WO2009057019A1

WO2009057019A1 - Tracer kinetic models for acoustic contrast imaging applications using photo-acoustics or thermo-acoustics

Info

Publication number: WO2009057019A1
Application number: PCT/IB2008/054390
Authority: WO
Inventors: Yao Wang
Original assignee: Koninklijke Philips Electronics N. V.
Priority date: 2007-10-31
Filing date: 2008-10-24
Publication date: 2009-05-07

Abstract

Systems and methods for generating and employing tracer kinetic models that can be constructed to quantify functional biology parameters (biomarkers) are provided to better differentiate disease using photo -acoustic contrast agent and diagnostic ultrasound equipment. The systems and methods utilize a small-molecule contrast agent capable of permeating capillary walls and possessing a long temporal clearance pattern. Production and utilization of tracer kinetic models specific to acoustic imaging applications are disclosed. A general tracer kinetic model derived for a particular contrast agent may serve as a basis of comparison for acoustic contrast imaging data later obtained, advantageously enabling probing of high value functional and metabolic parameters relating to in vivo biology/physiology, particularly for diagnostic purposes.

Description

TRACER KINETIC MODELS FOR ACOUSTIC CONTRAST IMAGING APPLICATIONS USING PHOTO-ACOUSTICS OR THERMO-ACOUSTICS

BACKGROUND

1. Technical Field

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.

2. Background Art

Tracer/pharmacologic kinetic models are routinely developed and utilized in nuclear medicine (e.g. using FDG-18 based PET) and dceMRI (e.g., using Gd-DTPA). Such models correlate in vivo functional and metabolic parameters (sometimes referred to as biomarkers in the medical and pharmaceutical communities) with various diseases, disorders and/or conditions. In current PET and MR imaging applications, biomarkers of particular interest and value include, but are not limited to, blood flow and permeability surface area product (PS). (See, e.g., S. Huang, M.E. Phelps, "Principle of Tracer Kinetic Modelling in Positron Emission Tomography and Autoradiography, " Chapter 7, pages 287-345, 1986; and P. Tofts, A. Kermode, "Measurement of the Blood-Brain Barrier permeability and leakage space using dynamic MR imaging - Fundamental concepts, " Magnetic Resonance in Medicine, 17:357-367, 1991.)

Once developed, tracer/pharmacologic kinetic models are extremely useful in the diagnoses of various diseases, disorders and/or conditions. For example, 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. (See, e.g., M. Leach, "Breast imaging technology: Application of magnetic resonance imaging to angiogenesis in breast cancer, " Breast Cancer Res. 3(1): 22-27, 2001; and http: V/www. allaboutvision.com/conditions/amd. htm .)

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. For instance, micro- bubble ultrasound contrast agents are currently too large (-3-5 μm) to permeate through a capillary wall and, thus, cannot effectively probe vascular permeability. Additionally, the temporal clearance pattern of these agents has no resemblance to those used in nuclear medicine and MRI. Moreover, 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. Zhou, N. Rognin, "A New Formalism for the Quantification of Tissue Perfusion by the Destruction-Replenishment Method in Contrast Ultrasound Imaging, " IEEE Trans. Ultra. Ferro, and Freq. Control, 53(6), pp. 1118-1129, 2006.)

In vivo photo-acoustic imaging has recently shown substantial promise as a modality based on optical contrast with ultrasound resolution. (See, e.g., X. Wang, Y. Pang, G. Ku, G. Stoica, L.H. Wang, "Three-dimensional laser-induced photoacoustic tomography of mouse brain with the skin and skull intact, " Optics Letters 28 (19), pp. 1739-1741, 2003.) By irradiating tissue with short laser pulses, chromophores (e.g., red blood cells) absorb optical energy and experience rapid temperature rise and thermal expansion followed by relaxation. This disturbance launches acoustic waves inside the tissue. A properly chosen ultrasound transducer (e.g., a detector array) may be used to capture the acoustic waves received on an aperture. The captured signals may then be used to reconstruct a map of the absorber spatial distributions.

More recently, photoacoustic contrast agents that enhance photoacoustic signal via increased optical absorption have been demonstrated in vivo in small animal models. (See, e.g., Y. Wang, X. Xie, X. Wang, G. Ku, K.L. Gill, D.P. O'Neal, G. Stoica, L.H. Wang, "Photoacoustic tomography of a nanoshell contrast agent in the in vivo rat brain, "Nano Letters 4 (9), pp 1689-1692, 2004.) These photoacoustic agents (e.g., nano-rods, quantum dots) are much smaller in size than micro-bubble ultrasound contrast agents and are able to permeate through desired substrates/structures (e.g., vascular walls). As with optical agents used in optical mammography and photo-dynamic therapy (PDT), the clearance of these agents is achieved in periods of time that are on the order of hours.

To date, there is a general lack of kinetic models and tools for photo-acoustics agents that specifically address and/or facilitate probing of biomarkers of interest. For example, recent studies have used empirical fitting based on time intensity or integrated time intensity data from dynamic scans during in vitro experiments. (See, e.g., C. Liao, S. Huang, C. Wei, P. Li, "A high frame rate photoacoustic imaging system and its applications to perfusion measurements, " Proc. SPIE 6086 Photons Plus Ultrasound: Imaging and Sensing 2006: The Seventh Conference on Biomedical Thermoacoustics, Optoacoustics and Acousto-optics, 2006.) Previous studies have only shown enhanced images after injection of a nano-shell contrast agent. (See, e.g., Y. Wang, X. Xie, X. Wang, G. Ku, KX. Gill, D.P. O'Neal, G. Stoica, L.H. Wang, "Photoacoustic tomography of a nanoshell contrast agent in the in vivo rat brain, "Nano Letters 4 (9), pp 1689— 1692, 2004.) Unfortunately, there has been little or no advancement in tracer kinetic studies relating to the recently developed photoacoustic contrast agents and little or no advancement in the development of tracer kinetic models for these agents. Likewise, few systems and methods for effecting such studies and models currently exist, despite the clear need for such systems and methods.

Thus, despite efforts to date, there is a need for development of tracer kinetic models of bio -agents for acoustic contrast imaging applications using photo -acoustics as well as a need for systems and methods that may be used, in whole or in part, to produce such models. There is also a need for development of new tracer kinetic models specific to acoustic contrast imaging applications using thermo -acoustics (e.g. micro-wave) as well as a need for systems and methods that may be used, in whole or in part, to produce such models. These and other needs are met by the systems and methods disclosed herein.

SUMMARY

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. Thus, 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. 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. Of note, 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. In exemplary implementations of the disclosed systems/methods, 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. In further exemplary embodiments, 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. Thus, in exemplary applications of the disclosed tracer kinetic models, 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. by correlating acoustic contrast imaging data processed using tracer kinetic models, e.g. for the commonly sick. This identification may be assisted by in-vitro diagnostic biomarkers, such as rheumatoid factor (RF) and prostate specific antigen (PSA). 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. Thus, for example, 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.

BRIEF DESCRIPTION OF THE DRAWINGS To assist those of ordinary skill in the art in making and using the disclosed systems and methods, reference is made to the appended figures, wherein:

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.

DESCRIPTION OF EXEMPLARY EMBODIMENT(S)

As noted above, 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. In an exemplary embodiment, 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.

An exemplary system for producing tracer kinetic models of various biomarkers (e.g., vascular permeability) for photoacoustic applications is depicted in Figure 1. In this schematic set-up, 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. Thus, by properly synchronizing the beam irradiation with the US detection, ultrasound data associated with, inter alia, the range and distribution of the absorbing chromophores can be obtained.

Ultrasound data derived from the absorbing chromophores is advantageously processed according to the present disclosure. Thus, in exemplary embodiments, 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. Although 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.

In exemplary embodiments, 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.

In exemplary embodiments of the disclosed system and method, a single illumination beam and a single transducer may be used to produce/generate the desired imaging data. In alternative embodiments, multiple illumination beams and/or transducers may be used simultaneously in order to produce enhanced tomographic image data. Similarly, 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.

According to exemplary systems and methods disclosed herein, a variety of setups/procedures may be employed to generate tracer kinetic models and/or data required to produce such models. Thus, in a first embodiment/implementation, in vitro infusion may be employed, wherein an excised and isolated organ is infused with a contrast agent/tracer. In a second exemplary embodiment/implementation, in vivo intra-arterial bolus/infusion techniques are employed. In a third exemplary embodiment/implementation, in vivo intra-venous bolus/infusion techniques are employed. Of note, in vivo intra-venous bolus/infusion offers a particularly advantageous setup/procedure for routine clinical use and/or studies.

Signal detection according to the disclosed systems/methods 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). For indirect detection means/techniques, compartmental analysis may be advantageously used as the analytical mechanism/technique.

With reference to Figure 2, an exemplary construct of a compartmental model for an indirect detection means/technique is schematically depicted. As will be apparent to persons skilled in the art, a compartmental model can similarly be constructed for various physiological relations in order to effect tracer kinetic analysis of those relations. In the exemplary model depicted in Figure 2, 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. The fact that some of the agent may be metabolized into a derivative form is also generally taken into account, e.g., by detecting the derivative form and/or approximating the metabolic rate. Alternatively, in exemplary implementations of the present disclosure, the metabolic rate of the agent may be analyzed as a biomarker in itself. In the above described diffusion process, 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. Thus, the entire physiological system can be modeled as a group of differential equations with continuity conditions and initial conditions specific to the physiology. Such 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. In the exemplary model depicted in Figure 2, 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. Clearance is a measure of the uptake of tracer in an organ on the clearance pathway (e.g., renal uptake). Actual/clinical implementations of tracer kinetic data/models produced according to the present disclosure will often benefit from simplification to enhance speed and resource efficiency. For example, an exemplary simplification of flow characteristics associated with tracer kinetic data generated according to the present disclosure is schematically depicted in Figure 3. More particularly, 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) is present at time origin. 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. For purposes of 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, and C₂ 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). Alternatively, transfer rates (e.g., ki) 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. Once a particular simplified model is developed for a physiological system, there are many different mechanisms that may be used according to the present disclosure in order to optimize/validate the model. 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. For example, 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.

Thus, 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. Although 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.

Claims

CLAIMS:

1. A method for producing tracer kinetic models for acoustic contrast imaging applications using photo-acoustics or thermo-acoustics, the method including the steps of: a. providing an acoustic imaging apparatus; b. introducing a contrast agent to an environment-of-interest; c. obtaining acoustic imaging data for the environment-of-interest using the acoustic imaging apparatus and the contrast agent; d. processing the acoustic imaging data to develop a compartmental model for the environment-of-interest; and e. producing a tracer kinetic model for the environment-of-interest based on the compartmental model using acoustic imaging data.

2. The method according to claim 1 , wherein the contrast agent is a small-molecule contrast agent capable of permeating a vascular wall.

3. The method according to claim 2, wherein the small-molecule contrast agent exhibits a temporal clearance pattern of greater than 10 minutes.

4. The method according to claim 1, wherein the acoustic imaging data includes range and distribution of the contrasting agent.

5. The method according to claim 1, wherein the acoustic imaging data is processed in order to determine at least one of: (i) blood flow, (ii) transit time; (iii) extraction fraction, (iv) permeability and surface area product, (v) compartment transfer rates; (vi) uptake, and (vii) clearance.

6. The method according to claim 1, wherein the acoustic imaging data is processed in order to produce a dynamic spatial map for the environment-of-interest.

7. The method according to claim 1 , wherein the environment-of-interest is a physiological system.

8. The method according to claim 1, further comprising conducting at least one validation technique with respect to the tracer kinetic model.

9. The method according to claim 1, further comprising conducting at least one optimization technique with respect to the tracer kinetic model.

10. A method for probing a physiological system of a subject, the method including the steps of: a. obtaining one or more tracer kinetic models for the physiological system, wherein at least one of the tracer kinetic models was produced using a method comprising the steps of: i. providing an acoustic imaging apparatus; ii. introducing a contrast agent to an environment-of-interest; iii. obtaining acoustic imaging data for the environment-of-interest using the acoustic imaging apparatus and the contrast agent; iv. processing the acoustic imaging data to develop a compartmental model for the environment-of-interest; and v. producing a tracer kinetic model for the environment-of-interest based on the compartmental model using acoustic imaging data; b. obtaining acoustic contrast imaging data for the subject; and c. correlating the acoustic contrast imaging data to the one or more tracer kinetic models.

11. The method according to claim 10, wherein correlation of the acoustic contrast imaging data is used to diagnose at least one of: (i) a condition, (ii) a disease, and (iii) a disorder.

12. The method according to claim 10, wherein correlation of the acoustic contrast imaging data is used to validate the one or more tracer kinetic models.

13. The method according to claim 10, wherein at least one of the tracer kinetic models represents one of: (i) a diseased grouping of the physiological system, and (ii) a healthy grouping of the physiological system.

14. A system for production of tracer kinetic models for acoustic contrast imaging applications, the system comprising: a. acoustic imaging apparatus adapted to obtain and process acoustic contrast imaging data for a physiological system, wherein the acoustic imaging apparatus includes: i. one or more electromagnetic beam sources; ii. one or more transducer elements; and iii. a processing unit in communication with the one or more transducer elements; and b. at least one contrast agent adapted for introduction to the physiological system; wherein the processing unit of the acoustic imaging apparatus is adapted to develop a compartmental model for the physiological system, and wherein a tracer kinetic model is produced by the processing unit of the acoustic imaging apparatus based on the compartmental model using the obtained acoustic contrast imaging data.

15. The system according to claim 14, wherein the one or more transducer elements take the form of a transducer array.

16. The system according to claim 14, wherein the contrast agent is a small-molecule contrast agent capable of permeating a vascular wall.

17. The system according to claim 16, wherein the small-molecule contrast agent exhibits a temporal clearance pattern of greater than 10 minutes.

18. The system according to claim 14, wherein the acoustic contrast imaging data is processed to produce tomographic image data.

19. A system for probing a physiological system of a subject, the system comprising: a. an acoustic imaging apparatus adapted to obtain and process acoustic contrast imaging data for a physiological system, wherein the acoustic imaging apparatus includes: i. one or more electromagnetic beam sources; ii. one or more transducer elements; and iii. a processing unit in communication with the one or more transducer elements; and b. at least one contrast agent adapted for introduction to the physiological system; and c. one or more tracer kinetic models for the physiological system.

20. The system according to claim 19, wherein acoustic contrast imaging data for the physiological system is obtained and processed using the acoustic imaging apparatus and the at least one contrast agent.

21. The system according to claim 19, wherein the acoustic contrast imaging data is correlated to the one or more tracer kinetic models.