[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: In contrast to short-lived neutrophils, macrophages display persistent presence in the lung of animals after pulmonary exposure to carbon nanotubes. While effective in clearance of bacterial pathogens and injured host cells, the ability of macrophages to "digest" carbonaceous nanoparticles has not been documented. Here, we used chemical, biochemical, cell and animal models and demonstrated oxidative biodegradation of oxidatively functionalized single walled carbon nanotubes via superoxide/NO*-> peroxynitrite driven oxidative pathways of activated macrophages facilitating clearance of nanoparticles from the lung.
[Show abstract][Hide abstract] ABSTRACT: Hepatic steatosis or fatty liver disease occurs when lipids accumulate within the liver and can lead to steatohepatitis, cirrhosis, liver cancer and eventual liver failure requiring liver transplant. Conventional brightness mode (B-mode) ultrasound (US) is the most common noninvasive diagnostic imaging modality used to diagnose hepatic steatosis in clinics. However, it is mostly subjective or requires a reference organ such as the kidney or spleen with which to compare. This comparison can be problematic when the reference organ is diseased or absent. The current work presents an alternative approach to noninvasively detecting liver fat content using US-induced thermal strain imaging (US-TSI). This technique is based on the difference in the change in the speed of sound as a function of temperature between water- and lipid-based tissues. US-TSI was conducted using two system configurations including a mid-frequency scanner with a single linear array transducer (5-14 MHz) for both imaging and heating and a high-frequency (13-24 MHz) small animal imaging system combined with a separate custom-designed US heating transducer array. Fatty livers (n = 10) with high fat content (45.6 ± 11.7%) from an obese mouse model and control livers (n = 10) with low fat content (4.8 ± 2.9%) from wild-type mice were embedded in gelatin. Then, US imaging was performed before and after US induced heating. Heating time periods of ∼3 s and ∼9.2 s were used for the mid-frequency imaging and high-frequency imaging systems, respectively, to induce temperature changes of approximately 1.5 °C. The apparent echo shifts that were induced as a result of sound speed change were estimated using 2D phase-sensitive speckle tracking. Following US-TSI, histology was performed to stain lipids and measure percentage fat in the mouse livers. Thermal strain measurements in fatty livers (-0.065 ± 0.079%) were significantly (p < 0.05) higher than those measured in control livers (-0.124 ± 0.037%). Using histology as a gold standard to classify mouse livers, US-TSI had a sensitivity and specificity of 70% and 90%, respectively. The area under the receiver operating characteristic curve was 0.775. This ex vivo study demonstrates the feasibility of using US-TSI to detect fatty livers and warrants further investigation of US-TSI as a diagnostic tool for hepatic steatosis.
Physics in Medicine and Biology 02/2014; 59(4):881-895. · 2.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ultrasound-induced thermal strain imaging (USTSI) for carotid artery plaque detection requires both high imaging resolution (≪100 μm) and sufficient US-induced heating to elevate the tissue temperature (˜1°C to 3°C within 1 to 3 cardiac cycles) to produce a noticeable change in sound speed in the targeted tissues. Because the optimization of both imaging and heating in a monolithic array design is particularly expensive and inflexible, a new integrated approach is presented which utilizes independent ultrasound arrays to meet the requirements for this particular application. This work demonstrates a new approach in dual-array construction. A 3-D printed manifold was built to support both a high-resolution 20 MHz commercial imaging array and 6 custom heating elements operating in the 3.5 to 4 MHz range. For the application of US-TSI in carotid plaque characterization, the tissue target site is 20 to 30 mm deep, with a typical target volume of 2 mm (elevation) × 8 mm (azimuthal) × 5 mm (depth). The custom heating array performance was fully characterized for two design variants (flat and spherical apertures), and can easily deliver 30 W of total acoustic power to produce intensities greater than 15 W/cm(2) in the tissue target region.
IEEE transactions on ultrasonics, ferroelectrics, and frequency control 12/2013; 60(12):2645-56. · 1.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to evaluate the long-term performance of cell-free vascular grafts made from a fast-degrading elastic polymer. We fabricated small arterial grafts from microporous tubes of poly(glycerol sebacate) (PGS) reinforced with polycaprolactone (PCL) nanofibers on the outer surface. Grafts were interpositioned in rat abdominal aortas and characterized at 1 year post-implant. Grafts remodeled into "neoarteries" (regenerated arteries) with similar gross appearance to native rat aortas. Neoarteries mimic arterial tissue architecture with a confluent endothelium and media and adventita-like layers. Patent vessels (80%) showed no significant stenosis, dilation, or calcification. Neoarteries contain nerves and have the same amount of mature elastin as native arteries. Despite some differences in matrix organization, regenerated arteries had similar dynamic mechanical compliance to native arteries in vivo. Neoarteries responded to vasomotor agents, albeit with different magnitude than native aortas. These data suggest that an elastic vascular graft that resorbs quickly has potential to improve the performance of vascular grafts used in small arteries. This design may also promote constructive remodeling in other soft tissues.
[Show abstract][Hide abstract] ABSTRACT: Mechanical strength is a key design factor in tissue engineering of arteries. Most existing techniques assess the mechanical property of arterial constructs destructively, leading to sacrifice of a large number of animals. We propose an ultrasound-based non-invasive technique for the assessment of the mechanical strength of engineered arterial constructs. Tubular scaffolds made from a biodegradable elastomer and seeded with vascular fibroblasts and smooth muscle cells were cultured in a pulsatile-flow bioreactor. Scaffold distension was computed from ultrasound radiofrequency signals of the pulsating scaffold via 2-D phase-sensitive speckle tracking. Young's modulus was then calculated by solving the inverse problem from the distension and the recorded pulse pressure. The stiffness thus computed from ultrasound correlated well with direct mechanical testing results. As the scaffolds matured in culture, ultrasound measurements indicated an increase in Young's modulus, and histology confirmed the growth of cells and collagen fibrils in the constructs. The results indicate that ultrasound elastography can be used to assess and monitor non-invasively the mechanical properties of arterial constructs.
Ultrasound in medicine & biology 08/2013; · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study examined the feasibility of in vivo detection of lipids in atherosclerotic plaque (AP) by ultrasound (US) thermal strain imaging (TSI).
Intraplaque lipid content is thought to contribute to plaque stability. Lipid exhibits a distinctive physical characteristic of temperature-dependent US speed compared to water-bearing tissues. As tissue temperature changes, US radiofrequency (RF) echoes shift in time of flight which produces an apparent strain (temporal or thermal strain: TS).
US heating-imaging pulse sequences and transducers were designed and integrated into commercial US scanners for US-TSI of arterial segments. US-RF data were collected while gradually increasing tissue temperature. Phase-sensitive speckle tracking was applied to reconstruct TS maps co-registered to B-scans. Segments from injured atherosclerotic and uninjured non-atherosclerotic common femoral arteries (CFA) in cholesterol fed New Zealand rabbits, and segments from control normal diet fed rabbits (n=14 total) were scanned in vivo at different time points up to 12 weeks.
Lipid-rich atherosclerotic lesions exhibited distinct positive TS (+0.19±0.08%) compared with that in non-atherosclerotic (-0.10±0.13%) and control (-0.09±0.09%) segments (p<0.001). US-TSI enabled serial monitoring of lipids during atherosclerosis development. The co-registered set of morphological and compositional information of US-TSI showed good agreement with histology.
US-TSI successfully detected and longitudinally monitored lipid progression in atherosclerotic CFA. US-TSI of relatively superficial arteries may be a modality that could be integrated into a commercial US system for noninvasive lipid detection in AP.
Journal of the American College of Cardiology 07/2013; · 14.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Thermal strain imaging (TSI) can be used to differentiate lipid and water-based tissues in atherosclerotic arteries. However, detecting small lipid pools in vivo requires accurate and robust estimation of displacement over a wide range of displacement magnitudes. Phase-shift estimators such as Loupas' estimator and time-shift estimators like normalized cross-correlation (NXcorr) are commonly used to track tissue displacements. However, Loupas' algorithm is limited by phase-wrapping and NXcorr performs poorly in low SNR situations. In this paper, we present an adaptive displacement estimation algorithm that showed performance that was superior to either Loupas' estimator or NXcorr alone when the displacement estimates were used to reconstruct thermal strain. We evaluated this algorithm using simulation and phantom studies.
2013 IEEE International Ultrasonics Symposium (IUS); 07/2013
[Show abstract][Hide abstract] ABSTRACT: An ultrasound elasticity microscope was used to map 3-D strain volume in an ex vivo porcine cornea to illustrate its ability to measure the mechanical properties of this tissue. Mechanical properties of the cornea play an important role in its function and, therefore, also in ophthalmic diseases such as kerataconus and corneal ectasia. The ultrasound elasticity microscope combines a tightly focused high-frequency transducer with confocal scanning to produce high-quality speckle over the entire volume of tissue. This system and the analysis were able to generate volume maps of compressional strain in all three directions for porcine corneal tissue, more information than any previous study has reported. Strain volume maps indicated features of the cornea and mechanical behavior as expected. These results constitute a step toward better understanding of corneal mechanics and better treatment of corneal diseases.
Ultrasound in medicine & biology 05/2013; · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The evaluation of candidate materials and designs for soft tissue scaffolds would benefit from the ability to monitor the mechanical remodeling of the implant site without the need for periodic animal sacrifice and explant analysis. Toward this end, the ability of non-invasive ultrasound elasticity imaging (UEI) to assess temporal mechanical property changes in three different types of porous, biodegradable polyurethane scaffolds was evaluated in a rat abdominal wall repair model. The polymers utilized were salt-leached scaffolds of poly(carbonate urethane) urea, poly(ester urethane) urea and poly(ether ester urethane) urea at 85% porosity. A total of 60 scaffolds (20 each type) were implanted in a full thickness muscle wall replacement in the abdomens of 30 rats. The constructs were ultrasonically scanned every 2 weeks and harvested at weeks 4, 8 and 12 for compression testing or histological analysis. UEI demonstrated different temporal stiffness trends among the different scaffold types, while the stiffness of the surrounding native tissue remained unchanged. The changes in average normalized strains developed in the constructs from UEI compared well with the changes of mean compliance from compression tests and histology. The average normalized strains and the compliance for the same sample exhibited a strong linear relationship. The ability of UEI to identify herniation and to characterize the distribution of local tissue in-growth with high resolution was also investigated. In summary, the reported data indicate that UEI may allow tissue engineers to sequentially evaluate the progress of tissue construct mechanical behavior in vivo and in some cases may reduce the need for interim time point animal sacrifice.
[Show abstract][Hide abstract] ABSTRACT: Large lipid pools in vulnerable plaques, in principle, can be detected using ultrasound-based thermal strain imaging (US-TSI). One practical challenge for in vivo cardiovascular application of US-TSI is that the thermal strain is masked by the mechanical strain caused by cardiac pulsation. Electrocardiography (ECG) gating is a widely adopted method for cardiac motion compensation, but it is often susceptible to electrical and physiological noise. In this paper, we present an alternative time-series analysis approach to separate thermal strain from the mechanical strain without using ECG. The performance and feasibility of the time-series analysis technique was tested via numerical simulation as well as in vitro water tank experiments, using a vessel-mimicking phantom and an excised human atherosclerotic artery, for which the cardiac pulsation is simulated by a pulsatile pump.
IEEE Transactions on Ultrasonics Ferroelectrics and Frequency Control 01/2013; 60(8):1660-1668. · 1.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A new light illumination scheme to increase imaging depth in photoacoustic (PA) imaging was designed and evaluated by in silico simulations and tested by in vitro experiments. A relatively large portion of the light energy shining into the body of a human reflects off the skin surfaces. Collecting the reflected light and redirecting it onto skin surfaces will increase the effective input energy, resulting in an increase of light penetration depth for the same light source. Its performance in PA imaging was evaluated using a finite element (FE)-based numerical simulation model composed of four modules. In the in vitro experiments with the light catcher, PA image of multiple targets at different locations exhibited an enhancement both in uniformity and in depth of the light illumination.
[Show abstract][Hide abstract] ABSTRACT: Over the past three decades, revolutionary research in nanotechnology by the scientific, medical, and engineering communities has yielded a treasure trove of discoveries with diverse applications that promise to benefit humanity. With their unique electronic and mechanical properties, carbon nanomaterials (CNMs) represent a prime example of the promise of nanotechnology with applications in areas that include electronics, fuel cells, composites, and nanomedicine. Because of toxicological issues associated with CNMs, however, their full commercial potential may not be achieved. The ex vitro, in vitro, and in vivo data presented in this Account provide fundamental insights into the biopersistence of CNMs, such as carbon nanotubes and graphene, and their oxidation/biodegradation processes as catalyzed by peroxidase enzymes. We also communicate our current understanding of the mechanism for the enzymatic oxidation and biodegradation. Finally, we outline potential future directions that could enhance our mechanistic understanding of the CNM oxidation and biodegradation and could yield benefits in terms of human health and environmental safety. The conclusions presented in this Account may catalyze a rational rethinking of CNM incorporation in diverse applications. For example, armed with an understanding of how and why CNMs undergo enzyme-catalyzed oxidation and biodegradation, researchers can tailor the structure of CNMs to either promote or inhibit these processes. In nanomedical applications such as drug delivery, the incorporation of carboxylate functional groups could facilitate biodegradation of the nanomaterial after delivery of the cargo. On the other hand, in the construction of aircraft, a CNM composite should be stable to oxidizing conditions in the environment. Therefore, pristine, inert CNMs would be ideal for this application. Finally, the incorporation of CNMs with defect sites in consumer goods could provide a facile mechanism that promotes the degradation of these materials once these products reach landfills.
Accounts of Chemical Research 07/2012; 45(10):1770-81. · 20.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ultrasound (US) mediated microbubble (MB) destruction facilitates thrombolysis of the epicardial coronary artery in acute myocardial infarction (AMI) but its effect on microvascular thromboemboli remains largely unexplored. We sought to define the acoustic requirements for effective microvascular sonothrombolysis. To model microembolization, microthrombi were injected and entrapped in a 40 μm pore mesh, increasing upstream pressure, which was measured as an index of thrombus burden. MBs (2.0 × 10(6) MBs/mL) were then infused while pulsed US (1 MHz) was delivered to induce MB destruction immediately adjacent to the thrombus. Upstream pressure decreased progressively during US delivery, indicating a reduction in thrombus burden. More rapid and complete lysis occurred with increasing peak negative acoustic pressure (1.5 MPa > 0.6 MPa) and increasing pulse length (5000 cycles > 100 cycles). Additionally, similar lytic efficacy was achieved at 1.5 MPa without tPA as was at 1.0 MPa with tPA. This model uniquely provides a means to systematically evaluate multiple acoustic and microbubble parameters for the optimization of microvascular sonothrombolysis. This treatment approach for thrombotic microvascular obstruction may obviate the need for adjunctive rt-PA and could have important clinical cost and safety benefits.
Ultrasound in medicine & biology 07/2012; 38(9):1589-98. · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several in vitro and in vivo studies have established accelerated thrombolysis using ultrasound (US) induced microbubble (MB) cavitation. However, the mechanisms underlying MB mediated sonothrombolysis are still not completely elucidated. We performed three-dimensional (3-D) volumetric optical coherence tomography (OCT) imaging before and after the application of contrast US to thrombus. The most dramatic reduction in clot volume was observed with US + MB + recombinant tissue plasminogen activator (rt-PA). Thrombus surface erosion in this group on the side of the thrombus exposed to MB and ultrasound was evident on the OCT images. This technique may assist in clarifying the mechanisms underlying sonothrombolysis, especially regarding the importance of US transducer orientation on lytic efficacy and the effects of MB cavitation on thrombus structure.
Journal of Biomedical Optics 07/2012; 17(7):070502. · 2.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Strain developed under quasi-static deformation has been mostly used in ultrasound elasticity imaging (UEI) to determine the stiffness change of tissues. However, the strain measure in UEI is often less sensitive to a subtle change of stiffness. This is particularly true for Crohn's disease where we have applied strain imaging to the differentiation of acutely inflamed bowel from chronically fibrotic bowel. In this study, a new nonlinear elastic parameter of the soft tissues is proposed to overcome this limit. The purpose of this study is to evaluate the newly proposed method and demonstrate its feasibility in the UEI. A nonlinear characteristic of soft tissues over a relatively large dynamic range of strain was investigated. A simplified tissue model based on a finite element (FE) analysis was integrated with a laboratory developed ultrasound radio-frequency (RF) signal synthesis program. Two-dimensional speckle tracking was applied to this model to simulate the nonlinear behavior of the strain developed in a target inclusion over the applied average strain to the surrounding tissues. A nonlinear empirical equation was formulated and optimized to best match the developed strain-to-applied strain relation obtained from the FE simulation. The proposed nonlinear equation was applied to in vivo measurements and nonlinear parameters were further empirically optimized. For an animal model, acute and chronic inflammatory bowel disease was induced in Lewis rats with trinitrobenzene sulfonic acid (TNBS)-ethanol treatments. After UEI, histopathology and direct mechanical measurements were performed on the excised tissues. The extracted nonlinear parameter from the developed strain-to-applied strain relation differentiated the three different tissue types with 1.96 ± 0.12 for normal, 1.50 ± 0.09 for the acutely inflamed and 1.03 ± 0.08 for the chronically fibrotic tissue. T-tests determined that the nonlinear parameters between normal, acutely inflamed and fibrotic tissue types were statistically significantly different (normal/ fibrotic [p = 0.0000185], normal/acutely inflamed [p = 0.0013] and fibrotic/acutely inflamed [p = 0.0029]). This technique may provide a sensitive and robust tool to assess subtle stiffness changes in tissues such as in acutely inflamed bowel wall.
Ultrasound in medicine & biology 03/2012; 38(3):511-23. · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A finite element (FE)-based simulation model for photoacoustic (PA) has
been developed incorporating light propagation, PA signal generation,
and sound wave propagation in soft tissues using a commercial FE
simulation package, COMSOL Multiphysics. The developed simulation model
is evaluated by comparing with other known simulation models such as
Monte Carlo method and heat-pressure model. In this in silico
simulation, FE model is composed of three parts of 1) homogeneous
background soft tissues submerged in water, 2) target tissue inclusion
(or PA contrast agents), and 3) short pulsed laser source (pulse length
of 5-10 ns). The laser point source is placed right above the tissues
submerged in water. This laser source light propagation through the
multi-layer tissues using the diffusion equation is compared with Monte
Carlo solution. Photoacoustic signal generation by the target tissue
inclusion is simulated using bioheat equation for temperature change,
and resultant stress and strain. With stress-strain model, the process
of the PA signal generation can be simulated further in details step by
step to understand and analyze the photothermal properties of the target
tissues or PA contrast agents. The created wide-band acoustic pressure
(band width > 150 MHz) propagates through the background tissues to
the ultrasound detector located at the tissue surface, governed by sound
wave equation. Acoustic scattering and absorption in soft tissues also
have been considered. Accuracy and computational time of the developed
FE-based simulation model of photoacoustics have been quantitatively