Surgery – Diagnostic testing – Measuring or detecting nonradioactive constituent of body...
Reexamination Certificate
1999-07-13
2001-04-17
Winakur, Eric F. (Department: 3736)
Surgery
Diagnostic testing
Measuring or detecting nonradioactive constituent of body...
C600S322000, C600S310000, C356S317000
Reexamination Certificate
active
06219566
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method and device for measuring concentrations of luminescent materials in turbid media, and more particularly the invention relates to measurement of fluorophore concentrations in turbid media such as tissue in vivo using a combined fluorescence/reflectance measurement technique.
BACKGROUND OF THE INVENTION
Light directed into a turbid medium undergoes two phenomena; scattering and absorption. In tissue, for example, the amount of scattering is determined by the tissue structure such as cell and mitochondria size, while the absorption is determined by the quantity of endogenous absorbers such as melanin and porphyrins (e.g. hemoglobin in blood). Different tissue types scatter and absorb light in different amounts, i.e. liver versus muscle. Many recent pharmacokinetic studies are using fluorescent drugs to monitor body processes. Also, new forms of cancer treatments use fluorescent drugs. These treatment methods require accurate knowledge of the drug concentration for proper treatment.
A possible method of determining the concentration of the fluorescent drug is to measure its fluorescence. The strength of the fluorescence signal however, will depend on the intensity of excitation light, and the scattering and absorption properties of the turbid medium.
U.S. Pat. No. 4,178,917 to Shapiro discloses a method and system for non-invasive detection of zinc protoporphyrins using an excitation beam and two detectors, one being termed the reference detector for measuring scattered or reflected light S
2
at the excitation wavelength. The fluorescence detector measures the fluorescence S
1
from the red blood cells flowing through the measurement volume. The intent of this device, therefore, is to measure only the concentration of fluorophores within the blood stream and not in the surrounding tissue. As a result, the signal is influenced by the intervening tissues and the method described does not correct for differences in these tissues. A further drawback to this method is that it is not readily adaptable for measuring fluorophore concentrations in a wide range of turbid media.
It would therefore be very advantageous to provide a method for measuring in vivo concentration of a luminescent material in a turbid medium substantially independent of the scattering and absorption properties of the medium.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a non-invasive measurement of the concentration of a luminescent compound in a turbid medium regardless of the scattering and absorption properties of the medium.
In one aspect of the invention there is provided a method of measuring concentration of a luminescent compound in a turbid medium, comprising:
illuminating a turbid medium with a beam of light having an effective wavelength &lgr;
1
to excite luminescence in a luminescent compound being detected in the turbid medium;
measuring a luminescence signal F an effective distance of about D
1
from the beam of light;
measuring a reflectance signal R at wavelength &lgr;
1
an effective distance of about D
2
from the beam of light wherein the distances D
1
and D
2
are selected to reduce effects of scattering and absorption variations between turbid samples; and
processing the measured R and F signals to produce an effective function f(F, R) and comparing f(F, R) to a calibration curve of f
c
(F
c
, R
c
) versus concentration of the luminescent compound in a turbid medium to determine a concentration of the luminescent compound.
In another aspect of the present invention there is provided a method of determining pairs of distances D
1
and D
2
for measuring luminescence and reflectance respectively in order to reduce effects of scattering and absorption variations between turbid samples, the distances D
1
and D
2
being measured from a beam of light used to induce luminescence in one or more luminescent compounds in the turbid medium, the method comprising the steps of;
a) providing an effective reference turbid media having optical properties mimicking the turbid media and adding known amounts of a luminescent compound so as to increase the concentration of the luminescent compound and after addition of each known amount exciting the reference turbid medium with a beam of light at an effective wavelength and measuring a luminescence signal at a plurality of distances D
1
from the beam of light and measuring a reflectance signal at a plurality of distances D
2
from the beam of light;
b) repeat step a) for an effective number of reference turbid media possessing a range of optical properties;
c) for each pair of distances,
plot an effective function of both luminescence and reflectance (f(F, R)) versus concentration of the luminescent compound for all the reference turbid media and perform a regression analysis to calculate a best fit function and calculate a sum of squares of residuals; and
d) identify pairs of distances D
1
and D
2
corresponding to values of sum of squares of residuals lower than a threshold value for use in measuring luminescence and reflectance in the turbid medium in which concentration of the luminescent compound is to be determined.
The present invention also provides a device for measuring concentration
a light source for producing a beam of light of wavelength &lgr;
1
;
first detector means for measuring fluorescence;
second detector means for measuring light of wavelength &lgr;
1
; and
a holder for holding the light source, first and second detector means, the holder including a planar portion adapted to be placed on a surface of a tissue and an adjustment mechanism for adjusting a distance between the light source and the first detector and a distance between the light source and the second detector; and
processing means connected to said first and second detector means for processing measured fluorescence signals from said first and second detector means and calculating therefrom a concentration of a fluorescent compound in a tissue.
REFERENCES:
patent: 4476870 (1984-10-01), Peterson et al.
patent: 4768513 (1988-09-01), Suzuki
patent: 5203328 (1993-04-01), Samuels et al.
patent: 5280788 (1994-01-01), Janes et al.
patent: 5290275 (1994-03-01), Kittrell et al.
patent: 5419323 (1995-05-01), Kittrell et al.
patent: 5582168 (1996-12-01), Samuels et al.
patent: 5894340 (1999-04-01), Loree et al.
patent: 6070093 (2000-05-01), Oosta et al.
Patterson Michael S.
Weersink Robert A.
Hill & Schumacher
Photonics Research Ontario
Schumacher Lynn C.
Winakur Eric F.
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