Claims for Patent: 10,631,746

Summary for Patent: 10,631,746

Title:	Quantification of absolute blood flow in tissue using fluorescence-mediated photoplethysmography
Abstract:	A method, an apparatus, and a kit including the apparatus and a fluorescence agent are provided for measuring a time-varying change in an amount of blood in a tissue volume, and include exciting a fluorescence agent in the blood, acquiring a time-varying light intensity signal during a pulsatile flow of the blood through the tissue volume, the pulsatile flow having a systolic and a diastolic phase resembling a conventional photoplethysmogram, and processing the acquired signal by applying a modified Beer-Lambert law to obtain a measurement of the time-varying change in the amount of blood in the tissue volume. The instantaneous molar concentration of the fluorescence agent is determined by utilizing a concentration-mediated change in a fluorescence emission spectrum of the fluorescence agent. There is further provided a fluorescence agent for use in the method.
Inventor(s):	Flower; Robert W. (Hunt Valley, MD), Stead; Robert Anthony (Vancouver, CA), Bailey; Arthur E. (North Vancouver, CA)
Assignee:	Novadaq Technologies ULC (Burnaby, CA)
Application Number:	15/517,895
Patent Claims:	1. An apparatus for measuring a time-varying change in an amount of blood in a tissue volume, the apparatus comprising: an excitation light source configured to excite a fluorescence agent in the blood; a light intensity sensor configured to acquire a time-varying light intensity signal during a pulsatile flow of the blood through the tissue volume, the pulsatile flow having a diastolic and a systolic phase; and one or more processors configured to process the acquired time-varying light intensity signal to obtain a measurement of the time-varying change in the amount of blood in the tissue volume, wherein a modified Beer-Lambert law is applied at the diastolic and systolic phases to obtain: .DELTA.L=ln[(I.sub.e.PHI.-I.sub.m/I.sub.e.PHI.-I.sub.p)](.epsilon.C).sup.- -1 where: .DELTA.L is a change in aggregate blood layer thickness within a given tissue volume, I.sub.e is an intensity of an excitation light exciting the fluorescence agent in the blood, .PHI. is a quantum efficiency of the fluorescence agent, I.sub.m is an intensity of the time-varying light intensity signal during the diastolic phase minimum of the pulsatile flow of the blood through the tissue volume, I.sub.p is an intensity of the time-varying light intensity signal during the systolic phase maximum of the pulsatile flow of the blood through the tissue volume, .epsilon. is a molar absorption coefficient for the fluorescence agent, C is an instantaneous molar concentration of the fluorescence agent in the blood. 2. The apparatus of claim 1 wherein the means for exciting comprises an illumination module comprising a fluorescence excitation source, the fluorescence excitation source operatively configured to generate an excitation light having a suitable intensity and a suitable wavelength for exciting the fluorescence agent. 3. The apparatus of claim 2 wherein the fluorescence excitation source comprises a first excitation source and a second excitation source. 4. The apparatus of claim 2 wherein the illumination module further comprises an optical element operatively configured to shape and guide the excitation light exiting the illumination module to provide a uniform field of the excitation light across an area of interest comprising the tissue volume of the subject. 5. The apparatus of claim 4 wherein the optical element comprises a lens, a light guide, a diffractive element, or a combination thereof. 6. The apparatus of claim 1 wherein the means for acquiring comprises a fluorescence emission acquisition module comprising an image sensor. 7. The apparatus of claim 6 wherein the fluorescence emission acquisition module further comprises an optical element disposed in front of the image sensor operatively configured to capture, filter, and direct the time-varying light intensity signal produced by the fluorescence agent to the image sensor. 8. The apparatus of claim 1 wherein the means for processing comprises a processor module, the processor module being operatively configured to control an operation of the means for causing the fluorescence agent to produce the time-varying light intensity signal, to control an operation of the means for acquiring the time-varying light intensity signal, or a combination thereof. 9. A kit for measuring a time-varying change in an amount of blood in a tissue volume, the kit including the apparatus of claim 1 and a fluorescence agent. 10. A method for measuring a time-varying change in an amount of blood in a tissue volume, the method performed at an apparatus comprising an excitation light source, a light intensity sensor, and one or more processors, the method comprising: exciting, by the excitation light source, a fluorescence agent in the blood; acquiring, by the light intensity sensor, a time-varying light intensity signal during a pulsatile flow of the blood through the tissue volume, the pulsatile flow having a diastolic and a systolic phase; and processing, by the one or more processors, the acquired time-varying light intensity signal to obtain a measurement of the time-varying change in the amount of blood in the tissue volume, wherein a modified Beer-Lambert law is applied at the diastolic and systolic phases to obtain: .DELTA.L=ln[(I.sub.e.PHI.-I.sub.m/I.sub.e.PHI.-I.sub.p)](.epsilon.C).sup.- -1 where: .DELTA.L is a change in aggregate blood layer thickness within a given tissue volume, I.sub.e is an intensity of an excitation light exciting the fluorescence agent in the blood, .PHI. is a quantum efficiency of the fluorescence agent, I.sub.m is an intensity of the time-varying light intensity signal during the diastolic phase minimum of the pulsatile flow of the blood through the tissue volume, I.sub.p is an intensity of the time-varying light intensity signal during the systolic phase maximum of the pulsatile flow of the blood through the tissue volume, .epsilon. is a molar absorption coefficient for the fluorescence agent, C is an instantaneous molar concentration of the fluorescence agent in the blood. 11. The method of claim 10 wherein C is determined by utilizing a concentration-mediated change in a fluorescence emission spectrum of the fluorescence agent. 12. The method of claim 11 wherein the concentration-mediated change includes a spectral shift in the fluorescence emission spectrum of the fluorescence agent. 13. The method of claim 11 wherein the utilizing comprises: selecting first and second spectral bands of fluorescence emission spectrum of the fluorescence agent; acquiring first and second intensities of fluorescence emission integrated over wavelengths in the first and second spectral bands respectively; calculating a ratio of the first and second intensities; and deriving a value for C from the ratio. 14. The method of claim 13 wherein the selection of the first and second spectral bands is such that: one of the first and second intensities varies monotonically with C, and one of the first and second intensities is unchanged with C; (ii) the first and second intensities increase monotonically with C but at different rates; or (iii) the first intensity increases monotonically with C, and the second intensity decreases monotonically with C. 15. The method of claim 13 wherein the first spectral band comprises wavelengths ranging from about 780 nm to about 835 nm, or a subset thereof, and the second spectral band comprises wavelengths ranging from about 835 nm to about 1000 nm, or a subset thereof. 16. The method of claim 10 wherein the fluorescence agent is indocyanine green (ICG). 17. The method of claim 16 wherein C ranges from about 2 .mu.M to about 10 mM.