and phases is obtained. In some embodiments, a library of the collected or equation-decomposed particle signals during development can be cataloged and used when the magnitude of the system's inherent noise is very close to the size of the particles being observed, or under conditions of a low signal-to-noise ratio. In some embodiments, the collected particle signals have a unique structure specific to the design of the present invention, and signal processing techniques can be used to clarify the signals expected from the indistinguishable random signals representing the contaminated system noise.

[0106]

[0111] In some embodiments, the equation model, or filter, is considered to be the structure of the signal that may be of interest. In some embodiments, when attempting to identify the structure of the input signal, a mathematical filter is used and applied to the arriving signal. In some embodiments, various techniques of signal processing can be used, including convolving the arriving transformed signal with a catalog of filters (assuming that the arriving signal and the modeled signal are linear time-invariant). In some embodiments, the correlation between the arriving signal and the catalog of filters can be used. The recent development of convolution sparse modeling techniques can be used together with thresholding, relaxation, or approximation. In some embodiments, cross coherence is used to divide the arriving signal into smaller patches of variable delay (phase) and width (frequency), and assuming that the arriving signal is piecewise constant, it can be tested against the catalog of models.

[0107] Statement and Variations Regarding Incorporation by Reference

[0112] All references throughout this application, such as patent documents, patent application publications, and non-patent literature documents or other source materials, including issued or granted patents or equivalents, are hereby incorporated by reference in their entirety as if each reference were individually incorporated by reference to the extent that each reference does not at least partially conflict with the disclosure of this application (e.g., a partially inconsistent reference is incorporated by reference except for the partially inconsistent portion of the reference).

[0108]

[0113] The following patents and patent applications are related to interference particle detection using structured beams and are hereby incorporated by reference in their entirety: U.S. Patent No. 7,746,469; U.S. Patent Application Publication No. 20170176312; and PCT International Publication No. 2019 / 082186.

[0109]

[0114] The terms and expressions used herein are used as terms of explanation and not of limitation, and are not intended to exclude equivalents of the features shown and described or portions thereof. However, it is recognized that various modifications are possible within the scope of the invention as claimed. Accordingly, although the invention has been specifically disclosed by way of preferred embodiments, exemplary embodiments and optional features, modifications and variations of the concepts disclosed herein may be resorted to by those skilled in the art, and such modifications and variations are to be regarded as within the scope of the invention as defined by the appended claims. The specific embodiments provided herein are examples of useful embodiments of the invention, and it will be apparent to those skilled in the art that the invention can be practiced using numerous variations of the apparatus, apparatus components, and method steps described in this description. As will be apparent to those skilled in the art, the methods and apparatus useful in the methods of the invention can include numerous optional compositions and processing elements and steps.

[0110]

[0115] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells and their equivalents known to those skilled in the art. Similarly, the terms "a" (or "an"), "one or more", and "at least one" can be used interchangeably herein. It should also be noted that the terms "comprising", "including", and "having" can be used interchangeably. The expression "any of claims XX to YY" (where XX and YY refer to claim numbers) is intended to provide alternative forms of multiple dependent claims and, in some embodiments, is interchangeable with the expression "similarly to any one of claims XX to YY".

[0111]

[0116] When a group of replacement components is disclosed in this specification, it is understood that all individual elements of that group and all sub-groups are disclosed separately. When a Markush group or other group is used in this specification, all individual elements of the group, and all possible combinations and sub-combinations of the group, are intended to be included separately in the disclosure.

[0112]

[0117] All apparatuses, systems, formulations, combinations of components, or methods described or exemplified in this specification can be used to practice the present invention, unless otherwise specified.

[0113]

[0118] Whenever ranges are given in this specification, such as temperature ranges, time ranges, or composition or concentration ranges, all intermediate ranges and sub-ranges, as well as all individual values included in the given ranges, are intended to be included in the disclosure. It will be understood that any sub-range or individual value within a range or sub-range included in the description of this specification may be excluded from the claims of this specification.

[0114]

[0119] All patents and publications described in this specification indicate the level of skill in the art relevant to the present invention. References cited in this specification are hereby incorporated by reference in their entirety for the purpose of showing the prior art as of their publication date or filing date, and this information is intended to be used in this specification, if necessary, to exclude certain embodiments in the prior art. For example, when a composition of matter is claimed, it should be understood that compounds known and available in the art prior to the applicant's invention, including compounds for which effective disclosure is provided in the references cited in this specification, are not intended to be included in the claimed composition of matter of this specification.

[0115]

[0120] As used herein, "comprising" is synonymous with "including", "containing", or "characterized by", is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of" excludes any element, step, or ingredient not specified in the claim element. As used herein, "consisting essentially of" does not exclude materials or steps that do not substantially affect the basic and novel characteristics of the scope of the patent claim. In each case herein, any of the terms "comprising", "consisting essentially of", and "consisting of" can be replaced with either of the other two terms. The invention illustratively described herein can be suitably practiced in the absence of one or more elements, or with one or more limitations not specifically disclosed herein.

[0116]

[0121] One of ordinary skill in the art will appreciate that starting materials, biological materials, reagents, synthetic methods, purification methods, analytical methods, assay methods, and biological methods other than those specifically exemplified can be used in the practice of the invention without undue experimentation. All functional equivalents known in the art for such materials and methods are intended to be included in the invention. The terms and expressions used are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions to exclude equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed invention. Accordingly, although the invention has been specifically disclosed by preferred embodiments and optional features, it is to be understood that modifications and variations of the concepts disclosed herein can be resorted to by one of ordinary skill in the art, and such modifications and variations are considered to be within the scope of the invention as defined by the appended claims.

Description of the Reference Numerals

[0117] 150... fluid, 200... particle detection system, 205... transducer, 210... flow cell, 220... light source, 222... probe beam, 240... photodetector array.

Claims

1. 1. A system for detecting particles in a fluid, the system comprising: a flow cell for flowing a particle-containing fluid along a flow direction through a beam of electromagnetic radiation; a light source in optical communication with the flow cell for providing the beam of electromagnetic radiation; a focusing system in optical communication with the light source for focusing the beam of electromagnetic radiation to create a region of high radiation density within the flow cell, the focusing system including a diffractive optical element configured to shape the beam into a top hat beam profile; an on-axis optical collection system for collecting and directing at least a portion of the electromagnetic radiation to a forward looking optical detector; Equipped with the forward looking optical detector includes at least a first detector element and a second detector element, the first detector element configured to generate a first electrical signal and the second detector element configured to generate a second electrical signal, and the system configured to characterize a number and / or a size of the detected particles based on a differential signal derived from the first electrical signal and the second electrical signal.

2. The system described in claim 1, wherein the focusing system includes a plurality of diffractive optical elements in optical communication with the light source.

3. The system described in claim 1 or 2, wherein the diffractive optical element is configured to extend the focal depth of the beam of electromagnetic radiation, thereby generating a longer beam waist and a larger area of ​​high radiation density within the flow cell.

4. The system of any one of claims 1 to 3, wherein the focusing system directs the beam of electromagnetic radiation through the flow cell at least twice.

5. The system according to any one of claims 1 to 4, wherein the fluid is a liquid or a gas.

6. A system according to any one of claims 1 to 5, comprising an optical particle counter.

7. The system of any one of claims 1 to 6, configured to detect particles having an effective diameter between 10 nm and 0.5 μm.

8. A system described in any one of claims 1 to 7, configured for detection of particles having an effective diameter selected in the range of 1 to 1000 nm, and configured to have a signal-to-noise ratio sufficient to detect and count particles with a false positive rate of 50 counts / L or less.

9. A system as described in any one of claims 1 to 8, wherein the beam has an aspect ratio selected from the range of 10:1 to 200:

1.

10. A system as described in any one of claims 1 to 9, wherein the forward looking light detector includes a light detector array.

11. A method for detecting particles in a fluid, the method comprising: generating a beam of electromagnetic radiation by a light source; shaping the beam of electromagnetic radiation into a top-hat beam profile with a focusing system in optical communication with the light source, the focusing system including a diffractive optical element; flowing a particle-containing fluid in a flow cell along a flow direction through said beam of shaped electromagnetic radiation; collecting at least a portion of the electromagnetic radiation with an on-axis optical collection system and directing it to a forward looking optical detector, the forward looking optical detector including at least a first detector element and a second detector element; generating a first electrical signal by the first sensing element; generating a second electrical signal by the second sensing element; characterizing a number and / or a size of the detected particles based on a differential signal derived from the first electrical signal and the second electrical signal; A method comprising:

12. The method of claim 11, wherein the focusing system includes a plurality of diffractive optical elements in optical communication with the light source.

13. A method as described in claim 11 or 12, wherein the shaping step includes extending a focal depth of the beam of electromagnetic radiation, thereby producing a longer beam waist and a larger region of high radiation density within the flow cell.

14. A method according to any one of claims 11 to 13, comprising directing the beam of electromagnetic radiation through the flow cell at least twice.

15. The method of claim 11, wherein the particles have an effective diameter of 10 nm to 0.5 μm.

16. A method according to any one of claims 11 to 15, wherein the electrical signal has a signal-to-noise ratio sufficient to detect and count particles with a false positive rate of 50 counts / L or less for detection of particles having an effective diameter selected in the range of 1 to 1000 nm.

17. The method of claim 11, wherein the shaped beam has an aspect ratio selected from the range of 10:1 to 200:

1.

18. The method of claim 11, wherein the forward looking light detector comprises a light detector array.

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