Optical imaging of induced signals in vivo under ambient light conditions

• US 20040010192A1
• Filed: 05/13/2003
• Published: 01/15/2004
• Est. Priority Date: 06/15/2000
• Status: Active Grant

• Current Assignee: JB IP Acquisitions LLC
• Original Assignee: Spectros Corporation (AliphCom Corp.)
• Inventors: Benaron, David A., Parachikov, Ilian H., Talmi, Yair
• Granted Patent: US 7,668,587 B2
• Time in Patent Office: Days
• US Class Current: 600/431
• CPC Class Codes: A61B 2503/40 Animals
• CPC Class Codes: A61B 5/0071 by measuring fluorescence emission
• 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 5/415 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 5/7285 for synchronising or triggering a physiological measurement or image acquisition with a physiological event or waveform, e.g. an ECG signal A61B6/5205, A61B6/541, A61B8/5207, A61B8/543 take precedence
• 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

Abstract

A method for detecting and localizing a target tissue within the body in the presence of ambient light in which an optical contrast agent is administered and allowed to become functionally localized within a contrast-labeled target tissue to be diagnosed. A light source is optically coupled to a tissue region potentially containing the contrast-labeled target tissue. A gated light detector is optically coupled to the tissue region and arranged to detect light substantially enriched in target signal as compared to ambient light, where the target signal is light that has passed into the contrast-labeled tissue region and been modified by the contrast agent. A computer receives signals from the detector, and passes these signals to memory for accumulation and storage, and to then to image processing engine for determination of the localization and distribution of the contrast agent. The computer also provides an output signal based upon the localization and distribution of the contrast agent, allowing trace amounts of the target tissue to be detected, located, or imaged. A system for carrying out the method is also described.

Claims

1. A method of detecting a target tissue within a living subject in ambient light, comprising:

(a) illuminating the subject in ambient light with additional light from a light source, said source selected such that a target tissue may interact with and modify the illuminating light;

(b) providing a gated light detector;

(c) optically coupling the light detector to the subject;

(d) gating the detector, said gating performed such that the detector detects light substantially enriched in said modified light with respect to said ambient light;

(e) determining a measurable parameter of said target tissue using an analysis of the detected light, said parameter being more accurately or reliably determinable with said gating; and

,

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

2. The method of claim 1, wherein said detector is an imaging digital camera and said output signal is an image.

3. The method of claim 1 including the step of illuminating with additional light illuminates in short light pulses synchronized with detector gating.

4. A method of imaging target cells within a living subject in ambient light by enhancing the weak native signal of the target cells, comprising:

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

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

(c) illuminating the subject with light from a light source, said light source selected such that the contrast agent in vivo may interact with and modify the illuminating light, and said light source further arranged so as to be temporally variable in intensity;

(d) providing a time-gated camera optically coupled to said subject, and using said camera to monitor or image said subject;

(e) gating said camera as a function of said temporal variations of light source intensity such that said camera detects light enriched in said modified light with respect to ambient light;

(f) determining a measurable parameter of the target cells 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.

5. The method of claim 4 wherein the optical contrast agent is selected from the group of contrast agents consisting of isosulfan blue or other absorbing contrast agents, indocyanine green, cyanine dyes, 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.

6. The method of claim 4 wherein the step of administering the contrast agent includes a step selected from injection, ingestion, viral delivery, or synthesis within the subject using genetic mechanisms or encapsulated biofactories.

7. The method of claim 4 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.

8. The method of claim 4 wherein the step of administering the contrast agent includes the step of administering multiple optical contrast agents, and wherein the step of determination is based upon a function of the distribution and localization of each of said multiple contrast agents to yield a measure of signal depth.

9. The method of claim 4, wherein said contrast agent further requires an activation, inactivation, or synthesis step in vivo.

10. The method of claim 9, wherein said contrast agent is selected from the list of activatable agents consisting of cleavable indocyanine dye, acid-cleavable transferring bound dyes, and other activatable contrast agents.

11. The method of claim 4, wherein the optical contrast is coupled to a targeting moiety.

12. The method of claim 11, 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.

13. The method of claim 12 wherein said antibody is targeted to prostate specific membrane antigen.

14. The method of claim 13 wherein said antibody is targeted to the extracellular domain of membrane-bound prostate specific membrane antigen.

15. The method of claim 12 wherein said antibody is targeted against prostate specific core antigen.

16. The method of claim 4, wherein said contrast agent is a albumin-binding fluorescent dye, 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.

17. The method of claim 4, wherein said contrast agent is a fluorescent dye coupled to a antibody targeted toward breast cells of epithelial origin, said administration consists of intravenous injection, and said output signal is detection of the presence and location of tumor-positive lymph nodes.

18. The method of claim 4, wherein said camera is coupled to 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.

19. The method of claim 4, wherein said camera is suspended over the surgical field during radical prostatectomy, said contrast agent is targeted to a prostate-specific receptor, said administration consists of intravenous injection, and said output signal is a real-time image related to the presence and location of trace residual prostate cells in the surgical bed after prostate removal.

20. The method of claim 4, 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.

21. The method of claim 4, further including the step of comparison to a reference signal.

22. The method of claim 4, further including the step of comparison to a baseline signal in the absence of contrast.

23. The method of claim 4, wherein said measurable parameter is a function of the local environment of said contrast agent, such as pH or receptor internalization.

24. The method of claim 4, wherein said measurable parameter is a function of the depth of the target signal

25. A system for externally or internally measuring a target tissue within the body of a living subject in background room light, 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 gated light collector for collecting a portion of said modified radiation, said gated portion enriched in said modified radiation with respect to said background radiation, and for providing a detected signal in response to said collected portion;

(d) 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

(e) means for generating an output signal in response to said determination.

26. The system of claim 25, wherein said background room light is the ambient light in a surgical operating room.

27. The system of claim 25, wherein said light source is further comprised of multiple light sources.

28. The system of claim 25, wherein said illuminating radiation has at least one wavelength between 200 nm and 2 μ

m.

29. The system of claim 25, wherein said light collector is further comprised of multiple light detector elements.

30. The system of claim 29, wherein said multiple detector elements comprise an ICCD digital camera.

31. The system of claim 25, wherein said measurable parameter is the presence or absence of said target tissue in the body.

32. The system of claim 25, wherein said measurable parameter is a localization of said target tissue within the body in at least one dimension.

33. The system of claim 32, wherein said localization is a direction of said target tissue.

34. The system of claim 32, wherein said localization is a distance to said target tissue.

35. The system of claim 32, wherein said localization is a function of the depth of said target tissue.

36. The system of claim 25, wherein said measurement function is an image of the distribution of said target tissue within a region of the body.

37. The system of claim 25, wherein said measurement function is based upon an optical feature selected from the group of features consisting of absorbence, 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.

38. 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 and waiting until the contrast agent has achieved adequate distribution and localization within the body;

(b) providing a medical or surgical instrument, and using said instrument during an invasive medical or surgical procedure upon the subject;

(c) illuminating the subject with light from a light source in the presence of ambient light;

(d) providing a gated light imager;

(e) detecting modified light with said gated imager after possible interaction and modification of the source light by the contrast agent in vivo, said gating performed such that said imager detects light substantially enriched in said modified light with respect to said ambient light;

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

,

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

39. The method of claim 38, wherein said status comprises a location of the instrument.

40. The method of claim 38, wherein said status comprises the efficacy of a therapeutic intervention.

41. A system for targeting an invasive medical device or instrument toward a target location in a living subject in the presence of ambient light, 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 gated light collector for collecting a portion of the modified illuminating radiation, said collected portion having passed through an opaque region of the body and said collector optically coupled to the body, said gating performed such that said collector detects light substantially enriched in said modified illuminating radiation with respect to said ambient light, 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;

(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

(f) means for producing an output signal in response to said determination.

42. The system of claim 41, wherein said positional estimate is a function of the accuracy of placement of the probe at said target location.

43. The system of claim 42, wherein said function of the accuracy of placement is a true or false indication as to whether or not the probe is accurately placed.

44. The system of claim 41, wherein said positional estimate is a direction of a target tissue.

45. The system of claim 41, wherein said positional estimate is a distance to a target tissue.

46. The system of claim 41, wherein said positional estimate is a localization of the device with respect to tissue type.

47. 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-influenced prostate cell surface antigens;

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

(c) illuminating the subject with light from a light source;

(d) providing a gated imaging detector;

(e) detecting light with said light detector after passage of the source light through an opaque region of the body and after 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.

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

(a) intravenously administering an optical contrast agent to the subject, said agent selected so as to provide enhanced contrast between normal and cancerous breast tissue;

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

(c) providing a minimally invasive tissue removal device or instrument 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 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.

49. 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 other 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, after having passed through an opaque region of the body of the subject potentially containing said contrast agent and influenced by said contrast solution, said light collection providing a 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 source, said light collector, or both; and

,

(e) means for determining the location of said sentinel nodes, said determination based upon said detected signal; and

(f) means for generating an output signal related to a distribution and localization of said sentinel nodes in response to said determination.

50. A medical system for determining the presence or absence of recurrent 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 multi-element light collector for collecting a portion of said fluorescent radiation after having passed through an opaque region of the prostate and modified by the contrast agent, said multi-element light collector providing a detected signal in response to said collected portion;

(d) a medical ultrasound probe for rectal use during said prostate examination, said medical 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

(f) means for generating an output image related to a distribution and localization of said contrast agent in response to said determination.

51. A method for producing clean margins during prostate surgery, comprising:

(a) administering to the patient an optical contrast agent targeted to epithelial cells of prostate origin;

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

(c) providing a gated imaging detector;

(d) illuminating the subject with light from a 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 interaction and modification of the source light by the contrast agent;

(f) determining the location of residual cells of prostate origin within the surgical prostatectomy site, based upon the modified, detected light;

(g) removing tissue identified as prostate tissue; and

(h) repeating steps (d) through (g) until the amount of residual prostate tissue falls below a predetermined threshold.