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Ultrasound contrast agents (UCAs) are used to enhance ultrasound imaging of the cardiovascular system. Ultrasound contrast agents are administered intravenously as a solution of micrometer-sized bubbles, consisting of an inert gas encased in a shell of phospholipid or albumin. When ultrasound is applied to the heart or blood vessels, the ultrasonic waves interact with UCAs in the circulation, causing the bubbles to oscillate or collapse. The interaction of ultrasound with UCAs opacifies the blood, allowing for improved imaging of cardiac structure and function,1 arterial stenosis,2 vascularization of atherosclerotic plaques,3 and other aspects of the cardiovascular system. When used for cardiac left ventricular opacification, UCAs can enhance the visual quality of ultrasound scans in patients who are difficult to image and improve diagnostic accuracy.4,5 While UCAs have clear clinical utility in detection and diagnosis of cardiovascular disease, concerns have been raised over their safety. There have been reports of adverse cardiovascular events after ultrasound with UCA administration in animal models and humans. In experimental studies from our research group and others, UCAs have been shown to induce cardiac arrhythmias6 and hemorrhage,7–9 impair endothelium-dependent vasodilatation,10 and alter atheroma thickness and the circulating biomarker von Willebrand Factor (vWF).11 Reports of cardiopulmonary complications and deaths in human clinical patients associated with UCA administration added to these concerns, and patients with preexisting cardiovascular disease appeared to be at increased risk.12 As a result, the US Food and Drug Administration (FDA) mandated warning labels for 2 commercially available UCAs, Definity (Lantheus Medical Imaging, North Billerica, MA) and Optison (GE Healthcare, Princeton, NJ) in 2007. The reported adverse events highlight the importance of further research in this area. The biological effects of contrast ultrasound may be a function of the ultrasound pressure level or UCA concentration, so it is necessary to test for adverse events using a variety of scenarios and experimental models. In this study, we used the ApoE−/− mouse model of atherosclerosis to determine thresholds for arterial damage at several different ultrasound pressure levels, with concomitant UCA administration. We fed groups of mice either a standard chow diet or a high-fat, high-sugar, cholesterol-containing Western diet to modulate the progression of atherosclerosis after a single contrast ultrasound exposure. We hypothesized that contrast ultrasound would induce vascular injury and accelerate the progression of atherosclerosis, that this effect would be pressure dependent, and that the threshold for effects of contrast ultrasound on biomarkers would be lower than FDA limits established for clinical ultrasound imaging.

Currently, the evaluation of thyroid cancer relies on the use of fine needle aspiration biopsy as non-invasive imaging methods do not provide sufficient levels of accuracy for the diagnosis of this disease. In this study, the potential of quantitative ultrasound methods for characterizing thyroid tissues was studied using a rodent model ex vivo. A high-frequency ultrasonic scanning system (40 MHz) was used to scan thyroids extracted from mice that had spontaneously developed thyroid lesions (cancerous or benign). Three sets of mice were acquired having different predispositions to developing thyroid anomalies (a C-cell adenoma, a papillary thyroid carcinoma (PTC), and a follicular variant papillary thyroid carcinoma (FV-PTC)). A fourth set of mice did not develop thyroid anomalies (normal mice) and were used as controls. The backscatter coefficient was estimated from excised thyroid lobes for the different mice. From the backscatter coefficient versus frequency (25 to 45 MHz), the effective scatterer diameter (ESD) and effective acoustic concentration (EAC) were estimated. From the envelope of the backscattered signal, the homodyned K distribution was used to estimate the k parameter (ratio of coherent to incoherent signal energy) and the μ parameter (number of scatterers per resolution cell). Statistically significant differences were observed between the malignant thyroids and the normal thyroids based on the ESD, EAC and μ parameters. The mean values of the ESDs were 18.0 ± 0.92, 15.9 ± 0.81, and 21.5 ± 1.80 µm for the PTC, FV-PTC and the normal thyroids, respectively. The mean values of the EACs were 59.4 ± 1.74, 62.7 ± 1.61, and 52.9 ± 3.42 dB (mm−3) for the PTC, FV-PTC and the normal thyroids, respectively. The mean values of the μ parameters were 2.55 ± 0.37, 2.59 ± 0.43, and 1.56 ± 0.99 for the PTC, FV-PTC and the normal thyroids, respectively. Statistically significant differences were observed between the malignant thyroids and the C-cell adenomas based on the ESD and EAC parameters with estimated values for the ESD of 21.3 ± 1.50 µm and EAC of 54.7 ± 2.24 dB (mm−3) for the C-cell adenomas. These results suggest that high frequency quantitative ultrasound may enhance the ability to detect and classify diseased thyroid tissues.

This contribution demonstrates that quantitative ultrasound (QUS) capabilities are platform independent, using an in vivo model. Frequency-dependent attenuation estimates, backscatter coefficient, and effective scatterer diameter estimates are shown to be comparable across four different ultrasound imaging systems with varied processing techniques. The backscatter coefficient (BSC) is a fundamental material property from which several QUS parameters are estimated; therefore, consistent BSC estimates among different systems must be demonstrated. This study is an intercomparison of BSC estimates acquired by three research groups (UIUC, UW, ISU) from four in vivo spontaneous rat mammary fibroadenomas using three clinical array systems and a single-element laboratory scanner system. Because of their highly variable backscatter properties, fibroadenomas provided an extreme test case for BSC analysis, and the comparison is across systems for each tumor, not across the highly heterogeneous tumors. RF echo data spanning the 1 to 12 MHz frequency range were acquired in three dimensions from all animals using each system. Each research group processed their RF data independently, and the resulting attenuation, BSC, and effective scatterer diameter (ESD) estimates were compared. The attenuation estimates across all systems showed the same trends and consistently fit the power-law dependence on frequency. BSCs varied among the multiple slices of data acquired by each transducer, with variations between transducers being of a similar magnitude as those from slice to slice. Variation between BSC estimates was assessed via functional signal-to-noise ratios derived from back-scatter data. These functional signal-to-noise ratios indicated that BSC versus frequency variations between systems ranged from negligible compared with the noise level to roughly twice the noise level. The corresponding functional analysis of variance (fANOVA) indicated statistically significant differences between BSC curves from different systems. However, root mean squared difference errors of the BSC values (in decibels) between different transducers and imaging platforms were less than half of the BSC magnitudes in most cases. Statistical comparison of the effective scatterer diameter (ESD) estimates resulted in no significant differences in estimates from three of the four transducers used for those estimates, demonstrating agreement among estimates based on the BSC. This technical advance demonstrates that these in vivo measurements can be made in a system-independent manner; the necessary step toward clinical implementation of the technology.

Three-dimensional impedance maps (3DZMs) are virtual volumes of acoustic impedance values constructed from histology to represent tissue microstructure acoustically. From the 3DZM, estimations can be made for ultrasonic backscatter and scatterer properties, such as effective scatterer diameter (ESD). Additionally, the 3DZM can be exploited to visualize and identify possible scattering sites, which may aid in the development of more effective scattering models to better represent the ultrasonic interaction with underlying tissue microstructure. In this study, 3DZMs were created from several human fibroadenoma samples. ESD estimates were obtained using the fluid-filled sphere form factor model. These estimates were made using two regions of interest (ROIs) sizes: cubes of side length 300 µm and 150 µm. This estimation technique allowed a better understanding of the spatial distribution and variability of the estimates throughout the volume. For a collection of 33 3DZMs, the ESD was estimated to be 99±43 µm with the large ROI and 65±30 µm when using the small ROI. The 3DZMs were then investigated visually to identify possible scattering sources, which conformed to the estimated characteristic scatterer dimensions. This visualization and comparison resulted in the identification of possible ultrasonic scattering sources within human fibroadenomas.

A cell pellet biophantom technique is introduced, and applied to the ultrasonic backscatter coefficient (BSC) estimate using Chinese hamster ovary (CHO) cells. Also introduced is a concentric sphere scattering model because of its geometrical similarities to cells with a nucleus. BSC comparisons were made between the concentric sphere model and other well-understood models for mathematical verification purposes. BSC estimates from CHO cell pellet biophantoms of known number density were performed with 40 and 80 MHz focused transducers (overall bandwidth: 26-105 MHz). These biophantoms were histologically processed and then evaluated for cell viability. Cell pellet BSC estimates were in agreement with the concentric sphere model. Fitting the model to the BSC data yielded quantitative values for the outer sphere and inner sphere. The radius of the cell model was 6.8 ± 0.7 μm; the impedance of the cytoplasm model was 1.63 ± 0.03 Mrayl and the impedance of the nuclear model was 1.55 ± 0.09 Mrayl. The concentric sphere model appears as a new tool for providing quantitative information on cell structures and will tend to have a fundamental role in the classification of biological tissues.

Ischemia-related heart disease affects more than 80 million people in the United States.1 Current interventions include ablation, angioplasty, revascularization, and bypass surgery. The invasive nature of these techniques excludes patients with myocardial ischemia who are not amenable to surgical intervention. For this reason, alternative methods of revascularization in ischemic cardiac muscle have been explored. Over the past 2 decades, cellular, molecular, and genetic therapy attempts have been made to find a clinically relevant treatment.2–6 Ultimately, it is the invasiveness or lack of site specificity that provides the largest obstacle for therapeutic effectiveness of angiogenic treatments. Current research has suggested that ultrasound (US)-ultrasound contrast agent (UCA) treatment can be therapeutically beneficial, providing a noninvasive way to spatially and temporally target ischemic tissues.7–10 This type of angiogenic therapy can be used as an alternative to high-risk percutaneous intervention or bypass graft surgery. Several studies report a reparative response to US-UCA exposure and state that inertial cavitation, or microbubble collapse, is possibly required for angiogenesis to occur.8,11–14 Numerous small-scale studies have shown promising results; however, when large-scale double-blind studies were conducted, they showed limited effects.15 A major impediment for progress to clinical applicability is, perhaps, the lack of understanding of the biophysical mechanisms that connect US-UCAs to neovascularization. It is important to establish a basic knowledge of capillary changes that occur with US-UCA exposure so that US-UCA-induced angiogenesis can be assessed for therapeutic benefit and so that existing therapies can be improved. Current studies in the literature involving US-UCA-induced angiogenesis use peak rarefactional US pressure (Pr) varying between 0.1 and 1.0 MPa.8,12,16,17 These Pr values have been shown to collapse approximately 20% to 70% of UCAs at 1 MHz.18 Therefore, the question remains as to what causes the angiogenic response. Studies involving US-UCA-induced angiogenesis show increases in the collateral blood supply ranging from 5% to 35% with respect to their controls.8–12 However, the effectiveness of the therapy used in each study cannot be correlated to Pr levels or any other parameter used. Also, these studies do not directly correlate a UCA mechanism to the angiogenic response.8–12 In addition, most studies involving US-UCA therapy use ischemic models without exploring the underlying mechanism. Furthermore, the time points for angiogenic assessment (ie, days postexposure [DPE]) were quite varied, ranging from 3 to 28 DPE.8,16,17,19,20 The goals of this study were to explore the influence of UCA collapse cavitation, the angiogenic progression in a normal animal model, and determine whether and if so when the capillary density (as a measure of angiogenesis) increases subsequent to US-UCA exposure in an effort to connect the acute (0 day) bioeffect to the end goal of angiogenesis. This study used a Pr of 3.8 MPa to collapse about 100% of the UCAs18 in an effort to correlate a mechanism with the angiogenic response. Previous work has shown effectiveness at lower Pr values; however, the underlying premise is that angiogenesis is damage induced and involves a reparative response.9,12,13 This study inspects that underlying premise. Examination of UCA collapse cavitation and subsequent angiogenic effects is integral to understanding how to increase angiogenesis. In this study, rats were randomly assigned to 0, 3, 6, 13, 20, and 27 DPE groups to investigate the progression of capillary density and inflammation in response to a Pr sufficient to cause collapse cavitation of UCAs in a normal animal model. Capillary density was quantified in capillaries per square millimeter via immunohistochemical (IHC) staining (CD31 and CD34).

To translate quantitative ultrasound (QUS) from the laboratory into the clinic, it is necessary to demonstrate that the measurements are platform independent. Because the backscatter coefficient (BSC) is the fundamental estimate from which additional QUS estimates are calculated, agreement between BSC results using different systems must be demonstrated. This study was an intercomparison of BSCs from in vivo spontaneous rat mammary tumors acquired by different groups using 3 clinical array systems and a single-element laboratory scanner system.Radio frequency data spanning the 1- to 14-MHz frequency range were acquired in 3 dimensions from all animals using each system. Each group processed their radio frequency data independently, and the resulting BSCs were compared. The rat tumors were diagnosed as either carcinoma or fibroadenoma.Carcinoma BSC results exhibited small variations between the multiple slices acquired with each transducer, with similar slopes of BSC versus frequency for all systems. Somewhat larger variations were observed in fibroadenomas, although BSC variations between slices of the same tumor were of comparable magnitude to variations between transducers and systems. The root mean squared (RMS) errors between different transducers and imaging platforms were highly variable. The lowest RMS errors were observed for the fibroadenomas between 4 and 5 MHz, with an average RMS error of 4 x 10(-5) cm(-1)Sr(-1) and an average BSC value of 7.1 x 10(-4) cm(-1)Sr(-1), or approximately 5% error. The highest errors were observed for the carcinoma between 7 and 8 MHz, with an RMS error of 1.1 x 10(-1) cm(-1)Sr(-1) and an average BSC value of 3.5 x 10(-2) cm(-1)Sr(-1), or approximately 300% error.This technical advance shows the potential for QUS technology to function with different imaging platforms.

Quantitative ultrasound (QUS) imaging is hypothesized to map temperature elevations induced in tissue with high spatial and temporal resolution. To test this hypothesis, QUS techniques were examined to monitor high-intensity focused ultrasound (HIFU) exposure of tissue. In situ experiments were conducted on mammary adenocarcinoma tumors grown in rats and lesions were formed using a HIFU system. A thermocouple was inserted into the tumor to provide estimates of temperature at one location. Backscattered time-domain waveforms from the tissue during exposure were recorded using a clinical ultrasonic imaging system. Backscatter coefficients were estimated using a reference phantom technique. Two parameters were estimated from the backscatter coefficient (effective scatterer diameter (ESD) and effective acoustic concentration (EAC). The changes in the average parameters in the regions corresponding to the HIFU focus over time were correlated to the temperature readings from the thermocouple. The changes in the EAC parameter were consistently correlated to temperature during both heating and cooling of the tumors. The changes in the ESD did not have a consistent trend with temperature. The mean ESD and EAC before exposure were 120 ± 16 μm and 32 ± 3 dB/cm3, respectively, and changed to 144 ± 9 μm and 51 ± 7 dB/cm3, respectively, just before the last HIFU pulse was delivered to the tissue. After the tissue cooled down to 37°C, the mean ESD and EAC were 126 ± 8 μm and 35 ± 4 dB/cm3, respectively. Peak temperature in the range of 50-60°C was recorded by a thermocouple placed just behind the tumor. These results suggest that QUS techniques have the potential to be used for non-invasive monitoring of HIFU exposure.

The cholesterol-fed rabbit is useful for atherosclerosis research. We describe development of a low-magnesium (Mg) cholesterol-containing diet to accelerate atherosclerosis in this model. Male New Zealand White rabbits were fed either chow or one of four atherogenic diets: 1% cholesterol 10% fat 0.11% Mg, 1% cholesterol 10% fat 0.40% Mg, 2% cholesterol 20% fat 0.11% Mg, or 2% cholesterol 20% fat 0.40% Mg. While feed intake decreased in cholesterol-fed rabbits, they were able to maintain their body weights. Rabbits consuming cholesterol experienced profound hypercholesterolemia and tissue lipid accumulation, with plasma cholesterol levels above 1500 mg/dl for all groups at the completion of the study. Liver and spleen lipid content and liver cholesterol content also increased. Aortic arch atheroma thickness was greatest in 1% cholesterol 10% fat 0.11% Mg animals. Tissue Mg levels decreased in cholesterol-fed animals compared to chow-fed controls, despite equal or greater serum Mg levels. Our results indicate that the 1% cholesterol 10% fat 0.11% Mg diet was optimal at promoting hypercholesterolemia and atherosclerosis while minimizing health complications for the animals. The low Mg cholesterol diet will be useful to other biomedical researchers interested in utilizing the rabbit for cardiovascular disease research.

The incidence of diagnosed thyroid cancer has increased significantly over the last decades. Although advances in ultrasonic imaging have increased the malignancy detection rate, current ultrasonic imaging markers do not provide a sufficient level of diagnostic accuracy to replace biopsy. Recent studies suggest that ultrasound parameters derived from backscatter coefficients may allow differentiating among different types of thyroid tumors and normal tissues in a rodent model ex vivo. In this work, the potential use of attenuation coefficient (AC) estimates for the same purpose was explored. A sample set of 24 excised mice thyroids were scanned using a 40-MHz, f/3 single element transducer. The experimental dataset contained six animals that developed papillary thyroid carcinoma (PTC), five that developed follicular variant papillary thyroid carcinoma (FV-PTC), five that developed c-Cell adenoma (c-Cell) and eight that did not develop thyroid abnormalities (control). AC slope maps were generated with a spectral log difference method using 0.5mm by 0.5mm data blocks. Outliers of each slice due to artifacts in AC estimation were discarded using the Thompson Tau method. Finally, a Kruskal-Wallis test was conducted to analyze if statistically significant differences in the mean AC slope among the four groups existed. The median and interquartile range for each group were 1.29 and 0.22 dB/cm-MHz for the control group, 1.64 and 0.09 dB/cm-MHz for c-Cell, 1.16 and 0.12 dB/cm-MHz for PTC and 1.33 and 0.08 dB/cm-MHz for FV-PTC, respectively. These values are consistent with previous reports of attenuation in thyroid tissues. The Kruskal-Wallis test reported statistically significant differences between the c-Cell group and the other groups of study and between the PTC and FV-PTC groups (p

Although thyroid cancer has relatively good prognosis, the management of this disease is complicated by the large incidence of thyroid nodules in the adult population. Unfortunately, current imaging methods do not provide a sufficient level of accuracy in order to replace biopsy as a tool for diagnosis of thyroid cancer. A relatively recent study suggests that spectral-based quantitative ultrasonic methods may provide a new source of contrast when imaging thyroid nodules. In this study, two parameters (i.e., the effective scatterer diameter (ESD) and the effective acoustic concentration (EAC)) were estimated from a rodent model of follicular variant papillary thyroid carcinoma (FV-PTC) ex vivo. The mean ESD values were 21.5 ± 1.8 μm and 15.9 ± 0.8 μm for normal and diseased thyroids, respectively. Also, the mean EAC values were 52.9 ± 3.4 dB/cm and 62.7 ± 1.6 dB/cm for normal and diseased thyroids, respectively. A nonparametric Kruskal-Wallis test revealed statistically significant differences between FV-PTC and normal thyroids using both parameters (p

Ultrasound contrast agents (UCAs) are microbubbles encapsulating inert gases that serve to enhance the echogenicity of blood for cardiovascular imaging applications.1 The interaction of ultrasound (US) with circulating UCAs introduces the potential for unique biological effects. These bioeffects must be fully characterized and assessed before recommendations can be made regarding the appropriate uses of UCAs, and progress is urgently needed. The importance of medical imaging for early diagnosis is underscored by the fact that 2300 Americans die each day of cardiovascular disease by current estimates.2 Many in vitro and in vivo bioeffects of UCAs have been noted, including hemolysis,3 capillary rupture,4 endothelial cell damage,5 and elevations in troponin T, a biomarker of cardiac damage.6 Previous studies in our laboratory have demonstrated UCA-induced arterial endothelial and vascular smooth muscle injury7 and cardiac arrhythmias.8 These results suggest that the interactions of US with UCAs in the cardiovascular system may have important consequences, especially if exposure to contrast US hastens the onset or increases the severity of atherosclerosis in patients at risk. To this end, we used a cholesterol-fed rabbit model to evaluate the biological effects of the UCA Definity (Lantheus Medical Imaging, Inc, North Billerica, MA) when used in conjunction with US to image the descending aorta. To assess these bioeffects, we chose to focus on the biomarker von Willebrand factor (vWF), a multimeric protein produced and stored within endothelial cells and secreted both across the basolateral endothelial membrane into the vascular intima9 and across the apical membrane into the vessel lumen, where it circulates in the blood.10 von Willebrand factor has a physiologic role in platelet plug formation during thrombosis.11 In addition to its physiologic function, elevated vWF is a biomarker of endothelial damage12 and a clinical predictor of adverse cardiovascular events.13 It is positively associated with risk for cardiovascular disease and cardiac death in epidemiological studies,14,15 and it has been shown to increase experimentally in hypercholesterolemic rabbits.16 We hypothesized that plasma vWF would increase when rabbits consumed a cholesterol-containing diet, and any further increase after US exposure would indicate endothelial damage due to the contrast US procedure.

Previous work estimated the ultrasonic backscatter coefficient (BSC) from low-concentration (volume density 1). The concentric sphere model least squares estimates show a decrease in estimated cell radius with number density, suggesting that the concentric spheres model is becoming less applicable as concentration increases because the estimated cell radius becomes smaller than that measured. The critical volume density, starting from when the model becomes less applicable, is estimated to be between 10% and 30% cell volume density.

Three-dimensional impedance maps (3DZMs) are computational models of acoustic impedance of tissue constructed from histology images. 3DZMs can be analyzed to estimate model-based quantitative ultrasound parameters such as effective scatterer diameter (ESD). In this study, 3DZMs were constructed from normal and fatty rabbit livers. Estimates of ESD were made using the fluid-filled sphere scattering model. Weighting toward smaller scatterer sizes produced ESD estimates of 7.5 ± 1.3 and 7.0 ± 0.3 μm for normal and fatty liver, respectively, approximately the size of a liver cell nucleus. This suggests the nucleus could be a primary source of scattering in liver.

Bilateral synchronous intratesticular masses are rare but can be caused by metastatic disease to the testicle, primary testicular masses or benign etiologies such as congenital adrenal hyperplasia and granulomatous orchitis. We present an unusual case of McCune-Albright syndrome presenting with unilateral testicular enlargement and bilateral testicular masses secondary to Sertoli cell hyperplasia. To our knowledge, this is a unique case of testicular masses secondary to McCune-Albright syndrome.

Quantitative ultrasound (QUS) imaging is a model-based approach aimed at lesion detection and classification. In this study, the RF backscattered signals from rat fibroadenomas were fit to various mathematical models to yield effective scatterer diameter (ESD) estimates which are tied to tissue microstructure. The goal of these experiments was to understand potential sources of scattering in live tissue across a wide frequency range and how results from different models compare to one another.

Muir-Torre syndrome (MTS) is a rare disorder characterized by the presence of at least one sebaceous gland neoplasm and at least one visceral malignancy. Sebaceous adenomas, sebaceous carcinomas, and sebaceomas (sebaceous epitheliomas) are all characteristic glandular tumors of MTS. The most common visceral malignancies associated with MTS are colorectal, followed by genitourinary. These visceral malignancies frequently have a more indolent course in patients with MTS than they would otherwise. Muir-Torre syndrome is an autosomal dominant disorder; however, sporadic cases are known to develop. It often is associated with germ-line mutations in the mutS homolog 2, colon cancer, nonpolyposis type 1 (Escherichia coli) gene, MSH2, and the mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) gene, MLH1 (similar to hereditary nonpolyposis colon cancer [HNPCC]). The diagnosis of MTS currently is based on clinical criteria; however, immunohistochemical staining for MSH2 and MLH1 can confirm the diagnosis. We report 2 patients with MTS who developed colon adenocarcinomas in conjunction with sebaceous carcinomas. Both patients demonstrated loss of MSH2 expression in tumor cells on immunohistochemical staining. One of these patients later developed gastric carcinoma, a very uncommon malignancy associated with MTS. We conclude that the diagnosis of rare sebaceous lesions associated with MTS may represent a marker of visceral disease and warrants further investigation for internal malignancies in the individual and at-risk family members.

The ultrasonic backscatter coefficient (BSC) is the fundamental quantitative estimate from measurements that can be parametrized to yield the effective scatterer diameter and acoustic concentration. The ability to accurately estimate the BSC using different imaging systems (i.e., a system independent estimate) is significant for clinical application of QUS imaging. In this study, BSCs were estimated from spontaneous mammary tumors in rats using both single‐element transducers and linear arrays from a clinical imaging system. The BSC as a function of frequency was computed from the rf backscattered signals from Sprague Dawley rats that developed either fibroadenoma or carcinoma tumors. The tumors were scanned using three single‐element transducers with a collective −10‐dB bandwidth of 1.4–18 MHz and two linear arrays from the Ultrasonix RP system with a collective −10‐dB bandwidth of 2–8 MHz. For the single‐element transducers, a smooth Plexiglas plate was used to acquire a reference scan. For the linear a...

Three‐dimensional impedance maps (3DZMs) are virtual volumes of acoustic impedance values constructed from histology to represent tissue microstructure acoustically. From the 3DZM, estimations can be made for ultrasonic backscatter and scatterer properties, such as effective scatterer diameter (ESD). Additionally, the 3DZM can be exploited to visualize and identify possible scattering sites, which may aid in the development of more effective scattering models to better represent the ultrasonic interaction with underlying tissue microstructure. In this study, 3DZMs were created from several human fibroadenoma samples. ESD estimates were obtained using the fluid‐filled sphere form factor model. These estimates were made using two regions of interest (ROIs) sizes: cubes of side lengths of 300 and 150 μm. This estimation technique allowed a better understanding of the spatial distribution and variability of the estimates throughout the volume. For a collection of ten 3DZMs, the ESD was estimated to be 94±47 μ...