Laser diode uniform illuminator

A fluorescence imaging system including a light source, an optical system, camera and an excitation light filter, the optical system produces a non-uniform fluence excitation illumination beam for illuminating an object and promoting fluorescence emissions, the optical system is positioned between the light source and the object, the optical system modifies the non-uniform fluence illumination beam into a uniform fluence illumination beam and changes the divergence of the uniform fluence illumination beam, the camera has an array of pixels, the camera detects the fluorescence emissions and performs pixel intensity measurements for each of the pixels, the excitation light filter is positioned between the object and the camera and filters out the excitation illumination beam, such that the excitation illumination beam does not reach the camera.

This application claims benefit of Serial No. 234766, filed 21 Sep. 2014 in Israel and which application is incorporated herein by reference. To the extent appropriate, a claim of priority is made to the above disclosed application.

FIELD OF THE DISCLOSED TECHNIQUE

The disclosed technique relates to laser illumination devices, in general, and to methods and systems for producing uniform illumination for fluorescence imaging by employing a laser diode and a vibrating diffuser, in particular.

BACKGROUND OF THE DISCLOSED TECHNIQUE

Fluorescence imaging is employed for imaging tissues. The fluorescence imager detects fluorescence light emitted from a fluorescence agent that is excited by appropriate illumination. For example, a fluorescent microscope is an imaging system for imaging internal blood flow, visible through the skin, by promoting fluorescence radiation from a fluorescent dye added to the flowing blood. The microscope can be employed, for example, during surgery for visualizing the blood flow, and for evaluating tissue perfusion and vessel patency.

The excitation illumination should be strong (i.e., of high intensity) because the fluorescence signal is often fairly weak, especially when employing IndoCyanine Green (ICG) as the fluorescence agent. One approach to create such an excitation light source is to use a laser diode. A laser diode allows relatively high power to be concentrated in a narrow wavelength region. This is advantageous for exciting fluorescent agents without interfering with the fluorescence image (i.e., as the excitation radiation can be easily filtered out in the camera).

It is noted that the fluence (i.e., output distribution) of a laser diode is Gaussian, with the center of the beam having significantly higher energy than the edges of the beam. Put another way, the fluence of the laser diode beam is non-uniform. This presents a significant problem for fluorescence imaging since fluorescence intensity is generally proportional to excitation light. Any light source that is not uniform will create artificial differences in fluorescence intensity due to non-uniformity of the excitation light. These artificial differences may be misinterpreted as physiological effects by the user of the system viewing the image. Such a misinterpretation may have very significant clinical consequences. Additionally, if image pixel intensity measurements (of any kind) are used, a non-uniform source will produce incorrect measurement results.

When designing laser-based illumination systems, one design requirement is to provide systems that are skin-safe and eye-safe. That is, the output of the illumination system should be within the safety limits for light incident on human skin and on human eyes.

A diffuser that vibrates along its plane is known in the art. Reference is now made to Datasheet: LSR-3000 Series for Laser Speckle Reducer LSR-3000 Series, published on Mar. 10, 2013 at: http://www.optotune.com/images/products/Optotune%20LSR-000%20Series.pdf. LSR Speckle reducer is basically a diffuser that is moved (i.e., vibrated). Speckle noise from a laser-based system is reduced by dynamically diffusing the laser beam. The diffuser is bonded to a thin elastic membrane, which includes four independent electro-active polymer electrodes that induce a circular oscillation of the diffuser in X and Y directions. The oscillation frequency is set to the measured resonant frequency of the LSR speckle reducer during production. However, both voltage and frequency of the electro-active polymer can be controlled.

Semiconductor diode lasers are electrically pumped semiconductor lasers in which the active medium is formed by a p-n junction of a semiconductor diode. Semiconductor diode lasers include several configurations, such as edge-emitter laser diodes and Vertical-Cavity Surface-Emitting Diode Lasers (VCSEL). Edge-emitter laser diodes are made up of bars diced from the wafers on which the diode layers are grown. The high index of refraction contrast between air and the semiconductor material at the side facets of the diced bars act as mirrors. Thus, the light oscillates parallel to the layers and escapes side-ways.

In a VCSEL, the active layer is sandwiched between two highly reflective mirrors (also referred to as distributed Bragg reflectors) composed of several layers of alternating high and low refractive index. The light oscillates perpendicular to the layers and escapes through the top (or bottom) of the device. A VCSEL array is an X-Y array of thousands of laser sources packed into a rectangular illuminator (e.g., 2.8 millimeter×2.8 millimeter). Each individual illuminator in the array is fairly low power (e.g., a few milliwatts). However, taken together the thousands of illuminators make up a powerful illuminator array. VCSEL array products are known in the art, for example, a “6 W CW 808 nm VCSEL Array” by Princeton Optronics (http://www.princetonoptronics.com/products/pdfs/PCW-CS6-6-W0808%20revB-0514.pdf). It is noted that each ray (produced by a single illuminator) in the array has a non-uniform fluence (e.g., Gaussian shaped fluence). Therefore, while the fluence of a beam formed by the multitude of rays is more uniform than that of any of the rays, it still resembles a pin cushion, and cannot be considered as smoothly uniform.

Reference is now made to U.S. Pat. No. 8,016,449 issued to Liu et al., and entitled “Surface Light Emitting Apparatus Emitting Laser Light”. This publication relates to a surface light emitting apparatus, which can be employed, for example, as a backlight for a screen. The apparatus includes a laser light source, and an optical element. The surface of the optical element has optical power, and it converts the intensity distribution of the laser beam emitted by the laser light source into a uniform intensity distribution.

Reference is now made to International Patent Application Publication No. WO2011/059383 to Ivarsson et al., and entitled “Optical Sensor System Based on Attenuated Total Reflection and Method of Sensing”. This publication relates to an optical sensor system employing surface plasmon resonance (SPR). The system includes a laser light source, an SPR detector and a distribution device. The distribution device is located between the laser light source and the SPR detector. The laser light source can emit IR radiation. The distribution device distributes the laser beam emitted by the laser light source and converts it into a uniform intensity distribution beam. The system determines the dip in the detected spectrum intensity profile (i.e., the location of the low point in the intensity profile).

Reference is now made to an article by Reinhard Voelkel et al., and entitled “Laser Beam Homogenizing: Limitations and Constraints”, published at SPIE_7102_19, Optical Design Conf., Laser Beam Homogenizing, Glasgow 2008. This publication relates to laser homogenizing systems. For example, this publication describes a laser homogenizing system employing an array of lenses for converting the intensity distribution of a laser beam into a uniform intensity distribution.

SUMMARY OF THE DISCLOSED TECHNIQUE

It is an object of the disclosed technique to provide a novel method and system for fluorescence imaging, which overcomes the disadvantages of the prior art. In accordance with the disclosed technique, there is thus provided a fluorescence imaging system. The system includes a light source, an optical system, a camera, and an excitation light filter. The light source is configured to produce a non uniform fluence excitation illumination beam having a non uniform beam fluence. The excitation illumination beam illuminates an object for promoting fluorescence emissions. The optical system is optically coupled with the light source and is positioned between the light source and the object. The optical system is configured to modify the non uniform fluence illumination beam into a uniform fluence illumination beam having a uniform beam fluence. The optical system is further configured to change the divergence of the uniform fluence illumination beam. The camera has an array of pixels, and is configured for detecting the fluorescence emissions and for performing pixel intensity measurements for each of the pixels. The excitation light filter is positioned between the object and the camera. The excitation light filter is configured for filtering out the excitation illumination beam, such that the excitation illumination beam does not reach the camera.

DETAILED DESCRIPTION OF THE EMBODIMENTS

The disclosed technique overcomes the disadvantages of the prior art by providing a uniform illumination system including a light source and an optical system. The light source produces a non-uniform fluence light beam (having non-uniform beam fluence). The optical system modifies the non-uniform light beam into a uniform fluence light beam having uniform beam fluence (i.e., modifies the light beam to be a top hat light beam, also referred to as a flat top beam).

In accordance with an embodiment of the disclosed technique, the illumination system further includes a vibrating diffuser. The optical system includes an optical fiber transmitting the light beam produced by the light source. The optical system reimages the output of the optical fiber at an intermediate image plane. The vibrating diffuser is located on the intermediate image plane, and is vibrating along two non-parallel axes. The vibrations of the diffuser compensate for any irregularities on the diffuser surface, thereby smoothing spots on the diffused light beam.

In accordance with another embodiment of the disclosed technique, the light source is a VCSEL array producing an array of light rays forming together a non-uniform light beam. The array light source is positioned off the focal plane of the optical system, such that a slight defocus is introduced to the light beam, thereby smoothing the light beam and making it a uniform fluence beam.

Reference is now made toFIG. 1, which is a schematic illustration of a fluorescence imaging system, generally referenced100, constructed and operative in accordance with an embodiment of the disclosed technique. Fluorescence imaging system100includes an image detection system102and an illumination system104. Fluorescence imaging system100acquires images of an object106located at a distance D2from the imaging system (e.g., 20-40 Centimeters). Detection system102is located at a distance of D1from illumination system104.

Detection system102detects fluorescent emissions emitted from object106, and produces accordingly a fluorescent image of object106. Detection system102can further detect a visible image of object106by detecting visible light reflected from object106. The structure and components of detection system102are further elaborated herein below with reference toFIG. 2.

Illumination system104illuminates object106. In particular, illumination system104provides at least an excitation illumination beam that excites a fluorescent agent in object106, which emits fluorescent light in response to the excitation light. The excitation illumination beam produced by illumination system104should cover the Field of View (FOV) of detection system102. In other words, an area of object106which would not be illuminated with excitation light, would not emit fluorescent light even if it includes a fluorescent agent. Thereby, that area would not be captured in the fluorescent image, which might lead to clinical misinterpretations.

Additionally, the fluence of the illumination beam should be spatially uniform. That is, the excitation light intensity at each location within the FOV of the illumination beam should be substantially similar. The structure and components of illumination system104are further elaborated herein below with reference toFIG. 3.

It is noted that illumination system104and detection system102are not parallel, but are slightly angled toward each other. Thus, the overlap between the FOV of detection system102and the FOV of illumination system104is increased. In particular, the distance (D1) and the angle, between detection system102and illumination system104are determined according to the desired object distance (D2), such that the FOV of illumination system104would cover that of detection system102.

Reference is now made toFIG. 2, which is a schematic illustration of a fluorescence image detection system, generally referenced200, constructed and operative in accordance with another embodiment of the disclosed technique. Detection system200includes an excitation light filter202, a dichroic mirror204, a mirror206, a short pass filter208, a long pass filter210, a visible light camera212and an IR light camera214.

Excitation light filter202is located on the object side of dichroic mirror204and is optically coupled therewith. Dichroic mirror204is further optically coupled with a visible light camera212via short pass filter208, and with IR camera214via mirror206and long pass filter210.

Excitation light filter202blocks (or at least attenuates) reflected excitation light, and admits fluorescence light218and reflected visible light216into detection system200. It is noted that reflected visible light216is either reflected ambient light (i.e., preexisting light in the surroundings of the microscope), or is light provided from a dedicated light source other than the excitation light source. Dichroic mirror204reflects IR light218(i.e., the fluorescence emissions light) while enabling visible light216(i.e., the reflected visible light) to pass therethrough. Visible camera212detects a visible image of the object (e.g., object106ofFIG. 1), while IR camera214detects the fluorescence image of the object.

Reference is now made toFIG. 3, which is a schematic illustration of a uniform illumination system, generally referenced300, constructed and operative in accordance with a further embodiment of the disclosed technique. Uniform illumination system300includes a point light source302, an optical fiber303, a first aspheric lens304, a field lens306, a pre-diffuser window308, a vibrating diffuser310, a post-diffuser window312, a second aspheric lens314, a third aspheric lens316, and an output window318.

Point light source302can be, for example, a laser diode light source, or another laser light source. Generally speaking, point light source302can be any point light source providing excitation illumination adapted to excite the fluorescence agent, or otherwise to promote fluorescent emissions to be detected. It is noted that the output distribution (i.e., fluence) of point light source302is non-uniform. For example, for an edge-emitter laser diode light source, the fluence is Gaussian shaped with the center of the beam having significantly higher energy than the edges of the beam.

For acquiring fluorescence images, the FOV of an illumination beam324(i.e., the beam diameter at the imaged area) should cover at least the FOV of the fluorescence image detector (e.g., detection system102ofFIG. 1, or detection system200ofFIG. 2). Furthermore, the fluence of illumination beam324should be distributed substantially evenly (i.e. uniformly) across the FOV. Otherwise, for example in the case of Gaussian fluence, the fluorescent emissions at the center of the imaged area would be much stronger than those at the edges of the imaged area, thereby producing an erroneous image that may lead to clinical misinterpretation.

Optical fiber303is an optical fiber for transmitting the light produced by light source302toward lens304. For example, fiber303can be a 400 micrometer diameter fiber having a numerical aperture of 0.22. Alternatively fiber303can be of other dimensions to adapt to the dimensions of light source302and those of lens304. Fiber303receives illumination beam324at the output of light source302. The output port of fiber303(not referenced) is positioned next to lens304.

Lenses314and316expand the output of diffuser310to an angle required for the FOV of the fluorescence system. In other words, lenses314and316increase the divergence of beam324. It is noted that as lenses314and316are converging lenses, the lenses converge the illumination beam toward the focal point thereof, and the beam divergence is increase only after passing the focal point. Therefore, the illumination system is placed well away from the focal point of lens316. Windows308and312protect the diffuser surface, and window318protects the output of the illumination system300.

Vibrating diffuser310is a planar diffuser that is vibrated in two perpendicular axes along its plane (i.e., vibrated along the X axis and the Y axis ofFIG. 3). Diffuser310might have surface irregularities that might produce respective irregularities in the fluence of beam324. Any irregularities in the output beam will translate to artificial variations in the intensity of areas of the fluorescence image and may lead to clinical misinterpretations. The vibrations of diffuser310smooth the diffused beam at the output of diffuser310, thereby eliminating fluence irregularities caused by possible surface irregularities of diffuser310. In particular, the frequency of vibrations of vibrating diffuser310exceeds the frame rate of the camera, thereby compensating for structural irregularities of the diffuser surface and smoothing the illumination beam. In other words, the diffuser face is imaged as part of the illumination optics functionality and any microstructures on the face will show up in the output beam profile. Diffuser vibrations in two non-parallel axes eliminate the effect of microstructures on the diffuser.

Diffuser310also improves the safety of the illumination system, by diffusing the narrowly concentrated light emitted from point light source302. When designing laser-based illumination systems, one design requirement is to provide systems that are skin-safe and eye-safe. That is, the output of the illumination system should be within the safety limits for light incident on human skin and on human eyes. A standard laser diode is generally considered a point source. For a point source illuminator, skin safety and eye safety limits are much lower than for a diffused source. This is because a point source can be focused (by the lens of the eye for example) onto a very small area and can therefore cause thermal damage to the area. As such, a diffusion mechanism is highly desirable with laser diodes to convert the illuminator from a point source to a safer diffused source.

A vibrator (not shown) vibrates diffuser310. As mentioned above, vibrating diffuser310is vibrated in two non-parallel axes (e.g., perpendicular axes X and Y). The frequency and the amplitude of vibrations in each of the axes can be controlled.

In accordance with an alternative embodiment of the disclosed technique, diffuser310can be composed of several diffusers. For example, a first diffuser vibrating along the X axis and positioned at a first intermediate image plane of the output of the light source, and a second diffuser vibrating along the Y axis and positioned at a second intermediate image plane of the output of the light source.

In accordance with yet another alternative embodiment of the disclosed technique, the diffuser can be non-planar (e.g., dome shaped or an aspheric diffuser). Thereby, the shape of the diffuser can be employed to disperse the illumination beam evenly across its FOV.

As can be seen inFIG. 3illumination system300includes a light source (point light source302) and an optical system (i.e., fiber303and lenses304,306314and316). Specifically, the optical system of uniform illumination system300is formed of two optical subsystems, a first subsystem320includes fiber303, first aspheric lens304and field lens306. Fiber303receives the non-uniform illumination beam produced by light source302and relays it toward lens304. First optical subsystem320is a double telecentric system re-imaging an intermediate image of the output of fiber303on the plane of vibrating diffuser310. That is, diffuser310is positioned on a plane of an intermediate image of the output of fiber303for diffusing the illumination light beam. At the output of subsystem320(i.e., after diffuser310) the illumination beam is substantially a top hat beam having substantially uniform fluence. In other words, first optical subsystem320is configured to transform the fluence of beam324from a non-uniform fluence at the output of light source302to a uniform fluence at the input to diffuser310. That is, first optical subsystem320is composed of optical elements that are constructed and located so as to flatten the fluence of beam324.

Second optical subsystem322includes second and third aspheric lenses314and316. Subsystem322reimages a second image plane of the output of the light source onto a working plane (e.g., an open surgery area to be fluorescently imaged). The illumination beam at the second image plane remains a top hat beam (as is the beam at the output of diffuser310). Second optical subsystem322increases the divergence of light beam324to match the required field of view of the system.

It is noted that the optical system described herein above with reference toFIG. 3is an example optical system and can be replaced by other optical systems having different components. The optical system is designed to modify the illumination beam fluence to become substantially uniform, thereby producing a uniform top hat beam. Additionally, the optical system increases the beam diameter of beam324at the imaged area. The optical system of the uniform illumination system reimages the output of the fiber at an intermediate image plane, at which the vibrating diffuser would be located. The diffuser diffuses the light beam.

Reference is now made toFIG. 4which is a schematic illustration of an illumination system, generally referenced400, constructed and operative in accordance with yet another embodiment of the disclosed technique. Uniform illumination system400includes a Vertical-Cavity Surface-Emitting Laser (VCSEL) array light source402, a first aspheric lens404, a second aspheric lens406, and an output window408.

VCSEL array light source402provides excitation illumination adapted to excite the fluorescence agent, or otherwise to promote fluorescent emissions to be detected. VCSEL array light source402produces uniform output (i.e., producing a top hat beam having uniform fluence). Specifically, while each of the thousands of illuminators in the VCSEL array of light source402has a Gaussian beam profile, the illuminators placed in close proximity to each other and added together produce a uniform output. Additionally, the output of VCSEL array light source402is much larger (e.g.: 2.8 milimeter×2.8 milimeter) than that of a point source making it easier for the system to be skin-safe and eye-safe.

Each of first aspheric lens404and second aspheric lens406is a converging lens having positive optical power. Lenses404and406expand the output of light source402(i.e., increase the divergence of the light beam) to an angle required for illuminating the FOV of the fluorescence system. Window408protects the output of illumination system400. It is noted that the optical design of system400, including lenses404and406, and window408, is similar to subsystem322ofFIG. 3. Specifically, in accordance with the embodiment of the disclosed technique presented inFIG. 4, subsystem320ofFIG. 3, is replaced by VCSEL array light source402, while subsystem322(directed at expanding the excitation illumination beam) remains similar.

VCSEL array light source402is placed at some distance in front of an entry focal plane410of the optical system (lenses404and406) of illumination system400, to affect a desired degree of uniformity. In other words, by placing light source402off the focus plane of lens404a slight defocus (blur) is introduced to the array output. The amount of defocus can be adjusted as needed by changing the distance between the light source402and lens404while viewing the system illumination pattern.

As mentioned in the background section VCSEL array light source402actually produces an array of rays, each having a Gaussian output distribution. By introducing some defocus (by placing the light source off the focus plane of the optical system), the multitude of rays are merged for forming together a smoothed uniform beam. Essentially, the de-focused output of VCSEL array402is similar to the output of vibrating diffuser310ofFIG. 3. That is, the illumination system produces a uniform fluence light beam having uniform flat top fluence, and being skin-safe and eye-safe (within safety levels defined by applicable standards).

As can be seen inFIG. 4, the illumination system includes a light source (i.e., VCSEL array light source402) and an optical system (i.e., lenses404and406). The light source produces a non-uniform light beam. The optical system modifies the non-uniform light beam into a uniform light beam having uniform flat top fluence.

Reference is now made toFIGS. 5A, 5B and 5Cwhich are schematic illustrations of the FOV of an illumination system and a detection system of a fluorescence imaging system, operative in accordance with yet a further embodiment of the disclosed technique. With reference toFIG. 5A, FOV502of an illumination system and FOV504of a detection system are depicted for an object distance of 20 centimeters (i.e., the object is located 20 centimeters from the illumination and detection systems). With reference toFIG. 5B, FOV502of the illumination system and FOV504of the detection system are depicted for an object distance of 30 cm. With reference toFIG. 5C, FOV502of the illumination system and FOV504of the detection system are depicted for an object distance of 40 centimeters.

As can be seen inFIGS. 5A-5C, FOV502of the illumination system is larger than FOV504of the detection system, for fully illuminating the imaged object. At a relatively short object distance (e.g., 20 centimeters as inFIG. 5A), the FOVs of the illumination system and the detection system are at an offset to each other. This occurs because the systems are located adjacently to one another and not coaxially. At a relative longer distance (40 cm as depicted inFIG. 5C), the distance between the systems is small with respect to the object distance and the FOVs appear substantially concentric.

Reference is now made toFIG. 6, which is an illustration of an output distribution, generally referenced600, across one axis of an illumination beam, operative in accordance with yet another embodiment of the disclosed technique. As can be seen, output distribution600is substantially of a top hat shape. That is, the fluence of the illumination beam is dispersed evenly across its FOV. As mentioned above, for example with reference toFIG. 3, the optical system that reimages the output of the light source at an intermediate image plane (at which the diffuser is located) is configured to transform the light beam outputted by the light source into a uniform fluence light beam as depicted inFIG. 6.

It is noted that the imaging system described herein above with reference toFIG. 2, serves only as an example of a fluorescence imaging system, which employs the illumination system of the disclosed technique. Generally, the illumination system of the disclosed technique can be employed for any fluorescence imaging system having a non-uniform fluorescence light source. Moreover, in the examples set forth herein above, the uniform illumination system is employed for producing uniform excitation illumination beam for a fluorescence imaging system. It is noted however, that the uniform illumination system can be employed for other situations in which the light source output is non-uniform and its fluence should be made uniform and smooth. For example, microscope or endoscope imaging systems may also benefit from a uniform high power illumination source as described in this invention. In fact, any system that is intended to perform measurements of output intensity of image pixels will benefit from this type of illumination source.

It will be appreciated by persons skilled in the art that the disclosed technique is not limited to what has been particularly shown and described hereinabove. Rather the scope of the disclosed technique is defined only by the claims, which follow.