WO1993003672A1 - Optical histochemical analysis, in vivo detection and real-time guidance for ablation of abnormal tissues using a raman spectroscopic detection system - Google Patents
Optical histochemical analysis, in vivo detection and real-time guidance for ablation of abnormal tissues using a raman spectroscopic detection system Download PDFInfo
- Publication number
- WO1993003672A1 WO1993003672A1 PCT/US1992/007040 US9207040W WO9303672A1 WO 1993003672 A1 WO1993003672 A1 WO 1993003672A1 US 9207040 W US9207040 W US 9207040W WO 9303672 A1 WO9303672 A1 WO 9303672A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- raman
- abnormal
- tissue
- energy
- laser
- Prior art date
Links
- 238000001069 Raman spectroscopy Methods 0.000 title claims abstract description 94
- 230000002159 abnormal effect Effects 0.000 title claims abstract description 87
- 238000001727 in vivo Methods 0.000 title claims description 18
- 238000002679 ablation Methods 0.000 title claims description 8
- 230000003287 optical effect Effects 0.000 title abstract description 28
- 238000001514 detection method Methods 0.000 title description 13
- 238000004458 analytical method Methods 0.000 title description 8
- 230000001744 histochemical effect Effects 0.000 title description 3
- 239000013307 optical fiber Substances 0.000 claims abstract description 58
- 238000000034 method Methods 0.000 claims abstract description 52
- 230000001613 neoplastic effect Effects 0.000 claims abstract description 9
- 208000015924 Lithiasis Diseases 0.000 claims abstract description 5
- 210000001519 tissue Anatomy 0.000 claims description 114
- 238000001237 Raman spectrum Methods 0.000 claims description 46
- 239000000835 fiber Substances 0.000 claims description 34
- 230000005284 excitation Effects 0.000 claims description 30
- 208000037260 Atherosclerotic Plaque Diseases 0.000 claims description 15
- 238000001228 spectrum Methods 0.000 claims description 14
- 210000001124 body fluid Anatomy 0.000 claims description 12
- 239000010839 body fluid Substances 0.000 claims description 12
- 210000000481 breast Anatomy 0.000 claims description 12
- 208000026310 Breast neoplasm Diseases 0.000 claims description 10
- 206010006187 Breast cancer Diseases 0.000 claims description 9
- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 claims description 7
- 210000001367 artery Anatomy 0.000 claims description 7
- 230000003143 atherosclerotic effect Effects 0.000 claims description 7
- 235000013734 beta-carotene Nutrition 0.000 claims description 7
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 claims description 7
- 239000011648 beta-carotene Substances 0.000 claims description 7
- 229960002747 betacarotene Drugs 0.000 claims description 7
- 238000012545 processing Methods 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 239000011159 matrix material Substances 0.000 claims description 6
- 206010053648 Vascular occlusion Diseases 0.000 claims description 5
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 5
- 208000021331 vascular occlusion disease Diseases 0.000 claims description 5
- 206010001233 Adenoma benign Diseases 0.000 claims description 4
- 206010006253 Breast fibrosis Diseases 0.000 claims description 4
- 208000007659 Fibroadenoma Diseases 0.000 claims description 4
- 230000003213 activating effect Effects 0.000 claims description 4
- 201000003149 breast fibroadenoma Diseases 0.000 claims description 4
- 235000012000 cholesterol Nutrition 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 210000003734 kidney Anatomy 0.000 claims description 4
- 206010029148 Nephrolithiasis Diseases 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 210000001072 colon Anatomy 0.000 claims description 3
- 201000010897 colon adenocarcinoma Diseases 0.000 claims description 3
- 210000004185 liver Anatomy 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 201000001883 cholelithiasis Diseases 0.000 claims description 2
- 206010020718 hyperplasia Diseases 0.000 claims description 2
- 230000002390 hyperplastic effect Effects 0.000 claims description 2
- 244000005700 microbiome Species 0.000 claims 4
- 208000014018 liver neoplasm Diseases 0.000 claims 2
- 206010006220 Breast cyst Diseases 0.000 claims 1
- 206010007027 Calculus urinary Diseases 0.000 claims 1
- 206010061045 Colon neoplasm Diseases 0.000 claims 1
- 206010019695 Hepatic neoplasm Diseases 0.000 claims 1
- 208000008839 Kidney Neoplasms Diseases 0.000 claims 1
- 206010060862 Prostate cancer Diseases 0.000 claims 1
- 230000001580 bacterial effect Effects 0.000 claims 1
- 125000001409 beta-carotene group Chemical group 0.000 claims 1
- 201000011024 colonic benign neoplasm Diseases 0.000 claims 1
- 230000005670 electromagnetic radiation Effects 0.000 claims 1
- 201000007270 liver cancer Diseases 0.000 claims 1
- 210000004072 lung Anatomy 0.000 claims 1
- 208000020816 lung neoplasm Diseases 0.000 claims 1
- 230000002093 peripheral effect Effects 0.000 claims 1
- 208000023958 prostate neoplasm Diseases 0.000 claims 1
- 208000008281 urolithiasis Diseases 0.000 claims 1
- 230000003612 virological effect Effects 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 39
- 206010028980 Neoplasm Diseases 0.000 abstract description 16
- 230000005855 radiation Effects 0.000 abstract description 16
- 238000003745 diagnosis Methods 0.000 abstract description 11
- 230000002792 vascular Effects 0.000 abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 3
- 238000011065 in-situ storage Methods 0.000 abstract 1
- 238000003909 pattern recognition Methods 0.000 abstract 1
- 239000000523 sample Substances 0.000 description 13
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 8
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 230000003902 lesion Effects 0.000 description 6
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 6
- 206010006272 Breast mass Diseases 0.000 description 5
- 238000001574 biopsy Methods 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 230000001575 pathological effect Effects 0.000 description 5
- 230000003595 spectral effect Effects 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 230000036210 malignancy Effects 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- 108010014258 Elastin Proteins 0.000 description 3
- 102000016942 Elastin Human genes 0.000 description 3
- 201000007295 breast benign neoplasm Diseases 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 229920002549 elastin Polymers 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- HVYWMOMLDIMFJA-UHFFFAOYSA-N 3-cholesterol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 HVYWMOMLDIMFJA-UHFFFAOYSA-N 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 201000008275 breast carcinoma Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004590 computer program Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 238000002430 laser surgery Methods 0.000 description 2
- 238000002647 laser therapy Methods 0.000 description 2
- 238000013532 laser treatment Methods 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 238000009607 mammography Methods 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 201000010174 renal carcinoma Diseases 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 230000002485 urinary effect Effects 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 229910052691 Erbium Inorganic materials 0.000 description 1
- 208000000913 Kidney Calculi Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 238000001530 Raman microscopy Methods 0.000 description 1
- 208000000014 Ureteral Calculi Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 208000021328 arterial occlusion Diseases 0.000 description 1
- 238000013528 artificial neural network Methods 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 208000030270 breast disease Diseases 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 238000005253 cladding Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000001427 coherent effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000013171 endarterectomy Methods 0.000 description 1
- 238000011846 endoscopic investigation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- UYAHIZSMUZPPFV-UHFFFAOYSA-N erbium Chemical compound [Er] UYAHIZSMUZPPFV-UHFFFAOYSA-N 0.000 description 1
- 238000007387 excisional biopsy Methods 0.000 description 1
- 239000000834 fixative Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 238000002697 interventional radiology Methods 0.000 description 1
- 238000000608 laser ablation Methods 0.000 description 1
- 238000013147 laser angioplasty Methods 0.000 description 1
- 238000001499 laser induced fluorescence spectroscopy Methods 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 210000003741 urothelium Anatomy 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
- A61B5/0082—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes
- A61B5/0084—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes for introduction into the body, e.g. by catheters
-
- 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
- A61B18/22—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 the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor
- A61B18/24—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 the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor with a catheter
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
- A61B5/0075—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
- A61B5/0082—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes
- A61B5/0091—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes for mammography
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/43—Detecting, measuring or recording for evaluating the reproductive systems
- A61B5/4306—Detecting, measuring or recording for evaluating the reproductive systems for evaluating the female reproductive systems, e.g. gynaecological evaluations
- A61B5/4312—Breast evaluation or disorder diagnosis
-
- 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
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
- A61B5/0082—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes
- A61B5/0084—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes for introduction into the body, e.g. by catheters
- A61B5/0086—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes for introduction into the body, e.g. by catheters using infrared radiation
Definitions
- optical fibers or fiberoptics as known colloquially, are finding use in a wide variety of medical applications including remote sensing and laser surgery.
- An optical fiber is a clad core of plastic or glass fiber in which the cladding has a lower index of refraction than the core of the fiber and as a result of its manufacture is capable of transmitting light in a tortuous path as defined by placement of the optical fiber.
- the term "laser” is an acronym for Light Amplification by Stimulated Emission of Radiation. As used herein, the term “laser” is meant to encompass a device which utilizes the principle of amplification of electromagnetic waves by stimulated emission of radiation to produce coherent radiation of ultraviolet (UV), vi sibl e or infrared (IR) wavelengths.
- UV ultraviolet
- IR infrared
- Cardiovascular disease is the leading cause of death in the United States and most other industrialized nations.
- Percutaneous transluminal angioplasty a technique based on balloon dilatation, has gained acceptance as a revascularization modality due to its less invasive nature and substantial cost savings compared with arterial bypass graft surgery.
- This invention provides the surprising discovery that Raman spectroscopy, despite the presence of a blood field and the necessity to detect and ablate in real time, can be utilized clinically for the detection of abnormal tissue and ablation through body fluid for the guidance of laser surgery in vivo. Further, this invention
- the Raman spectrum of atherosclerotic plaque differs from normal arterial tissue and that this technique permits rapid diagnosis of tissues even when working through a blood field.
- the invention also provides that numerous neoplastic tissues (e.g. breast cancer, benign and malignant renal and hepatic tumors) or other abnormal conditions have unique Raman spectra which permits their rapid differentiation from their corresponding normal states.
- the invention provides adapting this method to Raman microscopy, in vivo and in vitro monitoring, through the use of an optical fiber probe.
- Raman spectroscopy allows the accurate detection of abnormal tissues both microscopically and in vivo with fingerprinting accuracy in real time. This invention therefore solves the problems of tissue ambiguity associated with the laser-induced fluorescence techniques.
- the invention provides a much needed means to utilize laser technology to detect and guide treatment of many disorders which heretofore were not subject to effective treatments.
- the invention provides a method of diagnosing abnormal tissue in real time through a body fluid, including an intervening medium, in a subject comprising determining the Raman spectrum from the tissue in vivo or in vitro and comparing the Raman spectrum to that of normal tissue, the presence of an abnormal spectrum indicating the presence of abnormal tissue.
- an apparatus for identifying and ablating abnormal tissue in real time through a body fluid including an intervening medium, in vivo, compromising: a sufficiently powered ablating laser, a monochromatic excitation laser, one or more fiber optic means to transmit the monochromatic energy, to collect Raman scattered energy and to transmit the energy from the ablating laser, a catheter means to house the fiber optic means, a Raman spectrometer to calibrate the collected Raman scattered energy, and a processing and activating means for analyzing the differences in Raman scattered energy to distinguish normal from abnormal tissue and activating the ablating laser, wherein the apparatus can detect and ablate the abnormal tissue in real time.
- the invention further provides an apparatus for identifying abnormal tissue in real time through a body fluid, including an intervening medium, in vivo or in vitro compromising: a monochromatic excitation laser, one or more fiber optic means to transmit the monochromatic energy and to collect Raman scattered energy, a catheter means to house the fiber optic means, a Raman spectrometer to
- FIG. 1 is a block diagram of a laser system embodying this invention.
- FIG. 2 is a schematic longitudinal section of the flexible optical fiber catheter and coupling elements.
- FIG. 3 is a schematic cross-sectional view of the flexible optical fiber catheter having optical fiber elements for collection of the Raman scattered signal arranged circumferentially about the distal end of the flexible conduit.
- FIG. 4 is a schematic showing cross-sectional and longitudinal views of a flexible optical fiber catheter incorporating an inflatable means in the distal end of the catheter which accomplishes varying the diameter from minimum to maximum.
- FIG. 5 is a schematic illustration of the operative use of a flexible optical fiber catheter wherein an inflatable means on the distal end of the catheter permits varying the diameter from minimum to maximum thereby allowing complete treatment of an obstructing lesion.
- FIG. 6 is a schematic cross-sectional and longitudinal section of a flexible optical fiber catheter incorporating multiple fibers arranged circumferentially around an excitation fiber distal ly with a linear arrangement proximally.
- FIG. 7 is a schematic of a dispersive Raman spectrometer system.
- FIG. 8 is a diagram of a Raman spectrometer having input from a multiple optical fiber catheter with a rectangular array
- FIG. 9 is a schematic illustration of the operative use of a flexible optical fiber probe for interrogating a mammographically detectable breast nodule.
- FIG. 10 is a diagram of absorbance versus wavelength for whole blood.
- FIG. 11 is a figure of the resonance Raman spectrum of atherosclerotic plaque obtained from atherectomy and endarterectomy
- FIG. 12 shows the Raman spectra of fatty atherosclerotic plaque and normal arterial intimal surface.
- FIG. 13 is a diagram of the Raman signal intensity versus distance for samples of plasma, saline and hemodi luted blood.
- FIG. 14 shows the Raman signal intensity of atherosclerotic plaque as a function of sample acquisition time.
- FIG. 15 shows the Raman spectra of breast fibrosis and a benign breast tumor (fibroadenoma).
- FIG. 16 shows the Raman spectra of normal liver
- FIG. 17 shows the Raman spectra of normal colon and colon adenocarcinoma.
- FIG. 18 shows the Raman spectra of normal kidney and renal cell carcinoma.
- FIG. 19 shows the Raman spectra of three specimens of breast carcinoma. DETAILED DESCRIPTION OF THE INVENTION
- the invention provides for an improved method and apparatus for diagnosing abnormal tissue in real time either within a subject through intervening tissues via the percutaneous placement of an optical fiber needle, within a body cavity though a body fluid via use of an optical fiber catheter, or of biopsy tissue specimens or of culture specimens studied microscopically in-vitro using Raman a spectroscopic microscope. Diagnosis is achieved in a subject comprising determining the Raman spectrum for the tissue in vivo or in vitro and comparing the Raman spectrum to that of normal tissues, compounds or organisms, the presence of an abnormal spectrum
- the invention provides a means to detect specific attributes of the tissue at the treatment site such that laser energy may be delivered to the treatment site for destroying abnormal tissues; as long as an abnormal condition is sensed, laser energy is delivered in pulsed fashion.
- the invention provides for the recognition of this change such that laser treatment is terminated, leaving the adjacent normal tissues undamaged.
- Scattered optical radiation from the illuminated target area will be collected by the light transfer conduit and delivered to a means for photoelectronically sensing the inelastically scattered component of this optical radiation.
- Attributes of the treatment area will be detected and, by comparison with known standards, are judged normal or abnormal through use of a computer based algorithm.
- pulses of laser energy will be delivered to the treatment area by the same flexible light transfer conduit when tissue at the treatment site has been deemed abnormal.
- the abnormal condition may be selectively destroyed by repeated delivery of laser pulses of suitable wavelength and energy.
- a means of enhancing the differences between healthy and abnormal tissues may be provided by introducing a suitable reagent, e.g. beta carotene or other Raman biochemical probe, into the body which will accumulate within the abnormal tissues, e.g., atherosclerotic plaque or neoplasm, and permit differentiation between normal and abnormal areas.
- a suitable reagent e.g. beta carotene or other Raman biochemical probe
- the treatment laser energy may then be delivered selectively to the abnormal sites based upon this augmented difference between healthy and abnormal tissues.
- a method of detecting and destroying abnormal tissues including atherosclerotic plaque or occluding thrombus within a vascular channel or lithiasis with a urinary collecting system or biliary tree or a hyperplastic or neoplastic condition within a body medium or cavity which is accessible by endoscopic or percutaneous means A flexible catheter system including optical fiber conduits for delivering excitation optical energy and collecting scattered optical energy can be introduced into the body cavity by appropriate means.
- Vascular occlusive diseases can be approached by percutaneous entry into the artery or vein.
- Nephrolithiasis can be approached by ureteroscopic or percutaneous access to the urinary collecting system.
- Bladder tumors can be accessed by cystoscopic means.
- lithiasis or tumors can be approached via endoscopic or percutaneous means
- breast or prostate neoplasms can be approached by radiographic or ultrasonographic directed means
- tumors of GI or pulmonary origin can be approached by endoscopic techniques, all of which permit use of optical fiber catheters, including needles and probes.
- an optical fiber catheter can be introduced and maneuvered until the distal end thereof is operatively positioned opposite the site of abnormal tissues.
- Monochromatic optical radiation from an excitation laser source can be delivered into the proximal end of the optical fiber catheter which can illuminate the treatment tissues opposite the distal end of the optical fiber catheter allowing an optical characteristic of the tissue at the treatment site to be detected.
- the inelastically scattered photons can be analyzed via techniques of Raman spectroscopy which can permit identifying normal and abnormal conditions by analysis of their characteristic Raman spectra.
- the invention permits the means by which laser pulses from a treatment laser can be periodically input to the proximal end of the optical fiber catheter and delivered to the treatment site opposite the distal end of the optical fiber catheter. The process of sensing optical properties from the treatment site and delivery of treatment pulses is alternated rapidly until the abnormal optical characteristics from the treatment site are no longer detected.
- one or more laser systems capable of generating wavelengths suitable for the induction of Raman scattering and for the treatment of an abnormal condition is delivered via a flexible catheter containing one or more optical fibers arranged in a manner suitable for efficiently sensing the target area.
- a diagnostic laser source generates excitation energy for inducing Raman scattering and is connected to the proximal end of at least one optical fiber, which is positioned in any efficient manner, such as a central or multiple circumferentially arranged optical fibers.
- optical fibers collecting the scattered radiation from the target site may be circumferentially arranged around the excitation fiber or fibers.
- a treatment laser source is coupled into the proximal end of the optical fiber catheter with this treatment energy delivered via either the same optical fibers used for collection of scattered energy or via closely adjacent optical fibers.
- the proximal end of the collecting optical fiber or fibers which deliver scattered optical radiation from the target site is coupled in an efficient manner into a dispersive type Raman spectrometer system.
- holographic notch (interference) filter blocks Rayleigh scattered light and a diffraction grating or other dispersive optical element within the Raman spectrometer separates the inelastically scattered photons by wavelength which are then photoelectronically transduced by a radiation detector means which converts the optical energy into electronic signals suitable for computer processing.
- a computerized algorithm incorporating neural network or other techniques of expert system implementation permits analysis of the Raman spectrum of the tissue at the treatment site to rapidly distinguish normal from abnormal conditions.
- the optical characteristics from multiple sectors or areas of the target site may be simultaneously detected, processed and analyzed such that, for example, the entire circumference of a vessel can be analyzed simultaneously with each discrete optical fiber conveying information about a unique sector or segment of the vessel or region under study.
- Another implementation of this invention is a modification to the optical fiber catheter which provides an
- Yet another implementation of the invention is a simplified system utilized strictly for diagnosis, and is embodied by a single excitation source, a single optical fiber catheter which may be utilized as a percutaneous optical fiber needle or probe in conjunction with a Raman spectrometer for remote optical histochemical tissue sampling and analysis. Such a system utilizes the same principles of detecting abnormal characteristics from the treatment site but does not provide for a means of treating the abnormal condition once detected.
- the invention provides an apparatus for identifying abnormal tissue in real time through a body fluid, including an intervening body medium, in a subject comprising determining the Raman spectrum for the tissue in vivo or of a culture specimen or biopsy specimen in vitro and comparing the Raman spectrum to that of known normal tissue, the presence of an abnormal spectrum indicating the presence of abnormal tissue.
- an apparatus for identifying abnormal tissue in real time through a body fluid including an intervening medium, in vivo comprising: a monochromatic excitation laser, one or more fiber optic means to transmit the monochromatic energy and to collect Raman scattered energy, a catheter means to house the fiber optic means, a Raman spectrometer to calibrate the collected Raman scattered energy, and a processing means for analyzing differences in Raman energy to distinguish normal from abnormal tissue.
- a laser catheter 10 is inserted into the vascular tree 12 to the site of an obstructing lesion 14 using techniques known in the field of vascular interventional radiology.
- This laser catheter 10 houses within in it one or more optical fibers 16 that may be coupled at their proximal ends 18 to a source of laser energy (either diagnostic 20 and/or treatment 22) as well as to a dispersive Raman spectrometer 24.
- the distal end 26 of the laser catheter 10 is positioned opposite an area of occlusive narrowing or obstructing lesion 14.
- a computer system 28 controls the operation of the Raman spectrometer system 24 and lasers 20 and 22 and provide both a means of viewing the measured spectra on a monitor 30 as well as a means of providing feedback through use of a keyboard 32, mouse 34 or other well-known display means (not shown).
- a diagnostic laser 20 serves as the source of monochromatic excitation energy; such sources may include UV, visible, NIR or IR wavelengths as appropriate for the clinical situation and
- a monochromator or filter (not shown) that will provide essentially monochromatic excitation energy may be incorporated into the diagnostic laser system.
- a single laser system may be used for both diagnostic and treatment source.
- Such a system could be represented by an erbium:YAG laser operating in the long pulse mode with a frequency multiplier for the diagnosis mode and operating in the Q switched mode with direct output for tissue ablation in the treatment mode.
- the present invention includes at least one central optical fiber 16a coupled to a plug-in optical coupler 36 which permits efficient transmission of excitation energy into the central optical fiber 16a transforming the laser beam into a smaller diameter, but still collimated beam.
- a single optic fiber 16 is utilized for both sample excitation and scattered radiation collection via signals 38 and 40 respectively.
- the optical coupler 36 also incorporates a beam splitter assembly 42 for the efficient bi-directional transmission of light energy for simultaneous excitation and collection of Raman scattered photons.
- a plug-in optical fiber connector 36 may be utilized to simplify the optical fiber alignment procedure and make the laser catheter 10 easily attached or detached from the Raman diagnostic system 24 and treatment laser(s) 20 and 22.
- FIG. 3 illustrates one preferred catheter configuration wherein a circumferential array of optical fibers 16b are arranged around a central excitation fiber 16a for collection of the Raman scattered energy.
- a central lumen permits guidewire delivery and placement of a central optical fiber 16a delivering excitation energy.
- a further modification allows for a a combination
- the catheter 10 is initially positioned to the site of vascular occlusion 14 with the balloon deflated, e.g. using over-the-guidewire guidance.
- the circumference of the vessel 14 is interrogated and treated using Raman guided laser ablation.
- the balloon catheter 10 is slowly advanced and inflated as shown in FIGS. 5b-5d and the vessel further treated until the vessel which includes the obstructing lesion 14 is restored to its initial, undiseased diameter.
- FIGS. 6a and 6b illustrate a composite Raman fiberoptic catheter 10 which incorporates plurality signal collection fibers 16b circumferentially distributed around an excitation fiber 16a and can be used to permit the entire
- the signal collection fibers 16b are circumferentially arranged at the distal working end 26 of the optical fiber catheter 10. At the proximal end 18 of the catheter 10, this circumferential arrangement is mapped into a linear arrangement for input into the Raman
- the linear arrangement permits the Raman spectrometer system 24 to resolve the target in angular sections, thus permitting an eccentric plaque to be selectively targeted and treated.
- the Raman diagnostic catheter need not be limited to twelve signal collection fibers as diagrammed. A fewer or greater number could be incorporated as demanded by the dimensions of the target tissue. Furthermore, a single row or multiple circumferential rows may be provided to adequately cover the desired target area. To have a significant clinical impact, the laser diagnostic system must operate nearly in "real-time" meaning that the tissue under study must be evaluated several times each second, e.g. less than once every 200 milliseconds, preferably less than 150
- scattered optical energy 40 is the delivered and focused into the input of the Raman spectrometer 24.
- col limating optics 50 assure maximal coupling of the scattered photons 40 into the spectrometer apparatus 24.
- a line-rejection filter 52 such as a Rayleigh-line rejection filter, a band-rejection filter or Bragg diffraction grating may be utilized to enhance the performance of the Raman spectrometer system 24 by increasing the rejection of Rayleigh scattered photons 40.
- Adjustable slits 54 also permit the Raman spectrometer 24 to strongly reject the excitation laser wavelength while simultaneously allowing the Stokes or anti-Stokes scattered Raman photons 40 to pass through without attenuation to the principle diffraction grating 46. Because the resolution of the spectrometer 24 is a function of diffraction order, wavelength, grating size and separation between adjacent grooves of the grating, gratings of increasing number of lines/cm may be utilized for increased resolution or ability to separate closely adjacent wavelengths.
- a linear or rectangular array detector 48 which has elements and optical coatings to optimize its conversion efficiency at the excitation wavelength converts the scattered photons 40 into an electronic signal suited for computer processing and signal analysis. As illustrated in FIGS. 8a and 8b, an OMA (optical multichannel analyzer), CCD (charge coupled device) or photodiode array detector may function as the photoelectronic
- a system may be arranged to individually but simultaneously transduce this information.
- a linear arrangement of signal collection fibers 16b may be focused upon the principle diffraction grating 46 by using cylindrical collimating optics.
- the Raman scattered signals 40 are independently dispersed and projected onto a rectangular matrix array detector 48 for photoelectronic conversion.
- the rectangular matrix array detector 48 is composed of rows and columns of discrete elements. Each individual row of the matrix can be electronically addressed and interrogated to obtain the Raman spectrum from a discrete sector within the vessel lumen. This signal may be processed and classified as either "normal” or "abnormal” using a computerized algorithm.
- the circumference of the vessel is divided into a number of sectors equal to the number of circumferential fibers 16b in the fiberoptic catheter 10. As increased resolution is needed, the number of circumferential fibers 16b is increased accordingly.
- Each individual column of the matrix can be electronically addressed and interrogated and represents a Raman scattered photon of specific energy or wavenumber. Because only specific regions of the Raman spectrum contain information relating to the molecular structure of the target tissue, only discrete sections of the Raman spectrum need be analyzed. Thus, the speed with which the Raman diagnostic device operates can be optimized to permit its operation in real-time.
- the invention will now be described utilizing the illustrative example of spectroscopic interrogation of a mammographically detected breast nodule as diagrammed in FIG. 9. Once a breast nodule has been detected mammographically or
- puncture of the breast can be performed using the sharpened tip of a biopsy needle 56 or an optical fiber needle (not shown), which is then advanced to the site of the
- the laser catheter 10 or optical fiber needle may then be inserted into the breast 60 to abut the site of a mammographically or ultrasonographically detected lesion 60a.
- This laser fiberoptic catheter 10 houses within in it one or more optical fibers 16 that may be coupled at their proximal ends 18 to a source of diagnostic 20 or therapeutic laser energy 22 as well as to a dispersive Raman
- a computer system 28 controls the operation of the Raman spectrometer system 24 and laser(s) 20 and 22 and provides both a means of viewing the measured spectra on a monitor 30 as well as a means of providing feedback through use of a keyboard 32, mouse 34 or other well-known display means (not shown).
- a diagnostic laser 20 serves as the source of monochromatic excitation energy; such sources may include UV, visible, near-IR or IR wavelengths as appropriate for the clinical situation and
- liposarcoma and a variety of other pathological conditions include peaks associated with specific molecular constituents which differ between the normal and diseased conditions. These peaks are shown in the figures. In general, about ten wave numbers and especially four to six wave numbers on either side of the peak define the peak for purposes of defining the pathological condition. For example calcification, beta carotene and cholesterol are typically identified in atherosclerotic arteries, while normal vessel is characterized by the presence of collagen and elastin. Thus, for any pathological condition, a physician-operator skilled in the field may develop an appropriate computerized algorithm to distinguish a normal condition from an abnormal condition.
- a rapid computer algorithm will permit the acquired Raman signals to be analyzed and compared to an archived database of normal and abnormal tissues. For tissue diagnosis, a broad or narrow spectral region of the Raman scattered signal may be interpreted as appropriate for the tissue under study.
- the computer system will provide graphical and numeric information to the operator-physician who will then determine when the optical fiber probe is suitably positioned for accurate detection and effective laser therapy of the tissue under study.
- This Raman spectroscopic diagnostic system may also be limited to signal detection and tissue diagnosis without an associated treatment laser option. To permit identification of tissues, it must be possible to recognize specific signatures or fingerprints from tissues and to classify or categorize these as "normal” or "abnormal".
- This process is enabled by archiving a database of "normal” and “abnormal” tissues and storing the salient portions of these spectra in a database against which the computer system may then compare an unknown.
- this database may be updated permitting use of this Raman spectroscopic guidance system in a periodically updated role.
- tissues may be characterized spectrophotometrically using a Raman spectrometer through the analysis of inelastically scattered photons with certain unique details of the spectra allowing sample recognition.
- Raman spectroscopy is useful for in vivo recognition of atherosclerotic plaque and may serve as a practical guidance modality adaptable to controlling laser treatment of tissues.
- Fatty and fibrous atherosclerotic plaque may be easily distinguished from normal arterial tissue (FIGS. 11,12).
- Atherosclerotic plaque is also detectable through saline, plasma or hemodi luted blood (FIG. 13), making this modality effective for in vivo guidance.
- These abnormal conditions can be detected in a brief interval of time, less than 200msec, especially less than 150 msec and preferably less than 40 msec, which is rapid enough to permit real-time feedback control of a treatment laser for laser angioplasty (FIG. 14).
- FIGS. 11 and 12 Specimens of normal artery (intimal surface) and fatty atherosclerotic plaque are illustrated in FIGS. 11 and 12 while specimens of breast fibrosis, benign breast tumor (fibroadenoma) breast carcinoma, normal liver, hepatocellular carcinoma, normal colon, colon adenocarcinoma, normal kidney and renal cell carcinoma are illustrated in FIGS. 15-19.
- the spectra of each tissue being recorded utilizing a real-time Raman spectrometer as described above.
- the computer program will search for the characteristic spectral peaks associated with specific molecular components known to exist in atherosclerotic plaque, or other normal and malignant conditions as illustrated.
- the computer program determines that in the examined range of Raman scattered wavelengths, that normal intima has only identifiable Raman spectral peaks associated with collagen and elastin and thus meets the definition of being a normal, nonobstructed vessel.
- the sample of atherosclerotic plaque when illuminated at visible wavelengths shows prominent spectral peaks centered at approximately 1002, 1154 and 1516 wavenumbers and when NIR excitation is utilized a prominent spectral feature is noted at approximately 1440 wavenumbers.
- the Raman spectrum can be utilized as a feedback means for guiding laser angiosurgery.
- Raman spectroscopic detection shows peaks principally at 1004, 1078, 1157, 1268, 1300, 1444, 1519, and 1652 wavenumbers in normal breast tissue. With reference to TABLE I, it is determined that these represent the peaks of beta carotene and lipids which define the normal state. By contrast a new peak centered at approximately 1356 wavenumbers is identified with variable intensity of the lipid and beta carotene peaks. Again, with reference to TABLE I, the presence of a peak centered between 1318-1406 wavenumbers suggests the presence of a porphyrin-type compound and by definition is diseased.
- Tissues already characterized include arterial tissues, both normal and atherosclerotic, as well as normal urothelium including bladder, ureter and renal collecting systems, exophytic bladder tumor, renal/ureteral calculi, cholelithiasis, breast, kidney, liver tissues and silicone. Additional tissues are easily studied and characterized by the techniques described above. Future applications of these techniques will include thrombus (both acute and organized), biliary tumors, bronchogenic tumors, head and neck tumors, breast cancer, GI malignancies, skin malignancies as well as other tumors in addition to bacteria or other infectious agents. TABLE I is a partial list of the salient features of certain tissues which will permit use of Raman spectroscopic detection and guidance in a clinical device.
Abstract
A method and apparatus for diagnosis and treatment of abnormal tissues (14) is described in which a catheter (10) with one or more optical fibers (16) is either introduced into a body cavity (12) or through an intervening body medium with the distal end positioned opposite the treatment area (14) and wherein the proximal end (18) of the catheter (10) and optical fibers (16) are coupled to a source of optical radiation (20) as well as to a method for photoelectronically sensing a particular optical characteristic of the tissue within the treatment area. Specifically, the diagnostic system and guidance is based upon sensing inelastically scattered Raman radiation in a manner which permits rapid tissue diagnosis through a computerized process of pattern recognition. Tissues which may be diagnosed encompass both normal as well as abnormal conditions including vascular occlusive diseases, in situ tumors or neoplastic conditions, lithiasis and calculi or any other abnormal tissue.
Description
OPTICAL HISTOCHEMICAL ANALYSIS, IN VIVO
DETECTION AND REAL-TIME GUIDANCE FOR ABLATION OF ABNORMAL TISSUES
USING A RAMAN SPECTROSCOPIC DETECTION SYSTEM BACKGROUND OF THE INVENTION
Optical fibers, or fiberoptics as known colloquially, are finding use in a wide variety of medical applications including remote sensing and laser surgery. An optical fiber is a clad core of plastic or glass fiber in which the cladding has a lower index of refraction than the core of the fiber and as a result of its manufacture is capable of transmitting light in a tortuous path as defined by placement of the optical fiber. The term "laser" is an acronym for Light Amplification by Stimulated Emission of Radiation. As used herein, the term "laser" is meant to encompass a device which utilizes the principle of amplification of electromagnetic waves by stimulated emission of radiation to produce coherent radiation of ultraviolet (UV), vi sibl e or infrared (IR) wavelengths. Cancer is a major cause of death in the United States and other developed nations, alone will be responsible for approximately 20% of all female cancer deaths in 1992. Diagnosis and treatment of cancer consumes billions of health care dollars annually. Efforts at early detection and treatment of malignancy (e.g., screening mammography) have the goal of reducing mortality by detecting cancer at an earlier, more treatable stage. A consequence of screening techniques, such as mammography, is the dilemma created by the detection of indeterminate findings (e.g. small breast nodules which cannot be classified further mammographically) which requires tissue sampling for histopathological identification utilizing a surgical biopsy. Procedures like fine needle aspiration biopsy (FNAB) may increase the rate of malignancy detection in non-palpable masses at surgical excision to above 15-30%; but the problem of inadequate or non-representative sampling
(approximately 20%) still leaves large numbers of persons at risk of undetected disease. Improvements in the sampling accuracy of FNAB are therefore necessary to avoid false negative diagnoses and to reduce the need for excisional biopsy for benign pathological processes.
Cardiovascular disease is the leading cause of death in the United States and most other industrialized nations. Percutaneous transluminal angioplasty, a technique based on balloon dilatation, has gained acceptance as a revascularization modality due to its less invasive nature and substantial cost savings compared with arterial bypass graft surgery.
This invention provides the surprising discovery that Raman spectroscopy, despite the presence of a blood field and the necessity to detect and ablate in real time, can be utilized clinically for the detection of abnormal tissue and ablation through body fluid for the guidance of laser surgery in vivo. Further, this invention
demonstrates that the Raman spectrum of atherosclerotic plaque differs from normal arterial tissue and that this technique permits rapid diagnosis of tissues even when working through a blood field. The invention also provides that numerous neoplastic tissues (e.g. breast cancer, benign and malignant renal and hepatic tumors) or other abnormal conditions have unique Raman spectra which permits their rapid differentiation from their corresponding normal states. The invention provides adapting this method to Raman microscopy, in vivo and in vitro monitoring, through the use of an optical fiber probe. Thus, the use of Raman spectroscopy allows the accurate detection of abnormal tissues both microscopically and in vivo with fingerprinting accuracy in real time. This invention therefore solves the problems of tissue ambiguity associated with the laser-induced fluorescence techniques. Through these improvements, the invention provides a much needed means to utilize laser technology to detect and guide treatment of many disorders which heretofore were not subject to effective treatments.
SUMMARY OF THE INVENTION
The invention provides a method of diagnosing abnormal tissue in real time through a body fluid, including an intervening medium, in a subject comprising determining the Raman spectrum from the tissue in vivo or in vitro and comparing the Raman spectrum to that of normal tissue, the presence of an abnormal spectrum indicating the presence of abnormal tissue. Also provided is an apparatus for identifying and ablating abnormal tissue in real time through a body fluid, including an intervening medium, in vivo, compromising: a sufficiently powered ablating laser, a monochromatic excitation laser, one or more fiber optic means to transmit the monochromatic energy, to collect Raman scattered energy and to transmit the energy from the ablating laser, a catheter means to house the fiber optic means, a Raman spectrometer to calibrate the collected Raman scattered energy, and a processing and activating means for analyzing the differences in Raman scattered energy to distinguish normal from abnormal tissue and activating the ablating laser, wherein the apparatus can detect and ablate the abnormal tissue in real time.
The invention further provides an apparatus for identifying abnormal tissue in real time through a body fluid, including an intervening medium, in vivo or in vitro compromising: a monochromatic excitation laser, one or more fiber optic means to transmit the monochromatic energy and to collect Raman scattered energy, a catheter means to house the fiber optic means, a Raman spectrometer to
calibrate the collected Raman scattered energy, and a processing means for analyzing the differences in Raman scattered energy to distinguish normal from abnormal tissue.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a block diagram of a laser system embodying this invention.
FIG. 2 is a schematic longitudinal section of the flexible optical fiber catheter and coupling elements.
FIG. 3 is a schematic cross-sectional view of the flexible optical fiber catheter having optical fiber elements for collection of the Raman scattered signal arranged circumferentially about the distal end of the flexible conduit.
FIG. 4 is a schematic showing cross-sectional and longitudinal views of a flexible optical fiber catheter incorporating an inflatable means in the distal end of the catheter which accomplishes varying the diameter from minimum to maximum.
FIG. 5 is a schematic illustration of the operative use of a flexible optical fiber catheter wherein an inflatable means on the distal end of the catheter permits varying the diameter from minimum to maximum thereby allowing complete treatment of an obstructing lesion. FIG. 6 is a schematic cross-sectional and longitudinal section of a flexible optical fiber catheter incorporating multiple fibers arranged circumferentially around an excitation fiber distal ly with a linear arrangement proximally. FIG. 7 is a schematic of a dispersive Raman spectrometer system.
FIG. 8 is a diagram of a Raman spectrometer having input from a multiple optical fiber catheter with a rectangular array
photoelectronic detector.
FIG. 9 is a schematic illustration of the operative use of a flexible optical fiber probe for interrogating a mammographically detectable breast nodule. FIG. 10 is a diagram of absorbance versus wavelength for whole blood.
FIG. 11 is a figure of the resonance Raman spectrum of atherosclerotic plaque obtained from atherectomy and endarterectomy
FIG. 12 shows the Raman spectra of fatty atherosclerotic plaque and normal arterial intimal surface.
FIG. 13 is a diagram of the Raman signal intensity versus distance for samples of plasma, saline and hemodi luted blood.
FIG. 14 shows the Raman signal intensity of atherosclerotic plaque as a function of sample acquisition time. FIG. 15 shows the Raman spectra of breast fibrosis and a benign breast tumor (fibroadenoma).
FIG. 16 shows the Raman spectra of normal liver and
hepatocellular carcinoma.
FIG. 17 shows the Raman spectra of normal colon and colon adenocarcinoma.
FIG. 18 shows the Raman spectra of normal kidney and renal cell carcinoma.
FIG. 19 shows the Raman spectra of three specimens of breast carcinoma.
DETAILED DESCRIPTION OF THE INVENTION
The invention provides for an improved method and apparatus for diagnosing abnormal tissue in real time either within a subject through intervening tissues via the percutaneous placement of an optical fiber needle, within a body cavity though a body fluid via use of an optical fiber catheter, or of biopsy tissue specimens or of culture specimens studied microscopically in-vitro using Raman a spectroscopic microscope. Diagnosis is achieved in a subject comprising determining the Raman spectrum for the tissue in vivo or in vitro and comparing the Raman spectrum to that of normal tissues, compounds or organisms, the presence of an abnormal spectrum
indicating the presence of abnormal tissue. More specifically, the invention provides a means to detect specific attributes of the tissue at the treatment site such that laser energy may be delivered to the treatment site for destroying abnormal tissues; as long as an abnormal condition is sensed, laser energy is delivered in pulsed fashion.
When the abnormal condition has been totally destroyed, the invention provides for the recognition of this change such that laser treatment is terminated, leaving the adjacent normal tissues undamaged.
In accordance with this invention, there is provided a method of delivering monochromatic optical radiation to an area within a body to undergo treatment or diagnosis by the introduction of a flexible catheter system through an intervening body medium or into a body cavity until the distal end of the transfer conduit abuts the targeted area. Scattered optical radiation from the illuminated target area will be collected by the light transfer conduit and delivered to a means for photoelectronically sensing the inelastically scattered component of this optical radiation. Attributes of the treatment area will be detected and, by comparison with known standards, are judged normal or abnormal through use of a computer based algorithm. When laser therapy is indicated, pulses of laser energy will be delivered to the treatment area by the same flexible light transfer conduit when tissue at the treatment site has been deemed abnormal. By positioning the distal end of the light transfer conduit in abutment to the
treatment area, the abnormal condition may be selectively destroyed by repeated delivery of laser pulses of suitable wavelength and energy.
According to features of this invention, if the tissues at the treatment area display no abnormal intrinsic attributes, a means of enhancing the differences between healthy and abnormal tissues may be provided by introducing a suitable reagent, e.g. beta carotene or other Raman biochemical probe, into the body which will accumulate within the abnormal tissues, e.g., atherosclerotic plaque or neoplasm, and permit differentiation between normal and abnormal areas. Once the diseased tissues display an abnormal optical characteristic, the treatment laser energy may then be delivered selectively to the abnormal sites based upon this augmented difference between healthy and abnormal tissues.
In accordance with specific features of this invention, there is contemplated a method of detecting and destroying abnormal tissues including atherosclerotic plaque or occluding thrombus within a vascular channel or lithiasis with a urinary collecting system or biliary tree or a hyperplastic or neoplastic condition within a body medium or cavity which is accessible by endoscopic or percutaneous means. A flexible catheter system including optical fiber conduits for delivering excitation optical energy and collecting scattered optical energy can be introduced into the body cavity by appropriate means. Vascular occlusive diseases can be approached by percutaneous entry into the artery or vein. Nephrolithiasis can be approached by ureteroscopic or percutaneous access to the urinary collecting system. Bladder tumors can be accessed by cystoscopic means. Biliary
lithiasis or tumors can be approached via endoscopic or percutaneous means, breast or prostate neoplasms can be approached by radiographic or ultrasonographic directed means and tumors of GI or pulmonary origin can be approached by endoscopic techniques, all of which permit use of optical fiber catheters, including needles and probes. Once access has been established within the appropriate body cavity or medium, an optical fiber catheter can be introduced and maneuvered until the distal end thereof is operatively positioned opposite the site of abnormal tissues. Monochromatic optical radiation from an
excitation laser source can be delivered into the proximal end of the optical fiber catheter which can illuminate the treatment tissues opposite the distal end of the optical fiber catheter allowing an optical characteristic of the tissue at the treatment site to be detected. Specifically, the inelastically scattered photons can be analyzed via techniques of Raman spectroscopy which can permit identifying normal and abnormal conditions by analysis of their characteristic Raman spectra. When an abnormal condition is detected the invention permits the means by which laser pulses from a treatment laser can be periodically input to the proximal end of the optical fiber catheter and delivered to the treatment site opposite the distal end of the optical fiber catheter. The process of sensing optical properties from the treatment site and delivery of treatment pulses is alternated rapidly until the abnormal optical characteristics from the treatment site are no longer detected.
To implement the method of this invention, one or more laser systems capable of generating wavelengths suitable for the induction of Raman scattering and for the treatment of an abnormal condition is delivered via a flexible catheter containing one or more optical fibers arranged in a manner suitable for efficiently sensing the target area. A diagnostic laser source generates excitation energy for inducing Raman scattering and is connected to the proximal end of at least one optical fiber, which is positioned in any efficient manner, such as a central or multiple circumferentially arranged optical fibers. However, in a preferred embodiment of the present invention, optical fibers collecting the scattered radiation from the target site may be circumferentially arranged around the excitation fiber or fibers. A treatment laser source is coupled into the proximal end of the optical fiber catheter with this treatment energy delivered via either the same optical fibers used for collection of scattered energy or via closely adjacent optical fibers. The proximal end of the collecting optical fiber or fibers which deliver scattered optical radiation from the target site is coupled in an efficient manner into a dispersive type Raman spectrometer system. A
holographic notch (interference) filter blocks Rayleigh scattered light and a diffraction grating or other dispersive optical element
within the Raman spectrometer separates the inelastically scattered photons by wavelength which are then photoelectronically transduced by a radiation detector means which converts the optical energy into electronic signals suitable for computer processing. A computerized algorithm incorporating neural network or other techniques of expert system implementation permits analysis of the Raman spectrum of the tissue at the treatment site to rapidly distinguish normal from abnormal conditions. By arranging the circumferentially distributed optical fibers which detect the scattered optical radiation from the target site in a linear configuration at the input to the Raman spectrometer and by using cylindrical focusing optics and a rectangular matrix radiation detector, the optical characteristics from multiple sectors or areas of the target site may be simultaneously detected, processed and analyzed such that, for example, the entire circumference of a vessel can be analyzed simultaneously with each discrete optical fiber conveying information about a unique sector or segment of the vessel or region under study. Another implementation of this invention is a modification to the optical fiber catheter which provides an
inflatable means in the distal end of the catheter whereby the diameter of the distal end of the optical fiber catheter may be varied from minimum to maximum diameter thereby permitting its use in various sized bodily channels. This modification also provides a means to treat vascular occlusions in conjunction with or in the absence of a treatment laser. Yet another implementation of the invention is a simplified system utilized strictly for diagnosis, and is embodied by a single excitation source, a single optical fiber catheter which may be utilized as a percutaneous optical fiber needle or probe in conjunction with a Raman spectrometer for remote optical histochemical tissue sampling and analysis. Such a system utilizes the same principles of detecting abnormal characteristics from the treatment site but does not provide for a means of treating the abnormal condition once detected.
To accomplish these means, the invention provides an apparatus for identifying abnormal tissue in real time through a body fluid,
including an intervening body medium, in a subject comprising determining the Raman spectrum for the tissue in vivo or of a culture specimen or biopsy specimen in vitro and comparing the Raman spectrum to that of known normal tissue, the presence of an abnormal spectrum indicating the presence of abnormal tissue. Also provided is an apparatus for identifying abnormal tissue in real time through a body fluid, including an intervening medium, in vivo comprising: a monochromatic excitation laser, one or more fiber optic means to transmit the monochromatic energy and to collect Raman scattered energy, a catheter means to house the fiber optic means, a Raman spectrometer to calibrate the collected Raman scattered energy, and a processing means for analyzing differences in Raman energy to distinguish normal from abnormal tissue. EXAMPLES
The invention will now be described utilizing the examples of destruction of a vascular occlusive narrowing as diagrammed in FIG. 1, and of percutaneous diagnosis of a breast mass, FIG. 9, which examples are intended as illustrative only since numerous
modifications and variations therein will be apparent to those skilled in the art. In FIG. 1, once vascular access has been established, a laser catheter 10 is inserted into the vascular tree 12 to the site of an obstructing lesion 14 using techniques known in the field of vascular interventional radiology. This laser catheter 10 houses within in it one or more optical fibers 16 that may be coupled at their proximal ends 18 to a source of laser energy (either diagnostic 20 and/or treatment 22) as well as to a dispersive Raman spectrometer 24. The distal end 26 of the laser catheter 10 is positioned opposite an area of occlusive narrowing or obstructing lesion 14. A computer system 28 controls the operation of the Raman spectrometer system 24 and lasers 20 and 22 and provide both a means of viewing the measured spectra on a monitor 30 as well as a means of providing feedback through use of a keyboard 32, mouse 34 or other well-known display means (not shown).
A diagnostic laser 20 serves as the source of monochromatic excitation energy; such sources may include UV, visible, NIR or IR wavelengths as appropriate for the clinical situation and
characteristics of the tissue or obstructing lesion under study. An appropriate monochromator or filter (not shown) that will provide essentially monochromatic excitation energy may be incorporated into the diagnostic laser system. In accordance with the invention, a single laser system may be used for both diagnostic and treatment source. Such a system could be represented by an erbium:YAG laser operating in the long pulse mode with a frequency multiplier for the diagnosis mode and operating in the Q switched mode with direct output for tissue ablation in the treatment mode.
As shown in FIG. 2a, the present invention includes at least one central optical fiber 16a coupled to a plug-in optical coupler 36 which permits efficient transmission of excitation energy into the central optical fiber 16a transforming the laser beam into a smaller diameter, but still collimated beam. In its simplest embodiment (FIG. 2b), a single optic fiber 16 is utilized for both sample excitation and scattered radiation collection via signals 38 and 40 respectively. In this arrangement, the optical coupler 36 also incorporates a beam splitter assembly 42 for the efficient bi-directional transmission of light energy for simultaneous excitation and collection of Raman scattered photons. A plug-in optical fiber connector 36 (FIG. 2a) may be utilized to simplify the optical fiber alignment procedure and make the laser catheter 10 easily attached or detached from the Raman diagnostic system 24 and treatment laser(s) 20 and 22.
Because atherosclerotic plaque is distributed around the vessel lumen in either concentric or eccentric fashion and because a near-contact geometry will be essential for efficient collection of Raman scattered signals, it is preferred that the fiberoptic catheter system closely match the diameter of the vessel lumen within which it is operating. To facilitate this demand, FIG. 3 illustrates one preferred catheter configuration wherein a circumferential array of optical fibers 16b are arranged around a central excitation fiber 16a for collection of the Raman scattered energy. A central lumen permits
guidewire delivery and placement of a central optical fiber 16a delivering excitation energy.
A further modification allows for a a combination
balloon/fiberoptic catheter shown in FIGS. 4a and 4b. In this scheme, as shown in FIG. 5a, the catheter 10 is initially positioned to the site of vascular occlusion 14 with the balloon deflated, e.g. using over-the-guidewire guidance. The circumference of the vessel 14 is interrogated and treated using Raman guided laser ablation. As the plaque 44 is removed from the wall of the artery, the balloon catheter 10 is slowly advanced and inflated as shown in FIGS. 5b-5d and the vessel further treated until the vessel which includes the obstructing lesion 14 is restored to its initial, undiseased diameter.
Alternatively, the combination balloon/fiberoptic catheter for Raman spectrometry can be utilized without the ablating laser with only the balloon effecting treatment. Further, FIGS. 6a and 6b illustrate a composite Raman fiberoptic catheter 10 which incorporates plurality signal collection fibers 16b circumferentially distributed around an excitation fiber 16a and can be used to permit the entire
circumference of a vessel to be interrogated by the Raman diagnostic and treatment system. In this system as depicted in FIG. 6a, the signal collection fibers 16b are circumferentially arranged at the distal working end 26 of the optical fiber catheter 10. At the proximal end 18 of the catheter 10, this circumferential arrangement is mapped into a linear arrangement for input into the Raman
spectrometer system 24. The linear arrangement permits the Raman spectrometer system 24 to resolve the target in angular sections, thus permitting an eccentric plaque to be selectively targeted and treated. The Raman diagnostic catheter need not be limited to twelve signal collection fibers as diagrammed. A fewer or greater number could be incorporated as demanded by the dimensions of the target tissue. Furthermore, a single row or multiple circumferential rows may be provided to adequately cover the desired target area. To have a significant clinical impact, the laser diagnostic system must operate nearly in "real-time" meaning that the tissue under study must be evaluated several times each second, e.g. less
than once every 200 milliseconds, preferably less than 150
milliseconds, and most preferably less than 40 milliseconds, such that the treatment laser may be activated with equal frequency during the laser angiosurgery procedure. Such a demand requires use of a dispersive Raman spectrometer system such as that shown in FIG. 7 which is able to resolve signals of closely adjacent wavelength by using a diffraction grating 46 or other dispersive optical element. The resulting Raman spectrum is spread linearly over a finite distance and when projected upon a photoelectronic array detector 48, the optical spectrum may be converted into electronic signals suitable for computer analysis.
In such a dispersive Raman spectrometer system, as shown in FIG. 7, scattered optical energy 40 is the delivered and focused into the input of the Raman spectrometer 24. At the input to the Raman spectrometer 24, col limating optics 50 assure maximal coupling of the scattered photons 40 into the spectrometer apparatus 24. In this embodiment, a line-rejection filter 52 such as a Rayleigh-line rejection filter, a band-rejection filter or Bragg diffraction grating may be utilized to enhance the performance of the Raman spectrometer system 24 by increasing the rejection of Rayleigh scattered photons 40. Adjustable slits 54 also permit the Raman spectrometer 24 to strongly reject the excitation laser wavelength while simultaneously allowing the Stokes or anti-Stokes scattered Raman photons 40 to pass through without attenuation to the principle diffraction grating 46. Because the resolution of the spectrometer 24 is a function of diffraction order, wavelength, grating size and separation between adjacent grooves of the grating, gratings of increasing number of lines/cm may be utilized for increased resolution or ability to separate closely adjacent wavelengths. A linear or rectangular array detector 48 which has elements and optical coatings to optimize its conversion efficiency at the excitation wavelength converts the scattered photons 40 into an electronic signal suited for computer processing and signal analysis. As illustrated in FIGS. 8a and 8b, an OMA (optical multichannel analyzer), CCD (charge coupled device) or photodiode array detector may function as the photoelectronic
detector.
When multiple optical fibers 16b input scattered optical radiation from unique areas of the targeted tissues 14, a system may be arranged to individually but simultaneously transduce this information. At the input to the Raman spectrometer 24 such a linear arrangement of signal collection fibers 16b may be focused upon the principle diffraction grating 46 by using cylindrical collimating optics. The Raman scattered signals 40 are independently dispersed and projected onto a rectangular matrix array detector 48 for photoelectronic conversion. The rectangular matrix array detector 48 is composed of rows and columns of discrete elements. Each individual row of the matrix can be electronically addressed and interrogated to obtain the Raman spectrum from a discrete sector within the vessel lumen. This signal may be processed and classified as either "normal" or "abnormal" using a computerized algorithm. In such fashion, the circumference of the vessel is divided into a number of sectors equal to the number of circumferential fibers 16b in the fiberoptic catheter 10. As increased resolution is needed, the number of circumferential fibers 16b is increased accordingly. Each individual column of the matrix can be electronically addressed and interrogated and represents a Raman scattered photon of specific energy or wavenumber. Because only specific regions of the Raman spectrum contain information relating to the molecular structure of the target tissue, only discrete sections of the Raman spectrum need be analyzed. Thus, the speed with which the Raman diagnostic device operates can be optimized to permit its operation in real-time.
As an alternative example, the invention will now be described utilizing the illustrative example of spectroscopic interrogation of a mammographically detected breast nodule as diagrammed in FIG. 9. Once a breast nodule has been detected mammographically or
ultrasonographically, puncture of the breast can be performed using the sharpened tip of a biopsy needle 56 or an optical fiber needle (not shown), which is then advanced to the site of the
mammographically or ultrasonographically detectable nodule using techniques that are well known in the field of interventional
radiology. The laser catheter 10 or optical fiber needle may then be inserted into the breast 60 to abut the site of a mammographically or
ultrasonographically detected lesion 60a. This laser fiberoptic catheter 10 houses within in it one or more optical fibers 16 that may be coupled at their proximal ends 18 to a source of diagnostic 20 or therapeutic laser energy 22 as well as to a dispersive Raman
spectrometer 24. The distal end 26 of the laser catheter 10 is positioned opposite an abnormal area of breast tissue 62 as determined mammographically for breast. A computer system 28 controls the operation of the Raman spectrometer system 24 and laser(s) 20 and 22 and provides both a means of viewing the measured spectra on a monitor 30 as well as a means of providing feedback through use of a keyboard 32, mouse 34 or other well-known display means (not shown).
A diagnostic laser 20 serves as the source of monochromatic excitation energy; such sources may include UV, visible, near-IR or IR wavelengths as appropriate for the clinical situation and
characteristics of the tissue under study.
When developing such a computerized algorithm for Raman spectroscopic tissue identification, a physician-operator must have access to a number of pathological specimens of both normal and abnormal conditions. In the current.examples of treating
atherosclerotic arterial obstruction and breast cancers, it will suffice to have numerous specimens of normal and atherosclerotic artery, normal breast, benign and malignant breast tumors as well as other pathological conditions (e.g. silicone breast implant leakage). By acquiring and storing in computer 28 memory the Raman spectra associated with each condition, it will be discovered that there are specific locations of the Raman peaks which are characteristic, and thus diagnostic, of the related normal and diseased states. Specific Raman peaks (TABLE I) that are identified in abnormal atherosclerotic artery, normal breast tissue, a variety of breast cancers,
liposarcoma, and a variety of other pathological conditions include peaks associated with specific molecular constituents which differ between the normal and diseased conditions. These peaks are shown in the figures. In general, about ten wave numbers and especially four to six wave numbers on either side of the peak define the peak for purposes of defining the pathological condition. For example
calcification, beta carotene and cholesterol are typically identified in atherosclerotic arteries, while normal vessel is characterized by the presence of collagen and elastin. Thus, for any pathological condition, a physician-operator skilled in the field may develop an appropriate computerized algorithm to distinguish a normal condition from an abnormal condition.
Limitations exist for Raman spectrometer systems because the Raman effect is a weak one when compared to the energy of Rayleigh scattering and fluorescence. Competitive fluorescence is favored when using visible light energies for sample excitation. The efficiency and intensity of Raman scattering is favored as the excitation wavelength is shifted into the longer wavelength region. Because excitation of endogenous fluorophores in the samples is minimized, the Raman signals from the structural molecules of the sample are maximized such that the compositional makeup and major chemical constituents of tissues, e.g. water content, protein, elastin collagen, organic (e.g. lip.ids) and inorganic constituents (e.g.
calcium hydroxyapatite) are discernible. A second virtue of operating at wavelengths in the NIR is the fact that the absorbance of blood is near minimum at these wavelengths (>700nm) as shown in FIG. 10.
A rapid computer algorithm will permit the acquired Raman signals to be analyzed and compared to an archived database of normal and abnormal tissues. For tissue diagnosis, a broad or narrow spectral region of the Raman scattered signal may be interpreted as appropriate for the tissue under study. The computer system will provide graphical and numeric information to the operator-physician who will then determine when the optical fiber probe is suitably positioned for accurate detection and effective laser therapy of the tissue under study. This Raman spectroscopic diagnostic system may also be limited to signal detection and tissue diagnosis without an associated treatment laser option. To permit identification of tissues, it must be possible to recognize specific signatures or fingerprints from tissues and to classify or categorize these as "normal" or "abnormal". This process
is enabled by archiving a database of "normal" and "abnormal" tissues and storing the salient portions of these spectra in a database against which the computer system may then compare an unknown. As future tissues are characterized, this database may be updated permitting use of this Raman spectroscopic guidance system in a periodically updated role. As future specific clinical applications arise, tissues may be characterized spectrophotometrically using a Raman spectrometer through the analysis of inelastically scattered photons with certain unique details of the spectra allowing sample recognition.
Raman spectroscopy is useful for in vivo recognition of atherosclerotic plaque and may serve as a practical guidance modality adaptable to controlling laser treatment of tissues. Fatty and fibrous atherosclerotic plaque may be easily distinguished from normal arterial tissue (FIGS. 11,12). Atherosclerotic plaque is also detectable through saline, plasma or hemodi luted blood (FIG. 13), making this modality effective for in vivo guidance. These abnormal conditions can be detected in a brief interval of time, less than 200msec, especially less than 150 msec and preferably less than 40 msec, which is rapid enough to permit real-time feedback control of a treatment laser for laser angioplasty (FIG. 14).
The Raman characteristics for various tissues have been determined (TABLE I and in FIGS. 11-19) such that this technique may be applied to specific clinical applications. Briefly, fresh and formalin fixed specimens were obtained and stored until use. Fresh specimens were stored chilled in physiologic saline and studied in the non-preserved state either in air, saline or immersed in body fluid. Formalin fixed tissues were also studied under similar experimental conditions. The Raman spectra of tissues were collected, analyzed and tabulated as follows. The results with in vivo tissues will be identical to those of fresh, nonpreserved specimens because they have been studied in the fresh, non-preserved state. There has been no alteration in the molecular structure in these tissues as would be accompanied by tissue fixation when stored in formalin or other fixative. Because Raman spectroscopy is sensitive to the molecular
composition of samples and because the molecular structures of these tissues is not altered upon harvesting and because these samples are studied shortly after collection, no change in the character or quality of these specimens is encountered from that which is found in the in vivo condition. Changes following formalin fixation have also been quantitated and are predictable in such fashion that results from fixed tissues may be extrapolated to the reults from in vivo tissues.
By using the example of atherosclerotic occlusive vascular disease and breast cancer, use of Raman spectroscopy for sample identification and laser guidance will be illustrated. Specimens of normal artery (intimal surface) and fatty atherosclerotic plaque are illustrated in FIGS. 11 and 12 while specimens of breast fibrosis, benign breast tumor (fibroadenoma) breast carcinoma, normal liver, hepatocellular carcinoma, normal colon, colon adenocarcinoma, normal kidney and renal cell carcinoma are illustrated in FIGS. 15-19. The spectra of each tissue being recorded utilizing a real-time Raman spectrometer as described above. The computer program will search for the characteristic spectral peaks associated with specific molecular components known to exist in atherosclerotic plaque, or other normal and malignant conditions as illustrated. The computer program determines that in the examined range of Raman scattered wavelengths, that normal intima has only identifiable Raman spectral peaks associated with collagen and elastin and thus meets the definition of being a normal, nonobstructed vessel. By contrast, the sample of atherosclerotic plaque when illuminated at visible wavelengths shows prominent spectral peaks centered at approximately 1002, 1154 and 1516 wavenumbers and when NIR excitation is utilized a prominent spectral feature is noted at approximately 1440 wavenumbers. With reference to TABLE I, it is determined that these represent the peaks of beta carotene that are centered between 978-1043, 1126-1187 and 1482-1574 respectively or cholesterol centered between 1386-1500; thus by definition, tissue with this Raman spectrum is diseased due to the presence of beta carotene or cholesterol respectively for the
different conditions of laser excitation. By sequentially examining the Raman spectrum from this tissue and then directing laser pulses
onto the abnormal surface to destroy it, the Raman spectrum can be utilized as a feedback means for guiding laser angiosurgery.
In the example of breast disease (FIGS. 15, 19 and Table I), Raman spectroscopic detection shows peaks principally at 1004, 1078, 1157, 1268, 1300, 1444, 1519, and 1652 wavenumbers in normal breast tissue. With reference to TABLE I, it is determined that these represent the peaks of beta carotene and lipids which define the normal state. By contrast a new peak centered at approximately 1356 wavenumbers is identified with variable intensity of the lipid and beta carotene peaks. Again, with reference to TABLE I, the presence of a peak centered between 1318-1406 wavenumbers suggests the presence of a porphyrin-type compound and by definition is diseased.
Alternatively, with reference to FIG. 15, numerous Raman peaks of low intensity serve to differentiate either breast fibrosis or
fibroadenoma from normal breast tissue.
Tissues already characterized include arterial tissues, both normal and atherosclerotic, as well as normal urothelium including bladder, ureter and renal collecting systems, exophytic bladder tumor, renal/ureteral calculi, cholelithiasis, breast, kidney, liver tissues and silicone. Additional tissues are easily studied and characterized by the techniques described above. Future applications of these techniques will include thrombus (both acute and organized), biliary tumors, bronchogenic tumors, head and neck tumors, breast cancer, GI malignancies, skin malignancies as well as other tumors in addition to bacteria or other infectious agents. TABLE I is a partial list of the salient features of certain tissues which will permit use of Raman spectroscopic detection and guidance in a clinical device.
Claims
1. A method of diagnosing abnormal tissue in real time through a body fluid in a subject comprising determining the Raman spectrum for the tissue in vivo and comparing the Raman spectrum to that of normal tissue, the presence of an abnormal spectrum indicating the presence of abnormal tissue.
2. The method of claim 1, further comprising adding a reagent to the subject which causes the abnormal tissue to possess a predetermined detectable Raman spectrum when excited by a given wavelength of electromagnetic radiation.
3. The method of claim 2, wherein the reagent is beta carotene and the abnormal tissue is atherosclerotic artery.
4. The method of claim 1, further comprising ablating the abnormal tissue in real time with a suitable laser.
5. The method of claim 4, wherein the real time is less than 200 milliseconds.
6. The method of claim 4, wherein the real time is less than about 150 milliseconds.
7. The method of claim 4, wherein the real time is less than about 40 milliseconds.
8. The method of claim 4, wherein energy from the ablation laser is directed through a single optical fiber.
9. The method of claim 4, wherein energy from the ablation laser is directed through a plurality of optical fibers capable of transmitting the energy either alone or in conjunction with selected other fibers.
10. The method of claim 1, wherein the abnormal condition is selected from the group consisting of coronary or peripheral vascular
occlusions, a hyperplastic or neoplastic condition, and lithiasis.
11. The method of claim 10, wherein the lithiasis is selected from the group consisting of cholelithiasis, nephrolithiasis, and
urolithiasis.
12. The method of claim 10, wherein the neoplastic condition is selected from the group consisting of a breast, liver, kidney, colon, lung and prostate neoplasm.
13. The method of claim 1, wherein the comparison between the normal tissue and the test tissue is performed by a computer and the laser is signaled to ablate by a computer command under operator feedback when an abnormal condition is diagnosed.
14. The method of claim 1, wherein the abnormal tissue is an
atherosclerotic plaque and the Raman spectrum contains one or more abnormal peak shown in Figure 12.
15. The method of claim 14, wherein the atherosclerotic plaque contains cholesterol deposits and the Raman spectrum contains a peak centered at about 1004, 1155 or 1515 wavenumbers.
16. The method of claim 1, wherein the abnormal tissue is a breast cancer and the Raman spectrum contains one or more abnormal peaks shown in Figure 19.
17. The method of claim 16, wherein the Raman spectrum contains a peak centered at about 1057, 1093, 1130, 1274, 1358, 1362, 1392, or 1620 wave numbers.
18. The method of claim 1, wherein the abnormal tissue is
fibroadenoma and the Raman spectrum contains one or more abnormal peaks shown in Figure 15.
19. The method of claim 18, wherein the Raman spectrum contains a peak centered at about 1067, 1239, 1381, 1578, 1598 or 1629 wave numbers.
20. The method of claim 1, wherein the abnormal tissue is colon adenocarcinoma and the Raman spectrum contains one or more abnormal peaks shown in Figure 17.
21. The method of claim 20, wherein the Raman spectrum contains a peak centered at 1194, 1441, 1529, 1624 or 1652 wave numbers.
22. The method of claim 1, wherein the abnormal tissue is liver cancer and the Raman spectrum contains one or more abnormal peaks shown in Figure 16.
23. The method of claim 22, wherein the Raman spectrum contains a peak centered at 1115 or 1474 wavenumbers.
24. The method of claim 1, wherein the abnormal tissue is breast fibrosis or cyst and the Raman spectrum contains abnormal peaks shown in Figure 15.
25. A method of diagnosing a neoplastic condition in a tissue comprising detemrining the Raman spectrum for the tissue and comparing the Raman spectrum to that of a neoplastic condition, the presence of a spectrum of a neoplastic condition indicating the presence of the neoplastic condition.
26. A method of detecting the presence of a viral or bacterial microorganism in a sample from a subject comprising determining the Raman spectrum of the sample and comparing the Raman spectrum to that of the microorganism, the presence of a spectrum of a microorganism indicating the presence of the microorganism.
27. A method of detecting the presence of a compound of interest in a sample from a subject comprising determining the Raman spectrum of the sample and comparing the spectrum to that of the compound of interest, the presence of the spectrum of the compound of interest indicating the presence of the compound.
28. An apparatus for identifying and ablating abnormal tissue in real time through a body fluid in vivo, comprising: an ablating laser, a monochromatic excitation laser for generating monochromatic energy for Raman scattering, one or more fiber optic means to transmit the monochromatic energy to identify the presence of abnormal tissue, to collect the Raman scattered energy and to transmit the energy from the ablating laser through the body fluid to treat the abnormal tissue identified, a catheter means to house the fiber optic means, a Raman spectrometer to calibrate the collected Raman scattered energy, and a processing and activating means for analyzing differences in Raman scattered energy to distinguish normal from abnormal tissue and controllably activating the ablating laser to treat the abnormal tissue, wherein the apparatus can detect and ablate the abnormal tissue in real time.
29. The apparatus of claim 28, wherein the fiber optic means
comprises a plurality of circumferential optical fibers to transmit the monochromatic energy and collect Raman scattered energy.
30. The apparatus of claim 29, further comprising a central fiber to transmit the monochromatic energy.
31. The apparatus of claim 29, wherein the plurality of
circumferential optical fibers also can transmit energy from the ablating laser to the abnormal tissue.
32. The apparatus of claim 29, wherein the plurality of optical fibers selectively transmit ablating energy either alone or in conjunction with the remaining fibers.
33. The apparatus of claim 29, wherein the plurality of
circumferential optical fibers are configured as a linear array at their proximal end connectable to the Raman spectrometer.
34. The apparatus of claim 33, wherein the linear array of detecting fibers is focused into the Raman spectrometer utilizing cylindrical optics.
35. The apparatus of claim 28, further comprising a detector for the Raman spectrometer which is comprised of a horizontally and vertically arranged rectangular matrix of detecting elements to permit individual optical fibers to be analyzed simultaneously with the resultant Raman spectrum representing a sector of the test tissue.
36. The apparatus of claim 28, wherein the excitation laser and the ablation laser utilize a different fiber optic means to convey energy.
37. The apparatus of claim 28, wherein the real time is less than 200 milliseconds.
38. The apparatus of claim 28, wherein the real time is less than about 150 milliseconds.
39. The apparatus of claim 28, wherein the real time is less than about 40 milliseconds.
40. The apparatus of claim 28, wherein the ablating laser and the excitation laser are the same laser and frequency multipliers are used to generate excitation and ablation energies of different wavelength.
41. The apparatus of claim 28, further comprising an expandable means in the distal end of the catheter means such that the diameter of the distal end of the catheter means may be varied from minimum to maximum diameter thereby permitting its use in various size lumens or to treat a vascular occlusion.
42. An apparatus for identifying abnormal tissue in real time through body fluid in vivo comprising: a monochromatic excitation laser for generating monochromatic energy for Raman scattering, one or more fiber optic means to transmit the monochromatic energy to identify the presence of abnormal tissue and to collect the Raman scattered energy, a catheter means to house the fiber optic means, a Raman spectrometer to calibrate the collected Raman scattered energy, and a processing means for analyzing differences in Raman scattered energy to distinguish normal from abnormal tissue.
43. The apparatus of claim 42, further comprising an expandable means in a distal end of the catheter means such that the diameter of the distal end of the catheter means may be varied from minimum to maximum diameter thereby permitting its use in various size lumens or to treat a vascular occlusion.
44. The apparatus of claim 41, further comprising a needle to house the catheter and fiber optic means.
45. An apparatus comprising: one or more fiber optic means to transmit the monochromatic energy to identify the presence of abnormal tissue and to collect the Raman scattered energy, a catheter means to house the fiber optic means, and a needle to house the catheter and fiber optic means.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US74769891A | 1991-08-20 | 1991-08-20 | |
US747,698 | 1991-08-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993003672A1 true WO1993003672A1 (en) | 1993-03-04 |
Family
ID=25006244
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1992/007040 WO1993003672A1 (en) | 1991-08-20 | 1992-08-20 | Optical histochemical analysis, in vivo detection and real-time guidance for ablation of abnormal tissues using a raman spectroscopic detection system |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU2519892A (en) |
WO (1) | WO1993003672A1 (en) |
Cited By (92)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995011624A2 (en) * | 1993-10-29 | 1995-05-04 | Feld Michael S | A raman endoscope |
WO1996028084A1 (en) * | 1995-03-14 | 1996-09-19 | Board Of Regents, The University Of Texas System | Optical method and apparatus for the diagnosis of cervical precancers using raman and fluorescence spectroscopies |
WO1996029926A1 (en) * | 1995-03-31 | 1996-10-03 | The Board Of Regents, The University Of Texas System | Probe for the detection of cervical neoplasias using fluorescence spectroscopy |
WO1996041152A1 (en) * | 1995-06-07 | 1996-12-19 | Inphocyte, Inc. | A system and method for diagnosis of disease by infrared analysis of human tissues and cells |
WO1997048329A1 (en) * | 1996-06-19 | 1997-12-24 | Board Of Regents, The University Of Texas System | Near-infrared raman spectroscopy for in vitro and in vivo detection of cervical precancers |
US5891619A (en) * | 1997-01-14 | 1999-04-06 | Inphocyte, Inc. | System and method for mapping the distribution of normal and abnormal cells in sections of tissue |
WO2001074251A2 (en) * | 2000-03-31 | 2001-10-11 | Rita Medical Systems Inc. | Tissue biopsy and treatment apparatus and method |
EP1146930A2 (en) * | 1999-01-09 | 2001-10-24 | Intraluminal Therapeutics Inc. | System and method for controlling tissue ablation |
US6377841B1 (en) | 2000-03-31 | 2002-04-23 | Vanderbilt University | Tumor demarcation using optical spectroscopy |
WO2002088705A2 (en) * | 2001-05-01 | 2002-11-07 | The General Hospital Corporation | Method and apparatus for determination of atherosclerotic plaque type by measurement of tissue optical properties |
US6980299B1 (en) | 2001-10-16 | 2005-12-27 | General Hospital Corporation | Systems and methods for imaging a sample |
EP1498722A3 (en) * | 2003-03-25 | 2006-11-29 | Riken | Raman probe and raman spectrum measuring apparatus utilizing the same |
WO2007127228A2 (en) * | 2006-04-27 | 2007-11-08 | Lawrence Livermore National Security, Llc | Fiber optic evaluation of tissue modification |
WO2007138552A3 (en) * | 2006-05-30 | 2008-03-06 | Konink Philips Elecronics N V | Apparatus for depth-resolved measurements of properties of tissue |
US7647092B2 (en) | 2002-04-05 | 2010-01-12 | Massachusetts Institute Of Technology | Systems and methods for spectroscopy of biological tissue |
US7697576B2 (en) | 2004-05-05 | 2010-04-13 | Chem Image Corporation | Cytological analysis by raman spectroscopic imaging |
WO2010144081A1 (en) * | 2009-06-10 | 2010-12-16 | University Of Utah Research Foundation | Apparatus for raman spectroscopy having an optical fiber probe |
EP2274051A1 (en) * | 2008-05-09 | 2011-01-19 | Hugh Beckman | Medical device for diagnosing and treating anomalous tissue and method for doing the same |
US8253936B2 (en) | 2008-08-08 | 2012-08-28 | Chemimage Corporation | Raman characterization of transplant tissue |
USRE43875E1 (en) | 2004-09-29 | 2012-12-25 | The General Hospital Corporation | System and method for optical coherence imaging |
USRE44042E1 (en) | 2004-09-10 | 2013-03-05 | The General Hospital Corporation | System and method for optical coherence imaging |
US8416405B2 (en) | 2008-08-08 | 2013-04-09 | Chemimage Corporation | Raman chemical imaging of implantable drug delivery devices |
WO2014074678A1 (en) * | 2012-11-09 | 2014-05-15 | Ams Research Corporation | Surgical laser tool |
US8838213B2 (en) | 2006-10-19 | 2014-09-16 | The General Hospital Corporation | Apparatus and method for obtaining and providing imaging information associated with at least one portion of a sample, and effecting such portion(s) |
US8861910B2 (en) | 2008-06-20 | 2014-10-14 | The General Hospital Corporation | Fused fiber optic coupler arrangement and method for use thereof |
US8896838B2 (en) | 2010-03-05 | 2014-11-25 | The General Hospital Corporation | Systems, methods and computer-accessible medium which provide microscopic images of at least one anatomical structure at a particular resolution |
US8922781B2 (en) | 2004-11-29 | 2014-12-30 | The General Hospital Corporation | Arrangements, devices, endoscopes, catheters and methods for performing optical imaging by simultaneously illuminating and detecting multiple points on a sample |
US8928889B2 (en) | 2005-09-29 | 2015-01-06 | The General Hospital Corporation | Arrangements and methods for providing multimodality microscopic imaging of one or more biological structures |
US8937724B2 (en) | 2008-12-10 | 2015-01-20 | The General Hospital Corporation | Systems and methods for extending imaging depth range of optical coherence tomography through optical sub-sampling |
US8965487B2 (en) | 2004-08-24 | 2015-02-24 | The General Hospital Corporation | Process, system and software arrangement for measuring a mechanical strain and elastic properties of a sample |
US9060689B2 (en) | 2005-06-01 | 2015-06-23 | The General Hospital Corporation | Apparatus, method and system for performing phase-resolved optical frequency domain imaging |
US9069130B2 (en) | 2010-05-03 | 2015-06-30 | The General Hospital Corporation | Apparatus, method and system for generating optical radiation from biological gain media |
US9087368B2 (en) | 2006-01-19 | 2015-07-21 | The General Hospital Corporation | Methods and systems for optical imaging or epithelial luminal organs by beam scanning thereof |
WO2015114379A1 (en) * | 2014-01-31 | 2015-08-06 | The University Of Bristol | A low background raman probe for optical biopsy of brain tissue |
US9176319B2 (en) | 2007-03-23 | 2015-11-03 | The General Hospital Corporation | Methods, arrangements and apparatus for utilizing a wavelength-swept laser using angular scanning and dispersion procedures |
US9178330B2 (en) | 2009-02-04 | 2015-11-03 | The General Hospital Corporation | Apparatus and method for utilization of a high-speed optical wavelength tuning source |
US9186067B2 (en) | 2006-02-01 | 2015-11-17 | The General Hospital Corporation | Apparatus for applying a plurality of electro-magnetic radiations to a sample |
US9226660B2 (en) | 2004-08-06 | 2016-01-05 | The General Hospital Corporation | Process, system and software arrangement for determining at least one location in a sample using an optical coherence tomography |
US9226665B2 (en) | 2003-01-24 | 2016-01-05 | The General Hospital Corporation | Speckle reduction in optical coherence tomography by path length encoded angular compounding |
US9254102B2 (en) | 2004-08-24 | 2016-02-09 | The General Hospital Corporation | Method and apparatus for imaging of vessel segments |
US9254089B2 (en) | 2008-07-14 | 2016-02-09 | The General Hospital Corporation | Apparatus and methods for facilitating at least partial overlap of dispersed ration on at least one sample |
WO2016028749A1 (en) * | 2014-08-20 | 2016-02-25 | Memorial Sloan Kettering Cancer Center | Raman-triggered ablation/resection systems and methods |
US9282931B2 (en) | 2000-10-30 | 2016-03-15 | The General Hospital Corporation | Methods for tissue analysis |
US9295391B1 (en) | 2000-11-10 | 2016-03-29 | The General Hospital Corporation | Spectrally encoded miniature endoscopic imaging probe |
US9326682B2 (en) | 2005-04-28 | 2016-05-03 | The General Hospital Corporation | Systems, processes and software arrangements for evaluating information associated with an anatomical structure by an optical coherence ranging technique |
US9330092B2 (en) | 2011-07-19 | 2016-05-03 | The General Hospital Corporation | Systems, methods, apparatus and computer-accessible-medium for providing polarization-mode dispersion compensation in optical coherence tomography |
US9332942B2 (en) | 2008-01-28 | 2016-05-10 | The General Hospital Corporation | Systems, processes and computer-accessible medium for providing hybrid flourescence and optical coherence tomography imaging |
US9341783B2 (en) | 2011-10-18 | 2016-05-17 | The General Hospital Corporation | Apparatus and methods for producing and/or providing recirculating optical delay(s) |
US9351642B2 (en) | 2009-03-12 | 2016-05-31 | The General Hospital Corporation | Non-contact optical system, computer-accessible medium and method for measurement at least one mechanical property of tissue using coherent speckle technique(s) |
US9364143B2 (en) | 2006-05-10 | 2016-06-14 | The General Hospital Corporation | Process, arrangements and systems for providing frequency domain imaging of a sample |
US9375158B2 (en) | 2007-07-31 | 2016-06-28 | The General Hospital Corporation | Systems and methods for providing beam scan patterns for high speed doppler optical frequency domain imaging |
US9377290B2 (en) | 2003-10-27 | 2016-06-28 | The General Hospital Corporation | Method and apparatus for performing optical imaging using frequency-domain interferometry |
US9415550B2 (en) | 2012-08-22 | 2016-08-16 | The General Hospital Corporation | System, method, and computer-accessible medium for fabrication miniature endoscope using soft lithography |
US9441948B2 (en) | 2005-08-09 | 2016-09-13 | The General Hospital Corporation | Apparatus, methods and storage medium for performing polarization-based quadrature demodulation in optical coherence tomography |
US9510758B2 (en) | 2010-10-27 | 2016-12-06 | The General Hospital Corporation | Apparatus, systems and methods for measuring blood pressure within at least one vessel |
US9516997B2 (en) | 2006-01-19 | 2016-12-13 | The General Hospital Corporation | Spectrally-encoded endoscopy techniques, apparatus and methods |
US9557154B2 (en) | 2010-05-25 | 2017-01-31 | The General Hospital Corporation | Systems, devices, methods, apparatus and computer-accessible media for providing optical imaging of structures and compositions |
US9629528B2 (en) | 2012-03-30 | 2017-04-25 | The General Hospital Corporation | Imaging system, method and distal attachment for multidirectional field of view endoscopy |
USRE46412E1 (en) | 2006-02-24 | 2017-05-23 | The General Hospital Corporation | Methods and systems for performing angle-resolved Fourier-domain optical coherence tomography |
US9664615B2 (en) | 2004-07-02 | 2017-05-30 | The General Hospital Corporation | Imaging system and related techniques |
US9668652B2 (en) | 2013-07-26 | 2017-06-06 | The General Hospital Corporation | System, apparatus and method for utilizing optical dispersion for fourier-domain optical coherence tomography |
US9733460B2 (en) | 2014-01-08 | 2017-08-15 | The General Hospital Corporation | Method and apparatus for microscopic imaging |
US9777053B2 (en) | 2006-02-08 | 2017-10-03 | The General Hospital Corporation | Methods, arrangements and systems for obtaining information associated with an anatomical sample using optical microscopy |
US9784681B2 (en) | 2013-05-13 | 2017-10-10 | The General Hospital Corporation | System and method for efficient detection of the phase and amplitude of a periodic modulation associated with self-interfering fluorescence |
US9795301B2 (en) | 2010-05-25 | 2017-10-24 | The General Hospital Corporation | Apparatus, systems, methods and computer-accessible medium for spectral analysis of optical coherence tomography images |
EP2585811A4 (en) * | 2010-06-25 | 2017-12-20 | Cireca Theranostics, LLC | Method for analyzing biological specimens by spectral imaging |
US9897538B2 (en) | 2001-04-30 | 2018-02-20 | The General Hospital Corporation | Method and apparatus for improving image clarity and sensitivity in optical coherence tomography using dynamic feedback to control focal properties and coherence gating |
US10067051B2 (en) | 2010-06-25 | 2018-09-04 | Cireca Theranostics, Llc | Method for analyzing biological specimens by spectral imaging |
US10105456B2 (en) | 2012-12-19 | 2018-10-23 | Sloan-Kettering Institute For Cancer Research | Multimodal particles, methods and uses thereof |
US10117576B2 (en) | 2013-07-19 | 2018-11-06 | The General Hospital Corporation | System, method and computer accessible medium for determining eye motion by imaging retina and providing feedback for acquisition of signals from the retina |
US10228556B2 (en) | 2014-04-04 | 2019-03-12 | The General Hospital Corporation | Apparatus and method for controlling propagation and/or transmission of electromagnetic radiation in flexible waveguide(s) |
US10241028B2 (en) | 2011-08-25 | 2019-03-26 | The General Hospital Corporation | Methods, systems, arrangements and computer-accessible medium for providing micro-optical coherence tomography procedures |
US10285568B2 (en) | 2010-06-03 | 2019-05-14 | The General Hospital Corporation | Apparatus and method for devices for imaging structures in or at one or more luminal organs |
US10322194B2 (en) | 2012-08-31 | 2019-06-18 | Sloan-Kettering Institute For Cancer Research | Particles, methods and uses thereof |
US10413188B2 (en) | 2004-11-17 | 2019-09-17 | Lawrence Livermore National Security, Llc | Assessment of tissue or lesion depth using temporally resolved light scattering spectroscopy |
US10426548B2 (en) | 2006-02-01 | 2019-10-01 | The General Hosppital Corporation | Methods and systems for providing electromagnetic radiation to at least one portion of a sample using conformal laser therapy procedures |
USRE47675E1 (en) | 2003-06-06 | 2019-10-29 | The General Hospital Corporation | Process and apparatus for a wavelength tuning source |
US10460439B1 (en) | 2015-08-12 | 2019-10-29 | Cireca Theranostics, Llc | Methods and systems for identifying cellular subtypes in an image of a biological specimen |
US10478072B2 (en) | 2013-03-15 | 2019-11-19 | The General Hospital Corporation | Methods and system for characterizing an object |
US10534129B2 (en) | 2007-03-30 | 2020-01-14 | The General Hospital Corporation | System and method providing intracoronary laser speckle imaging for the detection of vulnerable plaque |
US10688202B2 (en) | 2014-07-28 | 2020-06-23 | Memorial Sloan-Kettering Cancer Center | Metal(loid) chalcogen nanoparticles as universal binders for medical isotopes |
US10736494B2 (en) | 2014-01-31 | 2020-08-11 | The General Hospital Corporation | System and method for facilitating manual and/or automatic volumetric imaging with real-time tension or force feedback using a tethered imaging device |
US10888227B2 (en) | 2013-02-20 | 2021-01-12 | Memorial Sloan Kettering Cancer Center | Raman-triggered ablation/resection systems and methods |
US10893806B2 (en) | 2013-01-29 | 2021-01-19 | The General Hospital Corporation | Apparatus, systems and methods for providing information regarding the aortic valve |
US10912462B2 (en) | 2014-07-25 | 2021-02-09 | The General Hospital Corporation | Apparatus, devices and methods for in vivo imaging and diagnosis |
US10912947B2 (en) | 2014-03-04 | 2021-02-09 | Memorial Sloan Kettering Cancer Center | Systems and methods for treatment of disease via application of mechanical force by controlled rotation of nanoparticles inside cells |
US10919089B2 (en) | 2015-07-01 | 2021-02-16 | Memorial Sloan Kettering Cancer Center | Anisotropic particles, methods and uses thereof |
US11123047B2 (en) | 2008-01-28 | 2021-09-21 | The General Hospital Corporation | Hybrid systems and methods for multi-modal acquisition of intravascular imaging data and counteracting the effects of signal absorption in blood |
US11179028B2 (en) | 2013-02-01 | 2021-11-23 | The General Hospital Corporation | Objective lens arrangement for confocal endomicroscopy |
US11452433B2 (en) | 2013-07-19 | 2022-09-27 | The General Hospital Corporation | Imaging apparatus and method which utilizes multidirectional field of view endoscopy |
US11490797B2 (en) | 2012-05-21 | 2022-11-08 | The General Hospital Corporation | Apparatus, device and method for capsule microscopy |
US11490826B2 (en) | 2009-07-14 | 2022-11-08 | The General Hospital Corporation | Apparatus, systems and methods for measuring flow and pressure within a vessel |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4669467A (en) * | 1985-03-22 | 1987-06-02 | Massachusetts Institute Of Technology | Mode mixer for a laser catheter |
-
1992
- 1992-08-20 WO PCT/US1992/007040 patent/WO1993003672A1/en active Application Filing
- 1992-08-20 AU AU25198/92A patent/AU2519892A/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4669467A (en) * | 1985-03-22 | 1987-06-02 | Massachusetts Institute Of Technology | Mode mixer for a laser catheter |
Non-Patent Citations (1)
Title |
---|
CIRCULATION; August 1988; PRINCE et al., "Increased Preferential Absorption in Human Atherosclerotic Plaque with Oral Beta Carotene", pp. 338-344. * |
Cited By (136)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995011624A2 (en) * | 1993-10-29 | 1995-05-04 | Feld Michael S | A raman endoscope |
WO1995011624A3 (en) * | 1993-10-29 | 1995-05-18 | Michael S Feld | A raman endoscope |
US6095982A (en) * | 1995-03-14 | 2000-08-01 | Board Of Regents, The University Of Texas System | Spectroscopic method and apparatus for optically detecting abnormal mammalian epithelial tissue |
US5697373A (en) * | 1995-03-14 | 1997-12-16 | Board Of Regents, The University Of Texas System | Optical method and apparatus for the diagnosis of cervical precancers using raman and fluorescence spectroscopies |
US5991653A (en) * | 1995-03-14 | 1999-11-23 | Board Of Regents, The University Of Texas System | Near-infrared raman spectroscopy for in vitro and in vivo detection of cervical precancers |
WO1996028084A1 (en) * | 1995-03-14 | 1996-09-19 | Board Of Regents, The University Of Texas System | Optical method and apparatus for the diagnosis of cervical precancers using raman and fluorescence spectroscopies |
WO1996029926A1 (en) * | 1995-03-31 | 1996-10-03 | The Board Of Regents, The University Of Texas System | Probe for the detection of cervical neoplasias using fluorescence spectroscopy |
WO1996041152A1 (en) * | 1995-06-07 | 1996-12-19 | Inphocyte, Inc. | A system and method for diagnosis of disease by infrared analysis of human tissues and cells |
US5733739A (en) * | 1995-06-07 | 1998-03-31 | Inphocyte, Inc. | System and method for diagnosis of disease by infrared analysis of human tissues and cells |
WO1997048329A1 (en) * | 1996-06-19 | 1997-12-24 | Board Of Regents, The University Of Texas System | Near-infrared raman spectroscopy for in vitro and in vivo detection of cervical precancers |
US5891619A (en) * | 1997-01-14 | 1999-04-06 | Inphocyte, Inc. | System and method for mapping the distribution of normal and abnormal cells in sections of tissue |
EP1146930A2 (en) * | 1999-01-09 | 2001-10-24 | Intraluminal Therapeutics Inc. | System and method for controlling tissue ablation |
EP1146930A4 (en) * | 1999-01-09 | 2003-02-19 | Intraluminal Therapeutics Inc | System and method for controlling tissue ablation |
WO2001074251A2 (en) * | 2000-03-31 | 2001-10-11 | Rita Medical Systems Inc. | Tissue biopsy and treatment apparatus and method |
WO2001074251A3 (en) * | 2000-03-31 | 2002-01-31 | Rita Medical Systems Inc | Tissue biopsy and treatment apparatus and method |
US6377841B1 (en) | 2000-03-31 | 2002-04-23 | Vanderbilt University | Tumor demarcation using optical spectroscopy |
WO2001074252A3 (en) * | 2000-03-31 | 2002-05-23 | Rita Medical Systems Inc | Tissue biopsy and treatment apparatus and method |
WO2001074252A2 (en) * | 2000-03-31 | 2001-10-11 | Rita Medical Systems Inc. | Tissue biopsy and treatment apparatus and method |
AU2001251134B2 (en) * | 2000-03-31 | 2006-02-02 | Angiodynamics, Inc. | Tissue biopsy and treatment apparatus and method |
US7025765B2 (en) | 2000-03-31 | 2006-04-11 | Rita Medical Systems, Inc. | Tissue biopsy and treatment apparatus and method |
US6869430B2 (en) | 2000-03-31 | 2005-03-22 | Rita Medical Systems, Inc. | Tissue biopsy and treatment apparatus and method |
US9282931B2 (en) | 2000-10-30 | 2016-03-15 | The General Hospital Corporation | Methods for tissue analysis |
US9295391B1 (en) | 2000-11-10 | 2016-03-29 | The General Hospital Corporation | Spectrally encoded miniature endoscopic imaging probe |
US9897538B2 (en) | 2001-04-30 | 2018-02-20 | The General Hospital Corporation | Method and apparatus for improving image clarity and sensitivity in optical coherence tomography using dynamic feedback to control focal properties and coherence gating |
AT503309B1 (en) * | 2001-05-01 | 2011-08-15 | Gen Hospital Corp | DEVICE FOR DETERMINING ATHEROSCLEROTIC BEARING BY MEASURING OPTICAL TISSUE PROPERTIES |
GB2408797A (en) * | 2001-05-01 | 2005-06-08 | Gen Hospital Corp | Method and apparatus for determination of atherosclerotic plaque type by measurement of tissue optical properties |
DE10297689B4 (en) * | 2001-05-01 | 2007-10-18 | The General Hospital Corp., Boston | Method and device for the determination of atherosclerotic coating by measurement of optical tissue properties |
WO2002088705A3 (en) * | 2001-05-01 | 2003-03-20 | Gen Hospital Corp | Method and apparatus for determination of atherosclerotic plaque type by measurement of tissue optical properties |
AU2008249176B2 (en) * | 2001-05-01 | 2012-05-24 | The General Hospital Corporation | Method and apparatus for determination of atherosclerotic plaque type by measurement of tissue optical properties |
GB2408797B (en) * | 2001-05-01 | 2006-09-20 | Gen Hospital Corp | Method and apparatus for determination of atherosclerotic plaque type by measurement of tissue optical properties |
WO2002088705A2 (en) * | 2001-05-01 | 2002-11-07 | The General Hospital Corporation | Method and apparatus for determination of atherosclerotic plaque type by measurement of tissue optical properties |
US6980299B1 (en) | 2001-10-16 | 2005-12-27 | General Hospital Corporation | Systems and methods for imaging a sample |
US7647092B2 (en) | 2002-04-05 | 2010-01-12 | Massachusetts Institute Of Technology | Systems and methods for spectroscopy of biological tissue |
EP2325623A3 (en) * | 2002-04-05 | 2013-03-20 | Massachusetts Institute of Technology | Systems and methods for spectroscopy of biological tissue |
US9226665B2 (en) | 2003-01-24 | 2016-01-05 | The General Hospital Corporation | Speckle reduction in optical coherence tomography by path length encoded angular compounding |
EP1498722A3 (en) * | 2003-03-25 | 2006-11-29 | Riken | Raman probe and raman spectrum measuring apparatus utilizing the same |
USRE47675E1 (en) | 2003-06-06 | 2019-10-29 | The General Hospital Corporation | Process and apparatus for a wavelength tuning source |
US9377290B2 (en) | 2003-10-27 | 2016-06-28 | The General Hospital Corporation | Method and apparatus for performing optical imaging using frequency-domain interferometry |
US9812846B2 (en) | 2003-10-27 | 2017-11-07 | The General Hospital Corporation | Method and apparatus for performing optical imaging using frequency-domain interferometry |
US8553732B2 (en) | 2004-05-05 | 2013-10-08 | Chemimage Corporation | Cytological analysis by raman spectroscopic imaging |
US7697576B2 (en) | 2004-05-05 | 2010-04-13 | Chem Image Corporation | Cytological analysis by raman spectroscopic imaging |
US9664615B2 (en) | 2004-07-02 | 2017-05-30 | The General Hospital Corporation | Imaging system and related techniques |
US9226660B2 (en) | 2004-08-06 | 2016-01-05 | The General Hospital Corporation | Process, system and software arrangement for determining at least one location in a sample using an optical coherence tomography |
US9254102B2 (en) | 2004-08-24 | 2016-02-09 | The General Hospital Corporation | Method and apparatus for imaging of vessel segments |
US9763623B2 (en) | 2004-08-24 | 2017-09-19 | The General Hospital Corporation | Method and apparatus for imaging of vessel segments |
US8965487B2 (en) | 2004-08-24 | 2015-02-24 | The General Hospital Corporation | Process, system and software arrangement for measuring a mechanical strain and elastic properties of a sample |
USRE44042E1 (en) | 2004-09-10 | 2013-03-05 | The General Hospital Corporation | System and method for optical coherence imaging |
USRE43875E1 (en) | 2004-09-29 | 2012-12-25 | The General Hospital Corporation | System and method for optical coherence imaging |
USRE45512E1 (en) | 2004-09-29 | 2015-05-12 | The General Hospital Corporation | System and method for optical coherence imaging |
US10413188B2 (en) | 2004-11-17 | 2019-09-17 | Lawrence Livermore National Security, Llc | Assessment of tissue or lesion depth using temporally resolved light scattering spectroscopy |
US8922781B2 (en) | 2004-11-29 | 2014-12-30 | The General Hospital Corporation | Arrangements, devices, endoscopes, catheters and methods for performing optical imaging by simultaneously illuminating and detecting multiple points on a sample |
US9326682B2 (en) | 2005-04-28 | 2016-05-03 | The General Hospital Corporation | Systems, processes and software arrangements for evaluating information associated with an anatomical structure by an optical coherence ranging technique |
US9060689B2 (en) | 2005-06-01 | 2015-06-23 | The General Hospital Corporation | Apparatus, method and system for performing phase-resolved optical frequency domain imaging |
US9441948B2 (en) | 2005-08-09 | 2016-09-13 | The General Hospital Corporation | Apparatus, methods and storage medium for performing polarization-based quadrature demodulation in optical coherence tomography |
US8928889B2 (en) | 2005-09-29 | 2015-01-06 | The General Hospital Corporation | Arrangements and methods for providing multimodality microscopic imaging of one or more biological structures |
US9513276B2 (en) | 2005-09-29 | 2016-12-06 | The General Hospital Corporation | Method and apparatus for optical imaging via spectral encoding |
US9304121B2 (en) | 2005-09-29 | 2016-04-05 | The General Hospital Corporation | Method and apparatus for optical imaging via spectral encoding |
US9516997B2 (en) | 2006-01-19 | 2016-12-13 | The General Hospital Corporation | Spectrally-encoded endoscopy techniques, apparatus and methods |
US9646377B2 (en) | 2006-01-19 | 2017-05-09 | The General Hospital Corporation | Methods and systems for optical imaging or epithelial luminal organs by beam scanning thereof |
US9087368B2 (en) | 2006-01-19 | 2015-07-21 | The General Hospital Corporation | Methods and systems for optical imaging or epithelial luminal organs by beam scanning thereof |
US9791317B2 (en) | 2006-01-19 | 2017-10-17 | The General Hospital Corporation | Spectrally-encoded endoscopy techniques and methods |
US10987000B2 (en) | 2006-01-19 | 2021-04-27 | The General Hospital Corporation | Methods and systems for optical imaging or epithelial luminal organs by beam scanning thereof |
US9186066B2 (en) | 2006-02-01 | 2015-11-17 | The General Hospital Corporation | Apparatus for applying a plurality of electro-magnetic radiations to a sample |
US9186067B2 (en) | 2006-02-01 | 2015-11-17 | The General Hospital Corporation | Apparatus for applying a plurality of electro-magnetic radiations to a sample |
US10426548B2 (en) | 2006-02-01 | 2019-10-01 | The General Hosppital Corporation | Methods and systems for providing electromagnetic radiation to at least one portion of a sample using conformal laser therapy procedures |
US9777053B2 (en) | 2006-02-08 | 2017-10-03 | The General Hospital Corporation | Methods, arrangements and systems for obtaining information associated with an anatomical sample using optical microscopy |
USRE46412E1 (en) | 2006-02-24 | 2017-05-23 | The General Hospital Corporation | Methods and systems for performing angle-resolved Fourier-domain optical coherence tomography |
WO2007127228A2 (en) * | 2006-04-27 | 2007-11-08 | Lawrence Livermore National Security, Llc | Fiber optic evaluation of tissue modification |
WO2007127228A3 (en) * | 2006-04-27 | 2008-01-03 | Univ California | Fiber optic evaluation of tissue modification |
US9364143B2 (en) | 2006-05-10 | 2016-06-14 | The General Hospital Corporation | Process, arrangements and systems for providing frequency domain imaging of a sample |
US10413175B2 (en) | 2006-05-10 | 2019-09-17 | The General Hospital Corporation | Process, arrangements and systems for providing frequency domain imaging of a sample |
US8417323B2 (en) | 2006-05-30 | 2013-04-09 | Koninklijke Philips Electronics N.V. | Apparatus for depth-resolved measurements of properties of tissue |
WO2007138552A3 (en) * | 2006-05-30 | 2008-03-06 | Konink Philips Elecronics N V | Apparatus for depth-resolved measurements of properties of tissue |
US8838213B2 (en) | 2006-10-19 | 2014-09-16 | The General Hospital Corporation | Apparatus and method for obtaining and providing imaging information associated with at least one portion of a sample, and effecting such portion(s) |
US9176319B2 (en) | 2007-03-23 | 2015-11-03 | The General Hospital Corporation | Methods, arrangements and apparatus for utilizing a wavelength-swept laser using angular scanning and dispersion procedures |
US10534129B2 (en) | 2007-03-30 | 2020-01-14 | The General Hospital Corporation | System and method providing intracoronary laser speckle imaging for the detection of vulnerable plaque |
US9375158B2 (en) | 2007-07-31 | 2016-06-28 | The General Hospital Corporation | Systems and methods for providing beam scan patterns for high speed doppler optical frequency domain imaging |
US11123047B2 (en) | 2008-01-28 | 2021-09-21 | The General Hospital Corporation | Hybrid systems and methods for multi-modal acquisition of intravascular imaging data and counteracting the effects of signal absorption in blood |
US9332942B2 (en) | 2008-01-28 | 2016-05-10 | The General Hospital Corporation | Systems, processes and computer-accessible medium for providing hybrid flourescence and optical coherence tomography imaging |
EP2274051A1 (en) * | 2008-05-09 | 2011-01-19 | Hugh Beckman | Medical device for diagnosing and treating anomalous tissue and method for doing the same |
CN102015020A (en) * | 2008-05-09 | 2011-04-13 | 休·贝克曼 | Medical device for diagnosing and treating anomalous tissue and method for doing the same |
EP2274051A4 (en) * | 2008-05-09 | 2011-07-20 | Hugh Beckman | Medical device for diagnosing and treating anomalous tissue and method for doing the same |
US8861910B2 (en) | 2008-06-20 | 2014-10-14 | The General Hospital Corporation | Fused fiber optic coupler arrangement and method for use thereof |
US9254089B2 (en) | 2008-07-14 | 2016-02-09 | The General Hospital Corporation | Apparatus and methods for facilitating at least partial overlap of dispersed ration on at least one sample |
US10835110B2 (en) | 2008-07-14 | 2020-11-17 | The General Hospital Corporation | Apparatus and method for facilitating at least partial overlap of dispersed ration on at least one sample |
US8416405B2 (en) | 2008-08-08 | 2013-04-09 | Chemimage Corporation | Raman chemical imaging of implantable drug delivery devices |
US8253936B2 (en) | 2008-08-08 | 2012-08-28 | Chemimage Corporation | Raman characterization of transplant tissue |
US8937724B2 (en) | 2008-12-10 | 2015-01-20 | The General Hospital Corporation | Systems and methods for extending imaging depth range of optical coherence tomography through optical sub-sampling |
US9178330B2 (en) | 2009-02-04 | 2015-11-03 | The General Hospital Corporation | Apparatus and method for utilization of a high-speed optical wavelength tuning source |
US9351642B2 (en) | 2009-03-12 | 2016-05-31 | The General Hospital Corporation | Non-contact optical system, computer-accessible medium and method for measurement at least one mechanical property of tissue using coherent speckle technique(s) |
WO2010144081A1 (en) * | 2009-06-10 | 2010-12-16 | University Of Utah Research Foundation | Apparatus for raman spectroscopy having an optical fiber probe |
US11490826B2 (en) | 2009-07-14 | 2022-11-08 | The General Hospital Corporation | Apparatus, systems and methods for measuring flow and pressure within a vessel |
US9642531B2 (en) | 2010-03-05 | 2017-05-09 | The General Hospital Corporation | Systems, methods and computer-accessible medium which provide microscopic images of at least one anatomical structure at a particular resolution |
US10463254B2 (en) | 2010-03-05 | 2019-11-05 | The General Hospital Corporation | Light tunnel and lens which provide extended focal depth of at least one anatomical structure at a particular resolution |
US9408539B2 (en) | 2010-03-05 | 2016-08-09 | The General Hospital Corporation | Systems, methods and computer-accessible medium which provide microscopic images of at least one anatomical structure at a particular resolution |
US8896838B2 (en) | 2010-03-05 | 2014-11-25 | The General Hospital Corporation | Systems, methods and computer-accessible medium which provide microscopic images of at least one anatomical structure at a particular resolution |
US9081148B2 (en) | 2010-03-05 | 2015-07-14 | The General Hospital Corporation | Systems, methods and computer-accessible medium which provide microscopic images of at least one anatomical structure at a particular resolution |
US9951269B2 (en) | 2010-05-03 | 2018-04-24 | The General Hospital Corporation | Apparatus, method and system for generating optical radiation from biological gain media |
US9069130B2 (en) | 2010-05-03 | 2015-06-30 | The General Hospital Corporation | Apparatus, method and system for generating optical radiation from biological gain media |
US9795301B2 (en) | 2010-05-25 | 2017-10-24 | The General Hospital Corporation | Apparatus, systems, methods and computer-accessible medium for spectral analysis of optical coherence tomography images |
US9557154B2 (en) | 2010-05-25 | 2017-01-31 | The General Hospital Corporation | Systems, devices, methods, apparatus and computer-accessible media for providing optical imaging of structures and compositions |
US10939825B2 (en) | 2010-05-25 | 2021-03-09 | The General Hospital Corporation | Systems, devices, methods, apparatus and computer-accessible media for providing optical imaging of structures and compositions |
US10285568B2 (en) | 2010-06-03 | 2019-05-14 | The General Hospital Corporation | Apparatus and method for devices for imaging structures in or at one or more luminal organs |
EP2585811A4 (en) * | 2010-06-25 | 2017-12-20 | Cireca Theranostics, LLC | Method for analyzing biological specimens by spectral imaging |
US10067051B2 (en) | 2010-06-25 | 2018-09-04 | Cireca Theranostics, Llc | Method for analyzing biological specimens by spectral imaging |
US9510758B2 (en) | 2010-10-27 | 2016-12-06 | The General Hospital Corporation | Apparatus, systems and methods for measuring blood pressure within at least one vessel |
US9330092B2 (en) | 2011-07-19 | 2016-05-03 | The General Hospital Corporation | Systems, methods, apparatus and computer-accessible-medium for providing polarization-mode dispersion compensation in optical coherence tomography |
US10241028B2 (en) | 2011-08-25 | 2019-03-26 | The General Hospital Corporation | Methods, systems, arrangements and computer-accessible medium for providing micro-optical coherence tomography procedures |
US9341783B2 (en) | 2011-10-18 | 2016-05-17 | The General Hospital Corporation | Apparatus and methods for producing and/or providing recirculating optical delay(s) |
US9629528B2 (en) | 2012-03-30 | 2017-04-25 | The General Hospital Corporation | Imaging system, method and distal attachment for multidirectional field of view endoscopy |
US11490797B2 (en) | 2012-05-21 | 2022-11-08 | The General Hospital Corporation | Apparatus, device and method for capsule microscopy |
US9415550B2 (en) | 2012-08-22 | 2016-08-16 | The General Hospital Corporation | System, method, and computer-accessible medium for fabrication miniature endoscope using soft lithography |
US10322194B2 (en) | 2012-08-31 | 2019-06-18 | Sloan-Kettering Institute For Cancer Research | Particles, methods and uses thereof |
WO2014074678A1 (en) * | 2012-11-09 | 2014-05-15 | Ams Research Corporation | Surgical laser tool |
CN104797210A (en) * | 2012-11-09 | 2015-07-22 | Ams研究公司 | Surgical laser tool |
US10568692B2 (en) | 2012-11-09 | 2020-02-25 | Boston Scientific Scimed, Inc. | Surgical laser tool |
US10105456B2 (en) | 2012-12-19 | 2018-10-23 | Sloan-Kettering Institute For Cancer Research | Multimodal particles, methods and uses thereof |
US10893806B2 (en) | 2013-01-29 | 2021-01-19 | The General Hospital Corporation | Apparatus, systems and methods for providing information regarding the aortic valve |
US11179028B2 (en) | 2013-02-01 | 2021-11-23 | The General Hospital Corporation | Objective lens arrangement for confocal endomicroscopy |
US10888227B2 (en) | 2013-02-20 | 2021-01-12 | Memorial Sloan Kettering Cancer Center | Raman-triggered ablation/resection systems and methods |
US10478072B2 (en) | 2013-03-15 | 2019-11-19 | The General Hospital Corporation | Methods and system for characterizing an object |
US9784681B2 (en) | 2013-05-13 | 2017-10-10 | The General Hospital Corporation | System and method for efficient detection of the phase and amplitude of a periodic modulation associated with self-interfering fluorescence |
US10117576B2 (en) | 2013-07-19 | 2018-11-06 | The General Hospital Corporation | System, method and computer accessible medium for determining eye motion by imaging retina and providing feedback for acquisition of signals from the retina |
US11452433B2 (en) | 2013-07-19 | 2022-09-27 | The General Hospital Corporation | Imaging apparatus and method which utilizes multidirectional field of view endoscopy |
US10058250B2 (en) | 2013-07-26 | 2018-08-28 | The General Hospital Corporation | System, apparatus and method for utilizing optical dispersion for fourier-domain optical coherence tomography |
US9668652B2 (en) | 2013-07-26 | 2017-06-06 | The General Hospital Corporation | System, apparatus and method for utilizing optical dispersion for fourier-domain optical coherence tomography |
US9733460B2 (en) | 2014-01-08 | 2017-08-15 | The General Hospital Corporation | Method and apparatus for microscopic imaging |
WO2015114379A1 (en) * | 2014-01-31 | 2015-08-06 | The University Of Bristol | A low background raman probe for optical biopsy of brain tissue |
US10736494B2 (en) | 2014-01-31 | 2020-08-11 | The General Hospital Corporation | System and method for facilitating manual and/or automatic volumetric imaging with real-time tension or force feedback using a tethered imaging device |
US10912947B2 (en) | 2014-03-04 | 2021-02-09 | Memorial Sloan Kettering Cancer Center | Systems and methods for treatment of disease via application of mechanical force by controlled rotation of nanoparticles inside cells |
US10228556B2 (en) | 2014-04-04 | 2019-03-12 | The General Hospital Corporation | Apparatus and method for controlling propagation and/or transmission of electromagnetic radiation in flexible waveguide(s) |
US10912462B2 (en) | 2014-07-25 | 2021-02-09 | The General Hospital Corporation | Apparatus, devices and methods for in vivo imaging and diagnosis |
US10688202B2 (en) | 2014-07-28 | 2020-06-23 | Memorial Sloan-Kettering Cancer Center | Metal(loid) chalcogen nanoparticles as universal binders for medical isotopes |
WO2016028749A1 (en) * | 2014-08-20 | 2016-02-25 | Memorial Sloan Kettering Cancer Center | Raman-triggered ablation/resection systems and methods |
US10919089B2 (en) | 2015-07-01 | 2021-02-16 | Memorial Sloan Kettering Cancer Center | Anisotropic particles, methods and uses thereof |
US10460439B1 (en) | 2015-08-12 | 2019-10-29 | Cireca Theranostics, Llc | Methods and systems for identifying cellular subtypes in an image of a biological specimen |
Also Published As
Publication number | Publication date |
---|---|
AU2519892A (en) | 1993-03-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO1993003672A1 (en) | Optical histochemical analysis, in vivo detection and real-time guidance for ablation of abnormal tissues using a raman spectroscopic detection system | |
EP3324832B1 (en) | Systems for lesion formation and assessment | |
US6208887B1 (en) | Catheter-delivered low resolution Raman scattering analyzing system for detecting lesions | |
US7979107B2 (en) | System and method for differentiation of normal and malignant in vivo liver tissues | |
US20080125634A1 (en) | Method and apparatus for identifying and treating myocardial infarction | |
EP2249737B1 (en) | Biopsy guidance by electromagnetic tracking and photonic needle | |
EP2015672B1 (en) | Fiber optic evaluation of tissue modification | |
US7499153B2 (en) | Use of high wavenumber Raman spectroscopy for measuring tissue | |
US5318023A (en) | Apparatus and method of use for a photosensitizer enhanced fluorescence based biopsy needle | |
US6201989B1 (en) | Methods and apparatus for detecting the rejection of transplanted tissue | |
KR100623212B1 (en) | System and method for controlling tissue ablation | |
JP2003102672A (en) | Method and device for automatically detecting, treating, and collecting objective site of lesion or the like | |
JP2002505900A (en) | Optical student examination device and tissue diagnosis method | |
JP2008522697A (en) | Raman spectroscopic analysis of subsurface tissues and fluids | |
WO2009144653A2 (en) | Needle with integrated photon detector | |
US20100069760A1 (en) | Methods and apparatus for analyzing and locally treating a body lumen | |
WO2022026625A1 (en) | Systems and methods for lesion formation and assessment | |
US20050165288A1 (en) | Systems and methods for treating breast tissue | |
Zharkova et al. | Laser-excited fluorescence spectrometric system for tissue diagnostics | |
Vo-Dinh et al. | Laser-induced fluorescence for the detection of esophageal and skin cancer | |
US20230404373A1 (en) | Magnetic catheter | |
Lyutskanov et al. | Autofluorescence spectra analysis of human arteries | |
Chen et al. | Laser-induced fluorescence spectroscopy of human normal and cancerous tissues | |
Manolopoulos et al. | Comparative studies of Laser Induced Fluorescence and Intravascular Ultrasound for the human coronary artery diagnosis of atherosclerosis | |
Katzir | Fiberoptic techniques in medicine and biology |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AT AU BB BG BR CA CH CS DE DK ES FI GB HU JP KP KR LK LU MG MN MW NL NO PL RO RU SD SE |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL SE BF BJ CF CG CI CM GA GN ML MR SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
122 | Ep: pct application non-entry in european phase | ||
NENP | Non-entry into the national phase |
Ref country code: CA |