Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
  • A61B8/12—Diagnosis using ultrasonic, sonic or infrasonic waves in body cavities or body tracts, e.g. by using catheters
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
  • A61B8/06—Measuring blood flow

Definitions

• Molecular imaging is a rapidly evolving area of medical imaging that is anticipated to have a substantial impact on the diagnosis and treatment of a range of disease processes.
• the general imaging approach is to introduce particles (e.g. bubbles or droplets) into the body, which can be detected with a medical imaging modality (e.g. magnetic resonance imaging, positron emission tomography or ultrasound), and which have been treated in such a way as to adhere to specific molecules that are only present in regions of diseased tissue or cells.
• a medical imaging modality e.g. magnetic resonance imaging, positron emission tomography or ultrasound
• gas-filled microvesicles are suspensions in which the gas bubbles are surrounded by a solid material envelope of natural or synthetic polymers, lipids, proteins or mixtures thereof.
• microvesicles are in general referred to in the art as “microcapsules” or “microballoons”, while the term “microbubbles” refers more commonly to surfactant-stabilized microvesicles.
• microcapsules or “microballoons”
• microbubbles refers more commonly to surfactant-stabilized microvesicles.
• contrast agents are small enough to pass safely through the capillaries, and are introduced into the body through injection.
• the bubbles are stimulated to produce acoustic emissions that are distinct from those of tissue, which are then exploited with specific imaging strategies to form images of the vasculature.
• Most current imaging strategies rely upon nonlinear bubble behaviour, which occurs when bubbles are stimulated with sufficient amplitude with ultrasound frequencies related to the bubble resonant frequency.
• the resonant frequency is related to bubble size, and most contrast agents are comprised primarily of bubbles in the 1 to 10 micron range in order to exhibit resonant behaviour in the conventional ultrasound frequency range.
• Bubbles may also be destroyed, which has enabled the implementation of ultrasound destruction- reperfusion techniques for assessing tissue perfusion. Detection of bubbles during destruction also can be used.
• the application of microbubble contrast agents in combination with specific detection techniques has enabled the detection of blood located in microvessels in many clinically relevant situations.
• Second harmonic imaging mode did not show improvements in contrast agent detection due to the presence of high levels of tissue second harmonic signals.
• These results for nonlinear imaging at high frequencies were achieved with a type of transducer (spherically focused polymer film transducer) that can only be used external to the body due to its size (typically 6 to 12 mm in diameter).
• Such transducers are well suited to nonlinear imaging since they are broad bandwidth (>100%) and can achieve high pressures through focusing. This technology is appropriate for use with small animal imaging, dermatology and ophthalmology.
• Figure 1 is a schematic diagram of a catheter-based intravascular ultrasound system in situ in the body at a region of interest;
• Figure 2 is a schematic diagram of transmit and receive subsystems for use with the catheter-based intravascular ultrasound transducer of figure 1;
• Figure 3 shows exemplary images of selectively located contrast agent bubbles produced using: (a) 20 MHz fundamental frequency imaging; (b) 40 MHz harmonic imaging from low amplitude excitation; and (c) 40 MHz harmonic imaging from high amplitude excitation;
• a contrast agent comprising bubbles below 1 micron in diameter can be used to effectively produce detectible nonlinear emissions at least up to 40 MHz, and under conditions (e.g. sufficiently low pressures) that are feasible to achieve with IVUS techniques.
• intravascular ultrasound imaging in a patient's body 10 provides for detection of encapsulated gaseous acoustic contrast agent 11 with intravascular ultrasound. It will be understood that other types of contrast agent particle may be used as the contrast agent 11.
• the ultrasound excitation signal transmitter and echo signal receiver comprises a transducer 12 mounted on a catheter 13 or guidewire introduced through a vessel 14 such as the coronary artery.
• the length of the catheter is in the range 60 to 200 cm (only partial length is- shown in the figure) and the outer diameter is in the range 0.7 to 3 mm.
• the contrast agent 11 (which expression includes free bubbles) preferably comprises encapsulated bubbles that are of a composition and a size distribution capable of oscillating in a nonlinear manner at intravascular ultrasound transmit centre frequencies of at least 10 MHz, preferably in the range 10 to 80 MHz, and more preferably in the range 15 to 60 MHz, and more preferably with centre frequency above 15 MHz or above 30 MHz.
• contrast agent bubbles 11 can be specifically manufactured to achieve such a size distribution.
• a suitable method for preparing bubbles with the desired high volume fractions in the specified ranges is disclosed in WO 2004/069284.
• existing commercially available contrast agent designed for use at lower frequencies but having a significant number of smaller bubbles can have its population distribution modified to some extent by decantation or mechanical filtration [13].
• the contrast agent bubbles 11 are preferably introduced into the blood stream either through a systemic steady infusion or in the form of a bolus.
• the steady state infusion may be administered through a systemic intravenous drip, as can be done for conventional frequency contrast agent use.
• the contrast agent may be introduced in combination with localised drug delivery.
• the expression "introducing contrast agent into the vicinity of the transducer” is intended to encompass both (i) 'local' introduction of the contrast agent at or very close to the transducer location, and (ii) 'remote' introduction of the contrast agent elsewhere in the body, relying on transport of the agent to the vicinity of the transducer using inherent action of the body, such as blood flow.
• the IVUS catheter 13 carrying the transducer 12 at an imaging tip 16 may be introduced into the vessel of interest 14 within a sheath or delivery catheter 17.
• the imaging tip 16 extends past the end 17a of the sheath 17 by a distance d which is preferably variable or pre-selectable. Li preferred arrangements, the distance d ⁇ s in the range 10 to 300 mm.
• Contrast agent 11 may be injected locally though the sheath 17, which defines a delivery conduit 17b, to an exit orifice 17c at or proximal to the end 17a. This facilitates the delivery of a high local concentration of contrast agent 11 at the site of interest.
• the exit orifice 17c will be formed as openings in the periphery of the delivery catheter 17 so as to permit the exit of contrast agent in a manner that encourages an even agent distribution towards the vessel wall 14.
• the exit orifice 17c openings may preferably be provided within about 10 cm of the end of the sheath 17.
• the transducer 12 is adapted to be capable of generating acoustic excitation pulses of sufficient pressure and other characteristics (e.g. length, frequency content) to initiate nonlinear scattering or response from the contrast agent.
• a transmit subsystem 21 is provided to generate sequences of excitation pulses 21a of sufficient amplitude characteristics (e.g. length, frequency content) to the transducer 12 in order to initiate the nonlinear scattering in the contrast agent.
• Part of the transmit subsystem may reside within the catheter 13.
• the excitation pulses are generated at frequencies greater than 10 MHz, more preferably at frequencies greater than 15 MHz.
• the excitation pulses have centre frequencies in the range 10 to 80 MHz and more preferably in the range 15 to 60 MHz.
• the excitation pulse centre frequency is in the range 15 to 50 MHz, and more preferably 15 MHz or higher, or above 30 MHz.
• Pulse sequences may be phase- and/or amplitude-modulated or frequency-band limited in order to sufficiently permit the isolation of bubble-specific scattering after reception of echo signals arising from interaction of the excitation signals with the tissue and with the contrast agent.
• any excitation pulse characteristic may be used to enable or enhance the ability to discriminate between echo signals respectively arising from interaction of ultrasound excitation signals with tissue and interaction with contrast agent.
• the sequence of excitation pulses may comprise pulses that are identical, that vary in amplitude, that vary in phase or that vary in length. Pulses may be derived from combinations of previously transmitted pulses, e.g. inverted copies and the like.
• Excitation pulses may be adapted to be used to destroy contrast agent, and to detect agent during the destruction thereof, or to use imaging pulses which follow destruction pulses.
• Part of the transmit subsystem 21 may reside within the catheter 13.
• Detection of nonlinear bubble behaviour may be achieved by way of detection of echo pulses of sufficient bandwidth, in the form of single or multiple frequency peaks, or through energy loss in the receive bandwidth or through the detection of transient bubble responses.
• a receive subsystem 22 conditions received echo signals 22a from the transducer (e.g. by amplification and filtering), digitizes the conditioned signal in a manner compatible with separating the tissue and blood signals (e.g. with sufficient phase coherence).
• Part of the receive subsystem 22 may reside within the catheter 13 which may have benefit with respect to overcoming electrical tuning effects and improving signal to noise ratio.
• Part of the system may be provided by a personal computer.
• the receive subsystem is adapted to receive echo signals in at least a part of the range 8 to 80 MHz.
• a signal processor 30 and an image processing subsystem 31 may be used to apply appropriate algorithms to extract bubble specific signals and thereby form images that have improved sensitivity and specificity to the contrast agent. It is to be understood that free bubbles located in vasa vasorum or targeted bubbles located anywhere may have specific acoustic signatures that may be exploited in transmission of excitation signals, in reception of echo signals and in signal processing.
• the echo signal analysis and imaging is performed on echo signals in a frequency band that is different to but potentially overlapping or non-overlapping with that of the transmit frequency band.
• the echo signal analysis and imaging is performed on echo signals in a frequency band comprising the second harmonic of a transmit frequency.
• the echo signal analysis and imaging is performed in a frequency band comprising a subharmonic of a transmit frequency.
• both harmonics and subharmonics are used in the echo signal analysis and imaging.
• subharmonic imaging from excitation signals having centre frequencies in the range 20 to 60 MHz is preferred, requiring for example acoustic pressures of at least 50 IcPa.
• Differentiation between contrast agent bubbles within the main vessel lumen 14 (e.g. the coronary vessel) and bubbles within vasa vasorum 15a situated in tissue immediately adjacent to the lumen 14 may be effected by using correlation-based techniques to differentiate between slowly moving bubbles 11 in the vasa vasorum 15a and more rapidly moving bubbles in the lumen 14. This may be done within a given image frame and/or between two or more consecutive image frames (frame rate is typically 20 to 30 frames per second).
• a local upstream bolus injection is used to introduce the contrast agent, this will result in a rapid passage of agent within the main lumen 14, followed by a time- delayed arrival of agent to the vasa vasorum.
• Analyzing the evolution of the signals in a region of interest (ROI) as a function of time after a bolus may therefore assist in discriminating between contrast agent in the main lumen and agent in the vasa vasorum.
• ROI region of interest
• Such approaches may use frame-to-frame image tracking due to tissue motion.
• Destruction-reperfusion techniques may also be used.
• a series of narrow bandwidth pulses (preferably at as low a frequency as achievable) is more appropriate to achieve destruction of the contrast agent bubbles.
• Imaging pulses may then follow.
• Two different transducers may be used within the catheter located at or near the imaging tip 16: a first transducer for destructive excitation pulses (e.g. with a frequency in the range 1 to 15 MHz, and preferably in the region of 5 MHz) and a second transducer for imaging, of the type described above. Imaging may be performed during destruction, or during reperfusion.
• Targeted and untargeted contrast agent bubbles may be differentiated using a number of techniques. Correlation-based techniques may be used to differentiate between bound and free bubbles. These techniques may be performed within a given frame and/or between two or more consecutive frames (frame rate is typically 20 to 30 frames per second). Such approaches may use frame-to-frame image tracking. Destruction techniques may be used, as previously described above. Imaging may be performed during destruction, or during re-accumulation at target sites. Differences between the acoustic response of bound and free bubbles located within the lumen may also be used.
• a waveform generator 23 provides a suitable pulse waveform to a power amplifier 24, to generate excitation signals from the transducer 16. Protection circuitry 25 in the form of an expander / limiter may be provided at the output of the power amplifier 24.
• a transmit-side filter 26 may be provided to pre-condition waveforms generated by the waveform generator 23. It will be understood that any or all of the elements 23 - 26 of the transmit subsystem 21 could be combined and/or incorporated into a single electronic circuit.
• an amplifier 27 receives echo signals 22a from the transducer 12, and passes these to a digitizer 29 for analogue-digital conversion.
• the digitised signals are passed to a signal processor 30 (which may be incorporated within a personal computer.
• the signal processor 30 may include, or be coupled to an appropriate image processing device 31, which also may be incorporated within a personal computer.
• An analogue filter 28 may be incorporated in the receive path, e.g. before and/or after amplification of the received echo signals. It will be understood that any or all of the elements 27 - 30 of the receive sub-system 22 could be combined and/or incorporated into a single electronic circuit.
• a flow phantom was constructed by creating a 1 mm flow channel through tissue mimicking phantom, and contrast agent was passed through this 'vessel' during the experiments.
• the contrast agent employed was an experimental phospholipid-stabilized composition prepared according to example Ii of WO 2004/069284. Images were constructed by pulse-inversion techniques from a series of pulse ensembles (10 or 25% bandwidth) acquired during continuous translation. The pulse-inversion technique effects cancellation of linear signals by exploiting differences in consecutive phase-inversed pulses due to nonlinear propagation or bubble responses. If there is substantial motion between the tissue and transducer between pulses, this will result in inefficient cancellation of the fundamental frequency.
• a needle-mounted IVUS transducer was employed (having a bandwidth of 15 to 45 MHz) to image free bubbles flowing freely through the vessel.
• the vessel was first imaged in 20 MHz fundamental mode (F20), which is linear imaging.
• the vessel was then imaged using the second harmonic of a 20 MHz transmit pulse (H40), and finally using the subharmonic of a 40 MHz transmit pulse, centred closer to 20 MHz (S20).
• F20 imaging shows little contrast between tissue and agent flowing in the vessel (figure 3a).
• H40 was found to produce improvements in contrast to tissue signal ratios (CTR).
• CTR tissue signal ratios
• the CTR degrades due to increases in nonlinear propagation giving rise to a stronger tissue harmonic signal. This indicates that lower pressure ranges will be appropriate for contrast agent imaging, and higher pressure amplitudes are appropriate for tissue harmonic imaging.
• the fundamental frequency image, F40 offers poor visualization of the vessel.
• SH20 mode results indicate tissue suppression approaching the noise floor, with up to 18 dB of contrast to noise ratio at higher transmit amplitudes.
• These results indicate the feasibility of nonlinear contrast imaging with IVUS.
• the feasibility to suppress tissue signals is critical in reliably detecting vasa vasorum with TVUS.
• figure 5a shows F20 imaging of free flowing bubbles
• figure 5b shows SHlO imaging of free flowing bubbles
• figure 5c shows SHlO imaging of bound bubbles.
• the imaging techniques using a catheter-based ultrasound probe may be used to assist in localised drug delivery by providing real-time image guidance to the drug delivery mechanism.
• the drug delivery mechanism may be incorporated with the contrast agent.
• Drugs or genetic material may be incorporated into, located within or in some manner attached to or imbedded in the contrast agent.
• the catheter-based IVUS transducer can be used to assess an appropriate location for drug or genetic material delivery and to facilitate its delivery.
• the delivery may be facilitated by the acoustic stimulation of either the imaging transducer or the second lower frequency transducer, if present.
• the acoustic stimulation may effect the disruption of contrast agent which contains drug or genetic material, or contrast agent that is in the presence of drug or genetic material.
• This may involve the stimulation of oscillations of contrast agent which contains drug or genetic material, or contrast agent that is in the presence of drug or genetic material, in a manner that facilitates the delivery of the drug or genetic material to the tissue or cells of interest.
• a two transducer approach is employed such that the lower frequency (1 to 15 MHz transducer) is used to facilitate the delivery of drug or genetic material, and the second transducer, the imaging transducer, being used to guide or monitor the treatment procedure.
• the contrast agent delivery system using conduit 17b formed by sheath 17 may also be configured with means for applying a saline (or heparinized saline) flush between contrast injections.
• the delivery system conduit may also be provided with a means (not shown) for displacing a smaller volume of agent to the catheter tip, particularly if the volume of the catheter sheath 17 may exceed the desired inj ection volume.
• existing syringe adaptors may be used to manually introduce the agent and saline flushes.
• An exemplary automated implementation consists of a two-plunger syringe pump (one for a saline syringe and the second for the agent).
• the agent injection volume and injection rate can be specified and the agent can then automatically be pushed slowly (to avoid pressurization of agent that would cause its disruption) towards the catheter tip. This can then be followed by the bolus injection phase (the timing of which may be electronically synchronised with the IVUS imaging and acquisition system.
• pulse centre frequencies in the range of 30 to 60 MHz, with total pulse frequency content between 10 and 80 MHz is preferred.
• Peak positive acoustic pressures within the beam lie between 20 kPa and 8 MPa when operating in contrast imaging mode.
• pulse centre frequencies in the range of 20 to 50 MHz, with total pulse frequency content between 10 and 80 MHz is preferred.
• Peak positive acoustic pressures within the beam lie between 5 kPa and 8 MPa when operating in contrast imaging mode.
• pulse centre frequencies in the range of 20 to 50 MHz, with total pulse frequency content between 10 and 80 MHz is preferred.
• Peak positive acoustic pressures within the beam lie between 5 IcPa and 8 MPa.
• a destruction pulse mode using a single element transducer transmit centre frequencies in the range of 10 to 40 MHz, with pulse bandwidths between 0.1 % and 50 %-6 dB relative bandwidths are preferred. Peak positive acoustic pressures within the beam (as measured in a water tank) lie between 100 kPa and 15 MPa.
• pulse centre frequencies in the range of 1 to 15 MHz, with pulse bandwidths lying between 0.1 % and 50 %-6 dB relative bandwidths are preferred.
• Peak positive acoustic pressures within the beam lie between 100 IcPa and 15 MPa.
• pulse centre frequencies in the range of 1 to 15 MHz, with pulse bandwidths between 0.1 % and 50 % -6 dB relative bandwidths are preferred.
• Peak positive acoustic pressures within the beam lie between 100 kPa and 5 MPa.
• pulse centre frequencies for the low frequency element in range of 1 to 15 MHz and pulse centre frequencies for high frequency element in range of 15 to 50 MHz, with pulse bandwidths between 0.1 % and 20 % -6 dB relative bandwidths are preferred.
• Peak positive acoustic pressures within the beam lie between 100 IcPa and 5 MPa.
• agent detection is achieved by means of the nonlinear behaviour of bubbles.
• the nonlinear signals are isolated by means of filtering and analysis of pulse sequences.
• pulse sequence' refers to a sequence of potentially different pulses that are transmitted and received as the transducer is rotating.
• Nonlinear echo signals at subharmonic or second harmonic frequencies are isolated by a combination of analog and digital filtering of the individual received echo signals.
• a single IVUS image is formed by taking the envelope of individual RF lines displayed in a linear, logarithmic or other compression scheme.
• the signals from a group of adjacent pulses are combined to form an image line, and in doing so benefit from signal averaging effects.
• the combination may take the form of direct averaging of the time domain, or power averaging or another scheme.
• Transmitted pulses may also be phase-inversed (i.e. have 180 degree phase differences) with respect to each other.
• a group of these pulses (two or more) may be combined to form an image line as a strategy for removing linear tissue signals.
• the operation to combine the pulses may take different forms, only one of which is to sum with equal weighting all the pulses.
• Transmitted pulses may also be phase shifted with respect to each other by an amount other than 180 degrees (e.g. 90 degrees).
• a group of these pulses (two or more) may be combined to form an image line as a strategy for removing linear tissue signals.
• the operation to combine the pulses may take different forms, only one of which is to sum with equal weighting all the pulses.
• Pulses may be transmitted with different amplitudes, referred to as power modulation. This will vary the amount of nonlinear bubble behaviour.
• a group of these pulses (two or more) may be combined to form an image line as a strategy for removing linear tissue signals.
• the operation to combine the pulses may take different forms. For example, if two pulses are transmitted, the first with half the amplitude of the second, then the received pulse pair is added by multiplying the first pulse by two before subtracting it from the second.
• Transmitted combinations of phase and amplitude modulation may be used to isolate nonlinear signals.
• Transmit pulse lengths may be varied.
• the received signals may then be processed to extract nonlinear transients or other pulse length dependant signals arising from bubble oscillations.
• Transmit frequency may be varied within a pulse.
• the received signals may then be processed to extract signals arising from bubble oscillations.
• Formation of images from the imaging transducer received signals when the transmit pulses are sent out by either the imaging transducer or a separate low frequency transducer to destroy agent may be effected in several ways, both for when destructive pulses are transmitted by the imaging transducer, or by a separate low frequency transducer.
• one or more entire rotations of the rVUS element can be conducted during which time high amplitude pulses are sent with the intention of destroying free or targeted agent with either transducer. Following the destructive frames, imaging is then performed using one of the methods described above. This can be used as a means of implementing destruction-reperfusion imaging or to assess re-accumulation of targeted agent.
• the changes of signals as a function of time in regions of interest may be used to differentiate agent located in vasa vasorum or targeted agent from free agent within the main lumen.
• targeted agent a different pressure, bandwidth and frequency range may be employed as a means of distinguishing targeted agent from bound agent.
• Pulse sequences may consist of non-destructive (or predominantly non-destructive) pulses sent on the low frequency transducer and nonlinear signals detected by the imaging transducer. These signals may include superharmonics, ultraharmonics or transients.
• Pulse sequences may consist of the simultaneous transmitting of different pulses on both the imaging transducer and the low frequency transducer.
• tissue imaging mode By being able to operate in either mode it is possible to superimpose contrast specific signals onto tissue structural images.
• Tissue signals may be isolated from the incoming received signals (which may also contain contrast-specific signals) through processing.
• tissue signals may be extracted from modifications of the pulse sequences (i.e. both transmit pulse characteristics and amplitudes) that would allow for tissue imaging pulses to be interleaved with contrast imaging pulses.
• Tissue imaging can be performed in linear or nonlinear imaging modes. Multiple pulse techniques such as pulse- inversion imaging or amplitude modulation can also be applied to nonlinear tissue imaging (both in the presence of contrast agent or not).
• the multiple pulse techniques will be optimised so that the level of harmonics generated are maximized, or are maximized after a certain distance, or to maximize the contrast in between tissue components.
• tissue harmonic imaging was illustrated on a continuously rotating single element transducer in a tissue mimicking phantom and in an atherosclerotic rabbit aorta.
• Gaussian enveloped pulses at centre frequencies of either 20 MHz or 40 MHz were generated. The fractional bandwidth of the pulses was 25 %.
• F20 fundamental 20 MHz mode
• F40 fundamental 40 MHz mode
• H40 harmonic 40 MHz mode
• SNR signal-to-noise ratio
• tissue harmonic imaging using pulse inversion has shown to be feasible in a tissue mimicking phantom and to improve image quality.
• tissue harmonic imaging using pulse inversion has shown to be feasible in vivo and to improve image quality.

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