Imaging of light scattering tissues with fluorescent contrast agents

• US 20020072677A1
• Filed: 05/31/2001
• Published: 06/13/2002
• Est. Priority Date: 08/23/1996
• Status: Active Grant

• Current Assignee: Texas A&M University System
• Original Assignee: Texas A&M University System
• Inventors: Reynolds, Jeffery S., Sevick-Muraca, Eva, Troy, Tamara L.
• Granted Patent: US 7,328,059 B2
• Time in Patent Office: Days
• US Class Current: 600/473
• CPC Class Codes: A61B 5/0059 using light, e.g. diagnosis by transillumination, diascopy, fluorescence A61B5/0093, A61B5/1455, A61B5/02416 and A61B5/0261 take precedence
• 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

Abstract

A system and method for non-invasive biomedical optical imaging and spectroscopy with low-level light is described. The technique consists of a modulated light source coupled to tissue to introduce excitation light. Fluorescent light emitted in response to the excitation light is detected with a sensor. The AC intensity and phase of the excitation and detected fluorescent light is provided to a processor operatively coupled to the sensor. A processor employs the measured emission kinetics of excitation and fluorescent light to “map” the spatial variation of one or more fluorescence characteristics of the tissue and generate a corresponding image of the tissue via an output device. The fluorescence characteristic may be provided by exogenous contrast agents, endogenous fluorophores, or both. A technique to select or design an exogenous fluorescent contrast agent to improve image contrast is also disclosed.

Claims

1. A method, comprising:

introducing an exogenous fluorescent contrast agent into a biologic tissue, the tissue multiply scattering light with a mean time-of-flight, and the agent having a fluorescence lifetime within a factor of about ten of the mean time-of-flight;

exposing the tissue to an excitation light with a predetermined time-varying intensity;

detecting a light emission from the tissue in response to said exposing;

generating an image of the tissue by mapping spatial variation of a level of a fluorescence characteristic of the tissue from the light emission in accordance with a mathematical expression modeling multiple light scattering behavior of the tissue; and

wherein the agent is selected in accordance with a predetermined relationship between degree of image contrast and at least one of fluorescence yield or the fluorescence lifetime.

5. The method of any of claims 1, 3, or 4, wherein the at least one is fluorescence lifetime.

6. The method of claims 1, 2, or 5, wherein the fluorescence lifetime is in a range of about 0.1 to 10 nanoseconds.

7. The method of claim 1, 2, or 5, wherein the fluorescence lifetime is in a range of about 0.5 to 5 nanoseconds.

8. The method of claim 1, 2, or 5, wherein the fluorescence lifetime is in a range of about 0.2 to 2 nanoseconds.

10. The method of any of claims 1-3 or 9 wherein the mathematical expression corresponds to a diffusion equation approximation of multiply scattered light.

11. The method of claim 10, further comprising applying the diffusion equation approximation in a frequency domain form.

13. The method of claim 1 or 12, wherein the fluorescence characteristic is at least one of fluorescence lifetime, fluorescence yield, or fluorescence quantum efficiency.

14. The method of any of claims 1, 12, or 13, wherein said generating includes determining a modulation amplitude change and a phase change of the light emission relative to the excitation light.

15. The method of any of claims 1, 13, or 14, wherein the fluorescence characteristic corresponds to the fluorescence lifetime.

17. The method of claim 1 or 3, wherein the mathematical expression is in a frequency domain form and the image contrast is provided in terms of at least one of phase shift contrast or modulation contrast.

2. A method, comprising:

selecting a fluorescent contrast agent as a function of a predetermined time-of-flight for a tissue to be imaged in accordance with a mathematical expression modeling the behavior of multiply scattered light traveling through the tissue, the fluorescent contrast agent having a fluorescence lifetime within a factor of ten of the predetermined time-of-flight; and

providing the fluorescent agent for introduction into the tissue.

12. The method of any of claims 2-4, further comprising generating an image of the tissue by mapping spatial variation of a level of a fluorescence characteristic of the tissue.

3. A method, comprising:

evaluating ability of a number of fluorescent agents to provide image contrast between different tissue types, said evaluating including determining a relationship between degree of image contrast and at least one of fluorescence lifetime or fluorescence yield of the agent;

selecting one of the agents based on said evaluating; and

providing the selected one of the agents for introduction into a biologic tissue to enhance imaging performed in accordance with a mathematical expression modeling the behavior of multiply scattered light traveling through the tissue.

4. A method, comprising:

exposing a biologic tissue to a first excitation light;

detecting a first emission from the tissue in response to the first excitation light;

introducing a fluorescent contrast agent into the tissue after said detecting;

exposing the tissue after said introducing to a second excitation light;

sensing a second emission in response to the second excitation light;

comparing data corresponding to the first emission with data corresponding to the second emission to evaluate contrast provided by the agent as a function of at least one of fluorescence lifetime, fluorescence yield, or quantum efficiency.

9. The method of claim 4, further comprising evaluating the first and s second emissions with a mathematical expression modeling the behavior of multiply scattered light traveling through the tissue.

16. The method of claim 4, wherein wavelength of the first excitation light is generally the same as wavelength of fluorescent light emitted by the agent in response to the second excitation light.