Ultrasound-on-chip platform for medical imaging, analysis, and collective intelligence.

Over the past half-century, ultrasound imaging has become a key technology for assessing an ever-widening range of medical conditions at all stages of life. Despite ultrasound's proven value, expensive systems that require domain expertise in image acquisition and interpretation have limited its broad adoption. The proliferation of portable and low-cost ultrasound imaging can improve global health and also enable broad clinical and academic studies with great impact on the fields of medicine. Here, we describe the design of a complete ultrasound-on-chip, the first to be cleared by the Food and Drug Administration for 13 indications, comprising a two-dimensional array of silicon-based microelectromechanical systems (MEMS) ultrasonic sensors directly integrated into complementary metal-oxide-semiconductor-based control and processing electronics to enable an inexpensive whole-body imaging probe. The fabrication and design of the transducer array with on-chip analog and digital circuits, having an operating power consumption of 3 W or less, are described, in which approximately 9,000 seven-level feedback-based pulsers are individually addressable to each MEMS element and more than 11,000 amplifiers, more than 1,100 analog-to-digital converters, and more than 1 trillion operations per second are implemented. We quantify the measured performance and the ability to image areas of the body that traditionally takes three separate probes. Additionally, two applications of this platform are described-augmented reality assistance that guides the user in the acquisition of diagnostic-quality images of the heart and algorithms that automate the measurement of cardiac ejection fraction, an indicator of heart health.

Three-Dimensional Field Optimization Method: Clinical Validation of a Novel Color Doppler Method for Quantifying Mitral Regurgitation.

BACKGROUND: Assessment of mitral regurgitation (MR) severity by echocardiography is important for clinical decision making, but MR severity can be challenging to quantitate accurately and reproducibly. The accuracy of effective regurgitant orifice area (EROA) and regurgitant volume (RVol) calculated using two-dimensional (2D) proximal isovelocity surface area is limited by the geometric assumptions of proximal isovelocity surface area shape, and both variables demonstrate interobserver variability. The aim of this study was to compare a novel automated three-dimensional (3D) echocardiographic method for calculating MR regurgitant flow using standard 2D techniques. METHODS: A sheep model of ischemic MR and patients with MR were prospectively examined. Patients with a range of severity of MR were examined. EROA and RVol were calculated from 3D color Doppler acquisitions using a novel computer-automated algorithm based on the field optimization method to measure EROA and RVol. For an independent comparison group, the 3D field optimization method was compared with 2D methods for grading MR in an experimental ovine model of MR. RESULTS: Fifteen 3D data sets from nine sheep (open-chest transthoracic echocardiographic data sets) and 33 transesophageal data sets from patients with MR were prospectively examined. For sheep data sets, mean 2D EROA was 0.16 ± 0.05 cm2, and mean 2D RVol was 21.84 ± 8.03 mL. Mean 3D EROA was 0.09 ± 0.04 cm2, and mean 3D RVol was 14.40 ± 5.79 cm3. There was good correlation between 2D and 3D EROA (R = 0.70) and RVol (R = 0.80). For patient data sets, mean 2D EROA was 0.35 ± 0.35 cm2, and mean 2D RVol was 58.9 ± 52.9 mL. Mean 3D EROA was 0.34 ± 0.29 cm2, and mean 3D RVol was 54.6 ± 36.5 mL. There was excellent correlation between 2D and 3D EROA (R = 0.94) and RVol (R = 0.84). Bland-Altman analysis revealed greater interobserver variability for 2D RVol measurements compared with 3D RVol using the 3D field optimization method measurements, but variability was statistically significant only for RVol. CONCLUSIONS: Direct automated measurement of proximal isovelocity surface area region for EROA calculation using real-time 3D color Doppler echocardiography is feasible, with a high correlation to current 2D EROA methods but less variability. This novel automated method provides an accurate and highly reproducible method for calculating EROA.

Three-Dimensional Field Optimization Method: Gold-Standard Validation of a Novel Color Doppler Method for Quantifying Mitral Regurgitation.

BACKGROUND: Accurate diagnosis of mitral regurgitation (MR) severity is central to proper treatment. Although numerous approaches exist, an accurate, gold-standard clinical technique remains elusive. The authors previously reported on the initial development and demonstration of the automated three-dimensional (3D) field optimization method (FOM) algorithm, which exploits 3D color Doppler ultrasound imaging and builds on existing MR quantification techniques. The aim of the present study was to extensively validate 3D FOM in terms of accuracy, ease of use, and repeatability. METHODS: Three-dimensional FOM was applied to five explanted ovine mitral valves in a left heart simulator, which were systematically perturbed to yield a total of 29 unique regurgitant geometries. Three-dimensional FOM was compared with a gold-standard flow probe, as well as the most clinically prevalent MR volume quantification technique, the two-dimensional (2D) proximal isovelocity surface area (PISA) method. RESULTS: Overall, 3D FOM overestimated and 2D PISA underestimated MR volume, but 3D FOM error had smaller magnitude (5.2 ± 9.9 mL) than 2D PISA error (-6.9 ± 7.7 mL). Two-dimensional PISA remained superior in diagnosis for round orifices and especially mild MR, as predicted by ultrasound physics theory. For slit-type orifices and severe MR, 3D FOM showed significant improvement over 2D PISA. Three-dimensional FOM processing was technically simpler and significantly faster than 2D PISA and required fewer ultrasound acquisitions. Three-dimensional FOM did not show significant interuser variability, whereas 2D PISA did. CONCLUSIONS: Three-dimensional FOM may provide increased clinical value compared with 2D PISA because of increased accuracy in the case of complex or severe regurgitant orifices as well as its greater repeatability and simpler work flow.

Radial basis functions for combining shape and speckle tracking in 4D echocardiography.

Quantitative analysis of left ventricular deformation can provide valuable information about the extent of disease as well as the efficacy of treatment. In this work, we develop an adaptive multi-level compactly supported radial basis approach for deformation analysis in 3D+time echocardiography. Our method combines displacement information from shape tracking of myocardial boundaries (derived from B-mode data) with mid-wall displacements from radio-frequency-based ultrasound speckle tracking. We evaluate our methods on open-chest canines (N=8) and show that our combined approach is better correlated to magnetic resonance tagging-derived strains than either individual method. We also are able to identify regions of myocardial infarction (confirmed by postmortem analysis) using radial strain values obtained with our approach.

Novel method of measuring valvular regurgitation using three-dimensional nonlinear curve fitting of Doppler signals within the flow convergence zone.

Mitral valve regurgitation (MR) is among the most prevalent and significant valve problems in the Western world. Echocardiography plays a significant role in the diagnosis of degenerative valve disease. However, a simple and accurate means of quantifying MR has eluded both the technical and clinical ultrasound communities. Perhaps the best clinically accepted method used today is the 2-D proximal isovelocity surface area (PISA) method. In this study, a new quantification method using 3-D color Doppler ultrasound, called the field optimization method (FOM), is described. For each 3-D color flow volume, this method iterates on a simple fluid dynamics model that, when processed by a model of ultrasound physics, attempts to agree with the observed velocities in a least-squares sense. The output of this model is an estimate of the regurgitant flow and the location of its associated orifice. To validate the new method, in vitro experiments were performed using a pulsatile flow loop and different geometric orifices. Measurements from the FOM and from 2-D PISA were compared with measurements made with a calibrated ultrasonic flow probe. Results show that the new method has a higher correlation to the truth data and has lower inter- and intra-observer variability than the 2-D PISA method.

Defining left ventricular apex-to-base twist mechanics computed from high-resolution 3D echocardiography: validation against sonomicrometry.

OBJECTIVES: To compute left ventricular (LV) twist from 3-dimensional (3D) echocardiography. BACKGROUND: LV twist is a sensitive index of cardiac performance. Conventional 2-dimensional based methods of computing LV twist are cumbersome and subject to errors. METHODS: We studied 10 adult open-chest pigs. The pre-load to the heart was altered by temporary controlled occlusion of the inferior vena cava, and myocardial ischemia was produced by ligating the left anterior descending coronary artery. Full-volume 3D loops were reconstructed by stitching of pyramidal volumes acquired from 7 consecutive heart beats with electrocardiography gating on a Philips IE33 system (Philips Medical Systems, Andover, Massachusetts) at baseline and other steady states. Polar coordinate data of the 3D images were entered into an envelope detection program implemented in MatLab (The MathWorks, Inc., Natick, Massachusetts), and speckle motion was tracked using nonrigid image registration with spline-based transformation parameterization. The 3D displacement field was obtained, and rotation at apical and basal planes was computed. LV twist was derived as the net difference of apical and basal rotation. Sonomicrometry data of cardiac motion were also acquired from crystals anchored to epicardium in apical and basal planes at all states. RESULTS: The 3D dense tracking slightly overestimated the LV twist, but detected changes in LV twist at different states and showed good correlation (r = 0.89) when compared with sonomicrometry-derived twist at all steady states. In open chest pigs, peak cardiac twist was increased with reduction of pre-load from inferior vena cava occlusion from 6.25 degrees +/- 1.65 degrees to 9.45 degrees +/- 1.95 degrees . With myocardial ischemia from left anterior descending coronary artery ligation, twist was decreased to 4.90 degrees +/- 0.85 degrees (r = 0.8759). CONCLUSIONS: Despite lower spatiotemporal resolution of 3D echocardiography, LV twist and torsion can be computed accurately.

Real-time three-dimensional color Doppler echocardiography overcomes the inaccuracies of spectral Doppler for stroke volume calculation.

Real-time 3-dimensional echocardiography is increasingly used in clinical cardiology. Studies have been shown that this technique can be accurately used to assess both cardiac mass and chamber volumes. We review the work showing that real-time 3-dimensional Doppler echocardiography can be used to accurately calculate intracardiac flow volumes that can potentially be used to assess cardiac function, intracardiac shunt, and valve regurgitation.

Towards pointwise motion tracking in echocardiographic image sequences--comparing the reliability of different features for speckle tracking.

In this paper, we studied the problem of feature-based motion tracking in echocardiographic image sequences. We described the relation between possible feature variations and different kinds of tissue motion using a linear convolution model. We also showed that motion-feature decorrelation (which means that the motion parameters estimated using feature tracking fail to represent the underlying tissue motion) compensation is an ill-posed inverse problem. Instead of finding a method that may provide better compensation results than previous approaches, we used an quantitative measure to compare the reliability of tracking features. Experiment results showed that the use of the reliability measure improved the robustness of displacement estimation. With the help of the reliability measure, we compared the performance of different features using simulations and phantom examples. While we noticed that the radio frequency (RF) signal outperforms the B-mode (BM) signal in the analysis of small deformation (e.g., less than 0.1% compression), we also found out that the BM signal works better than the RF signal in the analysis of large deformation (e.g., larger than 2% compression). The use of a band-passed filtered feature does not result in significant improvement in tracking.

Use of real-time 3-dimensional transthoracic echocardiography in the evaluation of mitral valve disease.

Three-dimensional (3D) echocardiography (3DE) provides unique orientations of the mitral valve (MV) not obtainable by routine 2-dimensional echocardiography. However, this modality has not been adopted in routine clinical practice because of its cumbersome and time-consuming process. The recent introduction of a full matrix-array transducer has enabled online real-time 3DE (RT3DE) and rendering. This study was designed to: (1) determine the clinical use of RT3DE in patients with MV pathology and in a control group selected for their good acoustic windows (protocol I); and (2) to investigate the feasibility of imaging the MV apparatus in a large group of consecutively imaged patients to determine the acoustic window or perspective from which the MV leaflets, commissures, and orifice are best visualized (protocol II). In protocol I, 65 patients were selected based on MV pathology and good 2-dimensional echocardiography image quality. Protocol II included 150 patients who were consecutively imaged using RT3DE. Images were viewed online (protocol I) and offline on a digital review station (protocol II). RT3DE visualization of the MV apparatus was graded based on the percentage of leaflet dropout and definition. In protocol I, 78% of patients had adequate 3D MV reconstructions with complete visualization of the anterior mitral leaflet (AML) in 84% versus the posterior mitral leaflet (PML) in 77%. The mitral leaflets, commissures, and MV orifice were well seen in 98%; however, the submitral apparatus was only observed in 76% of the patients. RT3DE: (1) correctly identified the prolapsed/flailed scallop in 6 of 8 patients; (2) obtained en face orientation of the MV orifice in 9 of 11 patients with mitral stenosis, allowing accurate measurements of the orifice area and evaluation of the immediate effects of balloon mitral valvuloplasty; and (3) allowed postoperative evaluation of MV repair and the integrity of the struts of a bioprosthetic leaflet. In protocol II, 70% of patients had adequate RT3DE with complete visualization of the AML noted in 55% versus 51% for PML. The mitral leaflets, commissures, and MV orifice were observed in 69%. Irrespective of acquisition window, the AML was best seen from a ventricular perspective. In contrast, the PML was optimally examined from a parasternal window. Both the medial and lateral commissures were equally assessed from either imaging window. In conclusion, RT3DE of the MV is feasible in a large majority of patients. Using different MV acquisitions RT3DE provides important clinical information such as: (1) identification of a prolapsed/flail scallop; (2) measurement of stenotic valve areas; (3) evaluation of MV leaflet integrity postrepair; and (4) identification of a MV perforation. In general the AML is better visualized than the PML. The parasternal window is the optimal approach to visualize both AML and PMLs.

A novel method for the assessment of the accuracy of computing laminar flow stroke volumes using a real-time 3D ultrasound system: In vitro studies.

AIMS: Laminar flow stroke volume (SV) quantification in the ascending aorta or pulmonary artery can provide a measure for determining cardiac output (CO). Comparing flows across different valves can also compute shunt volumes and regurgitant fractions. Quantification methods for 3D color Doppler laminar flow volumes have been developed using reconstructive 3D, but these are cumbersome and time-consuming both in acquisition and measurement. Our study evaluated newly developed color Doppler mapping with real-time live 3D echo to test velocity, spatial and temporal resolution for computing SV. METHODS AND RESULTS: Five rubber tubes (diameters=3.0, 2.25, 2.0, 1.9, 1.7 cm), a freshly dissected porcine aorta (Ao) and a pulmonary artery (PA) (both 2-3 cm diameter) were connected to a pulsatile pump in a water bath. Different SV, from 10 to 80 ml/beat, were studied at pump rates of 40-60 bpm in this phantom model with flow quantified by timed collection. The Nyquist limit was set between 43 and 100 cm/s and frame rate ranged from 14 to 23/s. ECG triggered 3D color Doppler volumes were acquired with a 2-4 MHz probe. The digital scan line data from the 3D volumes, with retained velocity assignments, was exported and analyzed offline by MatLab custom software. Close correlations were found between 3D calculated SV and reference data for all tubes (r=0.98, y=1.14x-1.69, SEE=2.82 ml/beat, p<0.0001). Both Ao and PA flows were also highly correlated with the reference measurements (PA: r=0.98, SEE=3.17 ml/beat; Ao: r=0.99, SEE=3.20 ml/beat). CONCLUSIONS: Real-time 3D color Doppler method could provide an efficient, accurate and reliable method for clinical evaluation and quantification of flow volumes in patients.

The use of live three-dimensional Doppler echocardiography in the measurement of cardiac output: an in vivo animal study.

OBJECTIVES: The purpose of this study was to investigate whether cardiac output (CO) could be accurately computed from live three-dimensional (3-D) Doppler echocardiographic data in an acute open-chested animal preparation. BACKGROUND: The accurate measurement of CO is important in both patient management and research. Current methods use invasive pulmonary artery catheters or two-dimensional (2-D) echocardiography or esophageal aortic Doppler measures, with the inherent risks and inaccuracies of these techniques. METHODS: Seventeen juvenile, open-chested pigs were studied before undergoing a separate cardiopulmonary bypass procedure. Live 3-D Doppler echocardiography images of the left ventricular outflow tract and aortic valve were obtained by epicardial scanning, using a Philips Medical Systems (Andover, Massachusetts) Sonos 7500 Live 3-D Echo system with a 2.5-MHz probe. Simultaneous CO measurements were obtained from an ultrasonic flow probe placed around the aortic root. Subsequent offline processing using custom software computed the CO from the digital 3-D Doppler DICOM data, and this was compared to the gold standard of the aortic flow probe measurements. RESULTS: One hundred forty-three individual CO measurements were taken from 16 pigs, one being excluded because of severe aortic regurgitation. There was good correlation between the 3-D Doppler and flow probe methods of CO measurement (y = 1.1x - 9.82, R(2) = 0.93). CONCLUSIONS: In this acute animal preparation, live 3-D Doppler echocardiographic data allowed for accurate assessment of CO as compared to the ultrasonic flow probe measurement.

Real-time three-dimensional echocardiography using a novel matrix array transducer.

Three-dimensional echocardiography has multiple advantages over two-dimensional echocardiography, such as accurate left ventricular quantification and improved spatial relationships. However, clinical use of three-dimensional echocardiography has been impeded by tedious and time-consuming methods for data acquisition and post-processing. A newly developed matrix array probe, which allows real-time three-dimensional imaging with instantaneous on-line volume-rendered reconstruction, direct manipulation of thresholding, and cut planes on the ultrasound unit may overcome the aforementioned limitations. This report will review current methods of three-dimensional data acquisition, emphasizing the real-time methods and clinical applications of the new matrix array probe.

A Homologous Series of Homoleptic Zinc Bis(1,4-di-tert-butyl-1,4-diaza-1,3-butadiene) Complexes: K(x)[Zn(t-BuNCHCHN-t-Bu)(2)], Zn(t-BuNCHCHN-t-Bu)(2), and [Zn(t-BuNCHCHN-t-Bu)(2)](OTf)(x) (x = 1, 2).

A homologous series of mono- and dicationic, neutral, and mono- and dianionic zinc diazabutadiene complexes, K(x)[Zn(t-BuNCHCHN-t-Bu)(2)], Zn(t-BuNCHCHN-t-Bu)(2), and [Zn(t-BuNCHCHN-t-Bu)(2)](OTf)(x) (x = 1, 2), have been prepared and isolated in pure form. The crystal structures of the mono- and dicationic as well as of the monoanionic complexes are reported. In this series, the formal charge on the t-BuNCHCHN-t-Bu ligands ranges from -2 to +2, and the way in which the molecular geometry of the ligands varies with the charge is discussed. [Zn(t-BuNCHCHN-t-Bu)(2)](OTf)(2) reacts with methanol to give 1,3-di-tert-butylimidazolium triflate. Crystal data: dicationic 2 ([Zn(t-BuNCHCHN-t-Bu)(2)](OTf)(2), C(22)H(40)F(6)S(2)N(4)O(6)Zn), monoclinic, space group C2/c, with a = 18.015(6) Å, b = 9.257(6) Å, c = 20.012(5) Å, beta = 109.63(3) degrees, and Z = 4; monocationic 3.thf ([Zn(t-BuNCHCHN-t-Bu)(2)]OTf.thf, C(25)H(48)F(3)N(4)O(3)SZn), orthorhombic, space group P2(1)2(1)2(1), with a = 10.3077(6) Å, b = 17.1974(6) Å, c = 17.8241(13) Å, and Z = 4; monoanionic 5.thf (K(thf)(3)[Zn(t-BuNCHCHN-t-Bu)(2)], C(36)H(72)KN(4)O(3)Zn), triclinic, space group P&onemacr;, with a = 10.8702(10) Å, b = 11.5175(9) Å, c = 18.2815(13) Å, alpha = 73.795(6) degrees, beta = 74.227(6) degrees, gamma = 75.736(7) degrees, and Z = 2; 7 (1,3-di-tert-butylimidazolium triflate, C(12)H(21)F(3)N(2)O(3)S), orthorhombic, space group Pbca, with a = 14.4086(8) Å, b = 12.0293(8) Å, c = 18.6985(12) Å, and Z = 8.

Synthesis and Properties of Lanthanum- Pyrene Complexes-Structure of [(Cp*La)3 (µ-Cl)3 (thf)(µ-η2 :η6 :η6 -C16 H10 )], the First Complex with a Pyrene Trianion.

Different bonding modes are characteristic for the lanthanum centers of the title compound, a trinuclear lanthanum-pyrene complex in which an arene trianion is present for the first time (see picture for the structure). Thus, La1 and La3 reside in a tetrahedral environment, the La2 center in a distorted trigonal-bipyramidal one.