Systems and methods for imaging fluorophores

Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation

Reexamination Certificate

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C250S458100, C356S318000

Reexamination Certificate

active

06304771

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to imaging of objects. More specifically, this invention relates to methods and apparatus for imaging objects using diffuse light.
BACKGROUND OF THE INVENTION
Techniques for imaging objects have been used for nearly a century in the medical arts for diagnosing and understanding the myriad diseases and maladies that afflict the human body. Imaging techniques have also found use in such diverse fields as radio astronomy, sonar, radar and other fields which require information about an object which is not readily visible to the naked eye and therefore not easily examined. Medical imaging techniques include, for example, X-ray imaging, positron emission tomography (PET), ultrasound imaging and the well known magnetic resonance imaging (MRI).
In all of the imaging techniques mentioned above, narrow band frequency radiation illuminates the object of interest to produce reflected or emitted radiation which is then gathered from the object by a detector. The reflected or emitted radiation is then processed by an imaging algorithm to obtain useful information about the object.
In medical applications, the use of ionizing radiation in imaging, for example with X-rays, involves significant health risks to a patient when the patient is exposed to the radiation for prolonged periods of time or in multiple imaging schemes. Furthermore, certain of these imaging techniques undesirably involve the use of invasive procedures which are both costly and painful. Yet other techniques such as MRI do not yield consistently useful clinical results.
There has thus arisen in the medical imaging art an interest in developing non-invasive, safe and relatively fast techniques which can take advantage of the natural scattering of visible and infrared light through media containing objects to be imaged. Techniques using diffuse light could be used in conjunction with other imaging schemes such as X-ray imaging or MRI to produce highly useful clinical images for diagnostic purposes.
Much of the progress in imaging with diffusive light has focused on ballistic techniques using lasers. With these techniques, an intense pulsed laser illuminates a sample. By time gating photons that have been scattered only a few times and rejecting all other photons, the optical absorption of the medium and objects found therein can be mapped. This technique works best when the allowed time window is short and the photons deviate the least from their “ballistic” trajectory. Unfortunately, the transmittal intensity of unscattered photons diminishes exponentially with increasing sample thickness.
Because of the limitations of ballistic imaging, it is difficult to obtain high quality images of relatively thick objects with low power lasers. Examples of ballistic imaging techniques are disclosed in K. M. Yoo, F. Lie and R. R. Alfano,
Optics Letters
, Vol. 16, p. 1068 (1991), and in D. A. Benaron and D. K. Stevenson,
Science
, Vol. 259, p. 1463 (1993).
A second technique for imaging using diffuse light is optical phase modulation. Phase modulation techniques have permitted the location of single absorbers using low power, continuous wavelength lasers. In accordance with these techniques, an amplitude modulated source creates photon density waves that acquire anomalous phase shifts due to the absorber. For the case of a single absorber, the distortions are readily interpreted; however for a more complicated object a general analysis is required.
An example of imaging with diffuse light is disclosed in U.S. Pat. No. 5,119,815, Chance where scattered light was applied to a biological imaging application. The Chance patent discloses a technique for solving the diffusion equation for a homogeneous medium to obtain the overall optical absorption characteristics. This was possible for the homogeneous medium because the long time limit of the logarithmic derivative of the detected intensity yields the absorption characteristics directly. Thus the absorption characteristics for uniform structures may be obtained with the methods and apparatus disclosed in the Chance patent.
Still other attempts to image with diffuse light are disclosed in U.S. Pat. No. 5,070,455, Singer et al. In the Singer et al. system, light intensities are measured at many sensor positions (pixels), initial values of absorption or scattering coefficients are assigned at each pixel, and then a new set of intensities at each pixel is calculated. The calculated intensities are compared to the real intensities, and the intensity differences are used to generate a subsequent interaction of absorption or scattering values for each pixel.
The methods described in Singer et al. usually require many iterations since the absorption or scattering values may not converge rapidly. Furthermore, the Singer et al. system utilizes cumbersome Monte-Carlo statistical techniques which consume large amounts of processing time without guaranteeing computational success. Singer et al.'s methods may also produce false local minima providing misleading results for the absorption characteristics.
Thus prior imaging techniques using diffuse light for scattering fail to solve a long-felt need in the art for robust imaging techniques which can produce reliable images in biological systems. Solution of the aforementioned problems has heretofore eluded the medical imaging art.
SUMMARY OF THE INVENTION
The aforementioned deficiencies in the imaging art are overcome by methods and apparatus provided in accordance with the present invention which provide imaging of objects in turbid media using diffuse light.
In a preferred embodiment of the invention an imaging system comprises an illumination source that generates oscillatory diffuse photon density waves to illuminate the object, a detector for detecting diffuse photon density waves produced as a result of the diffuse photon density waves interacting with the object, and a processor interfaced with the detector for processing data corresponding to the photon density waves detected by the detector to determine at least a position of the object. The turbid medium and the object have associated therewith at least one diffusion coefficient and the diffuse photon density waves which illuminate the object diffract around or refract through the object as a result of their interaction with it, thereby producing a distorted wavefront such that after the detector means detects the distorted wavefront the processor determines the diffusion coefficient of the turbid medium and the object. More preferably, the processor constructs phase and amplitude contours corresponding to propagation of the distorted wavefront and further determines at least the position of the object from the phase and amplitude contours, thereby imaging the object.
In yet a further preferred embodiment of imaging systems provided in accordance with the invention, a display are interfaced with the processor for displaying the image of the object, the illumination comprises at least one laser, and the detector comprises an optical fiber interfaced with a photomultiplier tube.
Further aspects of the invention provide imaging of a fluorescent object such that the diffuse photon density waves having a first wavelength cause the object to fluoresce, thereby producing re-radiated diffuse photon density waves having a second wavelength such that after the detector detects the re-radiated diffuse photon density waves, the processor can image the object.
In the embodiment of the invention where fluorescent, re-radiated diffuse photon density waves are detected, the illumination source preferably comprises a plurality of lasers oriented around the object which alternately irradiate the object with the diffuse photon density waves of the first wavelength to cause the object to fluoresce. The detector comprises an optical fiber that is placed in proximity to the object and a photomultiplier tube interfaced to the optical fiber. The imaging system further comprises switch means interfaced with each of the plurality of lasers for alternately and

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