Deformable 3D/3D CT-to-digital-tomosynthesis image registration in image-guided bronchoscopy interventions.

Traditional navigational bronchoscopy procedures rely on preprocedural computed tomography (CT) and intraoperative chest radiography and cone-beam CT (CBCT) to biopsy peripheral lung lesions. This navigational approach is challenging due to the projective nature of radiography, and the high radiation dose, long imaging time, and large footprints of CBCT. Digital tomosynthesis (DTS) is considered an attractive alternative combining the advantages of radiography and CBCT. Only the depth resolution cannot match a full CBCT image due to the limited angle acquisition. To address this issue, preoperative CT is a good auxiliary in guiding bronchoscopy interventions. Nevertheless, CT-to-body divergence caused by anatomic changes and respiratory motion, hinders the effective use of CT imaging. To mitigate CT-to-body divergence, we propose a novel deformable 3D/3D CT-to-DTS registration algorithm employing a multistage, multiresolution approach and using affine and elastic B-spline transformation models with bone and lung mask images. A multiresolution strategy with a Gaussian image pyramid and a multigrid strategy within the B-spline model are applied. The normalized correlation coefficient is included in the cost function for the affine model and a multimetric weighted cost function is used for the B-spline model, with weights determined heuristically. Tested on simulated and real patient bronchoscopy data, the algorithm yields promising results. Assessed qualitatively by visual inspection and quantitatively by computing the Dice coefficient (DC) and the average symmetric surface distance (ASSD), the algorithm achieves mean DC of 0.82±0.05 and 0.74±0.05, and mean ASSD of 0.65±0.29mm and 0.93±0.43mm for simulated and real data, respectively. This algorithm lays the groundwork for CT-aided intraoperative DTS imaging in image-guided bronchoscopy interventions with future studies focusing on automated metric weight setting.

Intravascular molecular-structural imaging with a miniaturized integrated near-infrared fluorescence and ultrasound catheter.

Coronary artery disease (CAD) remains a leading cause of mortality and warrants new imaging approaches to better guide clinical care. We report on a miniaturized, hybrid intravascular catheter and imaging system for comprehensive coronary artery imaging in vivo. Our catheter exhibits a total diameter of 1.0 mm (3.0 French), equivalent to standalone clinical intravascular ultrasound (IVUS) catheters but enables simultaneous near-infrared fluorescence (NIRF) and IVUS molecular-structural imaging. We demonstrate NIRF-IVUS imaging in vitro in coronary stents using NIR fluorophores, and compare NIRF signal strengths for prism and ball lens sensor designs in both low and high scattering media. Next, in vivo intravascular imaging in pig coronary arteries demonstrates simultaneous, co-registered molecular-structural imaging of experimental CAD inflammation on IVUS and distance-corrected NIRF images. The obtained results suggest substantial potential for the NIRF-IVUS catheter to advance standalone IVUS, and enable comprehensive phenotyping of vascular disease to better assess and treat patients with CAD.

Paclitaxel Drug-Coated Balloon Angioplasty Suppresses Progression and Inflammation of Experimental Atherosclerosis in Rabbits.

Paclitaxel drug-coated balloons (DCBs) reduce restenosis, but their overall safety has recently raised concerns. This study hypothesized that DCBs could lessen inflammation and reduce plaque progression. Using 25 rabbits with cholesterol feeding- and balloon injury-induced lesions, DCB-percutaneous transluminal angioplasty (PTA), plain PTA, or sham-PTA (balloon insertion without inflation) was investigated using serial intravascular near-infrared fluorescence-optical coherence tomography and serial intravascular ultrasound. In these experiments, DCB-PTA reduced inflammation and plaque burden in nonobstructive lesions compared with PTA or sham-PTA. These findings indicated the potential for DCBs to serve safely as regional anti-atherosclerosis therapy.

Optoacoustic microscopy at multiple discrete frequencies.

Optoacoustic (photoacoustic) sensing employs illumination of transient energy and is typically implemented in the time domain using nanosecond photon pulses. However, the generation of high-energy short photon pulses requires complex laser technology that imposes a low pulse repetition frequency (PRF) and limits the number of wavelengths that are concurrently available for spectral imaging. To avoid the limitations of working in the time domain, we have developed frequency-domain optoacoustic microscopy (FDOM), in which light intensity is modulated at multiple discrete frequencies. We integrated FDOM into a hybrid system with multiphoton microscopy, and we examine the relationship between image formation and modulation frequency, showcase high-fidelity images with increasing numbers of modulation frequencies from phantoms and in vivo, and identify a redundancy in optoacoustic measurements performed at multiple frequencies. We demonstrate that due to high repetition rates, FDOM achieves signal-to-noise ratios similar to those obtained by time-domain methods, using commonly available laser diodes. Moreover, we experimentally confirm various advantages of the frequency-domain implementation at discrete modulation frequencies, including concurrent illumination at two wavelengths that are carried out at different modulation frequencies as well as flow measurements in microfluidic chips and in vivo based on the optoacoustic Doppler effect. Furthermore, we discuss how FDOM redefines possibilities for optoacoustic imaging by capitalizing on the advantages of working in the frequency domain.

Blood vessel imaging using radiofrequency-induced second harmonic acoustic response.

We introduce a contrast mechanism for visualizing blood vessels based on radiofrequency-induced second harmonic acoustic (RISHA) signals sensing blood conductivity. We develop a novel imaging system using commonly available inexpensive components, and demonstrate in vivo RISHA visualization of blood vessels based on low-power quasi-continuous radiofrequency excitation of tissue at frequencies of a few MHz. We show how the novel approach also implicitly enables radiofrequency-induced passive ultrasound imaging and can be readily applied to non-invasive imaging of blood vessels ex vivo and in vivo. We discuss the implications of non-invasive conductivity measurements in the context of biomedical applications.

Quantitative intravascular biological fluorescence-ultrasound imaging of coronary and peripheral arteries in vivo.

AIMS: (i) to evaluate a novel hybrid near-infrared fluorescence-intravascular ultrasound (NIRF-IVUS) system in coronary and peripheral swine arteries in vivo; (ii) to assess simultaneous quantitative biological and morphological aspects of arterial disease. METHODS AND RESULTS: Two 9F/15MHz peripheral and 4.5F/40MHz coronary near-infrared fluorescence (NIRF)-IVUS catheters were engineered to enable accurate co-registrtation of biological and morphological readings simultaneously in vivo. A correction algorithm utilizing IVUS information was developed to account for the distance-related fluorescence attenuation due to through-blood imaging. Corrected NIRF (cNIRF)-IVUS was applied for in vivo imaging of angioplasty-induced vascular injury in swine peripheral arteries and experimental fibrin deposition on coronary artery stents, and of atheroma in a rabbit aorta, revealing feasibility to intravascularly assay plaque structure and inflammation. The addition of ICG-enhanced NIRF assessment improved the detection of angioplasty-induced endothelial damage compared to standalone IVUS. In addition, NIRF detection of coronary stent fibrin by in vivo cNIRF-IVUS imaging illuminated stent pathobiology that was concealed on standalone IVUS. Fluorescence reflectance imaging and microscopy of resected tissues corroborated the in vivo findings. CONCLUSIONS: Integrated cNIRF-IVUS enables simultaneous co-registered through-blood imaging of disease related morphological and biological alterations in coronary and peripheral arteries in vivo. Clinical translation of cNIRF-IVUS may significantly enhance knowledge of arterial pathobiology, leading to improvements in clinical diagnosis and prognosis, and helps to guide the development of new therapeutic approaches for arterial diseases.

Ionoacoustic tomography of the proton Bragg peak in combination with ultrasound and optoacoustic imaging.

Ions provide a more advantageous dose distribution than photons for external beam radiotherapy, due to their so-called inverse depth dose deposition and, in particular a characteristic dose maximum at their end-of-range (Bragg peak). The favorable physical interaction properties enable selective treatment of tumors while sparing surrounding healthy tissue, but optimal clinical use requires accurate monitoring of Bragg peak positioning inside tissue. We introduce ionoacoustic tomography based on detection of ion induced ultrasound waves as a technique to provide feedback on the ion beam profile. We demonstrate for 20 MeV protons that ion range imaging is possible with submillimeter accuracy and can be combined with clinical ultrasound and optoacoustic tomography of similar precision. Our results indicate a simple and direct possibility to correlate, in-vivo and in real-time, the conventional ultrasound echo of the tumor region with ionoacoustic tomography. Combined with optoacoustic tomography it offers a well suited pre-clinical imaging system.

Magnetoacoustic Sensing of Magnetic Nanoparticles.

The interaction of magnetic nanoparticles and electromagnetic fields can be determined through electrical signal induction in coils due to magnetization. However, the direct measurement of instant electromagnetic energy absorption by magnetic nanoparticles, as it relates to particle characterization or magnetic hyperthermia studies, has not been possible so far. We introduce the theory of magnetoacoustics, predicting the existence of second harmonic pressure waves from magnetic nanoparticles due to energy absorption from continuously modulated alternating magnetic fields. We then describe the first magnetoacoustic system reported, based on a fiber-interferometer pressure detector, necessary for avoiding electric interference. The magnetoacoustic system confirmed the existence of previously unobserved second harmonic magnetoacoustic responses from solids, magnetic nanoparticles, and nanoparticle-loaded cells, exposed to continuous wave magnetic fields at different frequencies. We discuss how magnetoacoustic signals can be employed as a nanoparticle or magnetic field sensor for biomedical and environmental applications.

Wavelength-Modulated Differential Photoacoustic Spectroscopy (WM-DPAS) for noninvasive early cancer detection and tissue hypoxia monitoring.

This study introduces a novel noninvasive differential photoacoustic method, Wavelength Modulated Differential Photoacoustic Spectroscopy (WM-DPAS), for noninvasive early cancer detection and continuous hypoxia monitoring through ultrasensitive measurements of hemoglobin oxygenation levels (StO2 ). Unlike conventional photoacoustic spectroscopy, WM-DPAS measures simultaneously two signals induced from square-wave modulated laser beams at two different wavelengths where the absorption difference between maximum deoxy- and oxy-hemoglobin is 680 nm, and minimum (zero) 808 nm (the isosbestic point). The two-wavelength measurement efficiently suppresses background, greatly enhances the signal to noise ratio and thus enables WM-DPAS to detect very small changes in total hemoglobin concentration (CHb ) and oxygenation levels, thereby identifying pre-malignant tumors before they are anatomically apparent. The non-invasive nature also makes WM-DPAS the best candidate for ICU bedside hypoxia monitoring in stroke patients. Sensitivity tunability is another special feature of the technology: WM-DPAS can be tuned for different applications such as quick cancer screening and accurate StO2 quantification by selecting a pair of parameters, signal amplitude ratio and phase shift. The WM-DPAS theory has been validated with sheep blood phantom measurements. Sensitivity comparison between conventional single-ended signal and differential signal.

Frequency domain optoacoustic tomography using amplitude and phase.

We introduce optoacoustic tomographic imaging using intensity modulated light sources and collecting amplitude and phase information in the frequency domain. Imaging is performed at multiple modulation frequencies. The forward modeling uses the Green's function solution to the pressure wave equation in frequency domain and the resulting inverse problem is solved using regularized least squares minimization. We study the effect of the number of frequencies and of the bandwidth employed on the image quality achieved. The possibility of employing an all-frequency domain optoacoustic imaging for experimental measurements is studied as a function of noise. We conclude that frequency domain optoacoustic tomography may evolve to a practical experimental method using light intensity modulated sources, with advantages over time-domain optoacoustics.

Wideband optical detector of ultrasound for medical imaging applications.

Optical sensors of ultrasound are a promising alternative to piezoelectric techniques, as has been recently demonstrated in the field of optoacoustic imaging. In medical applications, one of the major limitations of optical sensing technology is its susceptibility to environmental conditions, e.g. changes in pressure and temperature, which may saturate the detection. Additionally, the clinical environment often imposes stringent limits on the size and robustness of the sensor. In this work, the combination of pulse interferometry and fiber-based optical sensing is demonstrated for ultrasound detection. Pulse interferometry enables robust performance of the readout system in the presence of rapid variations in the environmental conditions, whereas the use of all-fiber technology leads to a mechanically flexible sensing element compatible with highly demanding medical applications such as intravascular imaging. In order to achieve a short sensor length, a pi-phase-shifted fiber Bragg grating is used, which acts as a resonator trapping light over an effective length of 350 µm. To enable high bandwidth, the sensor is used for sideway detection of ultrasound, which is highly beneficial in circumferential imaging geometries such as intravascular imaging. An optoacoustic imaging setup is used to determine the response of the sensor for acoustic point sources at different positions.

Fast Fourier backprojection for frequency-domain optoacoustic tomography.

We present a time-efficient backprojection image reconstruction approach applied to frequency-domain (FD) optoacoustic tomography based on tissue illumination at multiple, discrete frequencies. The presented method estimates the Fourier transform of a spatial, circular profile of the underlying image using the amplitude and phase data. These data are collected over multiple frequencies using an acoustic transducer positioned at several locations around the sample. Fourier-transform values for absent frequencies are estimated using interpolation based on low-pass filtering in the image domain. Reconstruction results are presented for synthetic measurements using numerical phantoms, and the results are compared with FD model-based reconstructions.

Spatial characterization of the response of a silica optical fiber to wideband ultrasound.

Optical fibers have long been recognized as a promising technology for remote sensing of ultrasound. Nonetheless, very little is known about the characteristics of their spatial response, which is significantly affected by the strong acoustic mismatches between the fiber and surrounding medium. In this Letter, a new method is demonstrated for wideband spatial acoustic characterization of optical fibers. The method is based on the excitation of a point-like acoustic source via the opto-acoustic effect, while a miniature fiber sensor is implemented by a π-phase-shifted fiber Bragg grating. Despite the relative complexity of acoustic wave propagation in the fiber, its spatial sensitivity in the high frequency band (6-30 MHz) exhibited an orderly pattern, which can be described by a simple model. This property reveals new possibilities for high-performance imaging using fiber-based ultrasound sensors, where knowledge of the sensor's spatial sensitivity map is generally required.

Near-field thermoacoustic imaging with transmission line pulsers.

PURPOSE: Near-field radiofrequency thermoacoustic (NRT) tomography has been recently introduced for imaging electromagnetic (EM) properties of tissues using ultrawideband, high-energy impulses, which induce thermoacoustic responses. Operation in the near-field allows for more effective energy coupling into tissue, compared to using radiating sources, which in turn enables the use of shorter excitation pulses and leads to higher image resolution. This work aimed at investigating transmission lines as a method to generate excitation pulses to improve the NRT resolution over previous implementations without compromising the energy coupled into tissue. METHODS: The authors implemented a number of custom-made transmission lines to overcome the challenges of the broadband nature of the impulse excitation required in NRT. The authors further constructed phantoms and investigated the performance of the lines in regard to the pulse duration, energy coupling and the resulting resolution, and image quality achieved. Finally, the authors employed mice in order to investigate the performance of the approach in tissue imaging. RESULTS: The authors found that the use of transmission lines resulted in the generation of RF impulses in the range of tens of nanoseconds and shorter. This performance resulted to resolution improvements over previous thermoacoustic imaging implementations, reaching 45 µm resolution, while retaining several tens to hundreds of milli-Joules of energy per pulse. This performance further allowed the visualization and clear differentiation of different mouse structures such as the heart, lung, or spinal cord. CONCLUSIONS: The use of transmission lines significantly improved the NRT performance leading to high thermoacoustic tomography imaging quality by coupling adequate amounts of energy within short times at a relatively low cost.

In vivo frequency domain optoacoustic tomography.

Optoacoustic imaging has been primarily implemented in the time domain, i.e., using ultrashort nanosecond laser pulses for illumination. Alternatively, frequency domain optoacoustic imaging can be performed when employing amplitude modulated light sources. We present herein a tomographic implementation of optoacoustic imaging using a linear frequency modulated laser source. The method developed demonstrated the ability to produce tomographic images of optical absorbing phantoms and in vivo images, by enabling visualization of the mouse tail following ICG injection.

Near-field thermoacoustic tomography of small animals.

Near-field radiofrequency thermoacoustic (NRT) tomography is a new imaging method that was developed to mitigate limitations of conventional thermoacoustic imaging approaches, related to hard compromises between signal strength and spatial resolution. By utilizing ultrahigh-energy electromagnetic impulses at ∼20 ns duration along with improved energy absorption coupling in the near-field, this method can deliver high-resolution images without compromising signal to noise ratio. NRT is a promising modality, offering cost-effectiveness and ease of implementation and it can be conveniently scaled to image small animals and humans. However, several of the performance metrics of the method are not yet documented. In this paper, we characterize the expected imaging performance via numerical simulations based on a finite-integration time-domain (FITD) technique and experiments using tissue mimicking phantoms and different biological samples. Furthermore, we show for the first time whole-body tomographic imaging results from mice, revealing clear anatomical details along with highly dissipative inclusions introduced for control. The best spatial resolution achieved for those experiments was 150 µm.

Near-field radiofrequency thermoacoustic tomography with impulse excitation.

PURPOSE: Imaging performance of radiofrequency and microwave-based thermoacoustic tomography systems is mainly determined by the ability to deposit a substantial amount of electromagnetic energy within ultrashort time duration. Pulses of nanosecond-range duration that can carry hundreds of millijoules energy are ideal for obtaining good signal-to-noise and spatial resolution in many biological imaging applications. However, existing implementations are based on modulated-carrier-frequency amplification solutions, which are generally costly and cannot achieve ultrahigh-peak-power requirements essential for optimal thermoacoustic signal generation. METHODS: Herein the authors suggest and experimentally validate a near-field radiofrequency tomography (NRT) method for high resolution imaging of biological tissues using ultrashort electromagnetic impulses. The solution includes a low-cost pulsing system while the imaged objects are placed in the near field of the energy-emitting aperture for improved coupling using nonradiative fields. RESULTS: In the current design, the authors were able to achieve excitation impulse energies of hundreds of millijoules with durations in the order of a few nanoseconds, corresponding to peak power levels of multiple megawatts. The phantom imaging experiments demonstrated image features with characteristic sizes of around 170 microm, but the impulse durations used herein allow in principle spatial resolutions in the order of a few tens of microns when using an appropriate ultrasonic detection bandwidth. CONCLUSIONS: The proposed NRT method makes it possible to attain very high spatial resolution without compromising the thermoacoustic signal strength. This makes the imaging performance to be limited by the available bandwidth of the ultrasonic detector rather than by the microwave pulse duration. It is overall expected that the combination of pulsed near-field coupling with optimal choice of energy dissipation elements will generate a practical modality that can scale its application to small and larger volumes alike, while optimally adjusting the resolution to match the acoustic resolution possible. Such an approach should find several applications in small animal and clinical imaging.