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A real-time clinical endoscopic system for intraluminal, multiplexed imaging of surface-enhanced Raman scattering nanoparticles.

Garai E, Sensarn S, Zavaleta CL, Loewke NO, Rogalla S, Mandella MJ, Felt SA, Friedland S, Liu JT, Gambhir SS, Contag CH - PLoS ONE (2015)

Bottom Line: This device enables rapid circumferential scanning of topologically complex luminal surfaces of hollow organs (e.g., colon and esophagus) and produces quantitative images of the relative concentrations of SERS NPs that are present.Human and swine studies have demonstrated the speed and simplicity of this technique.This approach also offers unparalleled multiplexing capabilities by simultaneously detecting the unique spectral fingerprints of multiple SERS NPs.

View Article: PubMed Central - PubMed

Affiliation: Department of Mechanical Engineering, Stanford University, Stanford, California, United States of America; Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California, United States of America.

ABSTRACT
The detection of biomarker-targeting surface-enhanced Raman scattering (SERS) nanoparticles (NPs) in the human gastrointestinal tract has the potential to improve early cancer detection; however, a clinically relevant device with rapid Raman-imaging capability has not been described. Here we report the design and in vivo demonstration of a miniature, non-contact, opto-electro-mechanical Raman device as an accessory to clinical endoscopes that can provide multiplexed molecular data via a panel of SERS NPs. This device enables rapid circumferential scanning of topologically complex luminal surfaces of hollow organs (e.g., colon and esophagus) and produces quantitative images of the relative concentrations of SERS NPs that are present. Human and swine studies have demonstrated the speed and simplicity of this technique. This approach also offers unparalleled multiplexing capabilities by simultaneously detecting the unique spectral fingerprints of multiple SERS NPs. Therefore, this new screening strategy has the potential to improve diagnosis and to guide therapy by enabling sensitive quantitative molecular detection of small and otherwise hard-to-detect lesions in the context of white-light endoscopy.

No MeSH data available.


Related in: MedlinePlus

Schematic of Raman-imaging system being used in parallel with white-light endoscopy.(a) The device is designed such that it can be inserted through the accessory channel of a clinical endoscope. As the endoscope is being retracted in the GI tract, the device simultaneously scans the lumen. The collected Raman-scattered light is analyzed, and an image is displayed to the user (also see S1 Video). (b) Expanded schematic of the distal end of the device. The schematic illustrates the position of the device relative to the end of the endoscope. A brushless DC motor that rotates a mirror causing the collimated beam to sweep 360 degrees, enabling luminal imaging of the colon wall. The device is not required to be in contact with the tissue, which is enabled through the use of the collimated illumination beam. A custom, miniature, concentrically segmented, air-spaced doublet lens having a non-reciprocal optical path consists of a plano-convex lens and an adjacent plano-concave lens with a central hole. The doublet lens increases collection efficiency at longer, clinically relevant working distances.
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pone.0123185.g001: Schematic of Raman-imaging system being used in parallel with white-light endoscopy.(a) The device is designed such that it can be inserted through the accessory channel of a clinical endoscope. As the endoscope is being retracted in the GI tract, the device simultaneously scans the lumen. The collected Raman-scattered light is analyzed, and an image is displayed to the user (also see S1 Video). (b) Expanded schematic of the distal end of the device. The schematic illustrates the position of the device relative to the end of the endoscope. A brushless DC motor that rotates a mirror causing the collimated beam to sweep 360 degrees, enabling luminal imaging of the colon wall. The device is not required to be in contact with the tissue, which is enabled through the use of the collimated illumination beam. A custom, miniature, concentrically segmented, air-spaced doublet lens having a non-reciprocal optical path consists of a plano-convex lens and an adjacent plano-concave lens with a central hole. The doublet lens increases collection efficiency at longer, clinically relevant working distances.

Mentions: We have created a small, flexible, fiber-optic-based Raman imaging device, designed for human use, that utilizes circumferential scanning to comprehensively image the lumen of a hollow organ (Figs 1 and 2). By utilizing this device in phantoms of hollow organs and in swine, we demonstrate simultaneous imaging of a panel of SERS NPs in clinically relevant models. Circumferential scanning during retraction of the endoscope by the endoscopist (Fig 1a) and S1 Video) allows mapping of the signal from SERS NPs located on a luminal surface. In order to achieve comprehensive imaging of a hollow organ during endoscopy, a rotating mirror is located between the collimating lens and the tissue and is angled at 50 degrees to provide a radial projection of the collimated beam (Fig 1b). As the scan mirror rotates about its axis, the 1-mm diameter collimated illumination beam sweeps around the device, resulting in a complete 360-degree circumferential scan of the tissue. The scan mirror is actuated with a small (2mm outer diameter) brushless DC motor (P/N: 0206B, Faulhauber) to provide rotational scanning at one revolution per second (Fig 2a–2b) and S1 Video). To compensate for astigmatism on the collimated beam caused by cylindrical lensing due to the window, we use a scan mirror with a compensating toroidal surface profile (see S1 File). In addition, the 50-degree angle of the mirror face redirects back reflections from the glass window away from the signal collection path, which significantly reduces noise in the system by more than 90 dB (please see S1 File for more details). A 785 nm continuous wave (CW) laser diode (iBeam Smart; Toptica Photonics) is used for illumination and is coupled into the single-mode fiber (5 μm mode-field-diameter) located at the center of the fiber bundle. This wavelength was chosen for illumination in order to minimize absorption and scattering from the tissue surrounding tissue. A plano-convex lens (4-mm outer diameter, 4.63-mm focal length) collimates the illumination beam after it passes through a central hole in the adjacent plano-concave lens (Fig 1b). As the laser beam sweeps around the circumference of the organ lumen, the collected signal passes through the window and is redirected by the scan mirror along the optical return path. The return path utilizes both the plano-convex and plano-concave lenses (4-mm outer diameter, 2.2-mm radius of curvature, 1-mm-diameteter central hole), which together form an optical system having a longer effective focal length for signal collection than in the illuminating direction. This results in an improvement in collection efficiency by more than 200% as compared to a single lens system (see S1 File). 36 separate multi-mode fibers (200 μm core diameter, 20 μm cladding) surround the single-mode fiber within the fiber bundle and guide the Raman scatter light from the distal end to the spectrometer at the proximal end. Further details of the proximal end of the system can be found in S1 File. The unique Raman spectra of the SERS nanoparticles used can be seen in Fig 3. Acquired spectra by the system are unmixed using a hybrid algorithm combining least squares and principal component analysis [9]. The algorithm produces weighting factors quantifying the relative amounts of each SERS NP flavor present in the sample, as well as quantifies and corrects for systematic background signal generated within the endoscope and subtle fluctuations in the acquired spectrum associated with outside noise sources.


A real-time clinical endoscopic system for intraluminal, multiplexed imaging of surface-enhanced Raman scattering nanoparticles.

Garai E, Sensarn S, Zavaleta CL, Loewke NO, Rogalla S, Mandella MJ, Felt SA, Friedland S, Liu JT, Gambhir SS, Contag CH - PLoS ONE (2015)

Schematic of Raman-imaging system being used in parallel with white-light endoscopy.(a) The device is designed such that it can be inserted through the accessory channel of a clinical endoscope. As the endoscope is being retracted in the GI tract, the device simultaneously scans the lumen. The collected Raman-scattered light is analyzed, and an image is displayed to the user (also see S1 Video). (b) Expanded schematic of the distal end of the device. The schematic illustrates the position of the device relative to the end of the endoscope. A brushless DC motor that rotates a mirror causing the collimated beam to sweep 360 degrees, enabling luminal imaging of the colon wall. The device is not required to be in contact with the tissue, which is enabled through the use of the collimated illumination beam. A custom, miniature, concentrically segmented, air-spaced doublet lens having a non-reciprocal optical path consists of a plano-convex lens and an adjacent plano-concave lens with a central hole. The doublet lens increases collection efficiency at longer, clinically relevant working distances.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4414592&req=5

pone.0123185.g001: Schematic of Raman-imaging system being used in parallel with white-light endoscopy.(a) The device is designed such that it can be inserted through the accessory channel of a clinical endoscope. As the endoscope is being retracted in the GI tract, the device simultaneously scans the lumen. The collected Raman-scattered light is analyzed, and an image is displayed to the user (also see S1 Video). (b) Expanded schematic of the distal end of the device. The schematic illustrates the position of the device relative to the end of the endoscope. A brushless DC motor that rotates a mirror causing the collimated beam to sweep 360 degrees, enabling luminal imaging of the colon wall. The device is not required to be in contact with the tissue, which is enabled through the use of the collimated illumination beam. A custom, miniature, concentrically segmented, air-spaced doublet lens having a non-reciprocal optical path consists of a plano-convex lens and an adjacent plano-concave lens with a central hole. The doublet lens increases collection efficiency at longer, clinically relevant working distances.
Mentions: We have created a small, flexible, fiber-optic-based Raman imaging device, designed for human use, that utilizes circumferential scanning to comprehensively image the lumen of a hollow organ (Figs 1 and 2). By utilizing this device in phantoms of hollow organs and in swine, we demonstrate simultaneous imaging of a panel of SERS NPs in clinically relevant models. Circumferential scanning during retraction of the endoscope by the endoscopist (Fig 1a) and S1 Video) allows mapping of the signal from SERS NPs located on a luminal surface. In order to achieve comprehensive imaging of a hollow organ during endoscopy, a rotating mirror is located between the collimating lens and the tissue and is angled at 50 degrees to provide a radial projection of the collimated beam (Fig 1b). As the scan mirror rotates about its axis, the 1-mm diameter collimated illumination beam sweeps around the device, resulting in a complete 360-degree circumferential scan of the tissue. The scan mirror is actuated with a small (2mm outer diameter) brushless DC motor (P/N: 0206B, Faulhauber) to provide rotational scanning at one revolution per second (Fig 2a–2b) and S1 Video). To compensate for astigmatism on the collimated beam caused by cylindrical lensing due to the window, we use a scan mirror with a compensating toroidal surface profile (see S1 File). In addition, the 50-degree angle of the mirror face redirects back reflections from the glass window away from the signal collection path, which significantly reduces noise in the system by more than 90 dB (please see S1 File for more details). A 785 nm continuous wave (CW) laser diode (iBeam Smart; Toptica Photonics) is used for illumination and is coupled into the single-mode fiber (5 μm mode-field-diameter) located at the center of the fiber bundle. This wavelength was chosen for illumination in order to minimize absorption and scattering from the tissue surrounding tissue. A plano-convex lens (4-mm outer diameter, 4.63-mm focal length) collimates the illumination beam after it passes through a central hole in the adjacent plano-concave lens (Fig 1b). As the laser beam sweeps around the circumference of the organ lumen, the collected signal passes through the window and is redirected by the scan mirror along the optical return path. The return path utilizes both the plano-convex and plano-concave lenses (4-mm outer diameter, 2.2-mm radius of curvature, 1-mm-diameteter central hole), which together form an optical system having a longer effective focal length for signal collection than in the illuminating direction. This results in an improvement in collection efficiency by more than 200% as compared to a single lens system (see S1 File). 36 separate multi-mode fibers (200 μm core diameter, 20 μm cladding) surround the single-mode fiber within the fiber bundle and guide the Raman scatter light from the distal end to the spectrometer at the proximal end. Further details of the proximal end of the system can be found in S1 File. The unique Raman spectra of the SERS nanoparticles used can be seen in Fig 3. Acquired spectra by the system are unmixed using a hybrid algorithm combining least squares and principal component analysis [9]. The algorithm produces weighting factors quantifying the relative amounts of each SERS NP flavor present in the sample, as well as quantifies and corrects for systematic background signal generated within the endoscope and subtle fluctuations in the acquired spectrum associated with outside noise sources.

Bottom Line: This device enables rapid circumferential scanning of topologically complex luminal surfaces of hollow organs (e.g., colon and esophagus) and produces quantitative images of the relative concentrations of SERS NPs that are present.Human and swine studies have demonstrated the speed and simplicity of this technique.This approach also offers unparalleled multiplexing capabilities by simultaneously detecting the unique spectral fingerprints of multiple SERS NPs.

View Article: PubMed Central - PubMed

Affiliation: Department of Mechanical Engineering, Stanford University, Stanford, California, United States of America; Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California, United States of America.

ABSTRACT
The detection of biomarker-targeting surface-enhanced Raman scattering (SERS) nanoparticles (NPs) in the human gastrointestinal tract has the potential to improve early cancer detection; however, a clinically relevant device with rapid Raman-imaging capability has not been described. Here we report the design and in vivo demonstration of a miniature, non-contact, opto-electro-mechanical Raman device as an accessory to clinical endoscopes that can provide multiplexed molecular data via a panel of SERS NPs. This device enables rapid circumferential scanning of topologically complex luminal surfaces of hollow organs (e.g., colon and esophagus) and produces quantitative images of the relative concentrations of SERS NPs that are present. Human and swine studies have demonstrated the speed and simplicity of this technique. This approach also offers unparalleled multiplexing capabilities by simultaneously detecting the unique spectral fingerprints of multiple SERS NPs. Therefore, this new screening strategy has the potential to improve diagnosis and to guide therapy by enabling sensitive quantitative molecular detection of small and otherwise hard-to-detect lesions in the context of white-light endoscopy.

No MeSH data available.


Related in: MedlinePlus