Intralipid as a contrast agent to enhance subsurface blood flow imaging
Inventors
Pan, Yingtian • Du, Congwu • Ren, Hugang • Volkow, Nora
Assignees
Research Foundation of the State University of New York • US Department of Health and Human Services
Publication Number
US-10531803-B2
Publication Date
2020-01-14
Expiration Date
2033-07-12
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Abstract
The present invention provides a method of imaging blood vessels or blood flow in blood vessels in an animal comprising: (i) injecting a lipid solution into the bloodstream of the animal;(ii) imaging the blood vessels by an imaging method; and(iii) calculating the blood flow velocity in the blood vessels.
Core Innovation
The invention provides a method of imaging blood vessels or blood flow in blood vessels in an animal by injecting a lipid solution, such as intralipid, into the bloodstream, then imaging the blood vessels using an imaging method like Optical Doppler Tomography (ODT), and calculating the blood flow velocity in the blood vessels. This approach enhances the sensitivity and capability to image microvascular blood flow, particularly in capillaries where blood flow velocity measurement is difficult without the lipid contrast agent.
The problem being solved arises from the limitations of existing optical imaging methods such as Laser Doppler flowmetry (LDF) and Optical coherence Doppler tomography (ODT) in detecting minute microcirculations, especially in capillaries. Challenges include the angle effect reducing Doppler signal when flow direction is perpendicular to the laser beam, phase noise due to tissue micromotion, and the low frequency of red blood cells in capillaries causing underestimation of blood flow velocity. These factors make quantitative imaging of capillary blood flow technically difficult, yet critical for brain functional imaging and other clinical diagnoses.
The invention addresses these challenges by using intralipid, a fat emulsion of micro-sized lipid particles, as a contrast agent that enhances backscattering signals in blood flow imaging. The intralipid particles fill in the gaps between red blood cells flowing in capillaries, producing continuous Doppler shifts that boost the sensitivity of ODT imaging. This enables enhanced detection and quantitative measurement of microcirculatory blood flow, including in capillaries where flow is otherwise impossible or difficult to measure. The method is also adapted to generate three-dimensional tomographic images of blood flow with high spatial resolution.
Claims Coverage
The patent includes multiple independent claims focusing on methods of distinguishing animal microvasculature using lipid solutions and Optical Doppler Tomography. The claims cover inventive features related to using lipid solutions as contrast agents to enhance Doppler imaging, calculation of blood flow velocity and direction, generating 3D images, and distinguishing tumor versus non-tumor microvasculature.
Use of lipid solution to enhance Doppler imaging of microvasculature
The method involves injecting a lipid solution, including fat emulsions such as intralipid or total parenteral nutrition solutions, into the animal's bloodstream to produce enhanced Doppler shifts detectable by Optical Doppler Tomography imaging scans.
Calculation of blood flow velocity and direction based on Doppler shifts
The method calculates both blood flow velocity and flow direction in microvasculature using the continuous Doppler frequency shifts generated by the lipid solution flowing through the vessels.
Distinguishing different types of microvasculature
The method distinguishes different types of animal microvasculature, including differentiation between tumor microvasculature (e.g., glioblastoma multiforme) and non-tumor microvasculature, based on calculated blood flow velocity and direction.
Generation of three-dimensional tomographic images
The method generates three-dimensional tomographic images of the blood vessels or capillaries using Optical Doppler Tomography data derived from the Doppler frequency shift caused by the lipid solution.
Repeated imaging over time post lipid injection
The method includes performing multiple imaging scans (two or more, including three or more) at various time points post lipid injection, such as within one, three, or six hours, to analyze blood flow changes over time.
Use of Optical Doppler Tomography with specified resolution
The method utilizes Optical Doppler Tomography systems having high resolution (axial resolution about 1.8 µm and transverse resolution about 3 µm) to provide detailed microvascular imaging enhanced by the lipid contrast agent.
The claims comprehensively cover methods of administering lipid solutions as contrast agents to improve Optical Doppler Tomography imaging of microvasculature, enable quantitative determination of blood flow dynamics, generate 3D images, and distinguish between microvascular types including tumor tissues. The claims emphasize the inventive use of lipid solutions to achieve continuous Doppler signals and improved flow measurement sensitivity over time.
Stated Advantages
Provides significant enhancement of microcirculatory blood flow imaging sensitivity, especially in capillaries where flow velocity is otherwise undetectable or underestimated.
Enables quantitative detection of blood flow velocity changes while maintaining accuracy for studying physiological, pharmacological, and functional brain changes.
Allows generation of high-resolution three-dimensional tomographic images of blood vessels and blood flow.
Facilitates distinction between different microvascular types, including tumor versus non-tumor microvasculature, helpful for diagnosis and therapeutic monitoring.
Offers a clinically approved, easily adoptable contrast agent for preclinical and clinical applications.
Supports time-lapse imaging over extended periods due to slow clearance of intralipid from the bloodstream.
Documented Applications
Imaging cerebral blood flow and microcirculatory networks in the brain, including capillary flow imaging.
Pharmacological imaging and functional brain studies to monitor blood flow changes responding to drug effects or physiological conditions such as hypercapnia and normocapnia.
Imaging and distinguishing tumor microenvironment, particularly tumor angiogenesis and hypoxia in glioblastoma multiforme microvasculature.
Imaging wound healing and monitoring therapy effects that require enhanced microvascular blood flow visualization.
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