Intravascular photoacoustic imaging using an IVUS imaging catheter

Catheter-based imaging of atherosclerosis with high resolution, albeit invasive, is extremely important for screening and characterization of vulnerable plaques. Currently, there is a need for an imaging technique capable of providing comprehensive morphological and functional information of plaques. In this paper, we present an intravascular photoacoustic imaging technique to characterize vulnerable plaques by using optical absorption contrast between normal tissue and atherosclerotic lesions. Specifically, we investigate the feasibility of obtaining intravascular photoacoustic (IVPA) images using a high-frequency intravascular ultrasound (IVUS) imaging catheter. Indeed, the combination of IVPA imaging with clinically available IVUS imaging may provide desired functional and morphological assessment of the plaque. The imaging studies were performed with tissue-mimicking arterial vessel phantoms and excised samples of rabbit artery. The results of our study suggest that catheter-based intravascular photoacoustic imaging is possible, and the combination of IVPA with IVUS has the potential to detect and differentiate atherosclerosis based on both the structure and composition of the plaque.     

Motion artifact reduction for IVUS-based thermal strain imaging

Thermal strain imaging (TSI) using intravascular ultrasound (IVUS) has the potential to identify lipid pools within rupture-prone arterial plaques and serve as a valuable supplement to current IVUS systems in diagnosing acute coronary syndromes. The major challenge for in vivo application of TSI will be cardiac motion, including bulk motion and tissue deformation. Simulations based on an artery model, including a lipid-filled plaque, demonstrate that effective bulk motion compensation can be achieved within a certain motion range using spatial interpolation. We also propose a practical imaging scheme to minimize mechanical strains caused by tissue deformation based on a linear least squares fitting strategy. This scheme was tested on clinical data by artificially superimposing thermal displacements corresponding to different temperature rises. Results suggest a 1-2 degrees C temperature rise is required to detect lipids in an atherosclerotic plaque in vivo.     

Lower-limb vascular imaging with acoustic radiation force elastography: Demonstration of in vivo feasibility

Acoustic radiation force impulse (ARFI) imaging characterizes the mechanical properties of tissue by measuring displacement resulting from applied ultrasonic radiation force. In this paper, we describe the current status of ARFI imaging for lower-limb vascular applications and present results from both tissue-mimicking phantoms and in vivo experiments. Initial experiments were performed on vascular phantoms constructed with polyvinyl alcohol for basic evaluation of the modality. Multilayer vessels and vessels with compliant occlusions of varying plaque load were evaluated with ARFI imaging techniques. Phantom layers and plaque are well resolved in the ARFI images, with higher contrast than B-mode, demonstrating the ability of ARFI imaging to identify regions of different mechanical properties. Healthy human subjects and those with diagnosed lower-limb peripheral arterial disease were imaged. Proximal and distal vascular walls are well visualized in ARFI images, with higher mean contrast than corresponding B-mode images. ARFI images reveal information not observed by conventional ultrasound and lend confidence to the feasibility of using ARFI imaging during lower-limb vascular workup.     

Quantitative blood speed imaging with intravascular ultrasound

Previously, we presented a method of real-time arterial color flow imaging using an intravascular ultrasound (IVUS) imaging system, where real-time RF A-scans were processed with an FIR (finite-impulse response) filter bank to estimate relative blood speed. Although qualitative flow measurements are clinically valuable, realizing the full potential of blood flow imaging requires quantitative flow speed and volume measurements in real time. Unfortunately, the rate of RF echo-to-echo decorrelation is not directly related to scatterer speed in a side-looking IVUS system because the elevational extent of the imaging slice varies with range. Consequently, flow imaging methods using any type of decorrelation processing to estimate blood speed without accounting for spatial variation of the radiation pattern will have estimation errors that prohibit accurate comparison of speed estimates from different depths. The FIR filter bank approach measures the rate of change of the ultrasound signal by estimating the slow-time spectrum of RF echoes. A filter bank of M bandpass filters is applied in parallel to estimate M components of the slow-time DFT (discrete Fourier transform). The relationship between the slow-time spectrum, aperture diffraction pattern, and scatterer speed is derived for a simplified target. Because the ultimate goal of this work is to make quantitative speed measurements, we present a method to map slow time spectral characteristics to a quantitative estimate. Results of the speed estimator are shown for a simulated circumferential catheter array insonifying blood moving uniformly past the array (i.e., plug flow) and blood moving with a parabolic profile (i.e., laminar flow)     

Annular-ring CMUT arrays for forward-looking IVUS: transducer characterization and imaging

In this study, a 64-element, 1.15-mm diameter annular-ring capacitive micromachined ultrasonic transducer (CMUT) array was characterized and used for forward-looking intravascular ultrasound (IVUS) imaging tests. The array was manufactured using low-temperature processes suitable for CMOS electronics integration on a single chip. The measured radiation pattern of a 43 X 140-microm2 array element depicts a 40 degrees view angle for forward-looking imaging around a 15-MHz center frequency in agreement with theoretical models. Pulse-echo measurements show a -10-dB fractional bandwidth of 104% around 17 MHz for wire targets 2.5 mm away from the array in vegetable oil. For imaging and SNR measurements, RF A-scan data sets from various targets were collected using an interconnect scheme forming a 32-element array configuration. An experimental point spread function was obtained and compared with simulated and theoretical array responses, showing good agreement. Therefore, this study demonstrates that annular-ring CMUT arrays fabricated with CMOS-compatible processes are capable of forward-looking IVUS imaging, and the developed modeling tools can be used to design improved IVUS imaging arrays.     

Intravascular ultrasound tissue harmonic imaging in vivo

Tissue harmonic imaging (THI) has been shown to increase image quality of medical ultrasound in the frequency range from 2 to 10 MHz and might, therefore, also be used to improve image quality in intravascular ultrasound (IVUS). In this study we constructed a prototype IVUS system that could operate in both fundamental frequency and second harmonic imaging modes. This system uses a conventional, continuously rotating, single-element IVUS catheter and was operated in fundamental 20 MHz, fundamental 40 MHz, and harmonic 40 MHz modes (transmit 20 MHz, receive 40 MHz). Hydrophone beam characterization measurements demonstrated the build-up of a second harmonic signal as a function of increasing pressure. Imaging experiments were conducted in both a tissue-mimicking phantom and in an atherosclerotic animal model in vivo. Acquisitions of fundamental 20 and 40 MHz and second harmonic acquisitions resulted in cross sections of the phantom and a rabbit aorta. The harmonic results of the imaging experiments showed the feasibility of intravascular THI with a conventional IVUS catheter both in a phantom and in vivo. The harmonic acquisitions also showed the potential of THI to reduce image artifacts compared to fundamental imaging.     

Synthetic aperture-based beam compression for intravascular ultrasound imaging

In this paper, intravascular ultrasound (IVUS) images acquired with a 64-element array transducer using a multistatic acquisition scheme are presented. The images are reconstructed from a collection of pulse-echo measurements using a synthetic aperture array imaging technique. The main limitations of IVUS imaging are a poor lateral resolution and elevated grating lobes caused by the imaging geometry. We propose a Synthetic Aperture Focusing Technique (SAFT), which uses a limited number of A-scan signals. The focusing process, which is performed in the Fourier domain, requires far less computation time than conventional delay-and-sum methods. Two different reconstruction kernel functions have been derived and are compared for the processing of experimental data     

应用血管内超声与X射线造影图像融合的血管三维重建

针对X射线血管造影和血管内超声各自显示血管形态的局限以及互补性问题,提出将两种数据进行融合,准确重建血管的方法。首先从在超声导管回撤路径起点拍摄的两个角度的造影图像对中提取出导管并进行三维重建。然后采用基于snake模型的半自动方法从各帧超声图像中提取出血管壁的内外膜边缘。最后,在Frenet-Serret标架中确定各相邻帧超声图像间的相对方位后,利用非迭代的统计优化方法确定各帧超声图像沿导管轴向的绝对方位,完成两种数据的融合。采用临床数据的实验结果验证了算法的可行性,并分析了可能存在的误差和计算成本。     

Low temperature fabrication of immersion capacitive micromachined ultrasonic transducers on silicon and dielectric substrates

A maximum processing temperature of 250/spl deg/C is used to fabricate capacitive micromachined ultrasonic transducers (CMUTs) on silicon and quartz substrates for immersion applications. Fabrication on silicon provides a means for electronics integration via post-complementary metal oxide semiconductor (CMOS) processing without sacrificing device performance. Fabrication on quartz reduces parasitic capacitance and allows the use of optical displacement detection methods for CMUTs. The simple, low-temperature process uses metals both as the sacrificial layer for improved dimensional control, and as the bottom electrode for good electrical conductivity and optical reflectivity. This, combined with local sealing of the vacuum cavity by plasma-enhanced chemical-vapor deposition of silicon nitride, provides excellent control of lateral and vertical dimensions of the CMUTs for optimal device performance. In this paper, the fabrication process is described in detail, including process recipes and material characterization results. The CMUTs fabricated for intravascular ultrasound (IVUS) imaging in the 10-20 MHz range and interdigital CMUTs for microfluidic applications in the 5-20 MHz range are presented as device examples. Intra-array and wafer-to-wafer process uniformity is evaluated via electrical impedance measurements on 64-element ring annular IVUS imaging arrays fabricated on silicon and quartz wafers. The resonance frequency in air and collapse voltage variations are measured to be within 1% and 5%, respectively, for both cases. Acoustic pressure and pulse echo measurements also have been performed on 128 /spl mu/m/spl times/32 /spl mu/m IVUS array elements in water, which reveal a performance suitable for forward-looking IVUS imaging at about 16 MHz.     

80-MHz intravascular ultrasound transducer using PMN-PT free-standing film

[Pb(Mg(1/3)Nb(2/3))O(3)](0.63)[PbTiO(3)](0.37) (PMN-PT) free-standing film of comparable piezoelectric properties to bulk material with thickness of 30 μm has been fabricated using a modified precursor coating approach. At 1 kHz, the dielectric permittivity and loss were 4364 and 0.033, respectively. The remnant polarization and coercive field were 28 μC/cm(2) and 18.43 kV/cm. The electromechanical coupling coefficient k(t) was measured to be 0.55, which was close to that of bulk PMN-PT single-crystal material. Based on this film, high-frequency (82 MHz) miniature ultrasonic transducers were fabricated with 65% bandwidth and 23 dB insertion loss. Axial and lateral resolutions were determined to be as high as 35 and 176 μm. In vitro intravascular imaging on healthy rabbit aorta was performed using the thin film transducers. In comparison with a 35-MHz IVUS transducer, the 80-MHz transducer showed superior resolution and contrast with satisfactory penetration depth. The imaging results suggest that PMN-PT free-standing thin film technology is a feasible and efficient way to fabricate very-high-frequency ultrasonic transducers.     

Intravascular ultrasound detection and delivery of molecularly targeted microbubbles for gene delivery

We are investigating the combination of microbubble-based targeted drug delivery and intravascular ultrasound (IVUS) imaging as a potential therapy to reduce incidence of restenosis following stent placement in atherosclerotic coronary arteries. The goal of these studies was to determine whether IVUS could be used to detect targeted microbubbles and enhance drug/gene delivery through targeting. Quiescent vascular smooth muscle cells (SMCs) were stimulated with cytokine IL-1β to induce the inflammatory cell surface marker vascular cell adhesion molecule 1 (VCAM-1). Molecular-targeted (VCAM-1 Ab or IgG control Ab), fluorescent-labeled microbubbles were conjugated with plasmid DNA expressing green fluorescent protein (GFP, pMax-GFP) and exposed to the inflamed SMCs under flow to measure adhesion compared with control microbubbles. Gene delivery was performed using a modified IVUS catheter to generate 1.5-MHz ultrasound at 200 kPa. Detection of adherent microbubbles to inflamed SMCs in culture and flow chambers was measured using an IVUS catheter and scanner. VCAM-1-targeted microbubbles enhanced adhesion to inflamed SMCs 100-fold over nontargeted microbubbles. Compared with noninflamed SMCs, VCAM-1-targeted microbubbles exhibited a 7.9-fold increase in adhesion to IL-1β-treated cells. Targeted microbubbles resulted in a 5.5-fold increase in plasmid DNA transfection over nontargeted microbubbles in conjunction with a focused 2.54-cm (1-in) diameter 1-MHz transducer and also enhanced transfection by the modified IVUS transducer at 1.5 MHz. Targeted microbubbles (at a density of 3 × 10? microbubbles/mm2) increased IVUS image intensity 13.2 dB over non-microbubble-coated surfaces. Rupture of microbubbles from the modified IVUS transducer resulted in a 53% reduction in image intensity. Taken together, these results indicate that IVUS may be used to detect targeted microbubbles to inflamed vasculature and subsequently deliver a gene/drug locally.     

Regularized autoregressive analysis of intravascular ultrasound backscatter: improvement in spatial accuracy of tissue maps

Autoregressive (AR) models are qualified for analysis of stochastic, short-time data, such as intravascular ultrasound (IVUS) backscatter. Regularization is required for AR analysis of short data lengths with an aim to increase spatial accuracy of predicted plaque composition and was achieved by determining suitable AR orders for short data records. Conventional methods of determining order were compared to the use of trend in the mean square error for determining order. Radio-frequency data from 101 fibrous, 56 fibro-lipidic, 50 calcified, and 70 lipid-core regions of interest (ROIs) were collected ex vivo from 51 human coronary arteries with 30 MHz unfocused IVUS transducers. Spectra were computed for AR model orders between 3-20 for data representing ROIs of two sizes (32 and 16 samples at 100 MHz sampling frequency) and were analyzed in the 17-42 MHz bandwidth. These spectra were characterized based on eight previously identified parameters. Statistical classification schemes were computed from 75% of the data and cross-validated with the remaining 25% using matched histology. The results determined the suitable AR order numbers for the two ROI sizes. Conventional methods of determining order did not perform well. Trend in the mean square error was identified as the most suitable factor for regularization of short record lengths.     

Dependence of the frequency spectrum of small amplitude vibrations superimposed on finite deformations of a nonlinear, cylindrical elastic body on residual stress

We model and analyze the response of nonlinear, residually stressed elastic bodies subjected to small amplitude vibrations superimposed upon large deformations. The problem derives from modeling the use of intravascular ultrasound (IVUS) imaging to interrogate atherosclerotic plaques in vivo in large arteries. The goal of this investigation is twofold: (i) introduce a modeling framework for residual stress that unlike traditional Fung type classical opening angle models may be used for a diseased artery, and (ii) investigate the sensitivity of the spectra of small amplitude high frequency time harmonic vibrations superimposed on a large deformation to the details of the residual stress stored in arteries through a numerical simulation using physiologic parameter values under both low and high blood pressure loadings. The modeling framework also points the way towards an inverse problem using IVUS techniques to estimate residual stress in healthy and diseased arteries.     

In vivo characterization of atherosclerotic plaque depositions by Raman-probe spectroscopy and in vitro coherent anti-stokes Raman scattering microscopic imaging on a rabbit model

Visualization as well as characterization of inner arterial plaque depositions is of vital diagnostic interest, especially for the early recognition of vulnerable plaques. Established clinical techniques provide valuable visual information but cannot deliver information about the chemical composition of individual plaques. Here, we employ Raman-probe spectroscopy to characterize the plaque compositions of arterial walls on a rabbit model in vivo, using a miniaturized filtered probe with one excitation and 12 collection fibers integrated in a 1 mm sleeve. Rabbits were treated with a cholesterol-enriched diet. The methodology can improve the efficiency of animal experiments and shows great potential for applications in cardiovascular research. In order to further characterize the plaque depositions visually, coherent anti-Stokes Raman scattering (CARS) microscopy images have been acquired and are compared with the Raman-probe results.     

An integrated semicompliant balloon ultrasound catheter for quantitative feedback and image guidance during stent deployment

An integrated balloon ultrasound catheter prototype was designed to image from inside the balloon for real-time guidance during stent deployment. It was fabricated using a semicompliant balloon material (polyethylene) and a 20 MHz, 64-element circumferential ultrasound array. A commercial stent, nominally 4.4 mm in diameter and 12 mm in length, was used for a phantom study and placed along the length of the integrated balloon ultrasound catheter. A rubber phantom was created with an elastic modulus of 175 kPa with a 4.36 mm diameter lumen. Real-time balloon pressure measurements were recorded using a digital pressure sensor, and real-time radio-frequency (RF) data were captured as the balloon was inflated. The slope of the area-pressure ratio (APR) was compared to a reference measure of the balloon and stent expanded in water to determine a measure for optimal stent deployment. The results clearly indicate stent deployment at 11.1 atm using this metric. The APR slope could serve as quantitative feedback parameter for guiding stent deployment to reduce arterial injury and subsequent restenosis. After the stent deployment experiment, RF data were captured as the balloon catheter was moved along the length of the stent in pullback mode to confirm successful stent deployment. Ultimately, an integrated balloon ultrasound catheter could serve as a single catheter intervention device by providing real-time intravascular ultrasound (IVUS) imaging and quantitative feedback during stent deployment.     

An ApoA-I mimetic peptide high-density-lipoprotein-based MRI contrast agent for atherosclerotic plaque composition detection

Cardiovascular disease is one of the prime causes of mortality throughout the world and there is a need for targeted and effective contrast agents to allow noninvasive imaging of the cholesterol-rich atherosclerotic plaques in arteries. A new, fully synthetic, high-density lipoprotein (HDL)-mimicking MRI contrast agent is developed, which enhances macrophage-rich areas of plaque in a mouse model of atherosclerosis by 94%. Confirmation of the targeting of this nanoparticulate agent is achieved using confocal microscopy by tracking a fluorescent lipid incorporated into the nanoparticle.     

Radial modulation of microbubbles for ultrasound contrast imaging

Over the past few years, extensive research has been carried out in the field of ultrasound contrast imaging. In addition to the development of new types of ultrasound contrast agents, various imaging methods dedicated to contrast agents have been introduced, and some of them are now commercially available. In this study, we present results of an imaging technique that is capable of detecting echoes from microbubbles and eliminating those emanating from nonoscillating structures (tissue), thereby enhancing contrast imaging. The method is based on mixing a low frequency (LF) modulator signal and a high frequency (HF) imaging signal to effectively modulate the size of the contrast microbubble through its volumetric oscillations using the LF signal and to probe the radial motion using the HF imaging signal. To evaluate the performances and limitations of the method, high-speed optical observations and acoustic measurements were carried out on soft-shelled microbubbles. The results showed that, by incorporating the modulator signal, the bubbles respond differently compared to the HF excitation alone. The decorrelation between the signals obtained at the compression and expansion phase of the modulator signal is significantly high to be used as a parameter to detect contrast microbubbles and discriminate them from tissue. The echo received from a solid reflector shows identical responses during the compression and rarefaction phase of the LF signal. In conclusion, these results demonstrate the feasibility of this fully linear approach for improving the contrast detection.     

A dual-modality probe utilizing intravascular ultrasound and optical coherence tomography for intravascular imaging applications

We have developed a dual-modality biomedical imaging probe utilizing intravascular ultrasound (IVUS) and optical coherence tomography (OCT). It consists of an OCT probe, a miniature ultrasonic transducer and a fixed mirror. The mirror was mounted at the head of the hybrid probe 45° relative to the light and the ultrasound beams to change their propagation directions. The probe was designed to be able to cover a larger area in blood vessel by IVUS and then visualize a specific point at a much finer image resolution using OCT. To demonstrate both its feasibility and potential clinical applications, we used this ultrasound-guide OCT probe to image a rabbit aorta in vitro. The results offer convincing evidence that the complementary natures of these two modalities may yield beneficial results that could not have otherwise been obtained.     

Optimizing the beam pattern of a forward-viewing ring-annular ultrasound array for intravascular imaging

Intravascular ultrasound (IVUS) imaging systems using circumferential arrays mounted on cardiac catheter tips fire beams orthogonal to the principal axis of the catheter. The system produces high resolution cross-sectional images but must be guided by conventional angioscopy. A real-time forward-viewing array, integrated into the same catheter, could greatly reduce radiation exposure by decreasing angiographic guidance. Unfortunately, the mounting requirement of a catheter guide wire prohibits a full-disk imaging aperture. Given only an annulus of array elements, prior theoretical investigations have only considered a circular ring of point transceivers and focusing strategies using all elements in the highly dense array, both impractical assumptions. In this paper, we consider a practical array geometry and signal processing architecture for a forward-viewing IVUS system. Our specific design uses a total of 210 transceiver firings with synthetic reconstruction for a given 3-D image frame. Simulation results demonstrate this design can achieve side-lobes under -40 dB for on-axis situations and under -30 dB for steering to the edge of a 60/spl deg/ cone.     

Motion compensation for intravascular ultrasound palpography

Rupture of vulnerable plaques in coronary arteries is the major cause of acute coronary syndromes. Most vulnerable plaques consist of a thin fibrous cap covering an atheromous core. These plaques can be identified using intravascular ultrasound (IVUS) palpography, which measures radial strain by cross-correlating RF signals at different intraluminal pressures. Multiple strain images (i.e., partial palpograms) are averaged per heart cycle to produce a more robust compounded palpogram. However, catheter motion due to cardiac activity causes misalignment of the RF signals and thus of the partial palpograms, resulting in less valid strain estimates. To compensate for in-plane catheter rotation and translation, we devised four methods based on block matching. The global rotation block matching (GRBM) and contour mapping (CMAP) methods measure catheter rotation, and local block matching (LBM) and catheter rotation and translation (CRT) estimate displacements of local tissue regions. These methods were applied to nine in vivo pullback acquisitions, made with a 20 MHz phased-array transducer. We found that all these methods significantly increase the number of valid strain estimates in the partial and compounded palpograms (P < 0.008). The best method, LBM, attained an average increase of 17% and 15%, respectively. Implementation of this method should improve the information coming from IVUS palpography, leading to better vulnerable plaque detection.