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WO2009057019A1 - Modèles cinétiques de traçage pour applications d'imagerie par contraste acoustique utilisant la photo-acoustique ou la thermo-acoustique - Google Patents

Modèles cinétiques de traçage pour applications d'imagerie par contraste acoustique utilisant la photo-acoustique ou la thermo-acoustique Download PDF

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Publication number
WO2009057019A1
WO2009057019A1 PCT/IB2008/054390 IB2008054390W WO2009057019A1 WO 2009057019 A1 WO2009057019 A1 WO 2009057019A1 IB 2008054390 W IB2008054390 W IB 2008054390W WO 2009057019 A1 WO2009057019 A1 WO 2009057019A1
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WIPO (PCT)
Prior art keywords
acoustic
imaging data
contrast agent
tracer kinetic
contrast
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2008/054390
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English (en)
Inventor
Yao Wang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Koninklijke Philips NV
Original Assignee
Koninklijke Philips Electronics NV
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Publication date
Application filed by Koninklijke Philips Electronics NV filed Critical Koninklijke Philips Electronics NV
Publication of WO2009057019A1 publication Critical patent/WO2009057019A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/1702—Systems in which incident light is modified in accordance with the properties of the material investigated with opto-acoustic detection, e.g. for gases or analysing solids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0093—Detecting, measuring or recording by applying one single type of energy and measuring its conversion into another type of energy
    • A61B5/0095—Detecting, measuring or recording by applying one single type of energy and measuring its conversion into another type of energy by applying light and detecting acoustic waves, i.e. photoacoustic measurements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0093—Detecting, measuring or recording by applying one single type of energy and measuring its conversion into another type of energy
    • A61B5/0097—Detecting, measuring or recording by applying one single type of energy and measuring its conversion into another type of energy by applying acoustic waves and detecting light, i.e. acousto-optic measurements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording for evaluating the cardiovascular system, e.g. pulse, heart rate, blood pressure or blood flow
    • A61B5/026—Measuring blood flow
    • A61B5/0275—Measuring blood flow using tracers, e.g. dye dilution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/48—Diagnostic techniques
    • A61B8/481—Diagnostic techniques involving the use of contrast agents, e.g. microbubbles introduced into the bloodstream

Definitions

  • the present disclosure relates to acoustic contrast imaging using photo-acoustics or thermo -acoustics. More particularly, the present disclosure relates to systems and methods for developing and utilizing tracer kinetic models specific to photoacoustic contrast imaging applications. The present disclosure also relates to systems and methods for quantifying and measuring biomarkers for photoacoustic contrast imagining diagnostics.
  • Biomarkers of particular interest and value include, but are not limited to, blood flow and permeability surface area product (PS).
  • PS blood flow and permeability surface area product
  • vascular permeability (the degree of leakage in the capillary level as determined by PS) is a key indicator in the prognosis of many conditions, including cancer, rheumatoid arthritis, age-related macular degeneration, etc.
  • PS vascular permeability
  • Acoustic contrast imaging (e.g., ultrasound) is in its infancy when compared with PET and MR contrast imaging.
  • Many factors have contributed to the early development stage of acoustic contrast imaging relative to other contrast imaging applications.
  • micro- bubble ultrasound contrast agents are currently too large (-3-5 ⁇ m) to permeate through a capillary wall and, thus, cannot effectively probe vascular permeability.
  • the temporal clearance pattern of these agents has no resemblance to those used in nuclear medicine and MRI.
  • the relationship between ultrasound signal intensity and contrast agent concentration is complex. Consequently, dynamic scanning applications using ultrasound contrast agents cannot draw on the vast pool of current knowledge in tracer kinetics. (See, e.g., M. Arditi, P. Frinking, X.
  • photoacoustic contrast agents that enhance photoacoustic signal via increased optical absorption have been demonstrated in vivo in small animal models.
  • the present disclosure provides systems and methods for producing and/or employing tracer kinetic models having particular utility in and for acoustic contrast applications using photo -acoustics or thermo-acoustics. More particularly, exemplary embodiments of the present disclosure provide systems and methods that utilize small-molecule contrast agent(s) capable of permeating capillary walls and possessing a long temporal clearance pattern, e.g., 10 minutes or greater, for acoustic contrast imaging applications, e.g., photoacoustic applications, thermoacoustic applications and the like.
  • Tracer kinetic model(s) derived for a particular contrast agent as disclosed herein may serve as a basis of comparison for acoustic contrast imaging data later obtained, advantageously enabling probing of high value functional and metabolic parameters, e.g., parameters relating to in vivo biology/physiology.
  • the disclosed tracer kinetic models and systems/methods for use thereof have wide ranging utility, e.g., for facilitating and/or enhancing diagnostic applications.
  • Exemplary methods disclosed herein facilitate production of tracer kinetic models, particularly those specific to acoustic contrast imaging applications using photo -acoustics or thermo-acoustics.
  • exemplary methods generally involve the steps of: (i) providing acoustic imaging apparatus, (ii) introducing small-molecule contrast agent(s) into an environment-of-interest; (iii) obtaining, over a period of time, acoustic contrast imaging data from the environment-of-interest based in part on responses of the small-molecule contrast agent(s) to stimulus, the acoustic contrast imaging data generally related to one or more predetermined parameters (e.g., range and distribution of the contrast agent(s)), and (iv) processing the acoustic contrast imaging data to produce a dynamic spatial map of the one or more predetermined parameters.
  • predetermined parameters e.g., range and distribution of the contrast agent(s)
  • the disclosed method may further include the steps of: (v) developing a compartmental model representative of a particular environment-of-interest, e.g., a physiological system, and (vi) generating a tracer kinetic model based on the compartmental model using the dynamic spatial map.
  • tracer kinetic models generated/produced by the disclosed method are generally specific to the contrast agent(s), compartmental model and environment-of-interest, e.g., the specific physiological system, subjected to the disclosed methodology.
  • one or more optimization and/or validation step(s) may be included and/or practiced in order to produce tracer kinetic models of greater reliability and/or quality.
  • the compartmental model representative of a particular physiological system may be simplified to a more general compartmental model, allowing for more efficient data processing and analysis.
  • Tracer kinetic models produced using the disclosed methods may be advantageously employed to probe physiological systems.
  • physiological systems are probed by: (i) obtaining a tracer kinetic model for a particular contrast agent, compartmental model and physiological system, (ii) obtaining acoustic contrast imaging data for a subject physiological system, (iii) comparing the acoustic contrast imaging data for the subject physiological system with predicted values using the tracer kinetic model. Probing of physiological systems as disclosed herein enables the identification of, various diseases, disorders, conditions, etc.
  • Exemplary systems of the present disclosure generally include photoacoustic or thermo-acoustic imaging apparatus, contrast agents and processing units adapted to generate and/or utilize the disclosed tracer kinetic models.
  • System variations may be employed for optimization and/or customization on an application-specific basis, e.g., for particular contrast imaging applications.
  • the disclosed system may be modified/optimized for use with a particular physiological system, contrast agent, parameter of interest and combinations thereof.
  • Modifications/enhancements may relate to various aspects of the disclosed system, e.g., the photoacoustic imaging apparatus used for a particular application.
  • Exemplary embodiments of the present disclosure also provide systems for real-time diagnostic photoacoustic contrast imaging using tracer kinetic models generated according to the disclosed methods. Additional features, functions and benefits of the disclosed systems and methods will be apparent from the description which follows, particularly when read in conjunction with the appended figures.
  • Figure 1 depicts an exemplary system for photoacoustic contrast imaging associated with the present disclosure.
  • Figure 2 depicts an exemplary construct of a compartmental model representing a particular physiology for indirect detection and data analysis purposes.
  • Figure 3 graphically depicts a representation of transit time and blood volume for an exemplary vessel.
  • Figure 4 depicts an exemplary simplified compartmental model of the physiological system and model depicted in Figure 2.
  • the present disclosure provides systems and methods for generating and/or utilizing tracer kinetic models in photoacoustic or thermoacoustic applications/implementations.
  • the disclosed tracer kinetic models may be constructed and/or used to quantify functional/biologic parameters (i.e., biomarkers) to better differentiate and/or quantify disease.
  • Tracer kinetic models of the present disclosure are generally produced using photo-acoustic contrast agent(s) and diagnostic ultrasound equipment.
  • a tracer kinetic model associated with a system of the present disclosure may be used to investigate various parameters and/or conditions. For example, one or more of the following parameters may be investigated according to the present disclosure: blood flow, transit time; extraction fraction, permeability and surface area product (PS), compartment transfer rates; uptake and clearance.
  • PS surface area product
  • an electromagnetic beam source e.g., a pulsed laser
  • irradiates an object of interest e.g., an organ/region to be studied.
  • the region under study may include arterial and/or venal blood vessels.
  • Chromophores e.g., associated with one or more contrast agents administered intra-venously
  • absorb energy delivered by the electromagnetic beam source and exhibit/undergo thermal expansion.
  • Acoustic waves resulting from this thermal expansion are detected by an ultrasound (US) transducer.
  • US ultrasound
  • the disclosed US unit includes processing capabilities and/or communicates with an ancillary processing unit.
  • the processing unit may be remotely located and in network communication with the ultrasound unit.
  • the processing unit is generally adapted to produce/generate a dynamic spatial map representing the changing concentration and distribution of chromophores.
  • exemplary applications of the system e.g., as schematically depicted in Figure 1, are particularly adapted for production of models related to vascular permeability, it is specifically contemplated that the disclosed systems and methods have far broader application and may be employed, inter alia, for producing tracer kinetic models relating to any biomarker.
  • the US transducer depicted in Figure 1 may take the form of a single transducer element or a transducer array.
  • the laser irradiation (or other form of EM irradiation) directed to the environment-of- interest can be of any polarity, frequency and/or amplitude, provided the selected polarity, frequency and amplitude are effective to generate sufficient energy absorption and thermal expansion of the chromophores to yield the desired data.
  • a single illumination beam and a single transducer may be used to produce/generate the desired imaging data.
  • multiple illumination beams and/or transducers may be used simultaneously in order to produce enhanced tomographic image data.
  • object illumination may be effected from single or multiple angles and from different positions/orientations sequentially, e.g., from a back-lit perspective wherein the illumination beam originates (at least in part) from the same side as the transducer.
  • a variety of setups/procedures may be employed to generate tracer kinetic models and/or data required to produce such models.
  • in vitro infusion may be employed, wherein an excised and isolated organ is infused with a contrast agent/tracer.
  • in vivo intra-arterial bolus/infusion techniques are employed.
  • in vivo intra-venous bolus/infusion techniques are employed.
  • in vivo intra-venous bolus/infusion offers a particularly advantageous setup/procedure for routine clinical use and/or studies.
  • Signal detection may involve (i) direct detection means/techniques, wherein detected concentrations associated with an object (e.g., an organ) are converted directly from signal intensities to local tracer concentrations, or (ii) indirect detection means/techniques, wherein detected arterial (input) and venous (output) concentrations are analytically used to determine an object's retention parameters (e.g., rate, concentration and the like).
  • direct detection means/techniques wherein detected concentrations associated with an object (e.g., an organ) are converted directly from signal intensities to local tracer concentrations
  • indirect detection means/techniques wherein detected arterial (input) and venous (output) concentrations are analytically used to determine an object's retention parameters (e.g., rate, concentration and the like).
  • compartmental analysis may be advantageously used as the analytical mechanism/technique.
  • a compartmental model for an indirect detection means/technique is schematically depicted.
  • a compartmental model can similarly be constructed for various physiological relations in order to effect tracer kinetic analysis of those relations.
  • arterial flow introduces a tracer (e.g., a photoacoustic contrast agent) into an object of interest (e.g., an organ, tumor, hyperplasia, etc.).
  • the small molecule tracer diffuses through capillary walls into the interstitial space and, from there, into the cellular space of that object. Each transfer along this pathway is bidirectional.
  • each transfer along the path between consecutive regions/compartments can be represented analytically as a pair of differential equations based on concentration in each compartment and the transfer rate associated with diffusion in each direction.
  • the entire physiological system can be modeled as a group of differential equations with continuity conditions and initial conditions specific to the physiology.
  • differential equations can be used in conjunction with detected data to produce a tracer kinetic model for the particular physiological system being modeled.
  • Exemplary tracer kinetic data/models that can be produced using the herein described systems and methods include, but are not limited to: (i) models associated with transit time, (ii) models associated with blood flow, (iii) models associated with extraction fractions, (iv) models associated with permeability surface area product (PS), (v) models associated with uptake, and (vi) models associated with clearance.
  • the PS value may be used to characterize the extent/degree of leakage of the vascular wall at the capillary level.
  • the extraction fraction in turn, relates to both the permeability and the flow rate of the clinical system. Uptake is an effective measure of the amount of tracer deposited into an area/volume of physiological interest.
  • Figure 3 provides a general depiction of transit time and blood volume associated with vessel flow.
  • a delta impulse corresponding to a bolus input e.g., tracer injection
  • a dispersed version of this delta impulse is then measured at a downstream location, the shape of which generally depends on the flow rate in the vessel and the size of the vessel.
  • the latency of the dispersed pulse is defined as the transit time, which can then be correlated to the flow rate for the particular vessel. For example, in the case of slower flow, the observed dispersed pulse will resemble the dashed line depicted in Figure 3, which is characterized by longer latency and greater spread.
  • the exemplary vessel analysis depicted in Figure 3 can be applied to many physiological systems and used to relate transit time to blood flow rate and volume, based on the actual abstraction of the underlying physiology.
  • An exemplary simplified model for measuring permeability and extraction fraction based on the exemplary physiological system of Figure 2 is depicted in Figure 4. By assuming instantaneous membrane diffusion, the physiological model in Figure 2 was reduced to the compartment model depicted in Figure 4.
  • C p is the concentration of tracer(s) in the plasma (blood pool)
  • Ci is the concentration of tracer(s) inside the tissue/cell compartment
  • C 2 is the tracer metabolized by cells.
  • Analytic solutions for each of the noted concentrations can be derived by solving the resultant set of differential equations governing the compartmental exchange using initial concentration values determined at the time of origin (e.g., the concentration effected by the initial tracer injection).
  • transfer rates e.g., ki
  • C p and Ci data can be determined using curve fitting/regression techniques based on inputted or detected concentration data (e.g., C p and Ci data).
  • a specific solution according to the present disclosure involves normalizing the analytic form using C p (t), which can be measured by blood sampling or dynamic imaging of a vessel (e.g., imaging of the source artery).
  • C p (t) is often referred to as the blood input function and can be used to calibrate individual responses, accounting for differences in blood circulation between subjects.
  • Exemplary optimizing/validating mechanisms/techniques include: a) Data calibration to correlate signal intensity with tracer concentration; b) Verification of dependence on the various periods of the kinetics for the underlying physiology (e.g., analytical compartment model); c) Establishment of curve-fit/regression standards (e.g., a weighted sum analysis depending on the underlying physiology); d) Sensitivity analysis of model parameters to optimize compartment modeling (e.g., quantification of the change in signal intensity required to resolve a percentage difference, e.g., 10%, in a rate -transfer constant) ; e) Comparisons of documented physiology measurements/estimates to predicted data obtained via curve fitting; f) In certain cases, in vitro analysis may be desirable, particularly cases where absolute values may be difficult, if not impossible, to validate in vivo.
  • curve-fit/regression standards e.g., a weighted sum analysis depending on the underlying physiology
  • in vitro analysis of known animal models with varying vascular leakage can be used to qualitatively confirm a trend. It may also be desirable in certain cases to extract tissue samples and perform direct bio-chemical analysis, e.g., high pressure liquid chromatography (HPLC), to confirm predicted or observed in vivo concentration and exchange.
  • HPLC high pressure liquid chromatography
  • the present disclosure thus provides advantageous systems and methods for tracer kinetic modeling in photoacoustic or thermoacoustic imaging applications, and utility of such tracer kinetic models.
  • the present disclosure has been described with reference to exemplary embodiments and implementations thereof, the disclosed systems and methods are not limited to such exemplary embodiments/implementations. Rather, as will be readily apparent to persons skilled in the art from the description provided herein, the disclosed systems and methods are susceptible to modifications, alterations and enhancements without departing from the spirit or scope of the present disclosure. Accordingly, the present disclosure expressly encompasses such modification, alterations and enhancements within the scope hereof.

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Abstract

Selon l'invention, des systèmes et des procédés de production et d'emploi de modèles cinétiques de traçage, qui peuvent être construits pour quantifier des paramètres de biologie fonctionnelle (biomarqueurs), sont mis en œuvre pour différencier une maladie à l'aide d'un agent de contraste photo-acoustique et un matériel de diagnostic ultrasonore. Les systèmes et procédés de l'invention utilisent un agent de contraste à petites molécules pouvant imprégner des parois capillaires et possédant une structure de clairance temporaire longue. L'invention concerne également la production et l'utilisation de modèles cinétiques de traçage spécifiques à des applications d'imagerie acoustique. Un modèle cinétique de traçage général conçu pour un agent de contraste particulier peut servir comme base de comparaison pour des données d'imagerie par contraste acoustique obtenues ultérieurement, ce qui autorise avantageusement une recherche par sondage de paramètres fonctionnels et métaboliques de grande valeur se rapportant à la biologie/physiologie in vivo, particulièrement à des fins de diagnostic.
PCT/IB2008/054390 2007-10-31 2008-10-24 Modèles cinétiques de traçage pour applications d'imagerie par contraste acoustique utilisant la photo-acoustique ou la thermo-acoustique Ceased WO2009057019A1 (fr)

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US60/983,991 2007-10-31

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107146218A (zh) * 2017-04-11 2017-09-08 浙江大学 一种基于图像分割的动态pet图像重建及示踪动力学参数估计方法
EP3243442A4 (fr) * 2015-01-08 2017-12-27 FUJI-FILM Corporation Dispositif de mesure photo-acoustique et système de mesure photo-acoustique
US11166691B2 (en) 2011-06-20 2021-11-09 Koninklijke Philips N.V. Agent imaging

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EGHTEDARI MOHAMMAD ET AL: "High sensitivity of in vivo detection of gold nanorods using a laser optoacoustic imaging system", NANO LETTERS JUL 2007,, vol. 7, no. 7, 1 July 2007 (2007-07-01), pages 1914 - 1918, XP002516822 *
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11166691B2 (en) 2011-06-20 2021-11-09 Koninklijke Philips N.V. Agent imaging
EP3243442A4 (fr) * 2015-01-08 2017-12-27 FUJI-FILM Corporation Dispositif de mesure photo-acoustique et système de mesure photo-acoustique
US10709337B2 (en) 2015-01-08 2020-07-14 Fujifilm Corporation Photoacoustic measurement apparatus and photoacoustic measurement system
CN107146218A (zh) * 2017-04-11 2017-09-08 浙江大学 一种基于图像分割的动态pet图像重建及示踪动力学参数估计方法
CN107146218B (zh) * 2017-04-11 2019-10-15 浙江大学 一种基于图像分割的动态pet图像重建及示踪动力学参数估计方法

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