Detecting, localizing, and targeting internal sites in vivo using optical contrast agents

• US 6,167,297 A
• Filed: 05/05/1999
• Issued: 12/26/2000
• Est. Priority Date: 05/05/1999
• Status: Expired due to Term

• Current Assignee: JB IP Acquisitions LLC
• Original Assignee: David A. Benaron
• Inventors: Benaron, David A.
• Primary Examiner(s): Walberg, Teresa
• Assistant Examiner(s): ROBINSON, DANIEL LEON
• Application Number:
  US09/305,855
• Time in Patent Office: 601 Days
• Field of Search: 600/431, 600/407, 600/411, 250/302, 250/303, 424/1, 424/1.1, 424/1.2, 424/1.21, 424/1.22, 424/1.23, 424/1.24, 424/1.25
• US Class Current: 600/431
• CPC Class Codes: A61B 2562/0238 Optical sensor arrangements for performing transmission measurements on body tissue
• CPC Class Codes: A61B 5/0071 by measuring fluorescence emission
• CPC Class Codes: A61B 5/0073 by tomography, i.e. reconstruction of 3D images from 2D projections A61B5/0066 takes precedence
• CPC Class Codes: A61B 5/0075 by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy A61B5/0071 takes precedence
• CPC Class Codes: A61B 5/0084 for introduction into the body, e.g. by catheters A61B5/1459 takes precedence
• CPC Class Codes: A61B 5/0091 for mammography
• CPC Class Codes: A61B 5/1455 using optical sensors, e.g. spectral photometrical oximeters
• CPC Class Codes: A61B 5/415 the glands, e.g. tonsils, adenoids or thymus
• CPC Class Codes: A61B 5/418 lymph vessels, ducts or nodes
• CPC Class Codes: A61B 5/4381 Prostate evaluation or disorder diagnosis
• CPC Class Codes: A61B 5/6848 Needles
• CPC Class Codes: B82Y 10/00 Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
• CPC Class Codes: B82Y 20/00 Nanooptics, e.g. quantum optics or photonic crystals
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: G01N 33/57415 of breast
• CPC Class Codes: G01N 33/57434 of prostate
• CPC Class Codes: Y10S 977/869 Optical microscope
• CPC Class Codes: Y10S 977/904 for medical, immunological, body treatment, or diagnosis

Abstract

A system for detecting, localizing and targeting a medical instrument toward a target tissue within the body using an optical contrast agent in which a light source (102) is optically coupled to the tissue to be diagnosed (135), a light detector (174) is optically coupled to the tissue to detect a portion of the light which passes through the tissue, and either one or both of the light source and light detector are coupled to a medical instrument (130) used in a medical procedure. A contrast locator engine (184) receives a signal from the detector and provides an target tissue output signal (195) based upon the localization and distribution of the contrast agent, allowing the target tissue to be detected, located, or imaged, and for the medical instrument to positioned or targeted relative to the target tissue, and for allowing the accuracy of placement or the progress of a procedure to be assessed in real time. A method for the system is also described.

Claims

1. A method of externally or internally measuring a target site within a living subject, comprising:

(a) administering to the subject an optical contrast agent selected so as to provide measurable contrast for said target site in vivo;

(b) waiting until said contrast agent has achieved sufficient distribution and localization within the body;

(c) providing a medical device or instrument optically coupled to a light source, a light detector, or both, and using said device or instrument during a medical or surgical procedure upon the subject;

(d) illuminating the subject with light from the light source, said light source selected such that the contrast agent in vivo may interact with and modify the illuminating light;

(e) detecting modified illuminating light after passage through an opaque region of the body using the light detector;

(f) determining a measurable parameter of the target site using the detected light based upon a function of the distribution and localization of said contrast agent; and

,

(g) generating an output signal in response to said determination.

2. The method of claim 1 wherein the optical contrast agent is selected from the group of contrast agents consisting of isosulfan blue or other absorbing contrast agents, indocyanine green, porphyrins, or other fluorophores, methyl red or other biologically responsive dyes, colored or fluorescent proteins and other gene products, quantum dots and other spectroscopically distinct physical constructs, contrast-filled micelles, or other optical contrast agents.

3. The method of claim 1 wherein the step of administering the contrast agent includes the step of injection, ingestion, viral delivery, or synthesis within the subject using genetic mechanisms or encapsulated biofactories.

4. The method of claim 1 wherein the step of administering the contrast agent includes the step of administering multiple optical contrast agents, each targeted to a different receptor, and wherein the step of determination is based upon a function of the distribution and localization of said multiple contrast agents.

5. The method of claim 1, wherein said contrast agent further requires an activation, inactivation, or synthesis step in vivo.

6. The method of claim 5, wherein said contrast agent is selected from the list of activatable agents consisting of cleavable indocyanine dye, acid-cleavable transferrin bound dyes, and other activatable contrast agents.

7. The method of claim 1, wherein the optical contrast is coupled to a targeting moiety.

8. The method of claim 7, wherein the targeting moiety is selected from the list of targeting moieties consisting of antibodies, antibody fragment, receptor binding site or substance, and translocator binding site or substance.

9. The method of claim 1, wherein said medical instrument is a scanning optical probe, said contrast agent is isosulfan blue, said administration consists of injection into the margin of a tumor, and said output signal is detection of the presence and location of contrast-absorbing sentinel lymph nodes.

10. The method of claim 1, wherein said medical instrument is a modified rectal ultrasound probe, said contrast agent is targeted to a prostate-specific receptor, said administration consists of oral ingestion, and said output signal is an ultrasound image overlaid with the presence and location of prostate cancer.

11. The method of claim 1, wherein one or more of steps (a) through (g) are repeated at one or more points in time, wherein said repeating is effective to track the said distribution and localization of said agent over time.

12. The method of claim 1, further including the step of comparison to a reference signal.

13. The method of claim 1, further including the step of comparison to a baseline signal in the absence of contrast.

14. The method of claim 1, wherein said measurable parameter is a function of the local environment of said contrast agent.

15. A system for externally or internally measuring a target tissue within an opaque portion of the body of a living subject, comprising:

(a) an optical contrast agent for providing a source of contrast, said agent selected so as to provide a differential contrast between said target tissue and other tissues, and said agent administered to the subject so as to have achieved distribution and localization within the body;

(b) a light source for illuminating a portion of said subject with illuminating radiation, said distributed contrast agent at least potentially disposed to interact with and modify said illuminating radiation;

(c) a light collector for collecting a portion of said radiation, said collected portion having passed through an opaque region of the body of the subject, and for providing a detected signal in response to said collected portion;

(d) a medical instrument for use on or within said subject during a medical procedure, said medical instrument coupled to said light emitter, said light collector, or both; and

,

(e) means for determining a measurable parameter of said target tissue based upon said detected signal, said measure based upon a measurement function of said distribution and localization of said contrast agent, and for generating an output signal in response to said determination.

16. The system of claim 15, wherein said light source is further comprised of multiple light sources.

17. The system of claim 15, wherein said illuminating radiation has at least one wavelength between 200 nm and 2 μ

m.

18. The system of claim 15, wherein said light collector is further comprised of multiple light detector elements.

19. The system of claim 18, wherein said multiple detector elements comprise a CCD array.

20. The system of claim 15, wherein said measurable parameter is a detection of the presence or absence of said target tissue in the body.

21. The system of claim 15, wherein said measurable parameter is a localization of said target tissue within the body in at least one dimension.

22. The system of claim 15, wherein said measurable parameter is a direction of said target tissue.

23. The system of claim 15, wherein said measurable parameter is a distance to said target tissue.

24. The system of claim 15, wherein said output signal is an image of the distribution of said target tissue within the body.

25. The system of claim 15, wherein said measurement function is based upon an optical feature selected from the group of features consisting of absorbance, fluorescence, Raman shift, excitation-emission maps, optical rotation, fluorescence decay, phase shift, time delay, or other optical features related to the interaction of said contrast agent with said illuminating radiation.

26. A method for targeting an invasive medical device or instrument toward a target location in a living subject, comprising:

(a) administering an optical contrast agent to the subject;

(b) waiting until the contrast agent has achieved adequate distribution and localization within the body;

(c) providing a medical instrument that is optically coupled to a light source, a light detector, or both, and using said instrument during an invasive medical or surgical procedure upon the subject;

(d) illuminating the subject with light from said light source;

(e) detecting modified light with said light detector after passage of the source light through an opaque region of the body and after possible interaction and modification of the source light by the contrast agent;

(f) determining the present location of the medical device or instrument with respect to said target location based upon the modified, detected light; and

,

(g) generating an output signal in response to said determination.

27. A system for targeting an invasive medical device or instrument toward a target location in a living subject, comprising:

(a) a contrast agent, said contrast agent administered to the subject so as to have achieved distribution and localization within the subject;

(b) a light emitter for illuminating a portion of the subject with illuminating radiation, said emitter optically coupled to the subject, and said administered contrast agent potentially disposed to interact with and modify said illuminating radiation;

(c) a light collector for collecting a portion of the illuminating radiation, said collected portion having passed through an opaque region of the body and said collector optically coupled to the body, and for providing a detected signal in response to said collected portion;

(d) a medical instrument for use within said subject during an invasive procedure, said medical instrument coupled to said light emitter, said light collector, or both;

(e) means for determining a positional estimate of the present location of said medical device or instrument with respect to a target location based upon said detected signal, said measure based upon a measurement function of said distribution and localization of said contrast agent in relation to a position of said medical device, and for producing an output signal in response to said determination.

28. The system of claim 27, wherein the optical coupling of the emitter, the collector, or both emitter and collector, to the subject is achieved by tissue penetration.

29. The system of claim 27, wherein said positional estimate is a finction of the accuracy of placement of the probe at said target location.

30. The system of claim 29, wherein said function of the accuracy of placement is a true or false indication as to whether or not the probe is accurately placed.

31. The system of claim 27, wherein said positional estimate is a direction of a target tissue.

32. The system of claim 27, wherein said positional estimate is a distance to a target tissue.

33. The system of claim 27, wherein said positional estimate is a localization of the device with respect to tissue type.

34. A method for targeting a prostate biopsy needle toward potential prostate cancer sites in a patient, comprising:

(a) administering to the patient an optical contrast agent targeted to cancer-specific prostate cell surface antigens;

(b) waiting until the contrast agent has achieved adequate distribution and localization within the body;

(c) providing a biopsy needle that is optically coupled to a light source, a light detector, or both, and inserting the needle into the patient'"'"'s prostate;

(d) illuminating the subject with light from said light source;

(e) detecting modified light with said light detector after passage of the source light through an opaque region of the body and after possible interaction and modification of the source light by the contrast agent;

(f) determining the present location of the biopsy needle with respect to the prostate cancer, based upon the modified, detected light; and

,

(g) positioning the biopsy needle at an identified potential cancer site and collecting a biopsy sample at that site;

(h) repeating steps (d) through (g) until a sufficient number of prostate biopsy samples have been collected.

35. A method for removing a breast tumor using a minimally invasive medical probe, comprising:

(a) intravenously administering an optical contrast agent to the subject;

(b) waiting until the contrast agent has achieved adequate distribution and localization within the body;

(c) providing a minimally invasive tissue removal device that is optically coupled to a light source, a light detector, or both, and using the device or instrument during an minimally invasive lumpectomy procedure upon the subject;

(d) illuminating the subject with light from the light source such that the contrast agent in vivo may interact with and modify the illuminating light;

(e) detecting modified light with the light detector after passage of source light through an opaque region of the body and possible interaction and modification of the source light by the contrast agent;

(f) determining a positional estimate of the present location of the medical device or instrument with respect to any remaining breast cancer based upon said modified, detected light; and

,

(g) generating an output signal in response to said measurement;

(h) removing tissue identified as breast cancer; and

,

(i) repeating steps (d) through (h) until a diagnostic or therapeutic endpoint is reached.

36. A medical system for determining the location of one or more sentinel nodes in breast cancer during a lymph node biopsy, comprising:

(a) a contrast solution of isosulfan blue for providing a source of contrast between said sentinel node tissue and normal lymph tissues, said agent injected into the periphery of said breast cancer so as to have achieved distribution and localization within the lymph nodes;

(b) a white light source for illuminating a portion of said subject with illuminating radiation;

(c) a light collector for collecting a portion of said illuminating radiation, said collected portion having passed through an opaque region of the body of the subject potentially containing said contrast agent, and for providing a contrast influenced detected signal in response to said collected portion;

(d) a medical probe for use on or within said subject during said node biopsy, said medical probe coupled to said light emitter, said light collector, or both; and

,

(e) means for determining the location of said sentinel nodes, said determination based upon said detected signal, and for generating an output signal related to a distribution and localization of said sentinel nodes in response to said determination.

37. A medical system for determining the presence or absence of prostate cancer during a rectal diagnostic procedure, comprising:

(a) a fluorescent contrast agent targeted to cancer-specific surface antigens for providing a source of contrast between prostate cancer cells and normal prostate tissues, said agent ingested orally and systemically absorbed so as to have achieved distribution and localization within the prostate;

(b) a monochromatic intensity modulated light source for illuminating the prostate with illuminating radiation, said distributed contrast agent at least potentially disposed to fluoresce in response to said illuminating radiation;

(c) a multielement light collector for collecting a portion of said fluorescent radiation, said collected portion having passed through an opaque region of the prostate, and for providing a detected phase and intensity signal in response to said collected portion;

(d) a medical ultrasound probe for rectal use during said prostate examination, said medical ultrasound probe coupled to said light emitter, said light collector, or both; and

,

(e) means for determining the presence and location of prostate cancer based upon said detected signal, and for generating an output image related to a distribution and localization of said contrast agent in response to said determination.