EP3182917A1 - Raman-triggered ablation/resection systems and methods - Google Patents
Raman-triggered ablation/resection systems and methodsInfo
- Publication number
- EP3182917A1 EP3182917A1 EP15756755.3A EP15756755A EP3182917A1 EP 3182917 A1 EP3182917 A1 EP 3182917A1 EP 15756755 A EP15756755 A EP 15756755A EP 3182917 A1 EP3182917 A1 EP 3182917A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- raman
- ablation
- tissue
- laser
- power level
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
- A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B2017/00017—Electrical control of surgical instruments
- A61B2017/00022—Sensing or detecting at the treatment site
- A61B2017/00057—Light
- A61B2017/00061—Light spectrum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B2018/00571—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for achieving a particular surgical effect
- A61B2018/00577—Ablation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B2018/00636—Sensing and controlling the application of energy
- A61B2018/00696—Controlled or regulated parameters
- A61B2018/00702—Power or energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B2018/00982—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body combined with or comprising means for visual or photographic inspections inside the body, e.g. endoscopes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
- A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
- A61B2018/2035—Beam shaping or redirecting; Optical components therefor
- A61B2018/20351—Scanning mechanisms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
- A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
- A61B2018/2035—Beam shaping or redirecting; Optical components therefor
- A61B2018/20361—Beam shaping or redirecting; Optical components therefor with redirecting based on sensed condition, e.g. tissue analysis or tissue movement
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
- A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
- A61B2018/2035—Beam shaping or redirecting; Optical components therefor
- A61B2018/205547—Controller with specific architecture or programmatic algorithm for directing scan path, spot size or shape, or spot intensity, fluence or irradiance
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
- A61B90/36—Image-producing devices or illumination devices not otherwise provided for
- A61B90/37—Surgical systems with images on a monitor during operation
- A61B2090/373—Surgical systems with images on a monitor during operation using light, e.g. by using optical scanners
Definitions
- a variety of surgical techniques have been developed for the physical removal of cancerous or other diseased tissue.
- a goal of these methods is to remove cancerous/diseased tissue with minimal damage to nearby healthy tissue.
- a surgeon resects tissue that appears to be abnormal from visual inspection.
- Surgical resection is the standard of care for most cancer types. However, complete resection is hindered by the ability of a surgeon to accurately identify tumor margins and small infiltrative tumor deposits. The degree of residual tumor post-surgery correlates with the probability of tumor recurrence and development of metastatic disease. To be certain that all tumor is removed, surgeons often perform "wide excisions" to achieve tumor-free margins. This may be problematic or impossible due to adjacent vital structures or organs which would need to be sacrificed. For example, limb amputation or exenteration, i.e., removal of adjacent organs, may be necessary. Alternatively, surgeons can spare adjacent structures, but risks for recurrence may be increased, due to tumor tissue remaining in the body.
- Tissue may be analyzed during surgery to aid in determination of abnormal tissue boundaries, but biopsy and analysis of tissue by a pathologist during surgery is time-consuming, and may be limited to only one or two areas during a single operation.
- Raman reporters such as Raman nanoparticles (e.g., surface-enhanced Raman spectroscopic (SERS) and/or surface-enhanced (resonance) Raman spectroscopic (SERRS) nanoparticles), and/or intrinsic species that produce(s) a characteristic, identifiable Raman signal (e.g., Raman spectrum).
- SERS surface-enhanced Raman spectroscopic
- SERRS surface-enhanced Raman spectroscopic
- the system employs an ablation laser that is used to both (i) interrogate for the presence of a Raman reporter that has been treated on or administered into a tissue and (ii) ablate the tissue once the presence of the Raman reporter has been determined.
- a single radiation source for both the interrogation and ablation simplify the optics assembly for an
- ablation/scannnig device while allowing for more precise resection of the tissue by employing the same laser path.
- the system and method leverage the natural frequency- related absorption characteristics and vibrational modes of the Raman reporter for both interrogation and ablation.
- the characteristics used to amplify the detection of the reporter when being scanned by a detector can also be employed to use the reporter as an agent for ablation.
- lower levels of radiation may be applied to the tissue that would not damage the tissue unless a Raman reporter that is tuned to that radiation is present.
- Raman reporters configured to bind or enter cancerous or diseased tissues, the system allows for the resection of such tissues with minimal damage to adjacent healthy tissue.
- a method for operating a Raman-based resection system includes producing, via an ablation laser of the resection system, an interrogation electromagnetic radiation over a scanning point of a sample having been treated with a Raman reporter, the ablation laser illuminating the scanning point at an interrogation power level.
- the method includes acquiring, via a detector of the system, a signal indicative of scattered photons emanating from the scanning point following illumination by the interrogation electromagnetic radiation.
- the method includes determining, via a processor of the system, whether the acquired signal is indicative of the presence of the Raman reporter in and/or upon the scanning point.
- the method includes producing, via the ablation laser, an ablation electromagnetic radiation over the scanning point to ablate tissue at the scanning point, wherein the ablation electromagnetic radiation is at a power level sufficient to ablate tissue.
- the spectrum of the scattered photons e.g., Raman scattered photons
- the spectrum of the scattered photons may be acquired in about or less than 100 ms (greater than 10 Hertz).
- the interrogation power level is less than 10% (e.g,. less than 20 milliwatt) of the maximum power level of the ablation laser.
- the ablation power level is greater than 50% (e.g., greater than 200 milliwatt) of the maximum power level of the ablation laser.
- the ablation electromagnetic radiation is at a power level (e.g., and the scanning point is exposed to the ablation electromagnetic radiation for a predetermined period of time) that does not cause damage to tissue exposed to the ablation electromagnetic radiation (e.g., for the predetermined period of time) unless the Raman reporter is present therein or thereupon (e.g., the ablation of tissue results from heating, vaporization, and/or vibrational damage caused by amplification of the Raman scattering by the Raman reporter due to the ablation radiation).
- the Raman reporter may include a particle selected from the group consisting of SERS nanoparticles, SERRS nanoparticles, SERS-MRI nanoparticles, and R-MR nanoparticles.
- the processor determines whether the acquired signal is indicative of the presence of the Raman reporter in and/or upon the scanning point by (i) determining a comparison index between the acquired signal and a referenced signal of the Raman reporter and (ii) evaluating the determined comparison index to determine if the index exceeds a pre-defined threshold.
- the comparison index may be calculated, for example, based n which Sj is the acquired spectrum at acquisition point i, r t is the
- s is the mean of the acquired spectrum
- r is the mean of the reference spectrum
- n is the number acquisition points.
- the processor determines whether the acquired signal is indicative of the presence of the Raman reporter in and/or upon the scanning point using a method selected from the group consisting of absolute different value search, first derivative absolute value search, least square search, first derivative least square search, Euclidean distance search, correlation coefficient, and correlation search.
- the method includes de-energizing the ablation laser when determining, via the processor of the system, whether the acquired spectrum is indicative of the presence of the Raman reporter.
- the outputs of the first and second excitation electromagnetic radiation are continuous.
- the system includes an ablation laser for directing
- the system includes an instrument operably linked to the ablation laser, the instrument including optics for directing the electromagnetic radiation onto or into the scanning point of the target tissue.
- the system includes a detector for detecting scattered photons emanating from the scanning point of the target tissue in which the scattered photons results from illumination with the electromagnetic radiation.
- the system includes a processor configured to regulate output power levels of the ablation laser and to process data corresponding to the scattered photons detected from the scanning point of the target tissue.
- the processor is configured to trigger a switch from an interrogation power level of the ablation laser to an ablation power level of the ablation laser upon a determination of a presence of a Raman reporter in the target tissue in and/or upon the scanning point (e.g., sufficiently near the scanning point) in which the ablation power level is sufficient to ablate tissue at the scanning point.
- the electromagnetic radiation has a wavelength of about 500 nm to about 11 ⁇ .
- the interrogation power level in some embodiments, is less than 10% (e.g., 10 milliwatt) of the maximum power level of the ablation laser.
- the ablation power level in some embodiments, is greater than 50% (e.g., greater than 200 milliwatt) of the maximum power level of the ablation laser.
- the ablation power level of the ablation laser is at a power level (e.g., and the scanning point is exposed to electromagnetic radiation at the ablation power level for a predetermined period of time) that does not cause damage to tissue exposed to electromagnetic radiation at the ablation power level (e.g., for the predetermined period of time) unless the Raman reporter is present therein or thereupon (e.g., the ablation of tissue results from heating, vaporization, and/or vibrational damage caused by amplification of the Raman scattering by the Raman reporter due to the ablation radiation).
- the instrument is an endoscopic instrument.
- the ablation laser is selected from the group consisting of a C02 laser, an Er:YAG laser, and a Nd:YAG laser.
- the instrument includes optics for imaging.
- the system includes a suction vacuum operably linked to the instrument.
- the system includes a raster scanning device for positioning the instrument over the target tissue.
- the processor determines whether the acquired signal is indicative of the presence of the Raman reporter in and/or upon the scanning point by (i) determining a comparison index between the acquired signal and a referenced signal of the Raman reporter and (ii) evaluating the determined comparison index to determine if the index exceeds a pre-defined threshold.
- an ablation laser or resection mechanism that is activated only at locations at which one or more Raman reporters are detected.
- an ablation laser or resection mechanism is activated at a location only when a Raman signal indicative of the presence of a Raman reporter at the location is recognized by a Raman spectrometer, where the Raman reporter is associated with tissue to be resected/ablated (e.g., cancerous, diseased, infected, or otherwise abnormal tissue). If the specific Raman signal associated with one or more Raman reporters is not detected, the ablation/resection mechanism is not activated. In this way, extremely precise destruction and/or removal of diseased tissue may be accomplished while limiting damage to nearby healthy tissue. For example, a precision of 500, 400, 300, 200, 100, or 50 micrometers or better may be achieved.
- a Raman reporter is a Raman nanoparticle (e.g., SERS and/or SERRS nanoparticle), or a component of a Raman nanoparticle.
- Raman nanoparticles are administered (e.g., by injection or topically) to a patient/subject and are allowed to accumulate in and/or around cancerous tissue, pre-cancerous tissue, or other diseased tissue (e.g., necrotic tissue, infected tissue, inflamed tissue, etc.).
- the Raman nanoparticles that may be used in the disclosed systems and methods include, for example, those described in Kircher et al, Nature Medicine 2012 Apr 15; 18(5): 829-34, the text of which is incorporated herein by reference in its entirety. These are based on surface enhanced Raman scattering (SERS). Other nanoparticles may be used, as long as they create a sufficiently detectable and distinguishable Raman signal (e.g., a Raman spectrum).
- SERS surface enhanced Raman scattering
- a Raman reporter is a molecule or substance present within, on, or near diseased tissue itself ("intrinsic species"), which is identified or targeted using an intrinsic Raman spectrum (e.g., a Raman spectrum detected following illumination of tissue).
- tissue is selected and/or resected/ablated if a detected Raman signal satisfactorily matches a predetermined Raman signal known to be indicative of the Raman reporter.
- the system includes a hand-held instrument of size and shape that may be customized depending on the application.
- the system may include a laser suitable to ablate/destroy tissue (such as, for example, a C0 2 , Er:YAG, or Nd:YAG laser).
- the system may include a motor-driven, controlled resection mechanism such as, for example, a small rotating blade, located at the tip of the handheld instrument.
- the system may include an electro-cautery mechanism, a cryoablation mechanism, and/or a radiofrequency ablation mechanism.
- an ablation mechanism is a robotic/remote controlled ablation mechanism (e.g., located at the tip of the hand-held instrument).
- the system may also include a vacuum suction mechanism connected to a collection bag for removal of destroyed/ablated/resected tissue as well as nanoparticles located within the target tissue.
- the system may also include an excitation laser and associated optics for determination of Raman spectra associated with detected photons emanating from the tissue.
- a rinsing mechanism may be included to keep optics clean during the procedure.
- the hand-held instrument may be connected to other components of the system via fiberoptic cable, for example, and suction tubing.
- the hand-held instrument may be connected to components of a box housing mechanics, optics, electronics, excitation laser, ablation laser, resection instrument motor, radiofrequency or cryoablation generator, suction motor, rinsing mechanism, Raman spectral analysis optics, and/or the CCD chip.
- a surgeon using the disclosed system can destroy or remove cancerous (or otherwise abnormal) tissue quickly and with high precision in a semiautomated fashion.
- the hand-held instrument may be positioned and moved over regions of tissue "blindly” or “semi-blindly” near the site of disease/cancer, as the system destroys only cancerous tissue, with no or minimal damage to adjacent healthy tissue.
- the system may be used, for example, during open surgical procedures, in-office (non-surgical) procedures, invasive procedures, noninvasive or minimally invasive procedures, endoscopic procedures, robotically-assisted procedures, or in external applications such as skin cancer removal.
- An automated or semi-automated X-Y (two-dimensional) or X-Y-Z (three- dimensional) scan of the tissue by the instrument may be performed.
- the detection+ablation/resection instrument may be positioned such that excitation light from the instrument is directed to a sequence of X-Y or X-Y-Z positions of the tissue.
- the processor of the system determines whether a Raman reporter is detected at that location. If so, the resection/ablation mechanism is activated at that location such that only tissue at that location is removed or destroyed.
- the resection/ablation mechanism is then deactivated prior to moving the instrument to a second location, whereupon excitation light is directed to the second position and light is detected from the second position and the resection/ablation mechanism is activated only if a Raman reporter is detected at that second position, and so on.
- a Raman reporter is a SERS nanoparticle (or a component thereof) that may be applied topically or injected prior to operation of the hand-held instrument.
- a topical application may include penetrating peptides to facilitate absorption of the SERS nanoparticles into the skin.
- a Raman reporter is an intrinsic species within, on, or near the skin cancer or other abnormal tissue.
- the invention encompasses a system comprising: an excitation light source for directing excitation light onto or into a target tissue; an instrument (e.g., hand-held instrument) operably linked to the excitation light source, the instrument comprising: optics for directing the excitation light onto or into the target tissue; a detector for detecting Raman scattered photons emanating from the target tissue, said Raman scattered photons resulting from illumination with the excitation light; a resector/ablator mechanism; a processor (e.g., a Raman spectrometer and associated computer processor and/or software) configured to process data corresponding to the Raman scattered photons detected from the target tissue; and a processor (e.g., a Raman spectrometer and associated computer processor and/or software) configured to process data corresponding to the Raman scattered photons detected from the target tissue; and a processor (e.g., a Raman spectrometer and associated computer processor and/or software) configured to process data corresponding to the Raman scattered photo
- resector/ablator controller operably linked to the processor and operably linked to the
- the excitation light source is a laser. In certain embodiments, the excitation light has a wavelength of about 500 nm to about 10 ⁇ . In some embodiments, the excitation light has a wavelength of about 785 nm. In certain embodiments, the excitation light is near-infrared light (e.g., where deeper penetration, e.g., up to about 1cm, is desired). In certain embodiments, the excitation is ultraviolet light (e.g., where shallow penetration, e.g., only up to 1 mm, up to 2 mm, or up to 3mm, is desired). In certain embodiments, the instrument is an endoscopic instrument.
- the resector/ablator mechanism comprises a laser.
- the laser of the resector/ablator mechanism is a C0 2 laser.
- the resector/ablator mechanism is a mechanical resector (e.g., rotary blade, vibrating knife, or percussing knife).
- the resector/ablator mechanism is an electro-cautery mechanism, a cryoablation mechanism, and/or a radiofrequency ablation mechanism.
- the resector/ablator controller is configured to activate the resector/ablator mechanism to resect, ablate, and/or destroy tissue at a given location only if Raman scattered photons detected from the given location (e.g., a detected Raman signal or spectrum) indicate the presence of a Raman reporter (e.g., SERS nanoparticles, SERRS nanoparticles, or an intrinsic species).
- a Raman reporter e.g., SERS nanoparticles, SERRS nanoparticles, or an intrinsic species.
- the system further comprises a suction vacuum operably linked to the instrument.
- the invention encompasses a method of resecting, ablating, and/or destroying diseased tissue, the method comprising the steps of: positioning an instrument in relation to a first location (e.g., (x,y,z) or (x,y) location) of a target tissue of a subject (e.g., human or animal), the instrument comprising: optics for directing excitation light onto or into the target tissue at a given location; a detector for detecting Raman scattered photons emanating from the target tissue at the given location; and a resector/ablator mechanism; detecting the Raman scattered photons emanating from the first location of the target tissue; analyzing the detected Raman scattered photons emanating from the first location to determine whether the detected photons are indicative of the presence of a Raman reporter (e.g., SERS nanoparticles, SERRS nanoparticles, or intrinsic species) at the first location; and activating the resector/ablator mechanism (e.
- a Raman reporter
- the method further comprises: deactivating the resector/ablator mechanism prior to repositioning of the instrument in relation to a second location of the target tissue (e.g., wherein the second location of the target tissue is adjacent to the first location); detecting the Raman scattered photons emanating from the second location of the target tissue; analyzing the detected Raman scattered photons emanating from the second location to determine whether the detected photons are indicative of the presence of a Raman reporter (e.g., SERS nanoparticles, SERRS nanoparticles, and/or intrinsic species) at the second location; and activating the resector/ablator mechanism to resect, ablate, and/or destroy the target tissue at the second location only if the analyzed photons from the second location are determined to be indicative of the presence of the Raman reporter at the second location.
- a Raman reporter e.g., SERS nanoparticles, SERRS nanoparticles, and/or intrinsic species
- the method further comprises administering
- the method further comprises scanning the subject prior to implementation of the instrument to confirm the absence of nanoparticles from healthy (e.g., normal, e.g., non-cancerous) tissue.
- healthy e.g., normal, e.g., non-cancerous
- the instrument is operably linked to an excitation light source.
- the excitation light source is a laser.
- the excitation light has a wavelength of about of about 500 nm to about 11 ⁇ .
- the excitation light has a wavelength of about 785 nm.
- the excitation light is near-infrared light (e.g., where deeper penetration, e.g., up to about 1cm, is desired).
- the excitation is ultraviolet light (e.g., where shallow penetration, e.g., only up to 1 mm, up to 2 mm, or up to 3mm, is desired).
- the instrument is an endoscopic device. In certain embodiments, the instrument is an endoscopic device.
- the resector/ablator mechanism comprises a laser.
- the laser of the resector/ablator mechanism is a C0 2 laser.
- the resector/ablator mechanism is a mechanical resector (e.g., rotary blade, vibrating knife, or percussing knife).
- the resector/ablator mechanism is an electro-cautery mechanism, a cryoablation mechanism, and/or a radiofrequency ablation mechanism.
- the analyzing step comprises using a computer processor (e.g., a Raman spectrometer and associated computer processor and/or software) to process data corresponding to the detected Raman scattered photons.
- the method further comprises removing resected tissue.
- the method is an in vivo method.
- the instrument can be a handheld instrument, a stationary instrument, and/or a robotically assisted instrument.
- the device is an endoscopic instrument.
- system may further include other optics, hardware, electronics, and/or software for imaging target cells or tissues.
- apparatus and methods are presented herein that permit realtime, accurate detection of residual tumor in the operating room.
- the Raman-based wide-field imaging apparatus and methods described herein permit real-time imaging of tumor-targeted nanoparticles in an operating bed - for example, across a 30 x 30 cm field of view.
- the wide field imaging apparatus is particularly useful for imaging Raman signals emitted by nanoparticles such as R-MR nanoparticles, as described in Nature Medicine, Vol. 18, pp.
- Raman scanners are pen-like point scanners which do not acquire images, or imaging microscopes built for use of in vitro samples or small animals.
- described herein is a wide field Raman scanner that is able to image an entire operative bed in near real-time.
- the invention relates to a wide field Raman imaging apparatus comprising: at least one light source for producing excitation light; optics for directing the excitation light onto and/or into a target tissue; a detector for detecting Raman scattered photons emanating from the target tissue following illumination by the excitation light, the Raman scattered photons indicative of the presence of a Raman reporter in and/or upon the target tissue; and a processor configured to process data corresponding to the Raman scattered photons detected from the target tissue and to produce an image depicting a wide field corresponding to the target tissue, the image visually indicating position and/or intensity of the Raman reporter within the wide field.
- the at least one light source, the detector, and the processor are configured to produce a substantially real-time series of images visually indicating position and/or intensity of the Raman reporter within the wide field.
- the processor is configured to produce each image of the real-time series of images by obtaining one or more monochromatic images within a given short interval of time (e.g., 500 milliseconds or less, e.g., 50 milliseconds or less), each monochromatic image obtained at a wavelength corresponding to a spectral peak characteristic of the Raman reporter, and to use the one or more monochromatic images to produce the image in the real-time series indicating the position and/or intensity of the Raman reporter within the wide field during the given short interval of time.
- a given short interval of time e.g., 500 milliseconds or less, e.g., 50 milliseconds or less
- the wide field is at least 100 cm 2 in area (e.g., at least 300, 500, 1000, or 1200 cm 2 ).
- the at least one light source comprises a tunable laser source.
- the optics comprise a tunable laser line filter (LLF) and/or a tunable notch filter (NF) (e.g., said filter(s) comprising tandem thick volume Bragg gratings).
- the detector is a hyperspectral imager with a spatial resolution no greater than about 10 mm 2 (e.g., from 0.1 mm 2 to 3 mm 2 , e.g., about 1 mm 2 ).
- the detector comprises an optical pathway configured to allow x-y imaging of the Raman reporter within the wide field regardless of depth (z) of the Raman reporter in relation to the detector.
- the apparatus further includes a visual display for viewing the image.
- the processor is configured to produce a substantially realtime series of images and transmit the images for display on a personal image display (e.g., worn by the surgeon), such that the series of images can be displayed on, in, or through a transparent display that superimposes the displayed series of images over a corresponding view of the wide field.
- the processor is configured to track the position of the personal image display and compensate the series of images for movement of the display (e.g., movement of the wearer of the display), accordingly (e.g., by tracking the location of markers affixed on or near the patient as they appear within a field of view of the personal image display).
- the apparatus further comprises a visual display, wherein the visual display is an adjustable tablet-shaped screen positionable in relation to the target tissue of a patient in an operating bed, wherein the optics for directing the excitation light onto and/or into the target tissue are positioned on the side of the tablet-shaped screen facing the operating bed, and the image is displayed on the side of the tablet-shaped screen facing away from the operating bed so as to be viewable by a surgeon.
- the visual display is an adjustable tablet-shaped screen positionable in relation to the target tissue of a patient in an operating bed, wherein the optics for directing the excitation light onto and/or into the target tissue are positioned on the side of the tablet-shaped screen facing the operating bed, and the image is displayed on the side of the tablet-shaped screen facing away from the operating bed so as to be viewable by a surgeon.
- the light source for producing excitation light comprises one or more lasers, and wherein the optics for directing the excitation light onto and/or into the target tissue are configured to disperse the excitation light evenly over the wide field
- the apparatus further includes a resection/ablation mechanism described herein, e.g., a resection/ablation mechanism that is activated only at locations at which one or more Raman reporters are detected.
- a resection/ablation mechanism described herein e.g., a resection/ablation mechanism that is activated only at locations at which one or more Raman reporters are detected.
- the invention in another aspect, relates to a method for performing wide field Raman imaging of target tissue of a patient during a surgical procedure, the method comprising: administering a first Raman reporter to the patient (e.g., intravenously, topically, intraarterially, intratumorally, intranodally, via lymphatic vessels, etc.); illuminating the target tissue with excitation light; detecting Raman scattered photons emanating from the target tissue following illumination by the excitation light, the Raman scattered photons indicative of the presence of the first Raman reporter in and/or upon the target tissue; obtaining, by the processor of a computing device, an image depicting a wide field corresponding to the target tissue, the image visually indicating position and/or intensity of the first Raman reporter within the wide field; and displaying the image.
- a first Raman reporter e.g., intravenously, topically, intraarterially, intratumorally, intranodally, via lymphatic vessels, etc.
- the first Raman reporter accumulates within and/or upon cancerous, diseased, and/or otherwise abnormal portions of the target tissue prior to the illuminating and detecting step.
- the method comprises obtaining, by the processor of the computing device, a substantially real-time series of images visually indicating position and/or intensity of the first Raman reporter within the wide field and displaying the series of images in real-time.
- the method comprises obtaining, for each image of the real-time series of images, by the processor of the computing device, one or more monochromatic images within a given short interval of time (e.g., 500 milliseconds or less, e.g., 50 milliseconds or less), each monochromatic image obtained at a wavelength corresponding to a spectral peak characteristic of the Raman reporter, and using the one or more monochromatic images to produce the image in the real-time series indicating the position and/or intensity of the Raman reporter within the wide field during the given short interval of time.
- a given short interval of time e.g., 500 milliseconds or less, e.g., 50 milliseconds or less
- the method comprises displaying the real-time series of images at a frame rate at least 10 frames per second (e.g., 20 to 25 frames per second).
- the first Raman reporter comprises Raman-MRI (R-MR) nanoparticles. In some embodiments, the first Raman reporter comprises SERRS nanoparticles.
- the method comprises administering a second Raman reporter to the patient with different Raman signature than the first Raman reporter, wherein the detected Raman scattered photons are indicative of the presence of the first Raman reporter and the second Raman reporter in and/or upon the target tissue, and wherein the image visually indicates position and/or intensity of the first Raman reporter and the second Raman reporter within the wide field in a manner such that the first Raman reporter is distinguishable from the second Raman reporter.
- the wide field is at least 100 cm2 in area (e.g., at least 300, 500, 1000, or 1200 cm2).
- the method comprises displaying the image on a visual display, wherein the visual display is an adjustable tablet-shaped screen positionable in relation to the target tissue of a patient in an operating bed, wherein the image is displayed on the side of the tablet-shaped screen facing away from the operating bed such that it is viewable by a surgeon during a surgical procedure.
- the method comprises producing, by the processor of the computing device, a substantially real-time series of images and displaying the images on a personal image display (e.g., worn by a surgeon operating on the patient), such that the series of images are displayed on, in, or through a transparent display that superimposes the displayed series of images over a corresponding view of the wide field.
- the method comprises tracking, by the processor of the computing device, the position of the personal image display, and compensating the series of images for movement of the display (e.g., movement of the wearer of the display), accordingly (e.g., by tracking the location of markers affixed on or near the patient as they appear within the field of view of the personal image display). Details regarding an exemplary personal image display are described in U.S. Patent Application Publication No. US 2013/0044042, published February 21, 2013.
- the method further includes resecting, ablating, and/or destroying diseased tissue using a resection/ablation apparatus, system, and/or method described herein.
- systems and methods are presented herein that provide automated laser ablation and/or tissue resection triggered by detection of one or more Raman reporters, such as Raman nanoparticles (e.g., surface-enhanced Raman spectroscopic (SERS) and/or surface-enhanced (resonance) Raman spectroscopic (SERRS) nanoparticles), and/or intrinsic species that produce(s) a characteristic, identifiable Raman signal (e.g., Raman spectrum).
- Raman nanoparticles e.g., surface-enhanced Raman spectroscopic (SERS) and/or surface-enhanced (resonance) Raman spectroscopic (SERRS) nanoparticles
- SERS surface-enhanced Raman spectroscopic
- SERRS surface-enhanced Raman spectroscopic
- a system is provided herein with a resection/ablation mechanism that is activated only at locations at which one or more Raman reporters are detected.
- an ablation laser or resection mechanism is activated at a location only when a Raman signal indicative of the presence of a Raman reporter at the location is recognized by a Raman spectrometer, where the Raman reporter is associated with tissue to be resected/ablated (e.g., cancerous, diseased, infected, or otherwise abnormal tissue). If the specific Raman signal associated with one or more Raman reporters is not detected, the ablation/resection mechanism is not activated. In this way, extremely precise destruction and/or removal of diseased tissue may be accomplished while limiting damage to nearby healthy tissue. For example, a precision of 500, 400, 300, 200, 100, or 50 micrometers or better may be achieved.
- a Raman reporter is a Raman nanoparticle (e.g., SERS and/or SERRS nanoparticle), or a component of a Raman nanoparticle.
- Raman nanoparticles are administered (e.g., by injection or topically) to a patient/subject and are allowed to accumulate in and/or around cancerous tissue, pre-cancerous tissue, or other diseased tissue (e.g., necrotic tissue, infected tissue, inflamed tissue, etc.).
- the Raman nanoparticles that may be used in the disclosed systems and methods include, for example, those described in Kircher et ah, Nature Medicine 2012 Apr 15; 18(5): 829-34, the text of which is incorporated herein by reference in its entirety. These are based on surface enhanced Raman scattering (SERS). Other nanoparticles may be used, as long as they create a sufficiently detectable and distinguishable Raman signal (e.g., a Raman spectrum).
- SERS surface enhanced Raman scattering
- a Raman reporter is a molecule or substance present within, on, or near diseased tissue itself ("intrinsic species"), which is identified or targeted using an intrinsic Raman spectrum (e.g., a Raman spectrum detected following illumination of tissue).
- tissue is selected and/or resected/ablated if a detected Raman signal satisfactorily matches a predetermined Raman signal known to be indicative of the Raman reporter.
- the system includes a hand-held instrument of size and shape that may be customized depending on the application.
- the system may include a laser suitable to ablate/destroy tissue (such as, for example, a C0 2 , Er:YAG, or Nd:YAG laser).
- the system may include a motor-driven, controlled resection mechanism such as, for example, a small rotating blade, located at the tip of the handheld instrument.
- the system may include an electro-cautery mechanism, a cryoablation mechanism, and/or a radiofrequency ablation mechanism.
- an ablation mechanism is a robotic/remote controlled ablation mechanism (e.g., located at the tip of the hand-held instrument).
- the system may also include a vacuum suction mechanism connected to a collection bag for removal of destroyed/ablated/resected tissue as well as nanoparticles located within the target tissue.
- the system may also include an excitation laser and associated optics for determination of Raman spectra associated with detected photons emanating from the tissue.
- a rinsing mechanism may be included to keep optics clean during the procedure.
- the hand-held instrument may be connected to other components of the system via fiberoptic cable, for example, and suction tubing.
- the hand-held instrument may be connected to components of a box housing mechanics, optics, electronics, excitation laser, ablation laser, resection instrument motor, radiofrequency or cryoablation generator, suction motor, rinsing mechanism, Raman spectral analysis optics, and/or the CCD chip.
- a surgeon using the disclosed system can destroy or remove cancerous (or otherwise abnormal) tissue quickly and with high precision in a semiautomated fashion.
- the hand-held instrument may be positioned and moved over regions of tissue "blindly” or “semi-blindly” near the site of disease/cancer, as the system destroys only cancerous tissue, with no or minimal damage to adjacent healthy tissue.
- the system may be used, for example, during open surgical procedures, in-office (non-surgical) procedures, invasive procedures, noninvasive or minimally invasive procedures, endoscopic procedures, robotically-assisted procedures, or in external applications such as skin cancer removal.
- An automated or semi-automated X-Y (two-dimensional) or X-Y-Z (three- dimensional) scan of the tissue by the instrument may be performed.
- the detection+ablation/resection instrument may be positioned such that excitation light from the instrument is directed to a sequence of X-Y or X-Y-Z positions of the tissue.
- the processor of the system determines whether a Raman reporter is detected at that location. If so, the resection/ablation mechanism is activated at that location such that only tissue at that location is removed or destroyed.
- the resection/ablation mechanism is then deactivated prior to moving the instrument to a second location, whereupon excitation light is directed to the second position and light is detected from the second position and the
- resection/ablation mechanism is activated only if a Raman reporter is detected at that second position, and so on.
- a Raman reporter is a SERS nanoparticle (or a component thereof) that may be applied topically or injected prior to operation of the hand-held instrument.
- a topical application may include penetrating peptides to facilitate absorption of the SERS nanoparticles into the skin.
- a Raman reporter is an intrinsic species within, on, or near the skin cancer or other abnormal tissue.
- the invention encompasses a system comprising: an excitation light source for directing excitation light onto or into a target tissue; an instrument (e.g., hand-held instrument) operably linked to the excitation light source, the instrument comprising: optics for directing the excitation light onto or into the target tissue; a detector for detecting Raman scattered photons emanating from the target tissue, said Raman scattered photons resulting from illumination with the excitation light; a resector/ablator mechanism; a processor (e.g., a Raman spectrometer and associated computer processor and/or software) configured to process data corresponding to the Raman scattered photons detected from the target tissue; and a processor (e.g., a Raman spectrometer and associated computer processor and/or software) configured to process data corresponding to the Raman scattered photons detected from the target tissue; and a processor (e.g., a Raman spectrometer and associated computer processor and/or software) configured to process data corresponding to the Raman scattered photo
- resector/ablator controller operably linked to the processor and operably linked to the resector/ablator mechanism.
- the excitation light source is a laser. In certain embodiments, the excitation light has a wavelength of about 500 nm to about 11 ⁇ . In some embodiments, the excitation light has a wavelength of about 785 nm. In certain embodiments, the excitation light is near-infrared light (e.g., where deeper penetration, e.g., up to about 1cm, is desired). In certain embodiments, the excitation is ultraviolet light (e.g., where shallow penetration, e.g., only up to 1 mm, up to 2 mm, or up to 3mm, is desired). In certain
- the instrument is an endoscopic instrument.
- the resector/ablator mechanism comprises a laser.
- the laser of the resector/ablator mechanism is a diode-pumped solid-state laser or an ion gas laser (such as a C0 2 laser).
- the resector/ablator mechanism is a mechanical resector (e.g., rotary blade, vibrating knife, or percussing knife).
- the resector/ablator mechanism is an electro-cautery mechanism, a cryoablation mechanism, and/or a radiofrequency ablation mechanism.
- the resector/ablator controller is configured to activate the resector/ablator mechanism to resect, ablate, and/or destroy tissue at a given location only if Raman scattered photons detected from the given location (e.g., a detected Raman signal or spectrum) indicate the presence of a Raman reporter (e.g., SERS nanoparticles, SERRS nanoparticles, or an intrinsic species).
- a Raman reporter e.g., SERS nanoparticles, SERRS nanoparticles, or an intrinsic species.
- the system further comprises a suction vacuum operably linked to the instrument.
- the invention encompasses a method of resecting, ablating, and/or destroying diseased tissue, the method comprising the steps of: positioning an instrument in relation to a first location (e.g., (x,y,z) or (x,y) location) of a target tissue of a subject (e.g., human or animal), the instrument comprising: optics for directing excitation light onto or into the target tissue at a given location; a detector for detecting Raman scattered photons emanating from the target tissue at the given location; and a resector/ablator mechanism; detecting the Raman scattered photons emanating from the first location of the target tissue; analyzing the detected Raman scattered photons emanating from the first location to determine whether the detected photons are indicative of the presence of a Raman reporter (e.g., SERS nanoparticles, SERRS nanoparticles, or intrinsic species) at the first location; and activating the resector/ablator mechanism (e.
- a Raman reporter
- the method further comprises: deactivating the resector/ablator mechanism prior to repositioning of the instrument in relation to a second location of the target tissue (e.g., wherein the second location of the target tissue is adjacent to the first location); detecting the Raman scattered photons emanating from the second location of the target tissue; analyzing the detected Raman scattered photons emanating from the second location to determine whether the detected photons are indicative of the presence of a Raman reporter (e.g., SERS nanoparticles, SERRS nanoparticles, and/or intrinsic species) at the second location; and activating the resector/ablator mechanism to resect, ablate, and/or destroy the target tissue at the second location only if the analyzed photons from the second location are determined to be indicative of the presence of the Raman reporter at the second location.
- a Raman reporter e.g., SERS nanoparticles, SERRS nanoparticles, and/or intrinsic species
- the method further comprises administering
- the method further comprises scanning the subject prior to implementation of the instrument to confirm the absence of nanoparticles from healthy (e.g., normal, e.g., non-cancerous) tissue.
- healthy e.g., normal, e.g., non-cancerous
- the instrument is operably linked to an excitation light source.
- the excitation light source is a laser.
- the excitation light has a wavelength of about of about 500 nm to about 11 ⁇ .
- the excitation light has a wavelength of about 785 nm.
- the excitation light is near-infrared light (e.g., where deeper penetration, e.g., up to about 1cm, is desired).
- the excitation is ultraviolet light (e.g., where shallow penetration, e.g., only up to 1 mm, up to 2 mm, or up to 3mm, is desired).
- the instrument is an endoscopic device. In certain embodiments, the instrument is an endoscopic device.
- the resector/ablator mechanism comprises a laser.
- the laser of the resector/ablator mechanism is a diode -pumped solid-state laser or an ion gas laser (such as a C0 2 laser).
- the resector/ablator mechanism is a mechanical resector (e.g., rotary blade, vibrating knife, or percussing knife).
- the resector/ablator mechanism is an electro-cautery mechanism, a cryoablation mechanism, and/or a radiofrequency ablation mechanism.
- the analyzing step comprises using a computer processor (e.g., a Raman spectrometer and associated computer processor and/or software) to process data corresponding to the detected Raman scattered photons.
- the method further comprises removing resected tissue.
- the method is an in vivo method.
- the instrument can be a handheld instrument, a stationary instrument, and/or a robotically assisted instrument.
- the device is an endoscopic instrument.
- system may further include other optics, hardware, electronics, and/or software for imaging target cells or tissues.
- Figure 1 A shows a Raman-MRI (R-MR) nanoparticle used in conjunction with the wide-field Raman scanner/imaging apparatus described herein, according to an illustrative embodiment.
- R-MR Raman-MRI
- Figure IB is a computer rendering and electron microscopy images of the R-MR nanoparticle.
- Figure 1C is an exemplary Raman spectrum and intensity comparison of the R- MR nanoparticles versus equimolar amounts of first generation nanoparticles.
- Figure ID shows R-MR nanoparticles suspended in a 384 well plate phantom imaged with a Renishaw In Via Raman microscope.
- Figure 2 shows a comparison of Raman signal intensity of R-MR nanoparticles and previous, first generation nanoparticles.
- FIG. 3 shows a comparison of detection sensitivity between the Raman signal of the R-MR nanoparticles and other imaging modalities.
- R-MR nanoparticles have a detection threshold of 1.8 x 10-15 femtomolar [fM], and are therefore at least 3 orders of magnitude more sensitive than other ultra-sensitive imaging methods such as Positron-Emission Tomography (PET) or fluorescence imaging.
- PET Positron-Emission Tomography
- fluorescence imaging fluorescence
- Figure 4. shows the Renishaw InVia Raman microscope utilized to provide data presented in other Figures.
- Figure 5 shows how R-MR nanoparticles can be used to detect microscopic infiltration at tumor margins in a mouse with dedifferentiated lipiosarcoma implanted in the flank, according to an illustrative embodiment.
- Figure 6 shows how R-MR nanoparticles can be used to detect microscopic infiltration at tumor margins in the same mouse as Figure 5, after resection of the bulk tumor by a board-certified surgeon using his unaided eye (blinded to Raman image), according to an illustrative embodiment. There is a residual rim of Raman signal in the resection bed around the resected tumor. Histological evaluation confirmed tumor in the locations of the Raman signal.
- Figure 7 shows how R-MR nanoparticles can be used to detect microscopic regional satellite metastases in a mouse with liposarcoma, according to an illustrative
- FIG. 8 shows how R-MR nanoparticles can be used to detect submillimeter- sized dysplastic (premalignant) polyps and adenocarcinomas, according to an illustrative embodiment.
- the experiment was performed in an APCmin mouse, which is a mouse model mimicking the human "adenomatosis polyposis coli" syndrome, a genetic disorder that causes many dysplastic polyps and adenocarcinomas to develop simultaneously.
- Raman imaging reveals many small foci (less than 1 mm in size) of R-MR nanoparticle uptake within the colon and small bowel of an APCmin mouse (excised 24 hours after nanoparticle injection). These foci were then processed with histology, which demonstrated that they represented dysplastic polyps or adenocarcinomas.
- Figure 9 shows how R-MR nanoparticles can be used to detect submillimeter- sized dysplastic (premalignant) polyps and adenocarcinomas, according to an illustrative embodiment - histological confirmation. Shown is a segment of colon from the mouse in Fig. 8. Two histological cross-sections through the Raman positive areas were obtained and stained with Hematoxylin-Eosin (H&E). Section 1 proved the lesion to represent an adenocarcinoma, section 2 a dysplastic polyp.
- H&E Hematoxylin-Eosin
- the R-MR nanoparticles are able to detect not only very small colon cancers, but also their premalignant form - dysplastic polyps - which will eventually develop into invasive adenocarcinomas.
- the R- MRs may therefore be used as a new method for early colon cancer detection.
- FIG. 10 shows how R-MR nanoparticles can be used to detect prostate cancer, according to an illustrative embodiment.
- Hi-Myc state-of-the-art genetic spontaneous
- Mice express human c-Myc in the mouse prostate.
- Upper row Images show a control animal (same mouse strain but without the Myc mutation) that was injected with R-MR-Nanoparticles: No Raman signal is seen in this normal prostate.
- Lower row Images from a prostate cancer bearing mouse (hi-Myc) with obvious deformity of the prostate due to tumor (photograph) that was injected with the same amount of R-MR- Nanoparticles.
- the Raman image shows accumulation of R-MR-Nanoparticle within the tumor areas.
- Figure 11 shows how R-MR nanoparticles can be used to detect microscopic residual tumor in resection bed in a transgenic mouse model of prostate cancer (Hi-Myc), according to an illustrative embodiment.
- a prostatectomy was performed in a tumor-bearing Hi- Myc mouse, and subsequently the resection bed scanned with Raman imaging.
- Figure 12 shows how R-MR nanoparticles can be used to detect breast cancer in a state-of-the-art genetic MMTV-PyMT breast cancer mouse model, according to an illustrative embodiment.
- Mice with this genetic mutation spontaneously develop multiple breast cancers in different mammary glands and closely mimic human breast cancer pathology.
- the Raman signal from the R-MR-Nanoparticles accurately depicts the extent of multiple 3-6 mm sized breast cancers in the same mice, including small submillimeter tumor extensions.
- Upper row Breast cancers developed along the upper and middle mammary glands of a MMTV-PyMT mouse.
- Lower row Breast cancers developed within the lower mammary glands of a MMTV- PyMT mouse.
- FIG. 13 shows how R-MR nanoparticles can be used to detect microscopic tumor infiltration into the skin, according to an illustrative embodiment.
- This experiment was performed in an orthotopic 4T1 breast cancer mouse model.
- the 4T1 breast cancer cell line was transfected to express mCherry fluorescence.
- the photograph on the left shows the bulk tumor after the overlying skin was lifted off. Within the skin overlying the tumor, a subtle area of thickening was observed, with a central area of discoloration (arrows in dashed white box).
- We then performed R-MR imaging of this area (middle image), which shows Raman signal (red) outlining the area.
- the Raman signal matches closely the mCherry fluorescence (right image) emitted from the skin, proving the presence of breast cancer cells in this location.
- Figure 14 shows how R-MR nanoparticles can be used to detect pancreatic cancer, according to an illustrative embodiment.
- Figure 15 shows an ex vivo high (1 micrometer) resolution Raman imaging of the excised pancreas from Figure 14.
- Figure 16 shows how R-MR nanoparticles can be used to detect brain cancers in a genetic, spontaneous RCAS/tv-a glioblastoma model, according to an illustrative embodiment.
- Figure 17 shows how R-MR nanoparticles allow detection of single brain tumor cells, according to an illustrative embodiment.
- Figure 18 is a schematic demonstrating differences between single point line scan methods and hyperspectral scanning/imaging, according to an illustrative embodiment.
- Figure 19 is a schematic showing a widefield hyperspectral imaging camera which can be used (or components of which can be used) in an illustrative embodiment.
- Figure 20 shows images of geological material acquired with a widefield hyperspectral camera developed by Photon etc. of Montreal QC Canada.
- Figure 21 is a schematic demonstrating advantages and challenges of traditional Raman spectroscopy.
- Figure 22 shows feasibility of applying hyperspectral imaging technology to Raman spectroscopy, according to an illustrative embodiment.
- Figure 23 shows data demonstrating that a Raman signal from the R-MR nanoparticles can be detected with a prototype Raman scanner.
- Figure 24A shows a constructive embodiment of a Raman wide field scanner for use in the operating room.
- a surgeon can view a Raman image on an LCD screen (or other screen) built into the scanner, and can operate hands-free using the Raman information as realtime guidance.
- the viewing screen may display video superimposed with graphical indication of the location of R-MR nanoparticles.
- the screen may show a real-time (or near real-time) view of the operating bed.
- the screen may show a real-time view of the patient and the surgeon's hands operating on the patient in real-time, thereby helping to guide the surgeon in removal of all portions of the tumor (or other abnormal material to be removed).
- Optics for directing and/or distributing a laser beam (or laser beams) over the wide field operating bed may be coupled to the screen (e.g., the back of the screen).
- a processor (not shown) is used for processing images and/or data for display. Resolution of the view may be adjusted during surgery. For example, once larger portions of tumor (or other abnormal) tissue are removed, the zoom may be adjusted for magnified viewing of the operating site, for example, for R-MR nanoparticle-enhanced microsurgical resection of tumor (or other abnormal) tissue.
- Figure 24B is a schematic diagram of a wide field Raman imaging apparatus including at least one light source for producing excitation light, optics for directing the excitation light onto and/or into a target tissue, a detector for detecting Raman scattered photons emanating from the target tissue following illumination by the excitation light, and a processor configured to process data corresponding to the Raman scattered photons detected from the target tissue and to produce an image depicting a wide field corresponding to the target tissue.
- the detected Raman scattered photons are indicative of the presence of a Raman reporter in and/or upon the target tissue, and the image produced by the processor visually indicates position and/or intensity of the Raman reporter within the wide field.
- the apparatus may additionally include a display for displaying the image, for example, a real-time series of such images, to a surgeon during surgery.
- Figure 25 is a schematic illustration of steps of an exemplary Raman reporter interrogation and ablation/resection method, according to an illustrative embodiment.
- Figure 26 is a schematic illustration of an exemplary Raman interrogation and ablation/resection system, according to an illustrative embodiment.
- Figure 27 is a schematic illustration of an exemplary Raman interrogation and ablation/resection system, according to an illustrative embodiment.
- Figure 28 is a schematic illustration of an exemplary Raman interrogation and ablation/resection system, according to an illustrative embodiment.
- Figure 29 is a schematic illustration of a system for controlling a Raman scanner according to an illustrative embodiment.
- Figure 30 is a schematic illustration of an imaging and ablation exemplary method of the disclosure.
- Figures 31 A and 3 IB are schematic illustrations of an exemplary method of controlling a laser ablation and Raman scanning device, according to an illustrative embodiment.
- Figure 32 is a schematic illustration of an exemplary graphic user interface for controlling a laser ablation and Raman scanning device, according to an illustrative embodiment.
- Figure 33 shows images of an exemplary Raman scanning and ablation system during interrogation and ablation, according to an illustrative embodiment.
- Figure 34 shows images after being scanned and ablated by the Raman scanning and ablation system.
- the left and right images shows the top and bottom side of the sample that was treated with the Raman reporter and exposed to scanning by the ablation system.
- Raman spectroscopy is an emerging technology that allows nondestructive analysis of matter by assessing wavelength shift of photons after interaction with specific atomic bonds. While intrinsic (non-amplified) Raman signatures of tissues have shown promise in distinguishing malignant tissues from benign ones, typical acquisition times for such spectra are at least 10 seconds per spectrum; such times simply cannot provide sufficient speed for surgical workflow.
- SERS Surface-enhanced Raman scattering
- R-MR Raman-MRI nanoparticles
- R-MR nanoparticles are formed from inert materials (FDA approved core, gold shell, and a silica coating) and include a Raman active reporter embedded within the silica coating.
- the signal of such a reporter is massively amplified by the gold shell via the so-called localized surface plasmon resonance effect.
- R-MRs exhibit a pharmacokinetic behavior that is fundamentally different from conventional fluorescent dyes or currently clinically used MRI contrast agents (e.g.
- R-MRs Fluorescent dyes and clinical MRI agents wash out of tumors rapidly (within minutes) after i.v. injection. The tumor contrast is therefore only transient. In contrast, R-MRs do not wash out of the tumor, but are retained stably within the tumor cells, typically with a retention time at least 7 days. Without wishing to be bound by any particular theory, we propose that this behavior of R-MRs may be due, at least in part, to the so-called “enhanced permeability and retention (EPR)" effect, a phenomenon observed in all tumor types. This EPR effect means that particles of a certain size and surface charge enter tumors due to their leaky vasculature and are retained mostly via phagocytosis by tumor cells and tumor-associated macrophages. Up until recently nanoparticles were not able to visualize the EPR effect, because the trapped particle concentration is low, requiring very sensitive detection methods.
- EPR enhanced permeability and retention
- the apparatus and methods described herein encompass the insight that development of a wide-field scanner would provide a variety of new and valuable uses for various types of Raman nanoparticles, including SERS, SERRS, SERS-MRI, R-MR and other nanoparticles.
- a wide-field scanner is provided that permits imaging of nanoparticles over an entire operative bed in real time.
- Previous Raman imaging systems include so-called Raman microscopes (e.g. In Via, Renishaw, Hoffman Estates, IL), which can only image in vitro samples or small animals up to the size of mice. They are large benchtop instruments that cannot be used in the operating room and require an imaging time of approx. 15 minutes to image a small field-of-view of 1 cm2. Hand-held Raman spectrometers (e.g. MiniRamlll®; B&WTek, Inc. Newark, DE) are commercially available, however these do not acquire images, but only individual Raman spectra from one point in space. The present invention appreciates that neither of these two systems is suitable for rapid wide-field imaging in the operating room.
- Nanoparticles which have a unique Raman spectrum consisting of several narrow peaks can be imaged without acquiring a full Raman spectrum; acquisition of the wavelengths located at the peaks is sufficient. Only 3-5 wavelengths (instead of > 1000 for full spectral acquisition) need be acquired.
- the use of such nanoparticles together with hyperspectral detection technology, which generates a series of monochromatic images at user-specified wavelengths, can achieve instantaneous images across the full field of view.
- the hyperspectral system can detect spectra of a field of view of up to 1.5 m 2 at a spatial resolution of 1mm 2 instantly.
- nanoparticles have unique Raman spectra with several very narrow peaks, it is not necessary to acquire the full Raman spectra, but sufficient to only acquire the wavelengths located at the peaks.
- An optical pathway can also be provided to acquire images that are "in focus" independent of the distance of the object from the detector, which may be important for imaging in the operating room, e.g., to account for an uneven operating bed, patient motion, and the like.
- the present Example describes development of a dedicated Raman imaging system with a field of view of 40 x 30 cm (sufficient for essentially all intraoperative scenarios) and a form factor that is optimized for the operating room.
- this system enables ultra-sensitive and -specific, real-time image guided cancer detection and resection.
- the wide field Raman imaging apparatus described herein provides a variety of particular advantages, including speed, a wide field of view, specificity, depth independence, and multiplexing capabilities.
- Use of the hyperspectral acquisition technique allows spectra to be obtained substantially instantaneously (i.e., within milliseconds), and allows acquisition of a plurality of spectra at the same time, in contrast to raster- or line-scanning methods that result in very long image acquisition times.
- the apparatus is based on Raman spectroscopy and therefore detects specific Raman "fingerprints", in contrast to currently available wide-field imaging systems based on fluorescence, which may suffer from nonspecific background and autofluorescence that leads to "false-positives” (e.g., confusion of healthy tissue with cancerous tissue).
- the apparatus uses an optical pathway design that acquires images "in focus” independent of the distance of the object from the detector. This feature provides particular advantages for imaging of uneven fields of view expected to be encountered in the operating room.
- the apparatus and methods also enable differentiation of specific kinds of Raman nanoparticles, i.e., Raman nanoparticles that differ in their Raman reporter.
- nanoparticles e.g., co-injected nanoparticles targeted against different cancer epitopes, or nanoparticles injected via different routes [e.g., intravenously, intraarterially, intratumorally, intranodal, into lymphatic vessels etc.]).
- routes e.g., intravenously, intraarterially, intratumorally, intranodal, into lymphatic vessels etc.
- This feature allows imaging of multiple parameters at the same time, in contrast to fluorescence imaging, which typically can only differentiate up to 3 different fluorochromes with certainty.
- features of provided apparatus and methods enable imaging of large field of views (e.g., of up to 1.5 m 2 ) in less than a second, and furthermore enable simultaneous imaging of multiple particles, even on uneven fields.
- a real-time (or near realtime) series of Raman-based images are obtained over a wide field.
- R-MR nanoparticles are used in apparatus, systems, and/or methods described herein.
- R-MR nanoparticle reporters have a Raman detection threshold of l .8 fM (1.8 x lO-15 M), an extremely high sensitivity.
- This sensitivity approaches in vitro detection assays such as PCR.
- This sensitivity permits definition of tumor outlines without the need for a targeting moiety, exploiting the so-called “enhanced permeability and retention (EPR)" effect that all tumors exhibit.
- EPR enhanced permeability and retention
- the sensitivity of fluorescence imaging is only 10-9 - 10-12 M which is significantly less sensitive than the R-MR nanoparticles described herein, and would not allow imaging of nanoparticle EPR effects.
- autofluorescence is common to all imaging methods based on fluorescence. Autofluorescence can cause an imaging system to mistakenly identify healthy for cancerous tissue. In contrast, Raman spectroscopy is based on a principle fundamentally different from fluorescence, and issues associated with autofluorescence are not observed.
- the high Raman signal amplification via the SERRS effect allows ultra-short acquisition times, as described herein.
- EPR effect is observed in all tumor types, R-MRs work in a wide variety of different tumor types, even without any associated targeting moiety.
- a targeted nanoparticle would have to be designed and FDA-approved for each target (tumor) separately.
- R-MRs require no targeting moiety (such as an antibody, affibody, peptide, etc.) on their surface.
- Non-targeted embodiments permit easier and less expensive production.
- R- MRs in contrast to organic fiuorochromes, do not photobleach.
- a problem with many imaging technologies is that photobleaching prevents imaging in contexts that involve or require prolonged laser exposure (e.g., as would be expected during a lengthy surgical procedure).
- Use of Raman reporters, such as the R-MR nanoparticles, that do not photobleach have the additional advantage that they can be useful in such contexts that involve or require prolonged laser exposure.
- R-MRs are based on an RDA-approved core. Gold and silica are inert materials, and nanoparticles made of these materials have been shown to be nontoxic in cell cultures, mice, and in several clinical trials. Furthermore, facile and rapid synthesis of R-MRs allows for their large scale production.
- apparatus and methods described herein are used in conjunction with Raman-based ablation and resection systems described herein.
- Raman reporters are used in apparatus, systems, and/or methods described herein as an ablating source for tumor or tissues.
- Raman reporters represent a way to amplify the Raman signal many orders of magnitude.
- the amplification when employed at sufficient energy levels, elevates the vibration modes of the Raman reporter (e.g., SERS, SERRS, SERS-MRI, R-MR and other nanoparticles) to a level to cause damage to or heating of nearby tissue or tumor in the vicinity of a given Raman reporter.
- the vibrational mode can cause vaporization of the Raman reporter and the nearby tissue.
- the present disclosure encompasses methods, systems, and devices for assessing and/or treating (e.g., ablating and/or resecting) cells and/or tissue in a subject.
- the methods and devices described herein provide for detection of Raman spectra from cells and/or tissues and subsequent targeted ablation and/or resection of cells and/or tissues from which Raman spectra are detected.
- systems and devices of the disclosure further include components to visually image target cells and/or tissues.
- methods, systems and devices of the disclosure do not need or include components to visually image target cells and/or tissues.
- the disclosure encompasses an automated surgical tissue resection instrument and/or an automated laser ablation instrument that resects and/or ablates only disease tissue at locations at which a Raman reporter is detected, e.g., by comparing detected Raman signal to specific Raman signals/spectra associated with one or more type of Raman nanoparticle or intrinsic species known to be associated with the presence of tissue to be resected or ablated.
- an instrument resects and/or ablates only diseased tissue, because a motorized resection mechanism and/or ablation laser included in the instrument is activated only when the specific spectrum of a Raman reporter is recognized by a Raman spectrometer included in the system.
- a Raman reporter is a Raman nanoparticle, which can optionally can be designed to target and/or accumulate within or proximate to diseased tissue of interest (e.g., cancer, infection, or inflammation).
- Figure 25 depicts a flowchart of an exemplary method of the disclosure.
- a diseased tissue e.g., a tumor
- a Raman reporter e.g., a Raman nanoparticle described herein or an intrinsic Raman species
- a Raman nanoparticle is administered to a subject, and the nanoparticle accumulates within diseased tissue.
- a Raman laser a Raman reporter present within the diseased tissue is excited, which emits Raman scattered photons.
- Raman scattered photons are filtered using a 785 nm bandpass filter and are spectrally separated using a prism.
- Raman scattered photons are detected using a detector, e.g., a CCD detector. Detected Raman scattered photons are then analyzed using an analyzer (e.g., a computer with Raman analysis software) to determine if a Raman reporter is present. If a Raman reporter is present, the analyzer activates a resector/ablation mechanism (e.g., a mechanical resector (e.g., rotary blade, vibrating knife, or percussing knife), an electro-cautery mechanism, a cryoablation mechanism, and/or a radiofrequency ablation mechanism), which destroys diseased tissue.
- a resector/ablation mechanism e.g., a mechanical resector (e.g., rotary blade, vibrating knife, or percussing knife), an electro-cautery mechanism, a cryoablation mechanism, and/or a radiofrequency ablation mechanism
- the analyzer determines that no Raman reporter is present, the analyzer does not activate (or, if previously activated, shuts off) the resector mechanism, preserving healthy tissue. In some embodiments, a Raman reporter is initially detected, and the steps of excitation, detection, and analysis are repeated until a Raman reporter is not detected.
- systems and devices of the disclosure enable more precise resection and/or ablation of diseased tissue. Surgeons often resect diseased tissue by visual inspection, which may be imprecise at the margins of diseased and non-diseased tissue, for example, at margins of infiltratively growing cancers or in the setting of metastic spread.
- a Raman reporter is a Raman nanoparticle, which specifically targets diseased tissue (e.g., cancer)
- methods, systems, and devices of the disclosure can allow a surgeon to resect and/or ablate diseased tissue (e.g., cancer) faster and with much higher precision, e.g., compared to visual inspection or other known methods.
- a Raman reporter is an intrinsic species within, on, or near diseased tissue, and a predetermined intrinsic Raman spectrum is used in the methods described herein.
- resection and/or ablation is performed in a semiautomated fashion, e.g., a device described herein is held approximately at or moved generally over a site of disease and automatically removes only diseased tissue but not adjacent healthy tissue.
- the methods, systems, and devices described herein have many applications, e.g., open surgical applications, endoscopic approaches, and robotically assisted approaches.
- Raman spectroscopy provides information about the vibrational state of molecules. Many molecules have atomic bonds capable of existing in a number of vibrational states. Such a molecule is able to absorb incident radiation that matches a transition between two of its allowed vibrational states and to subsequently emit the radiation. These vibrational transitions exhibit characteristic energies that permit definition and characterization of the bonds that are present in a compound. Analysis of vibrational transitions therefore permits spectroscopic molecular identification.
- absorbed radiation is re-radiated at the same wavelength, a process designated Rayleigh or elastic scattering.
- the re -radiated radiation can contain slightly more or slightly less energy than the absorbed radiation (depending on the allowable vibrational states and the initial and final vibrational states of the molecule).
- the energy difference is consumed by a transition between allowable vibrational states, and these vibrational transitions exhibit characteristic values for particular chemical bonds, which accounts for the specificity of vibrational spectroscopies such as Raman spectroscopy.
- the result of the energy difference between the incident and re -radiated radiation is manifested as a shift in the wavelength between the incident and re -radiated radiation, and the degree of difference is designated the Raman shift (RS), measured in units of wavenumber (inverse length).
- RS Raman shift
- the incident light is substantially monochromatic (single wavelength) as it is when using a laser source, the scattered light that differs in frequency can be more easily distinguished from Rayleigh scattered light.
- Raman spectroscopy may utilize high efficiency solid-state lasers, efficient laser rejection filters, and silicon CCD detectors.
- the wavelength and bandwidth of light used to illuminate a sample is not critical, so long as the other optical elements of the system operate in the same spectral range as the light source.
- a sample should be irradiated with monochromatic light (e.g., substantially monochromatic light).
- monochromatic light e.g., substantially monochromatic light.
- Suitable light sources include various lasers and
- Limitations in spectral resolution of the system can limit the ability to resolve, detect, or distinguish spectral features.
- the separation and shape of Raman scattering signals can be used to determine the acceptable limits of spectral resolution for the system for any Raman spectral features.
- a Raman peak that both is distinctive of a substance of interest e.g., a Raman nanoparticle or intrinsic species described herein
- exhibits an acceptable signal-to- noise ratio can be selected.
- Multiple Raman shift values characteristic of the substance e.g., Raman nanoparticle or intrinsic species
- shape of a Raman spectral region that may include multiple Raman peaks.
- methods of the disclosure include use of Raman nanoparticles, e.g., surface-enhanced Raman scattering (SERS) nanoparticles or surface- enhanced (resonance) Raman scattering (SERRS) nanoparticles.
- SERS and SERRS refer to an increase in Raman scattering exhibited by certain molecules in proximity to certain metal surfaces (see, U.S. Pat. No. 5,567,628; McNay et al, Applied Spectroscopy 65:825-837 (2011)).
- the SERS effect can be enhanced through combination with a resonance Raman effect.
- the SERS effect can be increased by selecting a frequency for an excitation light that is in resonance with a major absorption band of a molecule being illuminated.
- Nanoparticles that can be detected using Raman spectroscopy can be used in the methods and devices described herein.
- Raman nanoparticles and SERS nanoparticles and methods of their production are known and described in, e.g., U.S. Publ. No. 2012/0179029; Kircher et al, Nature Med. 18:829-834 (2012); Yigit et al, Am. J. Nucl. Med. Mol. Imaging 2:232-241 (2012); Zhang et al, Small. 7:3261-9 (2011); Zhang et al, Curr. Pharm. Biotechnol. 11 :654-661 (2010).
- Raman nanoparticles are administered to a subject having or suspected of having cancer. Without being bound to theory, it is believed that such nanoparticles target to and/or accumulate within, on the surface of, or proximate to cancer cells by enhanced permeability and retention (EPR) as described in, e.g., Kircher et al, Nature Med. 18:829-834 (2012); and Adiseshaiah et al, Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2:99-112 (2010). Thus, detection of Raman nanoparticles indicates such cells and/or tissues are cancerous.
- EPR enhanced permeability and retention
- the Raman nanoparticles are employed for ablation of the nearby cell tissue or tumor.
- Energy absorbed at selected frequencies of an excitation light that is in resonance with a major absorption band of a molecule being illuminated causes vibrational mode of the Raman nanoparticle that can cause ablation of the nearby cell tissue or tumor.
- the ablation causes damage to the cell and, in certain embodiments, the ablation causes heating and/or vaporization of the area situated near the nanoparticle.
- the wavelength and bandwidth of light are selected to minimize a mismatch between the depth of measurement employed for the spectroscopic imaging and the depth to which the tissue or tumor is ablated.
- Raman reporter detection is combined with one or more additional modalities for identification of tissue to be resected or ablated.
- Raman reporter detection can be combined with video imaging, MRI, NMR, PET, SPECT, CT, X-ray, ultrasound, photoacoustic detection, and/or fluorescent detection, for example.
- Raman nanoparticles may be designed such that they are detected by reporter detection combined with one or more other modalities, such as video imaging, MRI, NMR, PET, SPECT, CT, X-ray, ultrasound, photoacoustic detection, and/or fluorescent detection, for example.
- nanoparticles are described in, e.g., Kircher et ah, Nature Med. 18:829-834 (2012);
- Nanoparticles used in accordance with the present disclosure can be of any shape (regular or irregular) or design.
- a nanoparticle can be or comprise a sphere.
- a nanoparticle can be or comprises a star, a rod, a cube, a cuboid, a cone, a pyramid, a cylinder, a prism, a tube, a ring, a tetrahedron, a hexagon, an octagon, a cage, or any irregular shapes.
- a nanoparticle has a shape corresponding to that of its substrate; in some embodiments, a nanoparticle has a shape different from that of its substrate.
- one or more layers applied to the substrate has a thickness that varies at different locations within the nanoparticle [0152]
- the greatest dimension or at least one dimension of a nanoparticle may be about or less than 10 ⁇ , 5 ⁇ , 1 ⁇ , 800 nm, 500 nm, 400 nm, 300 nm, 200 nm, 180 nm, 150 nm, 120 nm, 110 nm, 100 nm, 90 nm, 80 nm, 70 nm, 60 nm, 50 nm, 40 nm, 30 nm, 20 nm, 10 nm, 5 nm, 2 nm, or even 1 nm.
- the greatest dimension or at least one dimension of a nanoparticle may be more than 10 ⁇ , 5 ⁇ , 1 ⁇ , 800 nm, 500 nm, 400 nm, 300 nm, 200 nm, 180 nm, 150 nm, 120 nm, 110 nm, 100 nm, 90 nm, 80 nm, 70 nm, 60 nm, 50 nm, 40 nm, 30 nm, 20 nm, 10 nm, 5 nm, 2 nm, or even 1 nm.
- the greatest dimension or at least one dimension of a nanoparticle may be in a range of about 1 ⁇ to about 5 nm or about 200 nm to about 5 nm. In some embodiments, the greatest dimension or at least one dimension of a nanoparticle may be in a range of about 300 nm to about 50 nm. In some embodiments, the greatest dimension or at least one dimension of a nanoparticle may be in a range of about 130 nm to about 90 nm. In some embodiments, the greatest dimension or at least one dimension of a nanoparticle may be in a range of any two values above. In some embodiments, the dimension of a nanoparticle is a diameter, wherein the diameter can be in a range as mentioned above. In some embodiments, the dimensions of a nanoparticle can be represented by a length, a width or a height in X, Y and Z axis, wherein each dimension can be in a range as mentioned above.
- nanoparticles for in vivo application typically have a size range from about 0.5 nm to about 200 nm; nanoparticles for in vitro application can have a size range from about 10 nm to about 1000 nm.
- nanoparticle sizes and surface charges are tuned to be provided to sites of interest for certain applications.
- a site of interest is a tumor.
- nanoparticles are designed and constructed to enter tumors via their leaky vasculature.
- nanoparticles are designed and constructed to enter and/or be retained in tumors via phagocytosis by tumor (associated) cells (known as "enhanced permeability and retention (EPR)" effect).
- EPR enhanced permeability and retention
- nanoparticles do not wash out of a tumor, but are retained stably within the tumor (e.g., retention time at least 7 days).
- a nanoparticle described herein can comprise a substrate, a plurality of layers (including one or more condensation layers; in some embodiments at least two condensation layers), and one or more dopant entities (in some embodiments at least two dopant entities).
- nanoparticles are susceptible to imaging by multiple modalities.
- a substrate comprises iron oxide for T2 MRI and/or gold substrate for photoacoustics, CT, and X-Rays.
- a plurality of layers are or comprise silica.
- the closest layer to a substrate comprises a surface- enhanced resonance Raman scattering (SE(R)RS)-active agent.
- SE(R)RS surface- enhanced resonance Raman scattering
- such a nanoparticle further comprises an outer layer doped with a NIR fluorescent agent.
- provided nanoparticles can be employed with other agents such as MRI, PET, SPECT, CT, X-Rays or US agents.
- a nanoparticle has at least one substrate, which can be or comprise one or more materials, for example depending on applications for which the nanoparticle will be utilized.
- substrate materials include, but are not limited to, metals, non-metals, and semi-metals, or oxides thereof (i.e., metal oxides, non-metal oxides, or semi-metal oxides) (e.g., iron oxide), liposomes, upconverting materials,
- a layer can be a nanoparticle's substrate.
- photoacoustic and/or photothermal enhancements can be achieved by associating agents/molecules which induce surface phonon enhancement, within the substrate or layers.
- a substrate can be or contain any metal or any other material capable of generating localized surface plasmon resonances (LSPRs).
- a metal is a SE(R)RS active metal.
- Such a metal can be any (metallic) substance capable of sustaining a (localized) surface plasmon resonance.
- a SE(R)RS active metal can be any (metallic) substance capable of sustaining a (localized) surface plasmon resonance.
- SE(R)RS active metal is or comprises Au, Ag, Cu, Na, K, Cr, Al, or Li.
- a substrate can also contain alloys of metals.
- a substrate is or contains Au, Ag or a combination thereof.
- a substrate can provide a detectable photoacoustic signal.
- a substrate can be of any shape or design, and may contain one or more structural elements.
- a nanoscale or at least one structural element of it is spherical.
- a substrate or at least one structural element of it is non-spherical.
- a substrate has structural elements selected from the group consisting of spheres, rods, stars, shells, ellipses, triangles, cubes, cages, pyramids and combinations thereof.
- a substrate can consist of or comprise a star overlaid with at least one shell.
- a substrate can consist of or comprise two or more concentric shells.
- a substrate can consist of or comprise a central structure surrounded by satellite structures.
- a substrate comprises at least two structural elements, separated from one another within a distance suitable for a plasmon hybridization effect.
- a distance can be an average distance.
- a distance between two separated structural elements is less than 100 nm, 50 nm, 30 nm, 20 nm, 15 nm, 10 nm, 8 nm, 5 nm or 3 nm, or 1 nm.
- a distance between two separated structural elements is in a range of about 100 nm to about 50 nm, about 50 nm to about 30 nm, about 30 nm to about 1 nm, or any two values above.
- individual structural elements are separated from one another or filled by a layer.
- a substrate is star-shaped.
- star shaped refers to a body portion from which a plurality of protrusions extend.
- a star shape is a true star shape.
- a "true star shape”, as that term is used herein, comprises a body portion from which a plurality of protrusions extend radially.
- a true star shape has at least one access of symmetry.
- a true star shape is substantially symmetrical.
- protrusions in a true star shape have approximately the same length.
- protrusions have
- protrusions have substantially identical structures.
- a true star shape has a body portion that is substantially spherical.
- a true star shape has a body portion that is substantially rectangular or square.
- protrusions substantially cover the body surface.
- protrusions are configured on the body surface for high polarizabilities, for example so that intense localized surface plasmons can arise. It is contemplated that when a particle contains radially-protruding spikes, the coordinated electron oscillation becomes corralled into narrow regions (i.e., the tips) resulting in the build-up of charge in a very small region.
- the greatest dimension or at least one dimension of a substrate or its each component may be about or less than 5 ⁇ , 1 ⁇ , 800 nm, 500 nm, 400 nm, 300 nm, 200 nm, 100 nm, 90 nm, 80 nm, 70 nm, 60 nm, 50 nm, 40 nm, 30 nm, 20 nm, 15 nm, 10 nm, 5 nm, 2 nm, 1 nm or 0.5 nm.
- the greatest dimension or at least one dimension of a substrate or its each component may be more than 5 ⁇ , 1 ⁇ , 800 nm, 500 nm, 400 nm, 300 nm, 200 nm, 100 nm, 90 nm, 80 nm, 70 nm, 60 nm, 50 nm, 40 nm, 30 nm, 20 nm, 15 nm, 10 nm, 5 nm, 2 nm, 1 nm or 0.5 nm.
- the greatest dimension or at least one dimension of a substrate or its each component may be in a range of about 500 nm to about 5 nm or about 150 nm to about 5 nm.
- the greatest dimension or at least one dimension of a substrate or its each component may be in a range of about 100 nm to about 90 nm, about 90 nm to about 80 nm, about 80 nm to about 70 nm, about 70 nm to about 60 nm, about 60 nm to about 50 nm, about 50 nm to about 40 nm, about 40 nm to about 30 nm, about 30 nm to about 20 nm, about 20 nm to about 10 nm, about 10 nm to about 5 nm.
- the greatest dimension or at least one dimension of a substrate or its each component may be in a range of any two values above.
- a substrate with a desired size can be grown as metal colloids by a number of techniques well known in the art. For example, chemical or photochemical reduction of metal ions in solution using any number of reducing agents has been described. Likewise, syntheses of substrates can be carried out in constrained volumes, e.g., inside a vesicle. Substrates can also be made via electrical discharge in solution. Substrates can also be made by irradiating a metal with a high intensity pulsed laser.
- Nanoparticles provided by the present disclosure may include a plurality of layers.
- one or more inner layers can construct a nanoparticle's substrate.
- a layer substantially covers at least one surface of the substrate (or of another layer that itself substantially covers at least one surface of the substrate or of another layer). In some such embodiments, a layer substantially encapsulates the substrate.
- adjacent layers are in direct physical contact with one another; in some embodiments, adjacent layers are separated from one another so that an inter- layer space is defined; in some embodiments, such an inter-layer space is empty; in some embodiments, such an inter-layer contains liquid, etc.
- a layer can have any size and shape.
- a layer can be porous.
- a layer is in a shape of a thin stripe or mat.
- one or more layers substantially or partially cover the surface of a substrate or another layer.
- layers are arranged as shells.
- at least two shells can be partially extended from at least one substrate, concentrically extended from at least one substrate, or extended asymmetrically from at least one substrate. Shells can have equal thicknesses, but can also have different thicknesses.
- a plurality of layers each can respectively contain one or more materials.
- Layers e.g., shells
- layers can be or comprise, but are not limited to, one and the same material (e.g., consisting of, but not limited to, compounds/materials from the group of metal/semi-metal/non- metal, -oxides, -sulfides, -carbides, -nitrides)
- layers can consist of at least two different materials (e.g., from the groups of metal/semi-metal/non-metal, -oxides, -sulfides, -carbides, -nitrides, polymers, and combinations thereof)
- layers can consist of the same or different materials in any combination (e.g., consisting of, but not limited to, compounds/materials from the groups of metal/semi-metal/non-metal, -oxides, -sulfide, -carbides, -n
- a layer is synthesized by reacting precursors and the resulting layer is a condensation layer.
- Nanoparticles described herein, in some embodiments, comprise at least a condensation layer and at least another layer, which can be another condensation layer or any other layers.
- a layer can be or comprise metal(e.g., gold, silver, and the like), semi-metal or non-metal, and metal/semi- metal/non-metal oxides including silica (Si0 2 ), titania (Ti0 2 ), alumina (A1 2 0 3 ), zirconia (Zr0 2 ), germania (Ge0 2 ), tantalum pentoxide (Ta 2 0 5 ), Nb0 2 , etc., and non-oxides including metal/semi- metal/non-metal borides, carbides, sulfide and nitrides, such as titanium and its combinations (Ti, TiB 2 , TiC, TiN, etc.).
- metal/semi- metal/non-metal oxides including silica (Si0 2 ), titania (Ti0 2 ), alumina (A1 2 0 3 ), zirconia (Zr0 2 ),
- materials of a layer can be polymers including PEG and PLGA/PEG, and polymeric chelators (e.g., poly DOTA, dendrimer backbone, poly DTP A, or dendrimer alone), (multiwalled) carbon nanotubes, graphene, silicone, peptides, nucleic acids, and combinations thereof.
- polymeric chelators e.g., poly DOTA, dendrimer backbone, poly DTP A, or dendrimer alone
- multiwalled carbon nanotubes graphene, silicone, peptides, nucleic acids, and combinations thereof.
- a layer is or comprises a dielectric.
- silica can serve as a dielectric.
- each layer in a nanoparticle can be or contain the same material(s).
- multilayers in the nanoparticle are all silica layers.
- a layer is or includes silica.
- a silica layer can be synthesized from a silica precursor including, but not limited to, alkylalkoxysilane;
- ethylpolysilicate tetraethylorthosilicate (TEOS); tetramethylortho silicate (TMOS); partially hydrolyzed TEOS; partially hydrolyzed TMOS or a combination thereof.
- TEOS tetraethylorthosilicate
- TMOS tetramethylortho silicate
- the present invention provides technologies that permit control of layer thickness.
- condensation layer thickness is controlled by selection of solvent composition and/or content in the precursor solution.
- water content can control layer thickness.
- the well-known Stober method can be adapted for use in preparing one or more silica layers in accordance with the present disclosure.
- the synthesis involves using a solution of one or more precursors in water and alcohol(s).
- a water content as used herein refers to the ratio of the volume of water to the total volume of a precursor solution.
- condensation reactions utilizing a water-containing solvent achieve different layer thicknesses with different water content.
- a water content for synthesis is about 1.0 v/v/%, about 2.0 v/v%, about 3.0 v/v%, about 4.0 v/v%, about 4.5 v/v%, about 5.0 v/v%, about 5.5 v/v%, about 6.0 v/v%, about 6.5 v/v%, about 7.0 v/v%, about 7.5 v/v%, about 8.0 v/v%, about 8.5 v/v%, about 9.0 v/v%, about 9.5 v/v%, or about 10.0 v/v%.
- water content for synthesis is in a range of any two values above.
- a layer is or includes one or more polymers, particularly polymers that which have been approved for use in humans by the U.S. Food and Drug
- polyesters e.g., polylactic acid, poly(lactic-co-glycolic acid), polycaprolactone, polyvalerolactone, poly(l,3- dioxan-2-one)
- polyanhydrides e.g., poly(sebacic anhydride)
- polyethers e.g., polyethylene glycol
- polyurethanes polymethacrylates; polyacrylates; polycyanoacrylates; copolymers of PEG and poly(ethylene oxide) (PEO).
- a layer is or includes at least a degradable material.
- a degradable material can be hydrolytically degradable, biodegradable, thermally degradable, enzymatically degradable, and/or photolytically degradable polyelectrolytes.
- degradation may enable release of one or more dopant entities (e.g., agent for delivery) associated with a particle described herein.
- dopant entities e.g., agent for delivery
- Degradable polymers known in the art include, for example, certain polyesters, polyanhydrides, polyorthoesters, polyphosphazenes, polyphosphoesters, certain
- biodegradable polymers that may be used include but are not limited to polylysine, poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(caprolactone) (PCL), poly(lactide-co-glycolide) (PLG), poly(lactide-co-caprolactone) (PLC), and poly(glycolide-co-caprolactone) (PGC).
- PLA poly(lactic acid)
- PGA poly(glycolic acid)
- PCL poly(caprolactone)
- PLA poly(lactide-co-glycolide)
- PLA poly(lactide-co-caprolactone)
- PLC poly(glycolide-co-caprolactone)
- PLC poly(glycolide-co-caprolactone)
- PLC poly(glycolide-co-caprolactone)
- Another exemplary degradable polymer is poly (beta- amino esters), which may be suitable for use in accordance with the
- any layer within a particle described herein can have a thickness independently and within any ranges. In some embodiments, some or all layers have the same thickness or within the same range.
- a layer on a substrate can have an average thickness in various ranges.
- an averaged thickness is about or less than 5 ⁇ , 1 ⁇ , 800 nm, 500 nm, 400 nm, 300 nm, 200 nm, 100 nm, 90 nm, 80 nm, 70 nm, 60 nm, 50 nm, 40 nm, 30 nm, 20 nm, 15 nm, 10 nm, 5 nm, 1 nm, 0.5 nm, or 0.1 nm.
- an averaged thickness is about or greater than 5 ⁇ , 1 ⁇ , 800 nm, 500 nm, 400 nm, 300 nm, 200 nm, 100 nm, 90 nm, 80 nm, 70 nm, 60 nm, 50 nm, 40 nm, 30 nm, 20 nm, 15 nm, 10 nm, 5 nm, 1 nm, 0.5 nm, or 0.1 nm. In some embodiments, an averaged thickness is in a range from about 0.1 nm to about 5 ⁇ , about 0.5 nm to about 200 nm, about 5 nm to about 50 nm or about 10 to about 30 nm. In some embodiments, an averaged thickness is in a range of any two values above.
- a layer can have or be modified to have one or more functional groups.
- Such functional groups (within or on the surface of a layer) can be used for association with any agents (e.g., detectable entities, targeting entities, or PEG).
- agents e.g., detectable entities, targeting entities, or PEG.
- associated agents can be dopant entities, if associated (e.g., doped) within layers.
- targeting entities and/or PEG can be associated within one or more layers comprising degradable polymers. When the degradable polymers degrade, the dopant entities can be exposed.
- the surface of an outer-most layer can be modified with reagents to add and/or modify the functional groups on the outer layer (e.g., compounds like, but not limited to, mercaptosilanols, aminosilanols can be used to introduce sulfhydryl or amine groups, respectively, to silica, tantalia, etc.; or catechol-amines can be used to introduce cationic amine-functionality to titania, etc.; oxidizing the newly introduced sulfhydryl-group with hydrogen peroxide to generate anionic sulfonate-functionality can further chemically alter the introduced groups).
- reagents e.g., compounds like, but not limited to, mercaptosilanols, aminosilanols can be used to introduce sulfhydryl or amine groups, respectively, to silica, tantalia, etc.; or catechol-amines can be used to introduce cationic amine-functionality to titania, etc.
- linkers e.g., (cleavable or (bio-)degradable) polymers such as, but not limited to, polyethylene glycol, polypropylene glycol, PLGA, etc.
- targeting/homing agents e.g., such as, but not limited to, small molecules (e.g., folates, dyes, etc), (poly)peptides (e.g., RGD, epidermal growth factor, chlorotoxin, etc), antibodies, proteins, etc.), contrast/imaging agents (e.g., fluorescent dyes, (chelated) radioisotopes (SPECT, PET), MR-active agents, CT-agents), therapeutic agents (e.g., small molecule drugs, therapeutic (poly)peptides, therapeutic antibodies, (chelated)
- linkers e.g., (cleavable or (bio-)degradable) polymers such as, but not limited to, polyethylene glycol, polypropylene glycol, PLGA, etc.
- radioisotopes etc
- dopant entities can be associated within one or more layers of a nanoparticle.
- dopant entities are attached directly or indirectly to layers.
- dopant entities are distributed within layer; in some embodiments, dopant entities are discretely localized within layers.
- dopant entities can be encapsulated independently within any possible distance from a substrate of a nanoparticle. Exemplary distance includes 5 ⁇ , 1 ⁇ , 800 nm, 500 nm, 400 nm, 300 nm, 200 nm, 100 nm, 90 nm, 80 nm, 70 nm, 60 nm, 50 nm, 40 nm, 30 nm, 20 nm, 15 nm, 10 nm, 5 nm, 1 nm, 0.5 nm, or 0.1 nm. [0187] In some embodiments, dopant entities are positioned within a predetermined distance from the surface of a substrate or an adjacent layer.
- Such a distance in various embodiments can be about or less than 1 nm, 2 nm, 3 nm, 4 nm, 5 nm, 6 nm, 7 nm, 8 nm, 9 nm, 10 nm, 15 nm, 20 nm, 30 nm, 40 nm, 50 nm, 100 nm, 200 nm, 300 nm, 400 nm, or 500 nm.
- a distance between a dopant entity and the surface of a substrate is a range of 2 nm to 5 nm, 5 nm to 10 nm, or 10 nm to 15 nm.
- dopant entities can be in direct contact to the surface of a substrate or an adjacent layer.
- surface primers can be used after substrate synthesis.
- exemplary surface primers include, but are not limited to, functionalized silica agents such as MPTMS and APTMS, or polymer (e.g., polyethyleneglycol-(PEG)-thiol).
- dopant entities have sufficient affinity for one or more components of a nanoparticle to permit displacement of a capping agent and/or to permit high density and/or close surface localized loading of the dopant entity(ies) into or onto the nanoparticle.
- a capping agent can be an entity that can be or is displaceable associated with a substrate. Without wishing to be bound by any particular theory, it is noted here that, in some embodiments, capping agents can play an important role in substrate synthesis. In some embodiments, capping agents control the size and geometry of a substrate.
- capping agents are present after synthesis as an adsorbed monolayer on the synthesized substrate. In some embodiments, capping agents are strongly adsorbed to the surface of a substrate. In some embodiments, capping agents provide stabilization and/or prevent aggregation of substrates. Exemplary capping agents include, but are not limited to, organic agents such as citrate, citric acid, ascorbic acid, ascorbate, palmitoylascorbate, tetrakis(hydroxymethyl)phosphonium chloride, and amino acids. In some such instances, some or all capping agents are ultimately removed from a substrate by surface primers. In contrast to traditional surface priming methods wherein capping agents are displaced by surface primers, in some embodiments of the present disclosure a capping agent itself is employed to enable substrate encapsulation.
- one or more layers can have one or more entities/agents (e.g., detectable entities, targeting entities, or PEG) doped within.
- entities/agents e.g., detectable entities, targeting entities, or PEG
- any entity of interest can be utilized as a dopant entity in accordance with the present invention.
- a single dopant entity (or a layer/substrate) can be susceptible to imaging in multiple modalities.
- a dopant entity is a detectable entity including, but not limited to, SE(R)RS-active agent, fluorochromes (e.g., near infrared (metal-enhanced
- fluorescence agent 2-photon fluorescence agent
- MRI agents photoacoustic-active dyes
- upconverting materials positron emission tomography (PET) tracers, single photon emission tomography (SPECT) tracers, computed tomography (CT) agents, X-Rays agents, ultrasound (US) agents and combinations thereof.
- PET positron emission tomography
- SPECT single photon emission tomography
- CT computed tomography
- US ultrasound
- layers can be doped with compounds/materials such as, but not limited to, SER(R)S-active dyes, (near infrared) fluorescent dyes, luminescent compounds, photoacoustic-active dyes, upconverting materials (e.g., consisting of materials from the group of the rare-earth metals and/or transition metals), (laser) pumping materials (e.g., consisting of, but not limited to, materials from the group of the rare-earth metal- and/or transition metal-based compounds), "slow ligh '-inducing materials (e.g., praseodymium-based compounds), MRI-active materials (e.g., consisting of, but not limited to rare-earth metals and/or transition metals such as gadolinium, manganese, iron(-oxides)).
- compounds/materials such as, but not limited to, SER(R)S-active dyes, (near infrared) fluorescent dyes, luminescent compounds, photoa
- At least one layer is doped with for instance a SERRS-active dye and at least one other layer is doped with for instance a near infrared fluorescent dye.
- some layers do not contain dopants but serve as spacers and/or separators between two dopant-containing shells.
- Layers can additionally be doped with therapeutic agents consisting of, but not limited by, (radiolabeled-) small molecule-, chelate-, peptide-, protein-, antibody, RNA, DNA, aptamer- based compounds/materials, and combinations thereof.
- a dopant entity is or comprises a dye, for example, a resonance dye.
- a dopant entity can be or comprise an agent useful in Raman spectroscopy (e.g., SE(R)RS-active agents).
- exemplary dopant entities include, but are not limited to, those agents described in the art such as in U.S. Pat. Nos. 5,306,403; 6,002,471; and 6,174,677, the contents of which are incorporated by reference.
- a dopant entity is SE(R)RS- and/or
- a high density of a SE(R)RS- active agent located close to a substrate contributes to unprecedented Raman sensitivity achieved by a particle described herein.
- SE(R)RS-active agents generally benefit from signal intensity enhancement in the proximity of a metal surface.
- a skilled artisan in the art would be capable to choose a SE(R)RS-active agent, to achieve chemical enhancement and/or electromagnetic enhancement, considering factors such as substrate materials, substrate configurations, layer material, etc.
- Such a SE(R)RS-active agent can have a charge transfer effect, from a metal to the molecule, or from the molecule to the metal.
- a SE(R)RS-active agent refers to a molecule that is capable of generating a SERS or SE(R)RS spectrum when appropriately illuminated.
- SE(R)RS- active agents include phthalocyanines such as methyl, nitrosyl, sulphonyl and amino phthalocyanines, naphthalocyanines, chalcogen-based dyes, azomethines, cyanines, squaraines, and xanthines such as the methyl, nitro, sulphano and amino derivatives. Each of these may be substituted in any conventional manner, giving rise to a large number of useful labels. It is noted that the choice of a SE(R)RS-active agent can be influenced by factors such as the resonance frequency of the molecule, the resonance frequency of other molecules present in a sample, etc.
- detecting a SE(R)RS signal involves using incident light from a laser.
- the exact frequency chosen will depend on the SE(R)RS-active agent, and metal surface.
- the Raman enhancement generally is proportional to the density of a SE(R)RS- active agent associated (e.g., adsorbed) on a metal surface.
- a SE(R)RS-active agent adsorbed on a substrate surface in accordance with the present disclosure may contribute to the superior sensitivity of particles disclosed herein.
- a dopant entity is or comprises a fluorescent dye/agent (e.g., near infrared (NIR) fluorescent dye).
- fluorescent dyes/agents including, but not limited to, polymethines, cyanines, (na)phthalocyanines, porphorines, merocyanines, (pe)rylene (bisimides), squaraines, anthocyanins, phycocyanins, bodipys, rotaxanes, rhodamines, certain organometallic complexes, can be used in accordance with the present invention.
- a fluorescent dye/agent has a predetermined distance from a substrate by means of synthesis method described therein.
- a fluorescent dye/agent has a predetermined distance from a substrate by means of synthesis method described therein.
- nanoparticle is doped with a near infrared (NIR) fluorescent dye and other agents.
- NIR near infrared
- a dopant entity is or comprises an MRI agent.
- the amount or number of MRI agents associated with a layer can be about 1 to 10,000,000 MRI agents or about 5,000 to 500,000 MRI agents. See US Patent Application Publication No. 20120179029, the contents of which are incorporated by references.
- a MRI agent can be Gd(-salts), iron oxide, paramagnetic chemical exchange saturation transfer (CEST) agents, 19F active materials, manganese, melanin, or a substance that shortens or elongates Tl or T2 and a combination thereof.
- a Gd MRI agent can be a compound such as DOTA-Gd, DTPA-Gd, Gd within a polymeric chelator, and Gd immobilized by negative charges on a layer.
- an iron oxide MRI agent can be a compound such as a small paramagnetic iron oxide (SPIO) or an ultrasmall SPIO with or without a dextran or other stabilizing layer.
- a paramagnetic CEST MRI agent can be a compound such as lanthanide complexes.
- MRI agents can be linked to a layer via a linkage such as a maleimide linkage, NHS ester, click chemistry, or another covalent or non-covalent approach or a combination thereof.
- MRI agents can also be loaded without addition of any exogenous agent, i.e., only layer(s) and MRI agent.
- one or more other agents can be associated with a particle.
- diagnostic agents including a PET (e.g., 18 F, 64 Cu, U C, 13 N, ' ⁇ , and the like), SPECT (e.g., yy Tc, 'Ga, iy 3 ⁇ 4 and the like), fluorochrome (e.g., Alexa 647, Alexa 488 and the like), radio nuclide (e.g., alpha-emitting radionuclides (e.g., At-211, Bi- 212, Bi-213, Ra-223, and Ac-225), beta-emitting radionuclides (e.g., Cu-67, Y-90, Ag-111, 1- 131, Pm-149, Sm-153, Ho-166, Lu-177, Re-186, and Re-188)), and the like, can be associated with a particle and be detected using appropriate detection systems.
- the use of a radionuclide e.g., 18 F, 64 Cu, U C, 13
- particles described herein can be prepared with dopant entities that are agents intended for administration or delivery.
- such an agent remains associated with the particle after administration of the particle; in some embodiments, such an agent is released or otherwise dissociated from the particle after administration.
- dopant entities may be or comprise any therapeutic agents (e.g., antibiotics, NSAIDs, angiogenesis inhibitors, neuroprotective agents), cytotoxic agents, diagnostic agents (e.g., contrast agents; radionuclides; and fluorescent, luminescent, and magnetic moieties), targeting agents, prophylactic agents (e.g., vaccines), and/or nutraceutical agents (e.g., vitamins, minerals, etc.), or other substances (e.g., salt) that may be suitable for introduction to biological tissues, including pharmaceutical excipients and substances for cosmetics, and the like.
- therapeutic agents e.g., antibiotics, NSAIDs, angiogenesis inhibitors, neuroprotective agents
- diagnostic agents e.g., contrast agents; radionuclides; and fluorescent, luminescent, and magnetic moieties
- targeting agents e.g., prophylactic agents (e.g., vaccines)
- nutraceutical agents e.g., vitamins, minerals, etc.
- exemplary dopant entities
- Raman nanoparticles described herein include one or more targeting agent to facilitate and/or enhance the targeting of nanoparticles to a diseased tissue.
- Targeting agents include, e.g., various specific ligands, such as antibodies, monoclonal antibodies and their fragments, folate, mannose, galactose and other mono-, di-, and
- targeting agents include, but are not limited to, nucleic acids (e.g., RNA and DNA), polypeptides (e.g., receptor ligands, signal peptides, avidin, Protein A, and antigen binding proteins), polysaccharides, biotin, hydrophobic groups, hydrophilic groups, drugs, and any organic molecules that bind to receptors.
- nucleic acids e.g., RNA and DNA
- polypeptides e.g., receptor ligands, signal peptides, avidin, Protein A, and antigen binding proteins
- polysaccharides e.g., biotin, hydrophobic groups, hydrophilic groups, drugs, and any organic molecules that bind to receptors.
- a targeting agent is an antigen binding protein (e.g., an antibody or binding portion thereof).
- Antibodies can be generated using known methods to allow for the specific targeting of antigens or immunogens (e.g., tumor, tissue, or pathogen specific antigens) on various biological targets (e.g., pathogens, or tumor cells).
- Such antibodies include, but are not limited to, polyclonal antibodies; monoclonal antibodies or antigen binding fragments thereof; modified antibodies such as chimeric antibodies, reshaped antibodies, humanized antibodies, or fragments thereof (e.g., Fv, Fab', Fab, F(ab')2); or biosynthetic antibodies, e.g., single chain antibodies, single domain antibodies (DAB), Fvs, or single chain Fvs (scFv).
- DAB single domain antibodies
- scFv single chain Fvs
- modified antibodies and antibody fragments e.g., chimeric antibodies, reshaped antibodies, humanized antibodies, or fragments thereof, e.g., Fab', Fab, F(ab')2 fragments
- biosynthetic antibodies e.g., single chain antibodies, single domain antibodies (DABs), Fv, single chain Fv (scFv), and the like
- DABs single domain antibodies
- scFv single chain Fv
- scFv single chain Fv
- the targeting agent is a nucleic acid (e.g., RNA or DNA).
- the nucleic acid targeting agents are designed to hybridize by base pairing to a particular nucleic acid (e.g., chromosomal DNA, mRNA, or ribosomal RNA).
- the nucleic acids bind a ligand or biological target.
- the nucleic acid can bind reverse transcriptase, Rev or Tat proteins of HIV (Tuerk et al., Gene 137:33-9 (1993)); human nerve growth factor (Binkley et al., Nuc. Acids Res.
- Nucleic acids that bind ligands can be identified by known methods, such as the SELEX procedure (see, e.g., U.S. Pat. Nos. 5,475,096; 5,270,163; and 5,475,096; and WO 97/38134; WO 98/33941; and WO 99/07724).
- the targeting agents can also be aptamers that bind to particular sequences.
- the targeting agents can recognize a variety of known epitopes on preselected biological targets (e.g., pathogens or tumor cells).
- the targeting agent targets nanoparticles to factors expressed by oncogenes.
- these can include, but are not limited to, tyrosine kinases (membrane-associated and cytoplasmic forms), such as members of the Src family; serine/threonine kinases, such as Mos; growth factor and receptors, such as platelet derived growth factor (PDDG), small GTPases (G proteins), including the ras family, cyclin- dependent protein kinases (cdk), members of the myc family members, including c-myc, N-myc, and L-myc, and bcl-2 family members.
- tyrosine kinases membrane-associated and cytoplasmic forms
- Src family serine/threonine kinases, such as Mos
- growth factor and receptors such as platelet derived growth
- a particle can include one or more agents for delivery after administration/implantation.
- agents may be or comprise small molecules, large (i.e., macro-) molecules, or any combinations thereof.
- an agent can be a formulation including various forms, such as liquids, liquid solutions, gels, hydrogels, solid particles (e.g., microparticles, nanoparticles), or combinations thereof.
- an agent can be selected from among amino acids, vaccines, antiviral agents, nucleic acids (e.g., siRNA, RNAi, and microRNA agents), gene delivery vectors, interleukin inhibitors, immunomodulators, neurotropic factors, neuroprotective agents, antineoplastic agents, chemotherapeutic agents, polysaccharides, anticoagulants, antibiotics, analgesic agents, anesthetics, antihistamines, anti-inflammatory agents, vitamins and/or any combination thereof.
- an agent may be selected from suitable proteins, peptides and fragments thereof, which can be naturally occurring, synthesized or recombinantly produced.
- an agent is or comprises a biologic.
- biologies including, but are not limited to, monoclonal antibodies, single chain antibodies, aptamers, enzymes, growth factors, hormones, fusion proteins, cytokines, therapeutic enzymes, recombinant vaccines, blood factors, and anticoagulants. Exemplary biologies suitable for use in accordance with the present disclosure are discussed in S. Aggarwal, Nature Biotechnology, 28: 11, 2010, the contents of which are incorporated by reference herein.
- compositions and methods in accordance with the present application are particularly useful to deliver one or more therapeutic agents.
- a therapeutic agent is a small molecule and/or organic compound with pharmaceutical activity.
- a therapeutic agent is a clinically-used drug.
- a therapeutic agent is or comprises an anti-cancer agent, antibiotic, anti-viral agent, anesthetic, anticoagulant, inhibitor of an enzyme, steroidal agent, anti-inflammatory agent, anti-neoplastic agent, antigen, vaccine, antibody, decongestant, antihypertensive, sedative, birth control agent, progestational agent, anti-cholinergic, analgesic, anti-depressant, anti-psychotic, ⁇ -adrenergic blocking agent, diuretic, cardiovascular active agent, vasoactive agent, anti-glaucoma agent, neuroprotectant, angiogenesis inhibitor, etc.
- anticancer agents included, but are not limited to, a cytokine, a chemokine, a growth factor, a photosensitizing agent, a toxin, an anti-cancer antibiotic, a chemotherapeutic compound, a radionuclide, an angiogenesis inhibitor, a signaling modulator, an anti-metabolite, an anti-cancer vaccine, an anti-cancer oligopeptide, a mitosis inhibitor protein, an antimitotic oligopeptide, an anti-cancer antibody, an anti-cancer agent, antibiotic, an immunotherapeutic agent, hyperthermia or hyperthermia therapy, a bacterium, radiation therapy and a combination of such agents.
- an anticancer agent is cisplatin, carboplatin, gemcitabine, irinotecan, an anti-EGFR antibody, an anti-VEGF antibody and any combinations thereof.
- a therapeutic agent used in accordance with the present application can be or comprise an agent useful in combating inflammation and/or infection.
- a therapeutic agent may be an antibiotic.
- antibiotics include, but are not limited to, ⁇ -lactam antibiotics, macrolides, monobactams, rifamycins, tetracyclines, chloramphenicol, clindamycin, lincomycin, fusidic acid, novobiocin, fosfomycin, fusidate sodium, capreomycin, colistimethate, gramicidin, minocycline, doxycycline, bacitracin, erythromycin, nalidixic acid, vancomycin, and
- ⁇ -lactam antibiotics can be ampicillin, aziocillin, aztreonam, carbenicillin, cefoperazone, ceftriaxone, cephaloridine, cephalothin, cloxacillin, moxalactam, penicillin G, piperacillin, ticarcillin and any combination thereof.
- Other anti-microbial agents such as copper may also be used in accordance with the present invention.
- anti- viral agents, anti-protazoal agents, anti-parasitic agents, etc. may be of use.
- a therapeutic agent may be an anti-inflammatory agent.
- a therapeutic agent may be a mixture of pharmaceutically active agents.
- a local anesthetic may be delivered in combination with an anti-inflammatory agent such as a steroid.
- Local anesthetics may also be administered with vasoactive agents such as epinephrine.
- an antibiotic may be combined with an inhibitor of the enzyme commonly produced by bacteria to inactivate the antibiotic (e.g., penicillin and clavulanic acid).
- a therapeutic agent may a therapeutic gene as known in the art.
- a therapeutic agent is a non-viral vector.
- Typical non-viral gene delivery vectors comprise DNA (e.g., plasmid DNA produced in bacteria) or RNA.
- a non-viral vectors is used in accordance with the present invention with the aid of a delivery vehicle. Delivery vehicles may be based around lipids (e.g., liposomes) which fuse with cell membranes releasing a nucleic acid into the cytoplasm of the cell. Alternatively or alternatively, peptides or polymers may be used to form complexes (e.g., in form of particles) with a nucleic acid which may condense as well as protect the therapeutic activity as it attempts to reach a target destination.
- Systems of the disclosure include detectors and associated components for detecting Raman spectra from cells and/or tissues.
- such systems include an excitation source (e.g., a light source), optics for directing such excitation source to a sample (e.g., cells and/or tissues), and a detector for detecting Raman spectra from such sample.
- the excitation source and optics are used to interrogate the presence of a Raman reporter and to ablate the area or region where presence of the Raman reporter is detected.
- the light source for producing excitation light may include one or more lasers, and optics for directing the excitation light onto and/or into the target tissue are configured to disperse the excitation light evenly over the wide field corresponding to the target tissue.
- NIR near-infrared
- the wavelength can be in the visible range, the near- infrared range, or in the mid-infrared range (e.g., about 500 nm to about 11 ⁇ ).
- a hyperspectral wide field imaging device is used with CCD detector and filter.
- monochromatic images of the whole wide field are obtained at each of a plurality of wavelengths (e.g., a limited set of 2 to 10 wavelengths), each wavelength corresponding to a spectral peak characteristic of the Raman reporter.
- the laser may be a tunable laser source.
- Optics may include a tunable laser line filter (LLF) and/or a tunable notch filter (NF), where the filters are tandem thick volume Bragg gratings.
- LLF laser line filter
- NF tunable notch filter
- the plurality of monochromatic images may be analyzed, by the detector, for graphical identification of the Raman reporters within the wide field. Images displaying the location of R-MR nanoparticle reporters (indicative of tumor or other abnormal tissue) may be superimposed, for example, on corresponding video images of the wide field, allowing the surgeon the ability to visualize such tissue and remove it with limited damage to surrounding healthy tissue.
- the system may allow scanning/imaging of a wide field of view of about 5 x 5 cm, 10 x 10 cm, 20 x 20 cm. In some embodiments, the field of view is about 25 cm 2 , 50 cm 2 ,
- Individual images of R-MR nanoparticles may be acquired within seconds, for example, or less than a second, such that a real-time or near real-time sequence of images may be viewed (e.g., 10 images per second or more, e.g., 20 or more images per second).
- systems of the disclosure include detectors and associated components for detecting Raman spectra from cells and/or tissues and implements for treating (e.g., ablating and/or resecting) cells and/or tissues from which Raman spectra are detected.
- such systems include an excitation source (e.g., a light source), optics for directing such excitation source to a sample (e.g., cells and/or tissues), a detector for detecting Raman spectra from such sample, and implements for treating (e.g., ablating and/or resecting) cells and/or tissues from which Raman spectra are detected.
- a system of the disclosure includes a handheld instrument of size and length that can be customized to a particular application.
- a system can include a resector/ablation mechanism (e.g., a mechanical resector (e.g., rotary blade, vibrating knife, or percussing knife), an electro-cautery mechanism, a cryoablation mechanism, and/or a resector/ablation mechanism (e.g., a mechanical resector (e.g., rotary blade, vibrating knife, or percussing knife), an electro-cautery mechanism, a cryoablation mechanism, and/or a resector/ablation mechanism (e.g., a mechanical resector (e.g., rotary blade, vibrating knife, or percussing knife), an electro-cautery mechanism, a cryoablation mechanism, and/or a resector/ablation mechanism (e.g., a mechanical resector
- a system can optionally include a vacuum suction mechanism connected to a collection bag that removes resected tissue from the site of resection. Adjacent and/or near the motorized resection mechanism within the handheld device can be located an excitation laser pathway and optics for measuring emitted Raman spectra. Optionally, a rinsing mechanism can be included within the device to help clean the optics.
- the hand-held device can be connected with a cable (e.g., fiberoptic cable) and tubing (e.g., suction tubing) to a box located adjacent to the operating site that houses mechanics, optics, and electronics (e.g., excitation laser, Raman spectral analysis optics, CCD chips, and optionally motors to drive the resection instrument, suction motor, and rinsing mechanism).
- a cable e.g., fiberoptic cable
- tubing e.g., suction tubing
- electronics e.g., excitation laser, Raman spectral analysis optics, CCD chips, and optionally motors to drive the resection instrument, suction motor, and rinsing mechanism.
- system 2600 of the disclosure includes a hand-held instrument/housing 2601 having a terminal end 2612.
- the instrument 2601 may include optics for directing an excitation light onto a target sample 2630 (e.g., cells, or tissue).
- excitation light source 2602 is a Raman laser, for example, having a wavelength of 785 nm.
- the excitation light is transmitted along cable 2610 from excitation light source 2602 through device 2601 and is directed to target tissue 2630 through terminal end 2612.
- the excitation light passes through one or more filters 261 1 before reaching target 2630.
- the filter(s) may or may not be contained within the hand-held instrument 2601.
- the excitation light is not directed onto the tissue 2630 by the hand-held instrument 2601, but instead is directed onto the tissue 2630 via optics, apart from the instrument 2601.
- the system 2600 also includes a detector for detecting a signal from target 2630. Such signal follows cable 2620 to signal analyzer 2603.
- signal analyzer 2603 is a Raman analyzer.
- signal analyzer 2603 Upon determination that an appropriate signal is detected, signal analyzer 2603 relays a positive signal to ablation controller 2604.
- Ablation controller 2604 is operably linked to instrument 2601 via cable 2605, which terminates in an ablation device near terminal end 2612 of instrument 2601.
- the ablation device Upon receiving a positive signal from ablation controller 2604, the ablation device ablates cells and/or tissue at or near target 2630.
- ablation controller 2604 includes a mechanical ablation controller operably linked to a suction vacuum mechanism near terminal end 2612 of instrument 2601 via tubing 2606.
- the system 2600 includes a motor-driven and controlled resection mechanism (e.g., a rotating blade) located at the tip 2612 of the handheld device 2601, such that activation of the resection mechanism is triggered upon detection of a Raman signal by the Raman Analyzer 2603.
- a motor-driven and controlled resection mechanism e.g., a rotating blade located at the tip 2612 of the handheld device 2601, such that activation of the resection mechanism is triggered upon detection of a Raman signal by the Raman Analyzer 2603.
- a system of the disclosure includes a handheld instrument of size and length that can be customized depending on application.
- a system can include a laser suitable for ablating/destroying tissue (e.g., a C0 2 , Er:YAG, or Nd:YAG laser).
- the ablating laser is also used as the excitation light source for interrogating an area of a tissue for the presence of the Raman reporter, e.g., where the power level is lower for interrogation and higher for ablation.
- a system can optionally include a vacuum suction mechanism connected to a collection bag that removes destroyed tissue (and, optionally, nanoparticles described herein) within targeted tissue.
- Adjacent to the ablation laser pathway within the handheld device can be located an excitation laser pathway and optics for measuring emitted Raman spectra.
- a rinsing mechanism can be included within the device to help clean the optics.
- the handheld device can be connected with a cable (e.g., fiberoptic cable) and tubing (e.g., suction tubing) to a box located adjacent to the operating site that houses mechanics, optics, and electronics (e.g., excitation laser, ablation laser, Raman spectral analysis optics, CCD chip(s), and optionally motors to drive the suction motor, and rinsing mechanism).
- system 2700 of the disclosure includes a hand-held instrument 2701 having a terminal end 2714.
- the instrument 2701 includes a housing 2702 for directing an excitation light to a target sample 2715.
- excitation light source 2704 is a Raman laser, for example, having a wavelength of 785 nm.
- the excitation light is transmitted along cable 2707 from excitation light source 2704 through instrument 2701 and is directed to target 2715 through terminal end 2714.
- the excitation light passes through one or more filters 2710 and 2712 before reaching target 2715.
- the filter(s) may or may not be contained within the hand-held instrument 2701.
- the excitation light is not directed onto the tissue 2715 by the hand-held instrument 2701, but instead is directed onto the tissue 2715 via optics apart from the instrument 2701.
- the system 2700 also includes a detector for detecting a signal from target 2715. Such signal travels through cable 2708 to signal analyzer 2705.
- signal analyzer 2705 is a Raman analyzer.
- Signal analyzer 2705 is operably linked to ablation laser 2706.
- ablation laser 2706 is a C0 2 laser.
- signal analyzer 2705 Upon determination that an appropriate signal is detected, signal analyzer 2705 relays a positive signal to ablation laser 2706.
- Ablation laser 2706 is operably linked to device 2701 via cable 2709, which directs the ablation laser through housing 2703 to target 2715. In some embodiments, ablation laser passes through filters 2711 and 2713 before reaching target 2715.
- Figure 27 also illustrates exemplary system 2750, which differs from system 2700 in the configuration of device 2751.
- device 2751 includes housing 2752 for directing excitation light from an excitation light source and for directing Raman signals to a signal analyzer as described for system 2700.
- Device 2751 also includes housing 2753 for directing ablation laser to target 2758, as described for system 2700.
- Device 2751 includes filter 2754 and deflector 2756, which directs ablation laser along or near the same pathway used by the excitation light to reach target 2758.
- FIG 28 illustrates another exemplary system 2800.
- the system 2800 employs an ablation laser 2802 that generates excitation light for interrogating the presence of a Raman reporter within or on the tissue sample 2814 and for ablating the area of the sample where the Raman signal is detected.
- Ablation laser 2802 may be operably linked to a separate, hand-held device/housing 2804 via cable 2810, which directs the ablation laser through housing 2804 to target 2814.
- the ablation laser 2802 first outputs the excitation light source at an interrogation power level sufficient to penetrate the tissue to a desired depth for detection of the Raman reporter in that region yet not high enough to cause damage (e.g., via thermal or ionizing energy) to the tissue or sample.
- the interrogation power level is less than 20 milliwatt or less than 10%, for example, of the maximum power level of the ablation laser.
- Other power levels may be employed for the interrogation and may be selected based on, for example, but not limited to, the type and/or density of the tissue, the depth of the intended interrogation, the type of Raman reporter used, and the wavelength/frequency of the outputted excitation light source.
- the ablation laser 2802 is also configured to output an excitation source at an ablation power level sufficient to ablate the tissue when the presence of the Raman reporter is detected from the interrogation of the tissue. This level may be sufficient to cause heating, and in instances, vaporization, of the area or region in the vicinity of the Raman reporter. In some implementations, the effect is the result of the vibrational state of the Raman reporter when excited by the excitation source. In other implementations, the ablation power level is sufficient to cause damage to the tissue through this vibrational mode of the Raman reporter when excited by the excitation source. In such implementations, the heating, vaporization, or vibration damage may be the result of amplification of the Raman scattering by the Raman reporter due to the resonance effect with the excitation source.
- the ablation power level can be at a level that does not cause damage to the tissue or the area/region exposed to the excitation source unless the Raman reporter is present therein, or the exposure time by the excitation source may not be of sufficient duration.
- an ablation power level can be employed that is sufficient to directly cause thermal effects on the tissue exposed to the excitation light source, whereby the thermal effects cause the ablation of the tissue.
- the laser 2802 is a C0 2 laser. In other embodiments, the laser is a different kind of laser, as described elsewhere herein.
- the elevated ablation power level is above 150 mW. In such implementations, the power level can be between 50% and 100% of the maximum power output of the ablation laser.
- the system 2800 includes a housing 2804 for directing the excitation light source to a target sample 2814.
- the ablation laser 2802 has a wavelength of about 500 nm to about 11 ⁇ .
- the ablation laser 2802 transmits the excitation light along cable 2810 through instrument 2804 and is directed to the target sample 2814 through a terminal end 2812.
- the system 2800 includes one or more filters and optics 2810 (such as prism) through which the excitation light passes 2712 before reaching the target 2814.
- the prism directs the returned light emanating from the tissue 2814 through one or more filters to cable 2808 to Raman analysis.
- the filters and optics 2810 include an optical assembly comprising one or more confocal lens to vary the focus length of the excitation light source outputted from the system 2800.
- the optical assembly may control the depth of the spectral measurement (e.g., during the interrogation of the Raman reporter) to match to the depth of the ablation.
- the system 2800 also includes a detector 2806 for detecting a signal from target 2814 received from cable 2808.
- the detector 2806 includes a charge- coupled device (CCD) coupled with a optics assembly and a transmission grating.
- CCD charge- coupled device
- the optic assembly may collimate the detected lights from a slit, located at the entrance of the detector assembly, to the transmission grating.
- the grating disperses the incident light to the CCD detector by way of a focusing mirror.
- the detector converts the light to a signal for processing by the Raman analyzer 2806.
- a controller (not shown) operatively links the ablation laser 2802 and the Raman analyzer 2806.
- the Raman analyzer 2806 employs a correlation anlaysis, for example, to determine for the presence of a Raman signal associated with the Raman reporter (e.g., SERS nanoparticles, SERRS nanoparticles, or an intrinsic species). Upon determination that a Raman signature is present, the Raman analyzer 2806 triggers a signal to the controller or the ablation laser 2802 to elevate the output power level of the laser for a predefined period to ablate the tissue sample 2814. In some implementations, the elevated power level is above 150 mW. In such implementations, the power level can be between 50% and 100% of the maximum power output of the ablation laser.
- the ablation power level and exposure time may be a function of the tissue type and density, the depth of the intended ablation, the type of Raman reporter, and the wavelength of outputted excitation light sources.
- Figure 30 is an example method 3000 of operation of an ablation/scanning device.
- the ablation/scanning device is energized, at a scanning, non-ablating power level, to produce an electromagnetic radiation on the sample in which the sample has been treated (e.g., injected) with a Raman Reporter (e.g., SERS, SERRS, SERS-MRI, R-MR and other nanoparticles or intrinsic species) (step 3002).
- the non-ablating power is less than about 10%) (e.g,. between about 1% to 10%>) of the maximum power of the laeser, which may be equivalent to about few milliwatts (e.g., l-20mW).
- the ablation/scanning device acquires a spectrum of the resulting Raman scattering from the test sample in which the scattering is caused by the generated electromagnetic radiation (step 3004). The acquired spectrum may be filtered for a specific bandwidth.
- the ablation/scannnig device compares the acquired laser spectrum to a stored reference spectrum to generate a comparison index value (step 3006).
- the reference spectrum is a correleative profile of the Raman reporter ((e.g., SERS nanoparticles, SERRS nanoparticles, or an intrinsic species).
- the reference spectrum is a correleative profile of a specific type of tissue or tumor treated with the Raman reporter.
- the reference spectrum is a correlative profile of the Raman reporter when binded to a specific type of tissue or tumor.
- the reference spectrum may be stored in memory of the ablation/scanning device.
- the ablation/scanning device determines that the current location of the tissue sample does not have the Raman reporter, the device moves to a next location (step 3010).
- the next location may be a pre-defined step from the current location.
- the ablation/scanning device continuously outputs the laser at the scanning, non-ablating power level while the laser is moved to the next location or the laser may be de-energized.
- the ablation/scanning device energizes the laser at an ablation power at the same point location (step 3008).
- the laser is outputted between about 50 percent and 100 percent of the maximum power output of the laser.
- the output may have a duration of, for example, about 1 to about 200 milliseconds.
- the Raman ablation device is rastered to a next location (step 3010).
- the Raman ablation device repeats steps 3002 to 3008 at a given ablated location or region.
- the Raman ablation device outputs a second ablation output, and subsequent ablantion outputs, if a Raman reporter is still detected there.
- Figures 31 A and 3 IB are schematic illustrations of an exemplary method of controlling a laser ablation and Raman scanning device of the disclosure.
- the interrogation source 3102 and ablation source 3104 may be outputted in pulses.
- the interrogation source 3102 may have duration less than 120 millseconds (equivalent to about 10 hertz).
- the interrogation source 3106 and ablation source 3108 may be continuous in which the interrogation source 3106 is continually output. Then, upon a Raman reporter being detected by the system, the interrogation source 3106 is elevated to a power level sufficient to ablate the tissue or sample (in some embodiments, the ablation due at least in part to additional energy provided by the Raman reporter, itself, to the nearby tissue).
- the instruments 2601, 2701, 2750, and 2800 described above may be endoscopic instruments designed for insertion into a patient, for example, into the gastrointestinal tract, the respiratory tract, the ear, the urinary tract, the female reproductive system, the abdominal or pelvic cavity, the interior of a joint (arthroscopy), organs of the chest, or the amnion.
- systems 2600, 2700, and 2800 described above additionally include one or more additional modalities for detecting a Raman nanoparticle, and/or for otherwise detecting tissue to be ablated or resected.
- the system further includes MRI, NMR, PET, SPECT, CT, X-ray, ultrasound, photoacoustic, and/or fluorescent detection modalities.
- Systems of the disclosure described herein may have components of small size (e.g., micromechanical components), such that the systems may be used in microsurgical procedures.
- Systems of the disclosure described herein may be robot-assisted or robot-guided.
- the instrument 2601, 2701, 2751, and 2800 may be part of a robotic system that positions and/or moves the instrument automatically or semi-automatically.
- Other components of known robotic surgical systems may be used in conjunction with the systems of this disclosure.
- a system described herein further includes a Raman raster scanning device.
- a Raman raster scanning device can be used to scan (e.g., systematically scan) a field having a particular dimension (e.g., a surface area of target tissue).
- Figure 29 illustrates an exemplary system for using a Raman scanning device, which can be used in any of the embodiments described herein.
- a controller is operably linked to a motor, which manipulates the position of a stage (e.g., an X-Y stage, an X-Y-Z stage, or an XYZ/rotation stage).
- the system may raster between sampling points at step sizes between 0.1 mm and 10 mm apart. In certain implementations, the step size is greater than 10 mm.
- the system may perform an initial scan at a coarse step size (e.g., 1 - 10 mm) to identify tissue areas of interest. Subsequently, the system then perform an ablation scan at a finer step size (e.g,. 0.1 mm to 2 mm) to scan and ablate the tissue.
- the finer step size may be a function of the laser spot (e.g., between 5 ⁇ um to 2mm) and the sample acquisition rate (e.g., greater than 10 Hz).
- excitation light for producing Raman photon scattering from a target cell and/or tissue is provided using a laser. Particular wavelengths useful in producing Raman scattering can be determined by the target to be excited.
- excitation light is in the visible to near infrared range (e.g., about 400 nm to about 1400 nm).
- excitation light of 244 nm, 325 nm, 442 nm, 488 nm, 514 nm, 532 nm, 633 nm, 785 nm, or 830 nm can be used.
- a Raman nanoparticle e.g., a SERS nanoparticle
- the composition of a particular Raman nanoparticle can be used to select an appropriate wavelength.
- a SERS nanoparticle described in Kircher et al, Nature Med. 18:829-834 (2012); Yigit et al, Am. J. Nucl. Med. Mol. Imaging 2:232-241 (2012); Zhang et al, Small. 7:3261-9 (2011); or Zhang et al, Curr. Pharm. Biotechnol. 11 :654-661 (2010) is used, and excitation light of 785 nm is used.
- an intrinsic non-enhanced or intrinsic enhanced (SERS) Raman spectrum of a tissue to be destroyed is excited.
- selection of a particular wavelength of excitation light can be determined by particular properties of the diseased tissue.
- Raman scattered photons from an illuminated sample can be collected and transmitted to one or more detectors.
- the detector(s) may be or may include a charge-coupled device (CCD) image sensor, for example, a time-gated intensified CCD camera (e.g., an ICCD camera).
- CCD charge-coupled device
- the detector(s) may include an active pixel sensor (CMOS), an electron-multiplying CCD (EMCCD), frame transfer CCD, or the like.
- CMOS active pixel sensor
- EMCD electron-multiplying CCD
- frame transfer CCD or the like.
- electromagnetic radiation used to obtain Raman images is transmitted to a detector in a "mappable” or “addressable” fashion, such that radiation (e.g., light) transmitted from different assessed regions of tissue can be differentiated by the detector.
- radiation e.g., light
- Light detected by a detector can be light transmitted, reflected, emitted, or scattered by the tissue through air interposed between the tissue surface and the detector.
- light can be transmitted by way of one or more optical fibers to the detector, for example.
- one or more additional optical elements can be interposed between a target cell and/or tissue and detector(s).
- optical elements are used to facilitate transmission from the surface to the detectors, other optical element(s) can be optically coupled with the fibers on either end or in the middle of such fibers.
- suitable optical elements include one or more lenses, beam splitters, diffraction gratings, polarization filters, bandpass filters, or other optical elements selected for transmitting or modifying light to be assessed by detectors.
- One or more appropriate optical elements may be coupled with a detector.
- a suitable filter can be a cut-off filter, a Fabry Perot angle tuned filter, an acousto-optic tunable filter, a liquid crystal tunable filter, a Lyot filter, an Evans split element liquid crystal tunable filter, a Sole liquid crystal tunable filter, or a liquid crystal Fabry Perot tunable filter.
- Suitable interferometers include a polarization-independent imaging interferometer, a Michelson interferometer, a Sagnac interferometer, a Twynam-Green interferometer, a Mach-Zehnder interferometer, and a tunable Fabry Perot interferometer.
- a Raman signal is detected from cells and/or tissue
- such cells and/or tissue are ablated or resected using known implements and/or methods for ablating or resecting cells and/or tissues, such as laser ablation, mechanical ablation, electrocautery, radiofrequency ablation, and/or cryoablation.
- ablation is achieved using radiofrequency energy.
- Additional forms of energy for ablation include, without limitation, microwave energy, or photonic or radiant sources such as infrared or ultraviolet light.
- Photonic sources can include, for example, semiconductor emitters, lasers, and other such sources.
- Light energy may be either collimated or non-collimated.
- ablation utilizes heatable fluids, or, alternatively, a cooling medium, including such non-limiting examples as liquid nitrogen, FreonTM, non-CFC refrigerants, C0 2 or N 2 0 as an ablation energy medium.
- a cooling medium including such non-limiting examples as liquid nitrogen, FreonTM, non-CFC refrigerants, C0 2 or N 2 0 as an ablation energy medium.
- an apparatus can be used to circulate heating/cool medium from outside a patient to a heating/cooling balloon or other element and then back outside the patient again.
- light energy is used to ablate cells and/or tissues, and laser light is precisely aimed to cut or destroy diseased cells and/or tissue (e.g., a tumor) according to methods of the disclosure.
- a method, system or device described herein is used to delivery laser-induced interstitial thermotherapy (LITT), or interstitial laser
- a method, system or device described herein is used to delivery photodynamic therapy (PDT).
- PDT photodynamic therapy
- a certain drug e.g., a photosensitizer or photosensitizing agent
- the agent is found mostly in cancer cells.
- Laser light is then used to activate the agent and destroy cancer cells.
- Lasers typically used to destroy cancerous tumors include solid state lasers, gas lasers, semiconductor lasers, and others.
- Typical wavelengths of electromagnetic radiation used in cancer treatments are from about 200 nm to about 5000 nm, and to about 12 ⁇ for C0 2 lasers.
- Typical power levels range from about 0.1 W to about 15 W, and to about 30 W for C0 2 lasers. However, greater or lesser power levels may be used in some circumstances.
- Typical treatment times for exposing cancerous cells to laser energy range from less than about 1 minute to greater than about 1 hour, although longer or shorter times may be used.
- the laser energy applied to the cancerous cells may also be modulated.
- Laser energy may be applied to cancerous cells by continuous wave (constant level), pulsing (on/off), ramping (from low to high energy levels, or from high to low energy levels), or other waveforms (such as sine wave, square wave, triangular wave, etc.). Modulation of laser energy may be achieved by modulating energy to the laser light source or by blocking or reducing light output from the laser light source according to a desired modulation pattern.
- Exemplary, nonlimiting lasers useful in the methods, systems, and devices described herein include carbon dioxide (C0 2 ) lasers, argon lasers, neodymium-doped yttrium-aluminum-garnet (Nd:YAG) lasers, and erbium-doped yttrium-aluminum-garnet (Er:YAG) lasers.
- C0 2 carbon dioxide
- argon lasers neodymium-doped yttrium-aluminum-garnet
- Er:YAG erbium-doped yttrium-aluminum-garnet
- cells and/or tissues are resected mechanically using, e.g., an electrically powered rotary blade. Additional mechanical resection mechanisms and/or methods may also be used. Resection mechanisms may include, for example, drills, dermatomes, scalpels, lancets, drill bits, rasps, trocars, and the like.
- Other surgical instruments may be used in conjunction with the ablation and resection mechanisms described above, including, for example forceps, clamps, retractors, dilators, suction tips and tubes, irrigation needles, injection needles, calipers, and the like.
- a sample comprised of Raman spectroscopic (SERRS) nanostar nanoparticles having a concentration of 5 nM is treated on a surface of workpiece.
- the sample was staged under a Raman spectrometer probe mounted on a linear scanning system.
- the probe is connected to a 240 milliwatt, 785nm, C0 2 laser.
- the probe and scanning system were controlled from a computing device operating a graphical user interface (GUI).
- GUI graphical user interface
- the Raman spectrometer probe used in this exemplary system is a Miniram Raman Spectrometer manufactured by BWTek of Newark, DE, model BAC-100.
- the GUI was programmed in Matlab of Mathworks of Natick, MA.
- the computing device evaluated the acquired spectral data with signal preprocessing, e.g., background 'dark' subtraction and mean normalization of the acquired data.
- signal preprocessing e.g., background 'dark' subtraction and mean normalization of the acquired data.
- Correlation Coefficient algorithm produced the most robust results in this exemplary system among the algorithm employed. Examples of correlative analysis may be found in Kwiatkowski et al., "Algorithms of Chemical Detection Using Raman Spectra," Metrol. Meas. Syst., Vol. XVII, No. 4, pp. 549-560 (2010).
- the device In each loop, the device energized the laser at a non-ablating power level to interrogate for the presense of Raman reporter in that area.
- the spectrometer probe directs the output of the laser to a point on the test sample.
- the device outputted an excitation source with a beam size of approximately 400 micrometer at a power level of about 3% of the maximum output power of the laser, or about 7-8 milliwatt.
- the interrogation beam was outputted for about 100 milliseconds.
- the device acquired a spectrum of the Raman scatter from the interrogated area during this 100 milliseconds.
- the acquired spectrum was compared to a reference spectrum (indicative of presence of the Raman reporter) to generate a comparison index by correlative analysis.
- the device is configured to energized the laser to the maximum power ( ⁇ 240mW) for a duration sufficient to heat and flash-burn the particles on the test sample (e.g., the treated paper).
- a threshold e.g. 0.75
- the device is configured to energized the laser to the maximum power ( ⁇ 240mW) for a duration sufficient to heat and flash-burn the particles on the test sample (e.g., the treated paper).
- the duration is set to 100 milliseconds.
- the comparison index is calculated, in some implementation, based m
- Si is the acquired spectrum at acquisition point i
- rj is the reference spectrum at point i
- s is the mean of the acquired spectrum
- r is the mean of the reference spectrum
- n is the number acquisition points.
- FIG 32 is a diagram of an example graphical user interface (GUI) used to control the Raman spectrometer in this exemplary system.
- GUI graphical user interface
- the GUI continuously generates and displays a comparison index (HQI) 3202 between the reference spectrum and the acquired spectrum.
- HQI comparison index
- the GUI also generates and plots the acquired spectrum (3206) and the reference spectrum (3204) used in the comparison.
- the index has a range of 0-100 (on a scale of 0-100) in which 100 means an identical data sets.
- Figure 33 shows data acquired via a Raman ablation and scanning device 3302.
- the sequence in the figure shows the device 3302 scanning over a test sample 3308.
- the test sample 3308 is a paper partially treated with a Raman reporter.
- the Raman reporter includes 5 nanomolar (nM), SERRS-nanostar nanoparticles.
- the probe 3302 is shown scanning a point 3306A on the test sample 3308 not treated with the Raman reporter. Each scan was performed at 3% of the maximum output of the laser (or 7-8 milliwatt) for approximately 100 milliseconds.
- the system determined that the acquired spectrum at point 3306 A does not have the Raman signature of interest when compared to a stored reference spectrum of the Raman reporter and moved to a next interrogation location.
- the total acquisition time took approximately 120 milliseconds to provide a scanning rate of about 10 Hertz.
- FIG. 33 Subfigure B, the system is shown interrogating a point 3306B near the border of the surface area 3304 treated with the SERRS-nanostar nanoparticles. The system determined that the point 3306B did not have the spectral signature of interest and subsequently moved to a next test location.
- FIG. 33 Subfigure C, the system is shown interrogating a point 3306C on the treated surface area 3304.
- the system determined that the acquired spectrum at point 3306C has the Raman signature of interest when compared to the stored reference spectrum and increased the laser output to an ablation power level (in this setup, at 100% of the maximum power, or about 240 milliwatt, of the C0 2 laser for a duration of 100 milliseconds) causing the paper and nanoparticle to heat up and flashburn. It was observed that the SERRS-nanostar nanoparticles assisted in the ablation of the test sample.
- FIG. 33 Subfigure D, the system is shown interrogating another point 3306D on the treated surface area 3304.
- the system determined that the point 3306C includes the Raman signature of interest and is also ablated.
- Figure 34 shows the thermal paper 3308 of Figure 33 subsequent to being scanned and ablated by the Raman scanning and ablation system 3302.
- the left image shows the top view 3402 of the thermal paper 3308 that was treated with the Raman reporter and was exposed to the laser beam during the interrogation and ablation.
- the right image shows the bottom view 3404 of the paper 3308. As shown, the areas 3406 treated with the Raman reporter were ablated by the laser if scanned by the system.
- the data demonstrate that an acquisition rate greater than 10 Hertz can be employed robustly using low interrogation power levels and that the ablation and interrogation may be performed by the same laser.
- the results also demonstrated that the Raman reporter can be employed to assist in the ablation event.
- the methods, systems, and devices described herein can be used to resect and/or ablate a variety of cells and/or tissues, e.g., diseased cells and/or tissues.
- the methods, systems, and devices described herein can also be used to identify and/or distinctly visualize a variety of cells and/or tissues, e.g., diseased cells and/or tissues.
- methods described herein identify hyperproliferative, hyperplastic, metaplastic, dysplastic, and pre-neoplastic tissues.
- hyperproliferative tissue is meant a neoplastic cell growth or proliferation, whether malignant or benign, including all transformed cells and tissues and all cancerous cells and tissues. Hyperproliferative tissues include, but are not limited to, precancerous lesions, abnormal cell growths, benign tumors, malignant tumors, and cancer.
- hyperproliferative tissues include neoplasms, whether benign or malignant, located in the brain, prostate, colon, abdomen, bone, breast, digestive system, liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary, thymus, thyroid), eye, head and neck, nervous (central and peripheral), lymphatic system, pelvic, skin, soft tissue, spleen, thoracic, or urogenital tract.
- neoplasms whether benign or malignant, located in the brain, prostate, colon, abdomen, bone, breast, digestive system, liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary, thymus, thyroid), eye, head and neck, nervous (central and peripheral), lymphatic system, pelvic, skin, soft tissue, spleen, thoracic, or urogenital tract.
- tumor or tumor tissue refers to an abnormal mass of tissue that results from excessive cell division.
- a tumor or tumor tissue comprises “tumor cells”, which are neoplastic cells with abnormal growth properties and no useful bodily function.
- Tumors, tumor tissue, and tumor cells may be benign or malignant.
- a tumor or tumor tissue can also comprise "tumor-associated non-tumor cells", such as vascular cells that form blood vessels to supply the tumor or tumor tissue.
- Non-tumor cells can be induced to replicate and develop by tumor cells, for example, induced to undergo angiogenesis within or surrounding a tumor or tumor tissue.
- malignancy refers to a non-benign tumor or a cancer.
- cancer means a type of hyperproliferative disease that includes a malignancy characterized by deregulated or uncontrolled cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
- squamous cell cancer e.g., epithelial squamous cell cancer
- lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung
- cancer of the peritoneum hepatocellular cancer
- gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
- cancer includes primary malignant cells or tumors (e.g., those whose cells have not migrated to sites in the subject's body other than the site of the original malignancy or tumor) and secondary malignant cells or tumors (e.g., those arising from metastasis, the migration of malignant cells or tumor cells to secondary sites that are different from the site of the original tumor).
- primary malignant cells or tumors e.g., those whose cells have not migrated to sites in the subject's body other than the site of the original malignancy or tumor
- secondary malignant cells or tumors e.g., those arising from metastasis, the migration of malignant cells or tumor cells to secondary sites that are different from the site of the original tumor.
- the methods described herein can be used to ablate and/or resect premalignant tissue and to prevent progression to a neoplastic or malignant state including, but not limited to, those disorders described above. Such uses are indicated in conditions known or suspected of preceding progression to neoplasia or cancer, in particular where non-neoplastic cell growth consisting of hyperplasia, metaplasia, or dysplasia has occurred (see, e.g., Robbins and Angell, Basic Pathology, 2d Ed., W.B. Saunders Co., Philadelphia, pp. 68-79 (1976)).
- the apparatus and methods described herein can also be used to identify premalignant tissue or hyperplastic tissue.
- the apparatus and methods described herein can further be used to identify premalignant tissue or hyperplastic tissue.
- Hyperplasia is a form of controlled cell proliferation, involving an increase in cell number in a tissue or organ, without significant alteration in structure or function.
- Hyperplastic disorders include, but are not limited to, angiofollicular mediastinal lymph node hyperplasia, angiolymphoid hyperplasia with eosinophilia, atypical melanocytic hyperplasia, basal cell hyperplasia, benign giant lymph node hyperplasia, cementum hyperplasia, congenital adrenal hyperplasia, congenital sebaceous hyperplasia, cystic hyperplasia, cystic hyperplasia of the breast, denture hyperplasia, ductal hyperplasia, endometrial hyperplasia, fibromuscular hyperplasia, focal epithelial hyperplasia, gingival hyperplasia, inflammatory fibrous hyperplasia, inflammatory papillary hyperplasia, intravascular papillary endothelial hyperplasia, nodular hyperplasia of prostate, nodular regenerative hyperplasia, pseudoepitheliomatous hyperplasia, senile sebaceous hyperplasi
- Metaplasia is a form of controlled cell growth in which one type of adult or fully differentiated cell substitutes for another type of adult cell.
- Metaplastic disorders include, but are not limited to, agnogenic myeloid metaplasia, apocrine metaplasia, atypical metaplasia, autoparenchymatous metaplasia, connective tissue metaplasia, epithelial metaplasia, intestinal metaplasia, metaplastic anemia, metaplastic ossification, metaplastic polyps, myeloid metaplasia, primary myeloid metaplasia, secondary myeloid metaplasia, squamous metaplasia, squamous metaplasia of amnion, and symptomatic myeloid metaplasia.
- Dysplasia can be a forerunner of cancer and is found mainly in the epithelia.
- Dysplasia is a disorderly form of non-neoplastic cell growth, involving a loss in individual cell uniformity and in the architectural orientation of cells.
- Dysplastic cells can have abnormally large, deeply stained nuclei, and exhibit pleomorphism.
- Dysplasia can occur, e.g., in areas of chronic irritation or inflammation.
- Dysplastic disorders include, but are not limited to, anhidrotic ectodermal dysplasia, anterofacial dysplasia, asphyxiating thoracic dysplasia, atriodigital dysplasia, bronchopulmonary dysplasia, cerebral dysplasia, cervical dysplasia, chondroectodermal dysplasia, cleidocranial dysplasia, congenital ectodermal dysplasia, craniodiaphysial dysplasia, craniocarpotarsal dysplasia, craniometaphysial dysplasia, dentin dysplasia, diaphysial dysplasia, ectodermal dysplasia, enamel dysplasia, encephalo-ophthalmic dysplasia, dysplasia epiphysialis hemimelia, dysplasia epiphysialis multiplex, dysplasia epiphysialis punctata, epithelial dys
- Additional pre-neoplastic tissue that can be identified by the apparatus and methods described herein include, but are not limited to, benign dysproliferative disorders (e.g., benign tumors, fibrocystic conditions, tissue hypertrophy, intestinal polyps, colon polyps, and esophageal dysplasia), leukoplakia, keratoses, Bowen's disease, Farmer's Skin, solar cheilitis, and solar keratosis.
- the apparatus, methods, and systems described herein can also be used to ablate/resect or identify infected cells and/or tissues. In some embodiments, apparatus and methods described herein identify tissues infected with a virus, bacterium, fungus, protozoan, and/or helminth.
- infected tissue is infected with one or more of an immunodeficiency virus (e.g., a human immunodeficiency virus (HIV), e.g., HIV-1, HIV-2), a hepatitis virus (e.g., hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis A virus, non-A and non-B hepatitis virus), a herpes virus (e.g., herpes simplex virus type I (HSV-1), HSV-2, Varicella-zoster virus, Epstein Barr virus, human cytomegalovirus, human herpesvirus 6 (HHV- 6), HHV-7, HHV-8), a poxvirus (e.g., variola, vaccinia, monkeypox, Molluscum contagiosum virus), an influenza virus, a human papilloma virus, adenovirus, rhinovirus, coronavirus, respiratory
- infected tissue is infected with one or more bacteria from the following genera and species: Chlamydia (e.g., Chlamydia pneumoniae, Chlamydia psittaci, Chlamydia trachomatis), Legionella (e.g., Legionella pneumophila), Listeria (e.g., Listeria monocytogenes), Rickettsia (e.g., R. australis, R. rickettsii, R. akari, R. conorii, R. sibirica, R. japonica, R. africae, R. typhi, R.
- Chlamydia e.g., Chlamydia pneumoniae, Chlamydia psittaci, Chlamydia trachomatis
- Legionella e.g., Legionella pneumophila
- Listeria e.g., Listeria monocytogenes
- Rickettsia e.
- Escherichia e.g., Escherichia coli
- Francisella e.g., Francisella tularensis
- Haemophilus e.g., Haemophilus influenzae
- Helicobacter e.g., Helicobacter pylori
- Klebsiella e.
- Mycoplasma e.g., Mycoplasma pneumoniae
- Neisseria e.g., Neisseria gonorrhoeae, Neisseria meningitidis
- Pseudomonas e.g., Pseudomonas aeruginosa
- Salmonella e.g., Salmonella typhi, Salmonella typhimurium, Salmonella enterica
- Shigella e.g., Shigella dysenteriae, Shigella sonnei
- Staphylococcus e.g., Staphylococcus aureus, Staphylococcus epidermidis
- Streptococcus e.g., Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes
- Treponoma e.g., Treponoma pallidum
- Vibrio e.g., Vibrio cholerae, Vibrio vulnificus
- Yersinia e.g., Yersinia pestis
- infected tissue is infected with one or more protozoa, for example, one or more of Cryptosporidium parvum, Entamoeba (e.g., Entamoeba histolytica), Giardia (e.g., Giardia lambila), Leishmania (e.g., Leishmania donovani), Plasmodium spp. (e.g., Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae),
- Entamoeba e.g., Entamoeba histolytica
- Giardia e.g., Giardia lambila
- Leishmania e.g., Leishmania donovani
- Plasmodium spp. e.g., Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae
- Toxoplasma e.g., Toxoplasma gondii
- Trichomonas e.g., Trichomonas vaginalis
- Trichomonas vaginalis e.g., Trichomonas vaginalis
- infected tissue is infected with one or more fungal pathogens such as Aspergillus, Candida (e.g., Candida albicans), Coccidiodes (e.g., Coccidiodes immitis), Cryptococcus (e.g., Cryptococcus neoformans), Histoplasma (e.g., Histoplasma capsulatum), and Pneumocystis (e.g., Pneumocystis carinii).
- fungal pathogens such as Aspergillus, Candida (e.g., Candida albicans), Coccidiodes (e.g., Coccidiodes immitis), Cryptococcus (e.g., Cryptococcus neoformans), Histoplasma (e.g., Histoplasma capsulatum), and Pneumocystis (e.g., Pneumocystis carinii).
- infected tissue is infected with one or more helminths, such as Ascaris lumbricoides, Ancylostoma, Clonorchis sinensis, Dracuncula medinensis, Enterobius vermicularis, Filaria, Onchocerca volvulus, Loa loa, Schistosoma, Strongyloides, Trichuris trichura, and Trichinella spiralis.
- helminths such as Ascaris lumbricoides, Ancylostoma, Clonorchis sinensis, Dracuncula medinensis, Enterobius vermicularis, Filaria, Onchocerca volvulus, Loa loa, Schistosoma, Strongyloides, Trichuris trichura, and Trichinella spiralis.
- Embodiments may include a computer which executes software that controls the operation of one or more instruments/de vices, and/or that processes data obtained by the system.
- the software may include one or more modules recorded on machine -readable media such as magnetic disks, magnetic tape, CD-ROM, and semiconductor memory, for example.
- the machine-readable medium may be resident within the computer or can be connected to the computer by a communication link (e.g., access via internet link).
- one can substitute computer instructions in the form of hardwired logic for software or one can substitute firmware (i.e., computer instructions recorded on devices such as PROMs, EPROMS, EEPROMs, or the like) for software.
- firmware i.e., computer instructions recorded on devices such as PROMs, EPROMS, EEPROMs, or the like
- machine-readable instructions as used herein is intended to encompass software, hardwired logic, firmware, object code and the like.
- the computer can be, for example, a general purpose computer.
- the computer can be, for example, an embedded computer, a personal computer such as a laptop or desktop computer, or another type of computer, that is capable of running the software, issuing suitable control commands, and/or recording information in real-time.
- the computer may include a display for reporting information to an operator of the system/device (e.g., displaying a view field to a surgeon during an operation), a keyboard and/or other I/O device such as a mouse for enabling the operator to enter information and commands, and/or a printer for providing a printout.
- some commands entered at the keyboard enable a user to perform certain data processing tasks.
- the Raman-based systems, methods, and devices described herein that are utilized in a surgical or non-surgical procedure may be used in combination with other imaging systems implemented before, during, or after the procedure.
- the Raman-based systems, methods, and devices may be used in combination with video, microscope, x-ray, Computed Tomography (CT), magnetic resonance imaging (MRI), ultrasound (US),
- thermography fluorescence imaging, Diffuse Optical Tomography (DOT), Positron Emission Tomography (PET), PET/CT, Single Photon Emission Computed Tomography (SPECT), and/or SPECT/CT systems.
- DOT Diffuse Optical Tomography
- PET Positron Emission Tomography
- PET/CT PET/CT
- SPECT Single Photon Emission Computed Tomography
- a target tissue e.g., diseased tissue
- an auxiliary imaging system includes hardware and/or software for co-registering the image with detected Raman signals.
- a video camera can be used in conjunction with the Raman system described herein, such that the video camera provides an image that serves to identify locations at which the ablation or resection device is inoperative (regardless of the presence of a Raman reporter at such location).
- detection modalities such as MRI, NMR, PET, SPECT, CT, X-ray, ultrasound, photoacoustic detection, and/or fluorescent detection can be used in conjunction with the Raman systems described herein to identify tissue to be resected/ablated.
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