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Pulsed micro-chip laser for malaria detection — Masimo Corporation (US12066426B1)

ABSTRACT

Abstract

A laser suitable for use under field conditions to generate pulsed laser for detecting malaria using transient vapor nanobubbles can include a frequency doubled passively Q-switched microchip laser. The passively Q-switched microchip lasers can include suppression techniques for the unwanted fundamental wavelength in addition to using anti-reflective coatings. The pulsed laser disclosed herein can generate pulses with a high peak power as a result of high energy in conjunction with short pulse duration in the range of hundreds of picoseconds. The high peak power can be enough to generate the photo-thermal transient vapor nanobubbles for malaria detection and/or treatment.

Description

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

Any and all applications for which a foreign or domestic priority claim is identified in the Application Data Sheet as filed with the present application are hereby incorporated by reference under 37 CFR 1.57. This application is a continuation of U.S. patent application Ser. No. 17/662,559, filed May 9, 2022, which is a continuation of U.S. patent application Ser. No. 16/742,247, filed Jan. 14, 2020, which claims the priority benefit of U.S. Provisional Application No. 62/793,247, filed Jan. 16, 2019, the entirety of which is incorporated herein by reference.

FIELD

The present application relates generally to the field of detection of malaria parasites in a patient's body, in particular, with the use of laser-induced transient vapor nanobubbles.

BACKGROUND

Malaria is a widespread and infectious disease that can cause serious illness and/or death in humans. A patient can be infected when a malaria parasite infects cells of the patient, also known as a host. The parasite can produce hemozoin (Hz), which are nanocrystals formed when the parasite digests the hemoglobin in the host's red blood cells. Malaria-infected red blood cells or other body tissue infected by malaria parasites contain Hz nanocrystals.

Current malaria diagnosis techniques include, for example, rapid diagnostic tests (RDTs), microscopy, and polymerase chain reaction (PCR). These diagnosis techniques analyze a patient's blood samples. RDT analyzes the proteins in the blood to look for presence of malaria parasites and is approved by the World Health Organization (WHO). Microscopy uses stain of a thick blood slide, such as with a 200 to 500 white blood cell count, to determine malaria parasite density and gametocyte counts. Microscopy is also WHO-approved for malaria diagnosis. PCR analyzes DNAs in the blood to determine presence of malaria parasites.

Malaria can be treated and/or prevented by administration of antimalarial drugs, such as quinine, chloroquine, atovaquone/proguanil, and others.

SUMMARY

Current malaria diagnosis and treatment generally employ invasive techniques which are costly, time-consuming, and have low accuracy. The diagnosis and treatment of malaria can require separate procedures. Current malaria diagnosis techniques also may not detect the Hz nanocrystals without an active and/or live malaria parasite, and/or tissue-sequestered malaria parasites.

Laser-induced transient vapor nanobubbles can be used to diagnose and/or treat malaria in a noninvasive, efficient, and reproducible manner. The transient vapor nanobubbles can be generated around malaria-specific nanoparticles (such as the Hz nanocrystals, with or without an active malaria parasite, and/or other malaria-specific nanoparticles that can be introduced into the host red blood cells) when laser pulses are applied to those nanoparticles. The laser pulses can cause rapid heating of the malaria-specific nanoparticles, but not of uninfected red blood cells or other host tissues. Liquid (such as water) around the malaria-specific nanoparticles can rapidly evaporate, leading to the generation of a transient vapor nanobubble. The generation of transient vapor nanobubbles can be detected by optical and/or acoustic detectors.

In order to use transient vapor nanobubbles to detect and/or treat malaria noninvasively, the laser pulses must penetrate a patient's skin and reach the malaria-specific nanoparticles despite attenuation of the laser pulses energy by the patient's body tissue (particularly by the melanin layer in the skin) as the laser pulses travel deeper under the skin. Example malaria sensors based on laser-induced transient vapor nanobubble technology are described in U.S. application Ser. No. 16/213,923, filed Dec. 7, 2018 and titled “APPARATUS FOR DIAGNOSING AND/OR TREATING MALARIA,” the entirety of which is incorporated herein by reference and should be considered part of the disclosure.

Malaria is a mosquito-borne infectious disease and known as a cause for poverty. Malaria outbreak tends to happen in tropical regions and/or other places having a rugged environment. As the malaria sensors may need to be used in places having a rugged environment, a reliable, rugged and/or compact pulsed laser can be desirable. A rugged environment can pose challenges such as limited healthcare resources, low levels of sanitation, extreme weather conditions (such as the tropical weather), and/or being in a remote location with low accessibility. For a pulsed laser reaching underneath a patient's skin to generate photo-thermal transient vapor nanobubbles around the malaria-specific nanoparticles for malaria detection and/or treatment, a pulsed laser needs to deliver laser pulses of several hundred picoseconds in duration (such as less than about 300 ps), and several tens of microjoule in energy (such as greater than about 20 μJ at the wavelength range of about 670 nm to about 675 nm). The pulsed laser also needs to operate under field conditions, such as in a rugged environment, to deliver, preferably reliably in repeated use, with the above-described parameters.

The above-described parameters of the laser pulse can be achieved with lasers having an optical parametric amplifier (OPA) and appropriate pulsed laser as a pump source. Lasers that can deliver pulses in a several tens of picoseconds duration can be amplified mode-locked oscillators. The duration also can be stretched up to several hundreds of picoseconds. The above-described parameters of the laser pulse can also be achieved with a single longitudinal mode laser delivering pulses of several nanoseconds, which can be compressed using a stimulated Brillouin scattering (SBS) effect. However, lasers of such approaches can be bulky, expensive, and/or may operate only under laboratory conditions and thus may not be suitable for use under the field conditions.

A pulsed micro-laser (“microchip”) can be more compact and less expensive than the lasers described above. Microchip pulsed laser is available for the above-described parameters required, but the currently available microchip lasers use an actively Q-switch component. Active Q-switch components are available as off-the-shelf products (such as Standa-Q1SH671), which are frequency doubled Nd:YVO4 based actively Q-switched lasers lasing at a fundamental wavelength of 1064 nm. Frequency doubling as used in the present disclosure has the plain meaning as understood by an ordinary person skilled in the art, such as a phenomenon wherein an input wave in a nonlinear material generates a wave with twice the optical frequency (and thus half the wavelength) of the input wave. However, microchip lasers with an active Q-switch component can still be complex, expensive, and/or unreliable under the field conditions.

The present disclosure provides embodiments of a pulsed laser that remedies one or more of the problems described and/or other problems. The pulsed laser can generate laser pulses of the above-described parameter under the field conditions, preferably reliably in repeated use. The pulsed laser embodiments described herein can have a frequency doubled passively Q-switched microchip laser with the desired and/or wanted wavelength at about 1340 nm to about 1350 nm. Passively Q-switched microchip lasers can be less expensive, more compact, and/or more robust than the aforementioned lasers. Because of the shorter cavity length due to the more compact size of a frequency doubled passively Q-switched microchip laser, embodiments of the pulsed laser disclosed herein can generate pulses with a higher peak power as a result of higher energy in conjunction with shorter pulse duration in the range of hundreds of picoseconds. The higher peak power in the generated laser pulses can be sufficient to generate the photo-thermal transient vapor nanobubbles around the malaria-specific nanoparticles for malaria detection and/or treatment. The passively Q-switched microchip laser embodiments disclosed herein can include suppression techniques for unwanted wavelengths in addition to using anti-reflective coatings for the unwanted wavelengths.

A passively Q-switched microchip laser configured for generating transient vapor nanobubbles around malaria-specific nanoparticles in a human can comprise a laser cavity bound by a reflector and an optical coupler; a gain element located in the cavity, the gain element having a first axis, a gain element surface that is generally perpendicular to the first axis, and an inclined gain element surface that is at an acute angle to the first axis, the perpendicular gain element surface being adjacent to one of the reflector or the optical coupler; a saturable absorber element in the cavity, the saturable absorber element having a second axis, a saturable absorber element surface that is generally perpendicular to the second axis, and an inclined saturable absorber element surface that is at an acute angle to the second axis, the perpendicular saturable absorber element surface being adjacent to another one of the reflector or the optical coupler, wherein, in response to pumping energy at a predetermined pumping wavelength, the gain element can be configured to produce simulated emission of at least a wanted wavelength and an unwanted wavelength, wherein a simulated emission cross-section of the unwanted wavelength is greater than a simulated emission cross-section of the wanted wavelength, wherein the saturable absorber element can be configured to output a pulsed laser beam substantially of the wanted wavelength, wherein the reflector and the optical coupler cam be anti-reflective of the unwanted wavelength, and the inclined surfaces of the gain element and the saturable absorber element can each be configured to direct light of the unwanted wavelength away from the first and/or second axis to reduce feedback of the unwanted wavelength along the first and/or second axis.

The system can include one or more of the following features: the pulsed laser beam can have a duration less than about 300 picoseconds; the pulsed laser beam can have an energy of at least about 20 microjoule; the pulse laser beam can have a wavelength of between 670 nm to about 675 nm; the inclined surface of the saturable absorber element can be reflective or highly reflective of the pump wavelength so that the saturable absorber element is protected from bleaching by pump radiation; the inclined surfaces of the gain element and the saturable absorber element can be anti-reflective of the wanted wavelength; the inclined surfaces of the gain element and the saturable absorber element can be separated by a gap, wherein at least a portion of light of the unwanted wavelength in the gap can be reflected away from the first and/or second axis to increase losses in the cavity; the pumping energy can be delivered into the cavity from the reflector or along a length of the cavity toward the inclined surface of the saturable absorber element; the pumping energy can be double-passed in the gain element to increase excitation of the gain element; the inclined surface of the saturable absorber element can be reflective or highly reflective of the unwanted wavelength; the first and second axes can be substantially collinear; the first and second axes can be offset from each other; the inclined surfaces of the gain element and the saturable absorber element are generally parallel; the first axis can be at an angle with second axis; the inclined surfaces of the gain element and the saturable absorber element can be generally not parallel; slopes of the inclined surfaces of the gain element and the saturable absorber element can extend away from each other so that light travels through a longer section of the gain element followed by a longer section of the saturable absorber element, or through a shorter section of the gain element followed by a shorter section of the saturable absorber element; the gain element and the saturable absorber element can each comprise a doped part and an undoped part, the doped part comprising a generally uniform cross-section normal to the first axis and/or the second axis; further comprising an exo-cavity element; the exo-cavity element can be located between a pump and the cavity along a length of the cavity, the exo-cavity element configured to isolate feedback of the unwanted wavelength from pump shaping optics; the exo-cavity element can be located on an opposite side of the gain element from a pump, the exo-cavity element configured to reflect back pump radiation into the cavity; the perpendicular surface of the gain element can comprise a two-wavelength coating for the wanted and unwanted wavelengths, the perpendicular surface of the gain element having an unspecified reflectivity for the pump wavelength; the system can comprise an intra-cavity element between the gain element and the saturable absorber element, the intra-cavity element configured to focus pump radiation into the gain element; the reflector can be at or next to the perpendicular gain element surface and the optical coupler can be at or next to the perpendicular saturable absorber element surface; and/or the reflector can be at or next to the perpendicular saturable absorber element surface and the optical coupler can be at or next to the perpendicular gain element surface.

A passively Q-switched microchip laser configured for generating transient vapor nanobubbles around malaria-specific nanoparticles in a human can comprise a laser cavity bound by a reflector and an optical coupler, the laser cavity having an optical axis; a gain element located in the cavity, the gain element having a gain element surface that is generally perpendicular to the optical axis, and an inclined gain element surface that is at an acute angle to the optical axis, the perpendicular gain element surface being adjacent to the reflector; a saturable absorber element in the cavity and adjacent to the gain element, the saturable absorber element having a saturable absorber element surface that is generally perpendicular to the optical axis, and an inclined saturable absorber element surface that is at an acute angle to the optical axis, the perpendicular saturable absorber element surface being adjacent to the optical coupler, wherein the inclined surfaces of the gain element and the saturable absorber element are generally parallel and separated by a predetermined distance; and an exo-cavity element located next to the perpendicular gain element surface and substantially collinear with the optical axis, the exo-cavity element configured to isolate feedback of an unwanted wavelength from pump shaping optics; wherein, in response to pumping energy at a predetermined pumping wavelength, the gain element can be configured to produce simulated emission of at least a wanted wavelength and the unwanted wavelength, wherein a simulated emission cross-section of the unwanted wavelength can be greater than a simulated emission cross-section of the wanted wavelength, wherein the saturable absorber element can be configured to output a pulsed laser beam substantially of the wanted wavelength, wherein the reflector and the optical coupler can be anti-reflective of the unwanted wavelength, and the inclined surfaces of the gain element and the saturable absorber element can each be configured to direct light of the unwanted wavelength away from the optical axis to reduce feedback of the unwanted wavelength along the optical axis and/or to increase losses in the cavity.

A passively Q-switched microchip laser configured for generating transient vapor nanobubbles around malaria-specific nanoparticles in a human can comprise: a laser cavity bound by a reflector and an optical coupler and having a laser cavity axis; a gain element and a saturable absorber element located in the cavity, the gain element and the saturable absorber element each having a first surface adjacent to one of the reflector or the optical coupler, the gain element and the saturable absorber element each having a second surface adjacent to another one of the reflector or the optical coupler, one or both of the second surfaces of the gain element and the saturable absorber element being inclined relative to the laser cavity axis; wherein, in response to pumping energy at a predetermined pumping wavelength, the gain element can be configured to produce simulated emission of at least a first wavelength and a second wavelength, wherein a simulated emission cross-section of the second wavelength can be greater than a simulated emission cross-section of the first wavelength, wherein the saturable absorber element can be configured to output a pulsed laser beam substantially of the first wavelength, and wherein the reflector and the optical coupler are configured to suppress the second wavelength.

The laser can include one or more of the following features: the reflector and the optical coupler can be anti-reflective of the second wavelength; the second gain element and saturable absorber element surfaces can be each configured to direct light of the second wavelength away from the laser cavity axis to reduce feedback of the second wavelength along the laser cavity second axis; the pulsed laser beam can have a duration less than about 300 picoseconds; the pulsed laser beam can have an energy of at least about 20 microjoule; the pulse laser beam can have a wavelength of between 670 nm to about 675 nm; the second surfa

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

Any and all applications for which a foreign or domestic priority claim is identified in the Application Data Sheet as filed with the present application are hereby incorporated by reference under 37 CFR 1.57. This application is a continuation of U.S. patent application Ser. No. 17/662,559, filed May 9, 2022, which is a continuation of U.S. patent application Ser. No. 16/742,247, filed Jan. 14, 2020, which claims the priority benefit of U.S. Provisional Application No. 62/793,247, filed Jan. 16, 2019, the entirety of which is incorporated herein by reference.

FIELD

The present application relates generally to the field of detection of malaria parasites in a patient's body, in particular, with the use of laser-induced transient vapor nanobubbles.

BACKGROUND

Malaria is a widespread and infectious disease that can cause serious illness and/or death in humans. A patient can be infected when a malaria parasite infects cells of the patient, also known as a host. The parasite can produce hemozoin (Hz), which are nanocrystals formed when the parasite digests the hemoglobin in the host's red blood cells. Malaria-infected red blood cells or other body tissue infected by malaria parasites contain Hz nanocrystals.

Current malaria diagnosis techniques include, for example, rapid diagnostic tests (RDTs), microscopy, and polymerase chain reaction (PCR). These diagnosis techniques analyze a patient's blood samples. RDT analyzes the proteins in the blood to look for presence of malaria parasites and is approved by the World Health Organization (WHO). Microscopy uses stain of a thick blood slide, such as with a 200 to 500 white blood cell count, to determine malaria parasite density and gametocyte counts. Microscopy is also WHO-approved for malaria diagnosis. PCR analyzes DNAs in the blood to determine presence of malaria parasites.

Malaria can be treated and/or prevented by administration of antimalarial drugs, such as quinine, chloroquine, atovaquone/proguanil, and others.

SUMMARY

Current malaria diagnosis and treatment generally employ invasive techniques which are costly, time-consuming, and have low accuracy. The diagnosis and treatment of malaria can require separate procedures. Current malaria diagnosis techniques also may not detect the Hz nanocrystals without an active and/or live malaria parasite, and/or tissue-sequestered malaria parasites.

Laser-induced transient vapor nanobubbles can be used to diagnose and/or treat malaria in a noninvasive, efficient, and reproducible manner. The transient vapor nanobubbles can be generated around malaria-specific nanoparticles (such as the Hz nanocrystals, with or without an active malaria parasite, and/or other malaria-specific nanoparticles that can be introduced into the host red blood cells) when laser pulses are applied to those nanoparticles. The laser pulses can cause rapid heating of the malaria-specific nanoparticles, but not of uninfected red blood cells or other host tissues. Liquid (such as water) around the malaria-specific nanoparticles can rapidly evaporate, leading to the generation of a transient vapor nanobubble. The generation of transient vapor nanobubbles can be detected by optical and/or acoustic detectors.

In order to use transient vapor nanobubbles to detect and/or treat malaria noninvasively, the laser pulses must penetrate a patient's skin and reach the malaria-specific nanoparticles despite attenuation of the laser pulses energy by the patient's body tissue (particularly by the melanin layer in the skin) as the laser pulses travel deeper under the skin. Example malaria sensors based on laser-induced transient vapor nanobubble technology are described in U.S. application Ser. No. 16/213,923, filed Dec. 7, 2018 and titled “APPARATUS FOR DIAGNOSING AND/OR TREATING MALARIA,” the entirety of which is incorporated herein by reference and should be considered part of the disclosure.

Malaria is a mosquito-borne infectious disease and known as a cause for poverty. Malaria outbreak tends to happen in tropical regions and/or other places having a rugged environment. As the malaria sensors may need to be used in places having a rugged environment, a reliable, rugged and/or compact pulsed laser can be desirable. A rugged environment can pose challenges such as limited healthcare resources, low levels of sanitation, extreme weather conditions (such as the tropical weather), and/or being in a remote location with low accessibility. For a pulsed laser reaching underneath a patient's skin to generate photo-thermal transient vapor nanobubbles around the malaria-specific nanoparticles for malaria detection and/or treatment, a pulsed laser needs to deliver laser pulses of several hundred picoseconds in duration (such as less than about 300 ps), and several tens of microjoule in energy (such as greater than about 20 μJ at the wavelength range of about 670 nm to about 675 nm). The pulsed laser also needs to operate under field conditions, such as in a rugged environment, to deliver, preferably reliably in repeated use, with the above-described parameters.

The above-described parameters of the laser pulse can be achieved with lasers having an optical parametric amplifier (OPA) and appropriate pulsed laser as a pump source. Lasers that can deliver pulses in a several tens of picoseconds duration can be amplified mode-locked oscillators. The duration also can be stretched up to several hundreds of picoseconds. The above-described parameters of the laser pulse can also be achieved with a single longitudinal mode laser delivering pulses of several nanoseconds, which can be compressed using a stimulated Brillouin scattering (SBS) effect. However, lasers of such approaches can be bulky, expensive, and/or may operate only under laboratory conditions and thus may not be suitable for use under the field conditions.

A pulsed micro-laser (“microchip”) can be more compact and less expensive than the lasers described above. Microchip pulsed laser is available for the above-described parameters required, but the currently available microchip lasers use an actively Q-switch component. Active Q-switch components are available as off-the-shelf products (such as Standa-Q1SH671), which are frequency doubled Nd:YVO4 based actively Q-switched lasers lasing at a fundamental wavelength of 1064 nm. Frequency doubling as used in the present disclosure has the plain meaning as understood by an ordinary person skilled in the art, such as a phenomenon wherein an input wave in a nonlinear material generates a wave with twice the optical frequency (and thus half the wavelength) of the input wave. However, microchip lasers with an active Q-switch component can still be complex, expensive, and/or unreliable under the field conditions.

The present disclosure provides embodiments of a pulsed laser that remedies one or more of the problems described and/or other problems. The pulsed laser can generate laser pulses of the above-described parameter under the field conditions, preferably reliably in repeated use. The pulsed laser embodiments described herein can have a frequency doubled passively Q-switched microchip laser with the desired and/or wanted wavelength at about 1340 nm to about 1350 nm. Passively Q-switched microchip lasers can be less expensive, more compact, and/or more robust than the aforementioned lasers. Because of the shorter cavity length due to the more compact size of a frequency doubled passively Q-switched microchip laser, embodiments of the pulsed laser disclosed herein can generate pulses with a higher peak power as a result of higher energy in conjunction with shorter pulse duration in the range of hundreds of picoseconds. The higher peak power in the generated laser pulses can be sufficient to generate the photo-thermal transient vapor nanobubbles around the malaria-specific nanoparticles for malaria detection and/or treatment. The passively Q-switched microchip laser embodiments disclosed herein can include suppression techniques for unwanted wavelengths in addition to using anti-reflective coatings for the unwanted wavelengths.

A passively Q-switched microchip laser configured for generating transient vapor nanobubbles around malaria-specific nanoparticles in a human can comprise a laser cavity bound by a reflector and an optical coupler; a gain element located in the cavity, the gain element having a first axis, a gain element surface that is generally perpendicular to the first axis, and an inclined gain element surface that is at an acute angle to the first axis, the perpendicular gain element surface being adjacent to one of the reflector or the optical coupler; a saturable absorber element in the cavity, the saturable absorber element having a second axis, a saturable absorber element surface that is generally perpendicular to the second axis, and an inclined saturable absorber element surface that is at an acute angle to the second axis, the perpendicular saturable absorber element surface being adjacent to another one of the reflector or the optical coupler, wherein, in response to pumping energy at a predetermined pumping wavelength, the gain element can be configured to produce simulated emission of at least a wanted wavelength and an unwanted wavelength, wherein a simulated emission cross-section of the unwanted wavelength is greater than a simulated emission cross-section of the wanted wavelength, wherein the saturable absorber element can be configured to output a pulsed laser beam substantially of the wanted wavelength, wherein the reflector and the optical coupler cam be anti-reflective of the unwanted wavelength, and the inclined surfaces of the gain element and the saturable absorber element can each be configured to direct light of the unwanted wavelength away from the first and/or second axis to reduce feedback of the unwanted wavelength along the first and/or second axis.

The system can include one or more of the following features: the pulsed laser beam can have a duration less than about 300 picoseconds; the pulsed laser beam can have an energy of at least about 20 microjoule; the pulse laser beam can have a wavelength of between 670 nm to about 675 nm; the inclined surface of the saturable absorber element can be reflective or highly reflective of the pump wavelength so that the saturable absorber element is protected from bleaching by pump radiation; the inclined surfaces of the gain element and the saturable absorber element can be anti-reflective of the wanted wavelength; the inclined surfaces of the gain element and the saturable absorber element can be separated by a gap, wherein at least a portion of light of the unwanted wavelength in the gap can be reflected away from the first and/or second axis to increase losses in the cavity; the pumping energy can be delivered into the cavity from the reflector or along a length of the cavity toward the inclined surface of the saturable absorber element; the pumping energy can be double-passed in the gain element to increase excitation of the gain element; the inclined surface of the saturable absorber element can be reflective or highly reflective of the unwanted wavelength; the first and second axes can be substantially collinear; the first and second axes can be offset from each other; the inclined surfaces of the gain element and the saturable absorber element are generally parallel; the first axis can be at an angle with second axis; the inclined surfaces of the gain element and the saturable absorber element can be generally not parallel; slopes of the inclined surfaces of the gain element and the saturable absorber element can extend away from each other so that light travels through a longer section of the gain element followed by a longer section of the saturable absorber element, or through a shorter section of the gain element followed by a shorter section of the saturable absorber element; the gain element and the saturable absorber element can each comprise a doped part and an undoped part, the doped part comprising a generally uniform cross-section normal to the first axis and/or the second axis; further comprising an exo-cavity element; the exo-cavity element can be located between a pump and the cavity along a length of the cavity, the exo-cavity element configured to isolate feedback of the unwanted wavelength from pump shaping optics; the exo-cavity element can be located on an opposite side of the gain element from a pump, the exo-cavity element configured to reflect back pump radiation into the cavity; the perpendicular surface of the gain element can comprise a two-wavelength coating for the wanted and unwanted wavelengths, the perpendicular surface of the gain element having an unspecified reflectivity for the pump wavelength; the system can comprise an intra-cavity element between the gain element and the saturable absorber element, the intra-cavity element configured to focus pump radiation into the gain element; the reflector can be at or next to the perpendicular gain element surface and the optical coupler can be at or next to the perpendicular saturable absorber element surface; and/or the reflector can be at or next to the perpendicular saturable absorber element surface and the optical coupler can be at or next to the perpendicular gain element surface.

A passively Q-switched microchip laser configured for generating transient vapor nanobubbles around malaria-specific nanoparticles in a human can comprise a laser cavity bound by a reflector and an optical coupler, the laser cavity having an optical axis; a gain element located in the cavity, the gain element having a gain element surface that is generally perpendicular to the optical axis, and an inclined gain element surface that is at an acute angle to the optical axis, the perpendicular gain element surface being adjacent to the reflector; a saturable absorber element in the cavity and adjacent to the gain element, the saturable absorber element having a saturable absorber element surface that is generally perpendicular to the optical axis, and an inclined saturable absorber element surface that is at an acute angle to the optical axis, the perpendicular saturable absorber element surface being adjacent to the optical coupler, wherein the inclined surfaces of the gain element and the saturable absorber element are generally parallel and separated by a predetermined distance; and an exo-cavity element located next to the perpendicular gain element surface and substantially collinear with the optical axis, the exo-cavity element configured to isolate feedback of an unwanted wavelength from pump shaping optics; wherein, in response to pumping energy at a predetermined pumping wavelength, the gain element can be configured to produce simulated emission of at least a wanted wavelength and the unwanted wavelength, wherein a simulated emission cross-section of the unwanted wavelength can be greater than a simulated emission cross-section of the wanted wavelength, wherein the saturable absorber element can be configured to output a pulsed laser beam substantially of the wanted wavelength, wherein the reflector and the optical coupler can be anti-reflective of the unwanted wavelength, and the inclined surfaces of the gain element and the saturable absorber element can each be configured to direct light of the unwanted wavelength away from the optical axis to reduce feedback of the unwanted wavelength along the optical axis and/or to increase losses in the cavity.

A passively Q-switched microchip laser configured for generating transient vapor nanobubbles around malaria-specific nanoparticles in a human can comprise: a laser cavity bound by a reflector and an optical coupler and having a laser cavity axis; a gain element and a saturable absorber element located in the cavity, the gain element and the saturable absorber element each having a first surface adjacent to one of the reflector or the optical coupler, the gain element and the saturable absorber element each having a second surface adjacent to another one of the reflector or the optical coupler, one or both of the second surfaces of the gain element and the saturable absorber element being inclined relative to the laser cavity axis; wherein, in response to pumping energy at a predetermined pumping wavelength, the gain element can be configured to produce simulated emission of at least a first wavelength and a second wavelength, wherein a simulated emission cross-section of the second wavelength can be greater than a simulated emission cross-section of the first wavelength, wherein the saturable absorber element can be configured to output a pulsed laser beam substantially of the first wavelength, and wherein the reflector and the optical coupler are configured to suppress the second wavelength.

The laser can include one or more of the following features: the reflector and the optical coupler can be anti-reflective of the second wavelength; the second gain element and saturable absorber element surfaces can be each configured to direct light of the second wavelength away from the laser cavity axis to reduce feedback of the second wavelength along the laser cavity second axis; the pulsed laser beam can have a duration less than about 300 picoseconds; the pulsed laser beam can have an energy of at least about 20 microjoule; the pulse laser beam can have a wavelength of between 670 nm to about 675 nm; the second surface of the saturable absorber element can be reflective or highly reflective of the pump wavelength so that the saturable absorber element is protected from bleaching by pump radiation; the second surfaces of the gain element and saturable absorber element can be anti-reflective of the first wavelength; the second surfaces of the gain element and saturable absorber element can be separated by a gap, wherein at least a portion of light of the second wavelength in the gap can be reflected away from the laser cavity axis to increase losses in the cavity; the pumping energy can be delivered into the laser cavity from the reflector or along a length of the cavity toward the second surface of the saturable absorber element; the pumping energy can be double-passed in the gain element to increase excitation of the gain element; the second surface of the saturable absorber element can be reflective or highly reflective of the second wavelength; the gain element can be at an angle with the saturable absorber element; or the second surfaces of the gain element and saturable absorber element can be at an angle with each other; slopes of the second surfaces of the gain element and saturable absorber element can extend away from each other so that light travels through a longer section of the gain element followed by a longer section of the saturable absorber element, or through a shorter section of the gain element followed by a shorter section of the saturable absorber element; the reflector can be at or next to the first gain element surface and the optical coupler can be at or next to the first saturable absorber element surface; or the reflector can be at or next to the first saturable absorber element surface and the optical coupler can be at or next to the first gain element surface.

A laser light generator device configured for generating transient vapor nanobubbles around malaria-specific nanoparticles in a human can comprise any of the example passively Q-switched microchip lasers described above; a pump coupled to the passively Q-switched microchip laser via a pump fiber; and an output fiber coupling the passively Q-switched microchip laser and one or more malaria detection sensors.

The device can include one or more of the following features: the device can comprise pump shaping optics between the pump fiber and the passively Q-switched microchip laser; the device can comprise second harmonic generation and filtering elements coupling the passively Q-switched microchip laser to the output fiber; and/or the device can be configured to sequentially switch the outputted pulsed laser beam among a plurality of optical fibers in the one or more malaria detection sensors.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments are depicted in the accompanying drawings for illustrative purposes and may not be drawn to scale, and should in no way be interpreted as limiting the scope of the embodiments. In addition, various features of different disclosed embodiments can be combined to form additional embodiments, which are part of this disclosure. In the drawings, similar elements have reference numerals with the same last two digits.

FIG. 1 A illustrates schematically basic components of a laser.

FIG. 1 B illustrates schematically energy levels of particles relating to generation of a laser beam.

FIG. 2 A illustrates schematically an example passively Q-switched micro-chip laser.

FIG. 2 B illustrates schematically example energy levels of a passively Q-switched micro-chip laser.

FIG. 3 A illustrates schematically an example passively Q-switched micro-chip laser.

FIG. 3 B illustrates schematically an example passively Q-switched micro-chip laser.

FIG. 4 illustrates schematically an example passively Q-switched micro-chip laser.

FIG. 5 A illustrates schematically an example passively Q-switched micro-chip laser.

FIG. 5 B illustrates schematically an example passively Q-switched micro-chip laser.

FIG. 6 A illustrates schematically an example passively Q-switched micro-chip laser.

FIG. 6 B illustrates schematically an example passively Q-switched micro-chip laser.

FIG. 6 C illustrates schematically an example passively Q-switched micro-chip laser.

FIG. 7 A illustrates an example laser incorporating a passively Q-switched micro-chip laser.

FIG. 7 B illustrates an exploded view of the passively Q-switched micro-chip laser in the laser of FIG. 7 A .

FIG. 8 A illustrates schematically an example passively Q-switched micro-chip laser.

FIG. 8 B illustrates schematically an example passively Q-switched micro-chip laser.

FIG. 8 C illustrates schematically an example passively Q-switched micro-chip laser.

FIG. 9 illustrates schematically an example passively Q-switched micro-chip laser.

FIG. 10 A illustrates schematically an example laser operably coupled to a malaria sensor.

FIG. 10 B illustrates schematically an example laser operably coupled to more than one malaria sensor.

FIG. 10 C- 10 E illustrates example sequential emissions of laser pulses using example lasers disclosed herein.

FIGS. 11 A- 11 B illustrate perspective views of an example laser generator with a passively Q-switched microchip laser.

FIG. 11 C illustrates a perspective view of certain internal components of the laser generator of FIGS. 11 A and 11 B .

FIG. 12 A illustrates a perspective view of a passively Q-switched microchip laser.

FIG. 12 B illustrates a top view of the passively Q-switched microchip laser of FIG. 12 A .

DETAILED DESCRIPTION

Although certain embodiments and examples are described below, this disclosure extends beyond the specifically disclosed embodiments and/or uses and obvious modifications and equivalents thereof. Thus, it is intended that the scope of this disclosure should not be limited by any particular embodiments described below.

Overview of Laser Technology

FIG. 1 A illustrates schematically an example laser 100 , which includes a gain element (also known as gain medium or active medium) 102 with energy levels configured to support laser action, and an energy pump 104 in order to establish a population inversion. The gain element 102 can be located in an optical cavity or optical resonator 106 , which can maintain the gain of the laser 100 .

The gain element 102 can produce gain and subsequent generation of laser light. The gain element 102 can be a crystal, solid, liquid, semiconductor, or gas medium and can be pumped by the energy pump 104 to a higher energy state. The gain element material has a metastable state that supports stimulated emission. Laser light generation can be based on 3- or 4-level energy level systems, depending on the type of gain element used. FIG. 1 B illustrates a 3 level energy level system. As shown in FIG. 1 B , the gain element 102 can be pumped from a ground level to an excited level, which decays rapidly to a metastate level through spontaneous emission, and further decays from the metastate level to the ground level through stimulated emission (also known as lasing). The light of stimulated emission is coherent and can be focused to a spot. The laser light or laser beam 120 generated by the laser 100 can have an energy that is the difference between the metastate level and the ground level, ΔE. The wavelength of the laser beam emitted through simulated emission can be calculated based on the equation ΔE=hv, where h is the Planck's constant and v is the frequency of the laser beam.

The pump 104 can provide energy to excite elements such as the atoms, electrons, ions or molecules in the gain element 102 to higher energy levels such as shown in FIG. 1 B . Under an equilibrium state, higher energy levels are much less populated than the lower energy levels. One of the requirements of laser action is population inversion, which can involve having a larger population of the elements in the gain element 102 in the higher levels than in the lower levels. The energy pump 104 can establish a population inversion in the gain element 102 . The pump 104 can be based on optical, electrical, thermal or chemical techniques, depending on the type of the gain element used.

The optical cavity or resonator 106 can be formed by bounding the gain element 102 by two reflectors or mirrors 105 , 107 . Light travels in both directions along the cavity axis 108 , bouncing back and forth between the two reflectors

105 , 107 . The light reflects back on itself on the reflectors

105 , 107 so that as light passes through the gain medium repeatedly, the light is amplified each time (known as feedback) before it is emitted from an output aperture or lost to diffraction or absorption. The optical resonator 106 can produce gain in the gain element 102 to overcome the losses due to, for example, photons straying away from the active medium 102 , and/or losses inside the active medium 102 due to absorption and/or scattering. The optical resonator 106 can also provide directionality to the laser beam 120 along an optical axis 108 . Photons which are either not of the correct frequency (and thus not of the correct energy) or do not travel along the optical axis 108 are lost. On one end of the active medium 102 , the mirror 105 can be a total reflector. On an opposite end of the active medium 102 , the mirror 107 can be partially reflecting and partially transmissive, also known as an output coupler. The laser beam 120 can exit the cavity 106 from the output coupler 107 , which is partially transmissive.

FIG. 2 A illustrates schematically a microchip pulsed laser 200 . The microchip pulsed laser 200 can include a gain element 202 and a Q- switch 209 bound by the mirrors or reflectors

205 , 207 , forming an optical cavity 206 . The gain element 202 and the Q- Switch 209 can be separated by another mirror or reflector 203 . Q switching is a method for obtaining energetic pulses from lasers by modulating intra-cavity losses. Including a Q-switch in the laser can allow the pulse duration to be in the nanosecond range. The energy of the pulse generated with a Q-switched microchip laser, such as the laser 200 , can be higher than the saturation energy of the gain element 202 .

Q switching can be achieved using active Q-Switch components or passive Q-Switch components. For active Q switching, an active control element modulates the intra-cavity losses. A laser pulse is formed shortly after an electrical trigger signal from the active control element arrives. Having an active control element (and the associated electronics) can make the pulsed laser more complex, more expensive, and/or reduces the reliability of the laser under the field conditions than having passive Q-switching components.

Passive Q-switching (also known as self Q-switching) can be achieved with a saturable absorber element 209 that automatically modulates the intra-cavity losses. As shown in FIG. 2 B , a laser pulse, as indicated by a spike, is formed as soon as the energy stored in the gain element 202 (and thus the gain) has reached a sufficiently high level. The saturable absorber element 209 can be cheaper and less complex than an active Q-switch element.

Passively Q-switched microchip lasers disclosed herein can be either monolithic or non-monolithic. When the passively Q-switched microchip lasers are monolithic, the amplifying laser medium or gain element, and the saturable absorbable element form a single component. The formation of a single component can be, for example, due to molecular adhesion and/or epitaxial growth. The cavity mirrors can be directly placed on the single component. Non-monolithic passively Q-switched microchip lasers have at least one part of the cavity that cannot maintain structural integrity without external mechanical support. The mechanical support can be a combination of external object and adhesive material (such as when the elements are glued to an external object), purely mechanical (such as being sustained by friction), or purely adhesive (such as being glued together).

The gain element 202 can include crystals. The crystals in the gain element 202 of the passively Q-switched microchip laser 200 can have a fundamental wavelength at 1064 nm. Many laser gain elements can amplify light of more than one wavelength. For example, Nd: YVO4 can amplify light having a wavelength of 1342 nm in addition to photons having a wavelength of 1064 nm.

However, the gain at the sub-optimal wavelengths (which is the wavelength of interest for malaria detection applications) is lower than the gain at the fundamental wavelength. As described above, the wavelength necessary for generating transient vapor nanobubbles around malaria-specific nanoparticles is between about 1340 nm to about 1350 nm, which are sub-optimal wavelengths of the crystals in the gain element 202 . A problem with current passively Q-switched microchip lasers working at sub-optimal wavelengths is that the laser beam at the sub-optimal wavelengths may not meet the required parameters for applications in malaria detection. For example, the energy of the laser light at the sub-optimal wavelengths may be too low and/or the pulse duration may be too long for applications in malaria detection. In order for the laser pulses to meet the requirement for malaria detection applications, the energy of the laser pulses at the sub-optimal wavelengths may need to be increased, and/or the pulse duration may need to be shortened.

The laser pulse output performance parameters (such as pulse duration and/or energy) of passively Q-switched lasers can depend on the design of the microchip laser cavity. Factors of the cavity that can affect the laser pulse output parameters include, but are not limited to, a length of the optical path in the gain element and/or the saturable absorber element, a gain magnitude in the gain element, saturable and non-saturable losses, output coupling, and/or a length of the cavity. The pulse duration is proportional to the cavity length and inversely proportional to the losses. The pulse energy is directly proportional to the pumped energy volume and to the losses.

Accordingly, one way to increase the energy of pulses of the sub-optimal wavelengths is to increase the pumped energy volume, such as by increasing a cross-sectional area of the pump beam. This approach can be limited by various unwanted instabilities caused by the appearance of additional transversal cavity modes that would not be present in a narrower pump beam.

Another way to increase the pulse energy is to increase total losses in the cavity, which in turn requires a higher initial gain in the gain element. Under this approach, a longer cavity is need to due to an increased length in the gain element to produce a higher initial gain. As a result, the output pulses have a longer duration, although the increased pulse duration can then be compensated by increasing the total losses using output coupling. In short, increasing the energy per pulse while maintaining the pulse duration (or vice versa) would require increasing the gain in the gain element.

The increase in the gain of the gain element can be limited and may not deliver the combination of the parameters required for malaria detection applications. The fundamental wavelength with a higher gain typically dominates in the laser cavity unless measures to suppress the fundamental wavelength are introduced. In most types of laser cavities, the fundamental wavelength is suppressed by introducing anti-reflective coatings for the fundamental wavelength, while keeping properties of the coatings favorable for the desired wavelength (for example, for the sub-optimal wavelength of 1342 nm). When the gain of the gain element is increased for the sub-optimal wavelength, the effect of exponential relative gain increase for the fundamental wavelength can eventually overcome the suppression of the unwanted fundamental wavelength provided by the anti-reflective coatings.

Specifically, the gain coefficient in the gain element depends on the density of excited ions and the probability of stimulated emission (also known as stimulated emission cross-section). Stimulated emission cross-section is wavelength dependent, while the density of exited ions is wavelength independent. In conjunction with an exponential overall gain dependency on the gain coefficient, the ratio of overall gains for different wavelengths is exponentially dependent on the excitation level. As a result, certain increases of the overall gain at sub-optimal wavelengths can lead to an even higher gain increase for the fundamental wavelength. In some instances, depending on the reflectivity of the

mirrors

203 , 205 , 207 of FIG. 2 A , lasing at the unwanted wavelength of 1064 nm can begin once the gain reaches about 166, whereas the gain for the desired wavelength of 1342 nm can be less than 3 at the same time, as the simulated emission cross-section of the wanted, sub-optimal wavelengths can be about 5 times smaller than the simulated emission cross-section of the fundamental wavelength.

In addition, using the laser 200 as an example, as the reflector surfaces in the laser 200 are generally parallel to one another, reflection of light along the cavity axis can add up to increase feedback to a high gain active medium. The parallel surfaces can also lead to resonant modes, which can result in an increased reflection from anti-reflective coating. The probability of resonant modes being present can also be increased when the gain element crystal increases in temperature.

The parameters of the output coupler and the saturable absorber element in the laser 200 may also not be favorable for outputting pulses of high energy and short duration. For example, the laser pulse energy can be increased and/or the pulse duration can be reduced in the laser 200 by increasing a modulation depth of the saturable absorbable element 209 . The modulation depth is the maximum change in absorption (or reflectivity) by the saturable absorber element that can be induced by incident light of a given wavelength. In addition, the pulse duration can be shortened by increasing the transmission of the output coupler 207 . However, as the parameters of the output coupler 207 and the saturable absorber elements 209 are related, generally the transmission of the output coupler 207 needs to be similar to the modulation depth of the saturable absorber 209 . As a result, increasing the transmission of the output coupler 207 is in tension with increasing the modulation depth of the saturable absorber element 209 .

In conclusion, relying solely on anti-reflective coatings with reduced reflection for the unwanted wavelengths fail to provide sufficient suppression of the unwanted wavelengths when higher energy and shorter pulse duration is demanded, such as in the malaria detection application.

Overview of Example Microchip Lasers Suitable for Malaria Detection

It can be desirable for passively Q-switched microchip lasers to include suppression techniques for the unwanted fundamental wavelength in addition to anti-reflective coatings, and/or to increase the pulse energy and/or shorten the pulse duration of a sub-optimal wavelength to deliver the required combination of the laser pulse parameters for malaria detection applications. The passively Q-switched microchip lasers also include other components that a person skilled in the art would understand to be included in such devices based on the disclosure herein, for example but not limited to, heat sinks or other thermal regulation structures. Such components are not discussed in this disclosure in detail for brevity.

The present disclosure provides unwanted fundamental wavelength suppression techniques, such as inclined surfaces with specific coatings on each surface and/or arranged in specific spatial orders. The inclined surfaces do not form the laser cavity or introduce additional elements. The inclined surfaces as disclosed herein are aimed and optimized for the suppression of unwanted, or unwanted and dominating, wavelengths.

The suppression techniques disclosed herein can also increase the pulse energy and/or shorten the pulse duration of the wanted, or wanted and sub-optimal, wavelengths by lowering the reflectivity of the output coupler and the transmission of the saturable absorber element of the wanted wavelengths. Higher energy and shorter pulses can be obtained despite the increase in cavity length due to a longer gain element and a longer saturable absorber. Although the pump to lasing efficiency may be lowered by the increased cavity length, the reduction in efficiency can be compensated by providing a more powerful pump.

The techniques disclosed herein can increase the output pulse energy and decrease the pulse duration for sub-optimal pulse wavelength by one or more of the following features and obvious variations thereof based on the disclosure herein: having inclined surfaces that can suppress optical feedback of unwanted wavelengths from internal surfaces along a laser cavity axis; having inclined surfaces that can reflect unwanted wavelengths away from the laser cavity axis, thus increasing losses along the laser cavity axis; having inclined surfaces that can be used as mirrors to pump the cavity from inside the cavity; double-passing the pump to increase excitation of gain element; protecting the saturable absorber element from bleaching by the pump radiation to increase the lifetime of the laser; having a folding mirror that can work as a filter for unwanted wavelengths to increase losses for unwanted wavelength; having two-wavelength coatings that can replace triple-wavelength coatings (for the pumping, lasing and wanted wavelengths) to reduce the complexity of coatings and/or improve parameters on important specifications (for example, reflectivity for unwanted wavelengths); and/or having additional elements (intra-cavity and/or exo-cavity) that can act as a part of the pump shaping optics.

Examples of a passively Q-switched microchip laser with additional unwanted wavelength suppression techniques, such as for malaria detection applications, are described below with reference to FIGS. 3 A to 9 . The passively Q-switched microchip lasers described below can be non-monolithic or monolithic. It should be appreciated from the disclosure herein that different features of the passively Q-switched microchip laser embodiments disclosed below are for illustration purposes, and any feature, structure, or component that is described and/or illustrated in one passively Q-switched microchip laser embodiment in this specification can be modified, and/or used with or instead of any feature, structure, or component that is described and/or illustrated in any other passively Q-switched microchip laser embodiments in this specification. Additionally, one or more of the features described for the illustrative embodiments herein can be excluded from these and other embodiments.

FIG. 3 A illustrates a passively Q-switched microchip laser 300 A having a laser cavity 306 bound by a reflector 305 and an optical coupler 307 . A gain element 302 can be located in the cavity 306 . The gain element 302 can be solid crystals. The gain element 302 can have a first axis 308 .

The gain element 302 can have a first, non-inclined gain element surface, which can optionally be generally perpendicular to the first axis 308

CLAIMS

Claims ( 20 )

What is claimed is:

1. A passively Q-switched microchip laser configured for generating transient vapor nanobubbles around malaria-specific nanoparticles in a human, the laser comprising:

a laser cavity bound by a reflector and an optical coupler;

a gain element located in the laser cavity, the gain element having a first axis, a first gain element surface, and a second gain element surface, the first gain element surface being adjacent to one of the reflector or the optical coupler;

a saturable absorber element in the laser cavity, the saturable absorber element having a second axis, a first saturable absorber element surface, and a second saturable absorber element surface, the first saturable absorber element surface being adjacent to another one of the reflector or the optical coupler,

wherein, in response to pumping energy at a predetermined pumping wavelength, the gain element is configured to produce simulated emission of at least a first wavelength and a second wavelength, wherein a simulated emission cross-section of the second wavelength is greater than a simulated emission cross-section of the first wavelength, wherein the second wavelength is a fundamental wavelength,

wherein the passively Q-switched microchip laser further comprises one or more fundamental wavelength suppression features such that the saturable absorber element is configured to output a pulsed laser beam substantially of the first wavelength.

2. The laser of claim 1 , wherein the pulsed laser beam has a duration less than about 300 picoseconds.

3. The laser of claim 1 , wherein the pulsed laser beam has an energy of at least about 20 microjoule.

4. The laser of claim 1 , wherein the pumping wavelength is between 670 nm to 675 nm.

5. The laser of claim 1 , wherein the one or more fundamental wavelength suppression features comprise the second gain element surface being at an angle to the first axis.

6. The laser of claim 5 , wherein the one or more fundamental wavelength suppression features further comprise the second saturable absorber element surface being at an angle to the second axis.

7. The laser of claim 1 , wherein the first and second axes are substantially collinear.

8. The laser of claim 1 , wherein the first and second axes are offset from each other.

9. The laser of claim 1 , wherein the second gain element surface and the second saturable absorber element surface are generally parallel.

10. The laser of claim 1 , wherein the first axis is at an angle with the second axis.

11. The laser of claim 1 , wherein the second gain element surface and the second saturable absorber element surface are at an angle with each other.

12. The laser of claim 1 , wherein the one or more fundamental wavelength suppression features comprise an exo-cavity element.

13. The laser of claim 12 , wherein the exo-cavity element is located on an opposite side of the gain element from a pump, the exo-cavity element configured to reflect back pump radiation into the cavity.

14. The laser of claim 12 , wherein the exo-cavity element is located next to the first gain element surface and substantially collinear with an optical axis of the laser cavity, the exo-cavity element configured to isolate feedback of a first wavelength from pump shaping optics.

15. The laser of claim 12 , further comprising an intra-cavity element between the gain element and the saturable absorber element, the intra-cavity element configured to focus pump radiation into the gain element.

16. The laser of claim 1 , wherein the first gain element surface is perpendicular to the first axis.

17. The laser of claim 1 , wherein the first saturable absorber element surface is perpendicular to the second axis.

18. A laser generator device outputting laser pulse(s) configured to generate transient vapor nanobubbles around malaria-specific nanoparticles in a human or ex vivo, the device comprising:

the passively Q-switched microchip laser of claim 1 ;

a laser pump coupled to the passively Q-switched microchip laser via a pump fiber; and

an output fiber coupling the passively Q-switched microchip laser and one or more malaria detection sensors.

19. The laser generator device of claim 18 , further comprising second harmonic generation and filtering elements coupling the passively Q-switched microchip laser to the output fiber.

20. The laser generator device of claim 18 , wherein the device is configured to sequentially switch the outputted pulsed laser beam among a plurality of optical fibers in the one or more malaria detection sensors.

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