Measurement of Wall Shear Rate Across the Entire Vascular Wall Using Ultrasound Speckle Decorrelation.

OBJECTIVE: The accurate measurement of the wall shear rate (WSR) plays a crucial role in the early diagnosis of cardiovascular disease progression and acute events such as aneurysms and atherosclerotic plaque ruptures. To address this need, the speckle decorrelation (SDC) technique has been used to measure WSR based on the 2-D out-of-plane blood flow speed. This technique is particularly advantageous because it enables the use of a 1-D array transducer to measure WSR over the entire luminal area. This study aims to develop a region-based singular value decomposition (SVD) filtering technique that selectively suppresses clutter noise in the vascular region to measure WSR using SDC. METHOD: Ultrasound simulations, in-vitro flow experiments, and an in-vivo human study were conducted to evaluate the feasibility of this method's clinical application. RESULTS: The results demonstrated that WSR can be effectively measured across entire vascular walls using a conventional 1-D array transducer along with the proposed methodology. CONCLUSION: This study successfully demonstrates a noninvasive and accurate SDC-based method for measuring vital vascular WSR. This approach holds significant promise for assessing vascular WSR in both healthy individuals and high-risk cardiovascular disease patients.

Ultrasound Speckle Decorrelation-Based Blood Flow Measurements.

Ultrasound imaging is the preferred noninvasive technique to measure blood flow to diagnose cardiovascular disease such as heart failure, carotid stenosis, and renal failure. Conventional ultrasound techniques such as Doppler ultrasound, ultrasound imaging velocimetry, vector Doppler and transverse oscillation beamforming have been used for blood flow velocity profile measurement. However, these techniques were limited to measuring blood flow velocities within the 2-D lateral (across the ultrasound beam) plane of a vessel, and the blood flow velocity profile was derived by assuming that blood vessels have a circular cross-section with axis symmetry. This assumption is incorrect because most vessels have complex geometries, such as tortuosity and branches, and an asymmetric flow profile in the presence of vascular plaque. Consequently, ultrasound speckle decorrelation has been proposed to measure blood flow from transverse views of blood vessels wherein the ultrasound beam is perpendicular to the vessel axis. In this review, we present a summary of recent progress in ultrasound speckle decorrelation-based blood flow measurement techniques.

Evaluation of Heat Generation in Unidirectional Versus Oscillatory Modes During K-Wire Insertion in Bone.

Heat generation during insertion of Kirschner wires (K-wires) may lead to thermal osteonecrosis and can affect the construct fixation. Unidirectional and oscillatory drilling modes are options for K-wire insertion, but understanding of the difference in heat generation between the two modes is lacking. The goal of this study was to compare the temperature rise during K-wire insertion under these two modes and provide technical guidelines for K-wire placement to minimize thermal injury. Ten orthopedic surgeons were instructed to drill holes on hydrated ex vivo bovine bones under two modes. The drilling trials were evaluated in terms of temperature, thrust force, torque, drilling time, and tool wear. The analysis of variance showed that the oscillatory mode generated significantly lowered peak bone temperature rise (13% lower mean value, p = 0.036) over significantly longer drilling time (46% higher mean time, p < 0.001) than the unidirectional mode. Drilling time had significant effect on peak bone temperature rise under both modes (p < 0.001) and impact of peak thrust force was significant under oscillatory mode (p < 0.001). These findings suggest that the drilling mode choice is a compromise between peak temperature and bone exposure time. Shortening the drilling time was the key under both modes to minimize temperature rise and thermal necrosis risk. To achieve faster drilling, technique analysis found that "shaky" and intermittent drilling with moderate thrust force are preferred techniques by small vibration of the drill about the K-wire axis and slight lift-up of the K-wire once or twice during drilling. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1903-1909, 2019.

Ultrasound shear wave simulation of wave propagation at oblique angles.

Shear wave elasticity imaging (SWEI) has been used to measure the local tissue elasticity. The local tissue shear modulus can be reconstructed from the displacement field of shear waves using an algebraic Helmholtz inversion (AHI) equation or a time-of-flight (TOF)-based algorithm. The shear waves, which are generated by successive focusing of ultrasonic beams at different depths, propagate at oblique angles rather than along the lateral position. The wave propagation at oblique angles can result in bias in shear modulus reconstruction using the AHI equation or the TOF-based algorithm. In this study, the effect of wave propagation at oblique angles on the tissue shear modulus reconstruction was investigated using in silico finite element (FE) simulation. An FE elastic tissue with a hard inclusion model was designed. The shear waves with propagation angles of 0°, 5°, and 10° were applied to the model. The shear modulus and the percentage error in the model were computed using the AHI equation and the TOF-based algorithm at each propagation angle from 0° to 10°. For the AHI equation, the percentage error was 0% at propagation angles of 0° and 5°, and 1% at a propagation angle of 10° in the inclusion. In the surrounding tissue, the percentage error was 0% at propagation angles of 0°, 5°, and 10°. For the TOF-based algorithm, the percentage error was 0% at propagation angles of 0° and 5°, and 40% at a propagation angle of 10° in the inclusion. In the surrounding tissue, the percentage error was 0% at propagation angles of 0° and 5°, and 35% at a propagation angle of 10° in the inclusion. Therefore, whereas the TOF-based algorithm produced critical bias in shear modulus reconstruction by the shear wave propagation at oblique angles, the AHI equation was not affected by the propagation.

A pilot study to measure vascular compliance changes during fistula maturation using open-source software.

PURPOSE:: Autogenous arteriovenous fistulas are the preferred access for hemodialysis. Yet when created, fistulas often fail to mature, requiring surgical or radiologic interventions before their use. This pilot study measures the vascular wall elasticity and flow gradient using an open-source ultrasound software program designed to aid in assessing fistula maturation. METHODS:: A total of seven end-stage renal disease patients were enrolled for our study after providing informed consent. Ultrasound scanning was performed for the inflow artery, post-arterial anastomotic segment, and outflow vein at initial and follow-up evaluation. Conventional digital imaging and communications in medicine data were collected from the ultrasound machine. The vessel diameter and distensibility of artery, post-arterial anastomotic segment, and vein were computed from the digital imaging and communications in medicine data using an open-source ultrasound software program. RESULTS:: The vessel diameter of artery and vein increased from 4.6 ± 1.1 mm to 6.0 ± 1.1 mm and from 5.8 ± 0.7 mm to 7.5 ± 0.9 mm from 1 to 6 weeks post-operation, respectively. Conversely, the vessel diameter of post-arterial anastomotic segment decreased from 4.2 ± 1.0 mm to 3.5 ± 0.9 mm from 1 to 6 weeks post-operation. The distensibility of artery and post-arterial anastomotic segment increased from 3.4% ± 0% to 5.9% ± 1.1% and 3.7% ± 1.2% to 4.9% ± 1.4%, respectively, while the distensibility of vein decreased from 5.0% ± 1.3% to 2.6% ± 0.4% from 1 to 6 weeks post-operation. CONCLUSION:: This study demonstrates that the change in vessel diameter and distensibility related to the healthy remodeling as the vein dilates during maturation.

Bone tumor resection guide using three-dimensional printing for limb salvage surgery.

BACKGROUND AND OBJECTIVES: The three-dimensional (3D)-printed bone tumor resection guide can be personalized for a specific patient and utilized for bone tumor surgery. It is noninvasive, eidetic, and easy to use. We aimed to categorize the use of the 3D-printed guide and establish in vivo accuracy data. METHODS: We retrospectively reviewed 12 patients, who underwent limb salvage surgery using the 3D-printed guide at a single institution. To confirm the achievement of a safe bone margin, we compared the actual and planned distances between the cutting surface and tumor, which were reported in the final pathological report and measured from the same virtual cutting plane using graphical data of the cutting guide design, respectively. RESULTS: The use of the 3D-printed guide was categorized as follows: (a) wide excision only, (b) wide excision and biological reconstruction with a structural bone allograft shaped in accordance with the 3D-printed guide, and (c) wide excision and reconstruction with a 3D-printed personalized implant. The maximal cutting error was 3 mm. CONCLUSIONS: The 3D-printed resection guide is easy to use and shows promise in the field of orthopedic oncology, with its application in bone tumor resection and reconstruction with a structural bone allograft or 3D-printed implant.

An Open-Source Ultrasound Software for Diagnosis of Fistula Maturation.

Vascular access is essential for hemodialysis patients. The mature native arteriovenous fistula has been the preferred vascular access for hemodialysis, because it has greater longevity than synthetic grafts. However, once surgically created, fistulas often fail to develop (mature) into viable points of vascular access, requiring surgical or radiologic interventions before their use. Because maturation depends on vascular mechanics (e.g., distensibility and wall shear), we developed open-source ultrasound software to investigate these metrics clinically. We demonstrated in a single patient the ability of the software for consistent measurements from various locations within a cardiac cycle and between different cardiac cycles. We further assessed the ability of the software to identify changes in distensibility of a patient's fistula from 1 to 6 weeks postoperation. The routine frame rates of clinical machines demonstrated high fidelity tracking within cardiac cycles (coefficient of variation [CV] = 2.4% ± 0.011) and between cardiac cycles (CV = 2.4% ± 0.004). The distensibility of the patient's fistula from 1 to 6 weeks postoperation increased from 4% to 7% in the arterial inflow and from 3% to 4% in the postarterial anastomotic segment (PAAS). In contrast, the distensibility of the outflow vein decreased from 4% to 2%. These results corroborate that in addition to diameter changes, the mechanical properties of the vascular segments changed during fistula maturation. This demonstrates that our software-based approach may allow ultrasound-based mechanical measurements to become more accessible for wider clinical research.

Quantification of Coupled Stiffness and Fiber Orientation Remodeling in Hypertensive Rat Right-Ventricular Myocardium Using 3D Ultrasound Speckle Tracking with Biaxial Testing.

Mechanical and structural changes of right ventricular (RV) in response to pulmonary hypertension (PH) are inadequately understood. While current standard biaxial testing provides information on the mechanical behavior of RV tissues using surface markers, it is unable to fully assess structural and mechanical properties across the full tissue thickness. In this study, the mechanical and structural properties of normotensive and pulmonary hypertension right ventricular (PHRV) myocardium through its full thickness were examined using mechanical testing combined with 3D ultrasound speckle tracking (3D-UST). RV pressure overload was induced in Sprague-Dawley rats by pulmonary artery (PA) banding. The second Piola-Kirchhoff stress tensors and Green-Lagrangian strain tensors were computed in the RV myocardium using the biaxial testing combined with 3D-UST. A previously established non-linear curve-fitting algorithm was applied to fit experimental data to a Strain Energy Function (SEF) for computation of myofiber orientation. The fiber orientations obtained by the biaxial testing with 3D-UST compared well with the fiber orientations computed from the histology. In addition, the re-orientation of myofiber in the right ventricular free wall (RVFW) along longitudinal direction (apex-to-outflow-tract direction) was noticeable in response to PH. For normotensive RVFW samples, the average fiber orientation angles obtained by 3D-UST with biaxial test spiraled from 20° at the endo-cardium to -42° at the epi-cardium (Δ = 62°). For PHRV samples, the average fiber orientation angles obtained by 3D-UST with biaxial test had much less spiral across tissue thickness: 3° at endo-cardium to -7° at epi-cardium (Δ = 10°, P<0.005 compared to normotensive).

Design of a Coupled Thermoresponsive Hydrogel and Robotic System for Postinfarct Biomaterial Injection Therapy.

BACKGROUND: In preclinical testing, ventricular wall injection of hydrogels has been shown to be effective in modulating ventricular remodeling and preserving cardiac function. For some approaches, early-stage clinical trials are under way. The hydrogel delivery method varies, with minimally invasive approaches being preferred. Endocardial injections carry a risk of hydrogel regurgitation into the circulation, and precise injection patterning is a challenge. An epicardial approach with a thermally gelling hydrogel through the subxiphoid pathway overcomes these disadvantages. METHODS: A relatively stiff, thermally responsive, injectable hydrogel based on N-isopropylacrylamide and N-vinylpyrrolidone (VP gel) was synthesized and characterized. VP gel thermal behavior was tuned to couple with a transepicardial injection robot, incorporating a cooling feature to achieve injectability. Ventricular wall injections of the optimized VP gel have been performed ex vivo and on beating porcine hearts. RESULTS: Thermal transition temperature, viscosity, and gelling time for the VP gel were manipulated by altering N-vinylpyrrolidone content. The target parameters for cooling in the robotic system were chosen by thermal modeling to support smooth, repeated injections on an ex vivo heart. Injections at predefined locations and depth were confirmed in an infarcted porcine model. CONCLUSIONS: A coupled thermoresponsive hydrogel and robotic injection system incorporating a temperature-controlled injectate line was capable of targeted injections and amenable to use with a subxiphoid transepicardial approach for hydrogel injection after myocardial infarction. The confirmation of precise location and depth injections would facilitate a patient-specific planning strategy to optimize injection patterning to maximize the mechanical benefits of hydrogel placement.

Decellularized zebrafish cardiac extracellular matrix induces mammalian heart regeneration.

Heart attack is a global health problem that leads to significant morbidity, mortality, and health care burden. Adult human hearts have very limited regenerative capability after injury. However, evolutionarily primitive species generally have higher regenerative capacity than mammals. The extracellular matrix (ECM) may contribute to this difference. Mammalian cardiac ECM may not be optimally inductive for cardiac regeneration because of the fibrotic, instead of regenerative, responses in injured adult mammalian hearts. Given the high regenerative capacity of adult zebrafish hearts, we hypothesize that decellularized zebrafish cardiac ECM (zECM) made from normal or healing hearts can induce mammalian heart regeneration. Using zebrafish and mice as representative species of lower vertebrates and mammals, we show that a single administration of zECM, particularly the healing variety, enables cardiac functional recovery and regeneration of adult mouse heart tissues after acute myocardial infarction. zECM-treated groups exhibit proliferation of the remaining cardiomyocytes and multiple cardiac precursor cell populations and reactivation of ErbB2 expression in cardiomyocytes. Furthermore, zECM exhibits pro-proliferative and chemotactic effects on human cardiac precursor cell populations in vitro. These contribute to the structural preservation and correlate with significantly higher cardiac contractile function, notably less left ventricular dilatation, and substantially more elastic myocardium in zECM-treated hearts than control animals treated with saline or decellularized adult mouse cardiac ECM. Inhibition of ErbB2 activity abrogates beneficial effects of zECM administration, indicating the possible involvement of ErbB2 signaling in zECM-mediated regeneration. This study departs from conventional focuses on mammalian ECM and introduces a new approach for cardiac tissue regeneration.

Controlled dual delivery of fibroblast growth factor-2 and Interleukin-10 by heparin-based coacervate synergistically enhances ischemic heart repair.

Myocardial infarction (MI) causes myocardial necrosis, triggers chronic inflammatory responses, and leads to pathological remodeling. Controlled delivery of a combination of angiogenic and immunoregulatory proteins may be a promising therapeutic approach for MI. We investigated the bioactivity and therapeutic potential of an injectable, heparin-based coacervate co-delivering an angiogenic factor, fibroblast growth factor-2 (FGF2), and an anti-inflammatory cytokine, Interleukin-10 (IL-10) in a spatially and temporally controlled manner. Coacervate delivery of FGF2 and IL-10 preserved their bioactivities on cardiac stromal cell proliferation in vitro. Upon intramyocardial injection into a mouse MI model, echocardiography revealed that FGF2/IL-10 coacervate treated groups showed significantly improved long-term LV contractile function and ameliorated LV dilatation. FGF2/IL-10 coacervate substantially augmented LV myocardial elasticity. Additionally, FGF2/IL-10 coacervate notably enhanced long-term revascularization, especially at the infarct area. In addition, coacervate loaded with 500 ng FGF2 and 500 ng IL-10 significantly reduced LV fibrosis, considerably preserved infarct wall thickness, and markedly inhibited chronic inflammation at the infarct area. These results indicate that FGF2/IL-10 coacervate has notably greater therapeutic potential than coacervate containing only FGF2. Overall, our data suggest therapeutically synergistic effects of FGF-2/IL-10 coacervate, particularly coacervate with FGF2 and 500 ng IL-10, for the treatment of ischemic heart disease.

Methods for using 3-D ultrasound speckle tracking in biaxial mechanical testing of biological tissue samples.

Being multilayered and anisotropic, biological tissues such as cardiac and arterial walls are structurally complex, making the full assessment and understanding of their mechanical behavior challenging. Current standard mechanical testing uses surface markers to track tissue deformations and does not provide deformation data below the surface. In the study described here, we found that combining mechanical testing with 3-D ultrasound speckle tracking could overcome this limitation. Rat myocardium was tested with a biaxial tester and was concurrently scanned with high-frequency ultrasound in three dimensions. The strain energy function was computed from stresses and strains using an iterative non-linear curve-fitting algorithm. Because the strain energy function consists of terms for the base matrix and for embedded fibers, spatially varying fiber orientation was also computed by curve fitting. Using finite-element simulations, we first validated the accuracy of the non-linear curve-fitting algorithm. Next, we compared experimentally measured rat myocardium strain energy function values with those in the literature and found a matching order of magnitude. Finally, we retained samples after the experiments for fiber orientation quantification using histology and found that the results satisfactorily matched those computed in the experiments. We conclude that 3-D ultrasound speckle tracking can be a useful addition to traditional mechanical testing of biological tissues and may provide the benefit of enabling fiber orientation computation.

Ultrasound Shear Wave Simulation of Breast Tumor Using Nonlinear Tissue Elasticity.

Shear wave elasticity imaging (SWEI) can assess the elasticity of tissues, but the shear modulus estimated in SWEI is often less sensitive to a subtle change of the stiffness that produces only small mechanical contrast to the background tissues. Because most soft tissues exhibit mechanical nonlinearity that differs in tissue types, mechanical contrast can be enhanced if the tissues are compressed. In this study, a finite element- (FE-) based simulation was performed for a breast tissue model, which consists of a circular (D: 10 mm, hard) tumor and surrounding tissue (soft). The SWEI was performed with 0% to 30% compression of the breast tissue model. The shear modulus of the tumor exhibited noticeably high nonlinearity compared to soft background tissue above 10% overall applied compression. As a result, the elastic modulus contrast of the tumor to the surrounding tissue was increased from 0.46 at 0% compression to 1.45 at 30% compression.

In vivo monitoring of structural and mechanical changes of tissue scaffolds by multi-modality imaging.

Degradable tissue scaffolds are implanted to serve a mechanical role while healing processes occur and putatively assume the physiological load as the scaffold degrades. Mechanical failure during this period can be unpredictable as monitoring of structural degradation and mechanical strength changes at the implant site is not readily achieved in vivo, and non-invasively. To address this need, a multi-modality approach using ultrasound shear wave imaging (USWI) and photoacoustic imaging (PAI) for both mechanical and structural assessment in vivo was demonstrated with degradable poly(ester urethane)urea (PEUU) and polydioxanone (PDO) scaffolds. The fibrous scaffolds were fabricated with wet electrospinning, dyed with indocyanine green (ICG) for optical contrast in PAI, and implanted in the abdominal wall of 36 rats. The scaffolds were monitored monthly using USWI and PAI and were extracted at 0, 4, 8 and 12 wk for mechanical and histological assessment. The change in shear modulus of the constructs in vivo obtained by USWI correlated with the change in average Young's modulus of the constructs ex vivo obtained by compression measurements. The PEUU and PDO scaffolds exhibited distinctly different degradation rates and average PAI signal intensity. The distribution of PAI signal intensity also corresponded well to the remaining scaffolds as seen in explant histology. This evidence using a small animal abdominal wall repair model demonstrates that multi-modality imaging of USWI and PAI may allow tissue engineers to noninvasively evaluate concurrent mechanical stiffness and structural changes of tissue constructs in vivo for a variety of applications.

Quantification of ultrasound correlation-based flow velocity mapping and edge velocity gradient measurement.

This study investigated the use of ultrasound speckle decorrelation- and correlation-based lateral speckle-tracking methods for transverse and longitudinal blood velocity profile measurement, respectively. By studying the blood velocity gradient at the vessel wall, vascular wall shear stress, which is important in vascular physiology as well as the pathophysiologic mechanisms of vascular diseases, can be obtained. Decorrelation-based blood velocity profile measurement transverse to the flow direction is a novel approach, which provides advantages for vascular wall shear stress measurement over longitudinal blood velocity measurement methods. Blood flow velocity profiles are obtained from measurements of frame-to-frame decorrelation. In this research, both decorrelation and lateral speckle-tracking flow estimation methods were compared with Poiseuille theory over physiologic flows ranging from 50 to 1000 mm/s. The decorrelation flow velocity measurement method demonstrated more accurate prediction of the flow velocity gradient at the wall edge than the correlation-based lateral speckle-tracking method. The novelty of this study is that speckle decorrelation-based flow velocity measurements determine the blood velocity across a vessel. In addition, speckle decorrelation-based flow velocity measurements have higher axial spatial resolution than Doppler ultrasound measurements to enable more accurate measurement of blood velocity near a vessel wall and determine the physiologically important wall shear.

In vivo vascular wall shear rate and circumferential strain of renal disease patients.

This study measures the vascular wall shear rate at the vessel edge using decorrelation based ultrasound speckle tracking. Results for nine healthy and eight renal disease subjects are presented. Additionally, the vascular wall shear rate and circumferential strain during physiologic pressure, pressure equalization and hyperemia are compared for five healthy and three renal disease subjects. The mean and maximum wall shear rates were measured during the cardiac cycle at the top and bottom wall edges. The healthy subjects had significantly higher mean and maximum vascular wall shear rate than the renal disease subjects. The key findings of this research were that the mean vascular wall shear rates and circumferential strain changes between physiologic pressure and hyperemia that was significantly different between healthy and renal disease subjects.

Arterial elasticity imaging: comparison of finite-element analysis models with high-resolution ultrasound speckle tracking.

BACKGROUND: The nonlinear mechanical properties of internal organs and tissues may be measured with unparalleled precision using ultrasound imaging with phase-sensitive speckle tracking. The many potential applications of this important noninvasive diagnostic approach include measurement of arterial stiffness, which is associated with numerous major disease processes. The accuracy of previous ultrasound measurements of arterial stiffness and vascular elasticity has been limited by the relatively low strain of nonlinear structures under normal physiologic pressure and the measurement assumption that the effect of the surrounding tissue modulus might be ignored in both physiologic and pressure equalized conditions. METHODS: This study performed high-resolution ultrasound imaging of the brachial artery in a healthy adult subject under normal physiologic pressure and the use of external pressure (pressure equalization) to increase strain. These ultrasound results were compared to measurements of arterial strain as determined by finite-element analysis models with and without a surrounding tissue, which was represented by homogenous material with fixed elastic modulus. RESULTS: Use of the pressure equalization technique during imaging resulted in average strain values of 26% and 18% at the top and sides, respectively, compared to 5% and 2%, at the top and sides, respectively, under physiologic pressure. In the artery model that included surrounding tissue, strain was 19% and 16% under pressure equalization versus 9% and 13% at the top and sides, respectively, under physiologic pressure. The model without surrounding tissue had slightly higher levels of strain under physiologic pressure compared to the other model, but the resulting strain values under pressure equalization were > 60% and did not correspond to experimental values. CONCLUSIONS: Since pressure equalization may increase the dynamic range of strain imaging, the effect of the surrounding tissue on strain should be incorporated into models of arterial strain, particularly when the pressure equalization technique is used.

High-resolution ultrasound elasticity imaging to evaluate dialysis fistula stenosis.

Accurate, noninvasive characterization of arterial wall mechanics and detection of fibrotic vascular lesions could vastly improve the ability to predict patient response to local treatments such as angioplasty. Current imaging and other techniques for determining wall compliance rely on imprecise or indirect estimates of wall motion. This study used high-resolution ultrasound imaging with phase-sensitive speckle tracking to obtain detailed and direct measurements of arterial stiffness in two subjects with dialysis fistula dysfunction. In both subjects, the absolute values of strain were much higher in normal regions of fistula than in regions of stenosis. The lower values of strain in stenotic fistula indicate greater stiffness of the vessel wall. The ultrasound speckle tracking technique used here may have potential to determine vascular mechanical properties noninvasively with a level of precision and accuracy not currently available.