Ultrasound Contrast Agent Dynamics
Contrast Agent Dynamics in Ultrasound Biomedical Applications
Tech Area / Field
- PHY-NGD/Fluid Mechanics and Gas Dynamics/Physics
- MED-DID/Diagnostics & Devices/Medicine
8 Project completed
Senior Project Manager
Ryzhova T B
Belarussian State University / Institute of Technologies of Informatization and Management of BSU, Belarus, Minsk
- MIFI, Russia, Moscow
- Service de physique de létat condensé, France, Saclay\nGoettingen University, Germany, Göttingen\nCardiff University, UK, Cardiff\nUniversity of Thessaly / School of Engineering, Volos\nBoston University / College of Engineering, USA, MA, Boston
Project summaryThe purpose of the proposed project is the development of new theoretical approaches in investigating the dynamics of contrast agent bubbles in ultrasound fields and, based on these approaches, the elaboration of numerical models, codes and software for the computer simulation of ultrasound biomedical applications employing contrast agent technologies.
The state of the art in the field of research
Ultrasound contrast agents (UCAs) are micron-sized artificial gas bubbles surrounded by a shell of albumin, lipid, or other biocompatible material (Goldberg, Raichlen & Forsberg 2001). The function of the shell is to prevent bubble clustering and gas dissolution. A solution of UCA microbubbles is generally injected into the bloodstream in order to enhance echogenicity in ultrasound examinations. Today this technique is widely used in diagnostic applications in cardiology, such as the evaluation of a cardiac condition, the visualization of blood flow and the assessment of myocardial perfusion (Becher & Burns 2000). But the potential of UCAs for clinical uses has been shown by investigations to be much wider. Radiology, oncology, transplant pathology, targeted imaging, localised drug and gene delivery are a few examples of the next exciting applications. At the same time, UCA bubbles can induce deleterious bioeffects and damage, such as undesirable destruction of tissues and cells, haemorrhage, detrimental production of free radicals in blood, etc., especially when the amplitude of ultrasound exceeds a certain threshold, which is determined by the physical properties of the involved biomaterials. There is therefore increased need for a thorough understanding of the physical mechanisms of the above applications. But adequate theoretical works in this field are still not available. Many interesting effects are unclear so far, in some cases even qualitatively, let alone quantitative theoretical models. One such effect is reparable sonoporation that is a transient, non-lethal “opening” of cell membranes to large foreign molecules when ultrasound is applied to a cell suspension that contains UCAs. This phenomenon allows highly selective drug/gene delivery to the interior of cells, and in particular holds great promise for the treatment of cancer in the near future. As a result of weak theoretical basis, to date, ultrasound biomedical applications are characterized by a high degree of empiricism. The common approach of most theoretical studies is a direct transfer of the achievements of classical physical acoustics to biological systems. In doing so, the specificity of the biological systems is often ignored, which results in loss of accuracy due to the exclusion of important effects. In particular, the radial pulsations of UCA microbubbles in blood flow are commonly described by various forms of the Rayleigh-Plesset (RP) equation. Effects of the encapsulating shell and the non-Newtonian properties of blood are taken into account by supplementing the RP equation with some damping terms. However, experiments show that the RP model is inadequate in describing the behaviour of UCA bubbles even at small diagnostic acoustic pressures. Attempts of using other models adopted from physical acoustics are not satisfactory either. Besides the model of radial motion, in the dynamics of UCAs there are lots of other unexplored problems. In particular, it remains unknown how the presence of the surface layer affects the backscatter spectrum of encapsulated bubbles (frequencies and intensities of harmonics, sub- and ultraharmonics), their translational motion, the acoustic radiation forces experienced by UCAs, mutual interactions between UCAs and cells, etc. It is now clear that the further progress of UCA technologies strongly requires a proper theoretical groundwork that should take a rigorous account of the peculiar features of biological systems involved, such as the viscoelastic properties of blood and the particular rheological properties of the shell encapsulating UCAs.
The impact of the proposed project on the progress in the field of research
The proposed research will provide a more thorough understanding of the physical mechanisms that underlie ultrasound biomedical applications employing contrast agent microbubbles as well as software tools for the computer modelling of the above applications. The results of the project will induce optimisation and further development of clinical uses of UCA technologies. This research activity is also necessary in order to adequately evaluate risks involved in medical ultrasound diagnostic and therapeutic applications and thereby to avoid detrimental side effects to the patient. Thus, the proposed research project is well-timed and meets actual needs of this area of knowledge.
Competence of the project team in the specified area
The project team consists of researchers from the Belarus State University (BSU) and the Moscow Engineering Physics Institute (MEPhI). The members of the team have a wide expertise in the development of physico-mathematical models and the numerical simulation of various natural and man-caused phenomena. The team involves experts in the fields of ultrasound, bubble dynamics and acoustic cavitation, equations of mathematical physics, computer modelling, numerical experimentation, software environment, computer analysis, processing and presentation of scientific data. The team members have more than 100 publications in well reputed international scientific journals and more than 50 presentations at international conferences, the research area of which is related to that of the proposed project. Thus the project team has competence and experience necessary for the proposed research activities.
Expected results and their application
Implementation of the project tasks will provide the following major results:
• Realistic physico-mathematical model of the radial motion of a contrast agent bubble in an ultrasound field and data of a comprehensive analytical and numerical examination of the above model over a wide parameter range for the cases of small-amplitude (linear) and finite-amplitude (nonlinear) bubble pulsations;
• Theory and data of numerical simulation for the effect of the encapsulating layer on the backscatter of contrast agents;
• Theory and data of numerical simulation for the effect of the encapsulating layer on the translational motion of contrast agents and the acoustic radiation forces experienced by contrast agents in ultrasound fields;
• Theory and data of numerical simulation for the collective dynamics of UCA clusters and UCA-cell suspensions;
• Dynamical equation of state of a contrast agent – liquid mixture and data on its examination;
• Continuum model describing the interaction of contrast agent – liquid mixtures with ultrasound fields on macrolevel and data on its examination;
Based on these results, software package for the numerical simulation of in vitro and in vivo experiments with UCAs will be elaborated. Suggestions on improvement and optimization of existing UCA technologies and forecasting of possible new techniques will also be made. The results of the project will provide a firm base for current and future applications of the UCA technology in the area of diagnostic and therapeutic medicine. They can be applied by organizations engaged in research and clinical use of contrast agents to numerical simulations and further development of respective biomedical applications. On project completion, a development stage is planned by the authors of the proposal so as to apply, with the help of the foreign collaborators, the obtained results to clinical practice.
How the project will address ISTC objectives
The proposed project is in conformity with the ISTC objectives as is obvious from the following:
• The weapon scientists, forming the main body of the project team, will be directly engaged in scientific effort in the field of public health, which will give them the opportunity to redirect their knowledge and skills to peaceful research activities;
• Work on the project will promote a deeper integration of the project participants into the international scientific community by strengthening the existing relations with the foreign collaborators as well as giving a strong incentive to new scientific contacts with foreign scientists working in biomedical areas;
• The proposed research is of pronounced peaceful purposes and its support will contribute to the solution of important scientific and practical problems of health protection;
• The results of the project will provide new theoretical knowledge and high-level computer technology developments in the area of ultrasound contrast agent biomedicine which is currently an area of active international interest.
Scope of activities
The project duration is 36 months and the total project effort is 7230 person*days. The project is composed of 6 tasks. Each of them includes theoretical investigation, development of physico-mathematical and numerical models, software development, numerical simulations, processing and analysis of the obtained results.
The research activities of the BSU participants will go along two main lines. The first line is formed by Tasks 1 and 2. Their ultimate goal is to develop theory and software for examining the backscatter of contrast agents for various spectrum components in order to reveal favourable field parameters for ultrasound diagnostic applications. The second line of the research is formed by Tasks 3 and 4 the aim of which is to develop theory and software for investigating the translational dynamics of inpidual and interacting contrast agent microbubbles under in vitro and in vivo conditions. Task 2 is fully based on Task 1, being in fact the extension of the latter to experimentally measurable (and used in clinical practice) quantities such as the intensities and frequencies of the backscattered echoes. Tasks 3 and 4 will utilize the results of Task 1 as well, at same time using also other models, which will make it possible to capture additional important effects.
The research effort of the MEPhI participants, Tasks 5 and 6, will be aimed at developing a continuum model that describes the interaction of a fluid medium containing contrast agent with an ultrasound field on macrolevel. This approach is complementary to the particle (microscopic) approach employed by the BSU participants. Development of both approaches makes it possible to extend the range of research as well as to compare certain results and thus enhance the validity of the research.
Role of foreign collaborators
The foreign collaborators will carry out theoretical and numerical investigations along similar lines and are thus strongly interested in regular cross-checks of the results obtained. Moreover, the British collaborators will conduct experimental investigations that will make it possible to check theory against experiment. These intentions imply a close cooperation which will be realized by means of permanent information exchange, conduction of joint seminars and project meetings, preparation of joint publications and conference reports, mutual working visits and joint efforts on application of the project results to clinical practice.
Technical approach and methodology
Methodology of the proposed research lies in combination of analytical approaches, based on the methods of mathematical physics, and numerical techniques generally applied in the fields of hydrodynamics and bubble dynamics. Implementation of the project tasks will be based on original scientific approaches elaborated by the authors of the project in the course of previous work, which were successfully employed by them in solving various physical tasks, including those on bubble dynamics in ultrasonically driven fluids, and are reflected in their publications. These approaches will be properly modified and applied to the objectives of the proposed project with allowance made for the specific biomedical environment.
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