Collagen Complexity Spatially Defines Microregions of Total Tissue Pressure in Pancreatic Cancer.

The poor efficacy of systemic cancer therapeutics in pancreatic ductal adenocarcinoma (PDAC) is partly attributed to deposition of collagen and hyaluronan, leading to interstitial hypertension collapsing blood and lymphatic vessels, limiting drug delivery. The intrinsic micro-regional interactions between hyaluronic acid (HA), collagen and the spatial origins of mechanical stresses that close off blood vessels was investigated here. Multiple localized pressure measurements were analyzed with spatially-matched histochemical images of HA, collagen and vessel perfusion. HA is known to swell, fitting a linear elastic model with total tissue pressure (TTP) increasing above interstitial fluid pressure (IFP) directly with collagen content. However, local TTP appears to originate from collagen area fraction, as well as increased its entropy and fractal dimension, and morphologically appears to be maximized when HA regions are encapsulated by collagen. TTP was inversely correlated with vascular patency and verteporfin uptake, suggesting interstitial hypertension results in vascular compression and decreased molecular delivery in PDAC. Collagenase injection led to acute decreases in total tissue pressure and increased drug perfusion. Large microscopic variations in collagen distributions within PDAC leads to microregional TPP values that vary on the hundred micron distance scale, causing micro-heterogeneous limitations in molecular perfusion, and narrows viable treatment regimes for systemically delivered therapeutics

Elastographic imaging of pancreatic cancer tumor microenvironment

Thesis (Ph. D.)--University of Rochester. Department of Electrical and Computer Engineering, 2019.Pancreatic ductal adenocarcinoma (PDAC) is a common and aggressive malignancy with a 5-year survival rate of less than 5%. Surgical resection with targeted neoadjuvant therapy remains the most effective treatment plan available. Despite extensive research, targeted therapies have made incremental improvement in efficacy for PDAC patients. The unique abnormal PDAC tumor microenvironment has been postulated to promote tumor growth and inhibit drug delivery. The role of the dense stroma contents and high interstitial pressure are under active investigation regarding their role in vascular compression. An imaging technique that can measure the tumor stroma stiffness would provide crucial information on how the tumor microenvironment changes during different therapies. Contrast agent-based computed tomography, and magnetic resonance imaging modalities are faced with contrast pooling and poor contrast delivery, also a result of the abnormal tumor microenvironment. The objective of this thesis is to establish shear modulus as a surrogate biomarker for tissue pressure in pancreatic tumors using ultrasound elastography including model-based iterative reconstruction schemes and shear wave elasticity imaging. To achieve this goal, the following objectives are to be satisfied: (1) establish the relationship between shear modulus and stromal components of the pancreatic cancer tumor microenvironment; (2) investigate how shear modulus impacts drug delivery and vascular patency in pancreatic tumors; (3) assess the effects of radiotherapy and immunotherapy on shear modulus and the underlying tissue components. The results of these studies showed that the shear modulus is an excellent surrogate imaging biomarker for tissue pressure in pancreatic tumors. We demonstrated through three animal studies that shear modulus is inversely related to drug delivery in pancreatic adenocarcinoma tumors. Shear modulus also changes in response to modifications in tumor stroma attributes due to emerging treatment regimens such as immunotherapy and stereotactic body radiation therapy

Acoustic characterization and nonlinear imaging of ultrasound contrast agents for intravascular assessment of atherosclerosis

Thesis (Ph. D.)--University of Rochester. Dept. of Electrical and Computer Engineering, 2014.Cardiovascular disease kills more Americans than all cancers combined, and is estimated to cost over 300 billion dollars annually. The majority of these deaths are caused when the rupture of atherosclerotic plaques triggers life-threatening conditions such as myocardial infarction and stroke. Although the histopathological features of life-threatening plaques are known, detecting them in vivo is challenging. The abnormal proliferation of the adventitial vasa vasorum, the microvessels that nourish arterial walls, may destabilize atherosclerotic plaques. Therefore, visualizing the vasa vasorum could help assess atherosclerotic plaques. Contrast-enhanced ultrasound can characterize the neovascular vasa vasorum in atherosclerotic arteries. However, the translation of vasa vasorum imaging to the clinic is hampered by the absence of techniques capable of reliably detecting microbubble contrast agents. The goal of the research reported in this thesis is to develop methods for the intravascular detection of the vasa vasorum. To achieve this goal, we conducted physical characterization and imaging studies with Targestar-P®, a commercial contrast agent. Specifically, we 1)investigated the impact of the size distribution of the agent on its nonlinear response; 2) discovered that temporal changes in the agent can be harnessed to enhance nonlinear emissions; 3) demonstrated using numerical simulations and acoustic measurements that chirp-coded pulsing can substantially enhance the nonlinear response of microbubbles; and 4) developed a prototype intravascular ultrasound system for vasa vasorum imaging. We validated the vasa vasorum imaging system by conducting experiments with hydrogelow phantoms. Further, we compared the performance achievable with this system in subharmonic and ultraharmonic imaging modes. The findings reported in this thesis could accelerate the development of efficacious contrast agents for intravascular ultrasound imaging. The vasa vasorum imaging system developed in this work can be useful in preclinical research and clinical imaging | for improving our understanding of the pathophysiology of atherosclerosis, evaluating new therapies, and assessing cardiovascular risk

Principal strain vascular elastography for imaging the carotid artery

Thesis (Ph. D.)--University of Rochester. Department of Electrical and Computer Engineering, 2017.Atherosclerosis kills more Americans than all forms of cancer combined. The onset of the disease is characterized by thickening and stiffening of the arterial wall, and in advanced stages it leads to formation of life-threatening plaques. Rupture of these advanced plaques can lead to myocardial or cerebral infarction, and the propensity of the plaques to rupture is governed by their composition and structure. Vascular elastography can visualize the strain distribution in the carotid artery, and serve as a useful screening tool to assess the stiffness of the arterial wall – for early detection of major cardiovascular and cerebrovascular diseases, and to assess plaque composition. Currently available vascular elastography techniques visualize polar strains across the transverse cross-section, and axial strain across the sagittal cross- section. It is difficult to produce reliable transverse polar strain elastograms (radial and circumferential) because the center of the carotid artery is typically unknown. Further, axial strain estimated along the sagittal plane can only measure a component of the radial strain in the vessel. In this thesis, we hypothesized that principal strain imaging can overcome these limitations, provided reliable estimates of lateral displacements were available. To enable high quality estimation of lateral displacements, multi-element synthetic aperture (MSA) vascular elastography was developed. The phantom and in vivo experiments demonstrated that MSA imaging can produce high quality axial and lateral strain estimates. Compared with synthetic aperture (SA) imaging and compounded plane wave (CPW) imaging, MSA imaging improved the elastographic contrast-to-noise ratio of the vascular elastograms by over 15 dB and 12 dB, respectively. Subsequently, it was demonstrated that principal strains reduced artifacts incurred when polar strains were computed with imprecise estimates of the vessel center. The feasibility of using principal strain imaging in characterizing transversely isotropic mechanical behavior of the carotid artery was also established. Further, principal strain imaging addressed the issue of dependency of axial strain on the geometry of the vessel, when imaging across the sagittal cross-section. More specifically, principal strain imaging enabled estimation of arterial strain in the radial direction, independent of the angle between the transducer and the vessel, which is typically governed by the geometry and anatomy of the vessel, and varies across subjects. The results obtained from this thesis suggest that principal strain imaging can be a very useful tool for translation of vascular elastography to the clinic. Future studies should involve the assessment of the mechanical properties of the carotid artery using principal strain elastography, and compare it to conventional markers of subclinical atherosclerosis

Shear wave elastographic imaging of pancreatic cancer murine models

Thesis (Ph. D.)--University of Rochester. Department of Electrical and Computer Engineering, 2020.The mechanical environment of a tumor directly impacts its growth, malignancy, and drug uptake. Imaging techniques that can visualize the mechanical properties of a tumor (stiffness, pressure, density etc.) can facilitate the diagnosis, treatment planning, and development of new therapies. Unfortunately, most parameters of tumor biomechanics cannot be estimated noninvasively, limiting their use in clinic. Although stiffness of a tumor can be quantitatively mapped in a noninvasive manner, it is not an established imaging biomarker. To validate stiffness as a useful imaging biomarker, naturallyoccurring or therapy-induced changes in stiffness need to be established in different types and stages of tumors. Since performing these studies in the clinic are time consuming and expensive, evaluation of tumor stiffness in preclinical small animal models can greatly improve our understanding of the tumor mechanical environment. However, shear wave elastography (SWE), the imaging technique that is used to map stiffness, often has inadequate spatial resolution in the preclinical domain. SWE uses transverse acoustical waves (shear waves) generated from acoustic radiation force to map the shear wave speed (SWS), which is directly related to the shear modulus of tissue. The propagation of the shear waves are tracked using conventional ultrasound imaging. However, speckle in the ultrasound images introduces a positional uncertainty in the wave-tracking process, which corrupts the SWS maps with noise. This noise is severely exacerbated at small observation scales, which is typical for preclinical imaging. Consequently, larger observation scales (often > 1 mm) need to be used, which degrade the spatial resolution of SWE. Single-tracking-location SWE (STL-SWE) is a recently proposed technique that overcame this fundamental challenge in speckle tracking by using a fixed tracking location. While STL-SWE is a suitable modality for preclinical imaging, there are challengesthat need to be overcome. STL-SWE is not immune to incoherent sources of noise under in vivo imaging conditions. Furthermore, the longer acquisition duration of STL-SWE makes it susceptible to physiological motion artifacts. The objective of this thesis is to develop a preclinical SWE technique that can be used to study the therapy response and natural progression of the tumor mechanical environment in small animal models. To achieve this objective, we developed beamforming approaches to reduce the estimation variance of SWE. We developed an approach to transmit multiple encoded-apertures simultaneously, which enhanced the transmit focusing quality of ultrasound beams and the signal-to-noise ratio. Next, we improved the noise robustness of STL-SWE by using coherently compounded plane wave imaging, a technique we named pSTL-SWE. We, then, extended pSTL-SWE to focused transmit-based parallel beamforming techniques that are applicable to commercially available clinical ultrasound scanners. We also developed a real-time automated respiration gating scheme that enabled us to use pSTL-SWE in preclinical mouse models of cancer. Using this technique, we studied the progression of liver stiffness longitudinally in a murine model of pancreatic ductal adenocarcinoma (PDAC) liver metastasis. We observed, for the first time, a direct correlation between elevated tumor stiffness and survival of untreated and chemotherapy-treated mice. We also used the pSTL-SWE technique to validate a recently developed immunotherapy treatment protocol for PDAC. The results presented in this thesis demonstrate the effectiveness of pSTL-SWE in imaging preclinical cancer models and represent a critical first-step toward establishing stiffness as a clinical imaging biomarker for cancer

Application of synthetic aperture imaging to non-invasive vascular elastography

Thesis (Ph. D.)--University of Rochester. Dept. of Electrical and Computer Engineering, 2012The health of the carotid artery is an important indicator of cardiovascular disease (CVD). The advent of CVD results in reduced elasticity and flexibility of the arterial wall. These changes in elasticity can be measured using non-invasive vascular elastography (NIVE). Elastography is performed by subjecting the tissue under investigation to a form of mechanical excitation. The resultant tissue displacement is measured and used to compute the spatial variation of strain within the tissue. These strain maps, known as elastograms, serve as surrogates for tissue elasticity. While elastography can be performed with any imaging modality, ultrasound is portable, inexpensive and has high frame rates, making it ideal for diagnostic screening purposes. However, linear array based elastography can accurately estimate displacement only in the axial direction. Consequently, NIVE cannot characterize strain across artery cross-sections, restricting the diagnostic value of this technique. The objective of this thesis was to investigate the feasibility of using synthetic aperture (SA) imaging to accurately estimate the 2D displacement vector, thereby enhancing the performance of NIVE. We demonstrated, through simulation and experiment, that SA imaging can accurately measure both axial and lateral displacements. These displacements generate high quality radial and circumferential strain elastograms of the arterial cross-section. Compared to conventional ultrasound elastography, SA elastography improved the error in lateral displacements and the resultant strain elastograms by an order of magnitude. However, the low frame rates and large data volumes required by SA imaging render this approach clinically inviable. To overcome this limitation, we developed a sparse array based elastography system. We demonstrated that as few as eight transmit elements can generate strain elastograms with a 16x improvement in frame rate and data volume, at a minimal loss of image quality. The efficacy of sparse array elastography was compared to that of a compounded plane wave imaging system. It was demonstrated that sparse array imaging displayed higher lateral sensitivity thereby producing strain elastograms with 20% improved image quality. From the success of this novel approach to elastography, it was concluded that further development and integration on a commercial ultrasound system would greatly enhance clinical use

Quantitative vascular elastography : stiffness and stress estimation for identifying rupture-prone plaques

Thesis (Ph. D.)--University of Rochester. Department of Electrical and Computer Engineering, 2015.Every 40 seconds, someone in the United States dies of cardiovascular disease, with many of these deaths occurring from the rupture of atherosclerotic plaques in the carotid and coronary arteries. These events cause thombi to form in the arteries, which prevent blood flow. Clots in the carotid artery may lead to stroke, while clots in the coronary artery may lead to myocardial infarction. Therefore, there is a need for an imaging technique that can identify rupture-prone plaques. One proposed method for this is ultrasound-based elastography, which maps the stiffness of the vessel based on the extent of observed tissue motion. Plaques have been shown to rupture when the internal stresses exceed 300 kPa, and conventional elastography measures strain, which is proportional to stress. Absolute values of stress are needed to determine the likelihood of plaque rupture. To obtain these stresses, one must measure Young’s modulus and all components of strain. Computing these using ultrasound is challenging due to the poor lateral resolution. The objective of this thesis was to investigate the feasibility of using a model-based approach to reconstruct the modulus and stresses within arteries using clinically available ultrasound systems. To achieve this goal the following objectives had to be satisfied: (1) Develop accurate inversion schemes for estimating the modulus distribution within vessels; (2) assess the impact of microvessels on the performance of the techniques developed in (1) and develop methods to overcome its limitations; (3) investigate the effects of material nonlinearity on the ability to visualize the stress distribution within vascular tissues; (4) assess the feasibility of producing clinically useful images. The results of these studies showed that the proposed reconstruction method could accurately compute modulus and stress elastograms. In all simulation studies, peak stresses could be recovered with under 15% error using the proposed reconstruction method. Phantom and in vivo studies were also able to accurately reconstruct these parameters despite the presence of measurement noise, attenuation, and sub-resolution features. This research may be useful in the further advancement of clinical vascular imaging

Beamforming strategies for plane wave vascular elastography

Thesis (Ph. D.)--University of Rochester. Department of Physics and Astronomy, 2017Cardiovascular disease (CVD) kills more Americans than all cancers combined. Ultrasound-based vascular elastography visualizes the strain distribution within the arteries, which can be very useful in early detection of CVD. Imaging of transverse cross-sections of the arteries requires reliable estimates of both axial and lateral components of displacements. However, conventional ultrasound imaging can accurately estimate displacements only in the axial direction. Poor lateral resolution limits the performance in lateral direction. Plane wave (PW) imaging achieves high resolution in the lateral direction by using boxcar apodization, albeit at the expense of high sidelobes. These compromise the performance of vascular elastography. In this thesis, we investigated different apodization strategies to suppress the sidelobe levels and improve the performance of plane wave imaging. Specifically, we evaluated the quality of strain elastograms produced with fixed apodization beamforming (FAB) using modified hyperbolic sine functions and minimum variance beamforming (MVB). We observed that MVB elastograms were marginally better than those produced with FAB. The performance of MVB was further improved by spatial compounding performed over small beam-steered angles. In addition to the resolution of the ultrasound system, elastographic performance depends on other factors such as applied strain and signal processing parameters. In order to analyze the impact of these factors on performance of elastography, we derived the Cramer Rao lower bound (CRLB) for axial and lateral displacements estimated from radio frequency echo data. The derived analytical expressions include the effects of signal decorrelation, electronic noise, point spread function (PSF), and signal processing parameters (window size and overlap between the successive windows). We modeled the 2-D PSF of a pulse-echo imaging system as a sincmodulated spatial sine pulse in the axial direction and as a sinc function in the lateral direction. For validation, we compared the variance in displacements and strains, incurred when quasi-static elastography was performed using conventional linear array (CLA), plane wave and compounded plane wave (CPW) imaging techniques. We also extended the theory to assess the performance of vascular elastograms. Synthetic aperture (SA) imaging can produce PSF with narrow lateral beam-width as well as low side-lobes. The sinc function is ineffective for the modeling SA PSF. Therefore, we derived the CRLB expressions for the case of SA imaging using Gaussian function to model the envelope of the PSF. Overall, the general trends in performance of these imaging techniques obtained from theory were supported by experiments and were consistent for all cases (axial, lateral and polar strain elastograms)