Supramolecular Nanofibers Ameliorate Bleomycin-Induced Pulmonary Fibrosis by Restoring Autophagy.

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease, with limited therapeutic options available. Impaired autophagy resulting from aberrant TRB3/p62 protein-protein interactions (PPIs) contributes to the progression of IPF. Restoration of autophagy by modulating the TRB3/p62 PPIs has rarely been reported for the treatment of IPF. Herein, peptide nanofibers are developed that specifically bind to TRB3 protein and explored their potential as a therapeutic approach for IPF. By conjugating with the self-assembling fragment (Ac-GFFY), a TRB3-binding peptide motif A2 allows for the formation of nanofibers with a stable α-helix secondary structure. The resulting peptide (Ac-GFFY-A2) nanofibers exhibit specific high-affinity binding to TRB3 protein in saline buffer and better capacity of cellular uptake to A2 peptide. Furthermore, the TRB3-targeting peptide nanofibers efficiently interfere with the aberrant TRB3/p62 PPIs in activated fibroblasts and fibrotic lung tissue of mice, thereby restoring autophagy dysfunction. The TRB3-targeting peptide nanofibers inhibit myofibroblast differentiation, collagen production, and fibroblast migration in vitro is demonstrated, as well as bleomycin-induced pulmonary fibrosis in vivo. This study provides a supramolecular method to modulate PPIs and highlights a promising strategy for treating IPF diseases by restoring autophagy.

Ultrasonic surface acoustic wave elastography: A review of basic theories, technical developments, and medical applications.

Physiological and pathological changes in tissues often cause changes in tissue mechanical properties, making tissue elastography an effective modality in medical imaging. Among the existing elastography methods, ultrasound elastography is of great interest due to the inherent advantages of ultrasound imaging technology, such as low cost, portability, safety, and wide availability. However, most current ultrasound elastography methods are based on the bulk shear wave; they can image deep tissues but cannot image superficial tissues. To address this challenge, ultrasonic elastography methods based on surface acoustic waves have been proposed. In this paper, we present a comprehensive review of ultrasound-based surface acoustic wave elastography techniques, including their theoretical foundations, technical implementations, and existing medical applications. The goal is to provide a concise summary of the state-of-the-art of this field, hoping to offer a reliable reference for the further development of these techniques and foster the expansion of their medical applications.

Intestinal metabolomics in premature infants with late-onset sepsis.

We aimed to investigate the characteristics of intestinal metabolomics and non-invasive biomarkers for early diagnosis of late-onset sepsis (LOS) by analyzing gut metabolites in preterm infants with LOS. We collected stool samples from septic and healthy preterm infants for analysis by liquid chromatography-mass spectrometry. 123 different metabolites were identified and 13 pathways were mainly involved. Glycine, serine, and threonine metabolism; glyoxylate and dicarboxylic acid metabolism; glutathione metabolism; primary bile acid biosynthesis; steroid synthesis; pentose and glucuronic acid interconversion may be involved in the pathogenesis of LOS in preterm infants. The significant changes of N-Methyldopamine, cellulose, glycine, gamma-Glutamyltryptophan, N-Ribosylnicotinamide and 1alpha, 25-dihydroxycholecalciferol showed specific diagnostic values and as non-invasive biomarkers for LOS.

Enhancement effect of carvacrol on yeast inactivation by mild pressure carbon dioxide.

Saccharomyces cerevisiae is one of the common spoilage microorganisms in fruit juices. This paper investigated the influences of carvacrol on S. cerevisiae inactivation by mild pressure carbon dioxide (MPCO2). The results demonstrated that carvacrol synergistically enhanced the antifungal activity against S. cerevisiae of MPCO2. With the increase of carvacrol concentration (20-160 µg/mL), CO2 pressure (1.5-3.5 MPa), process temperature (20-40 °C), and treatment time (15-60 min), the inactivation effect of carvacrol combined with MPCO2 on S. cerevisiae was gradually increased and significantly stronger than either single treatment. In the presence of carvacrol, MPCO2 severely disordered the plasma membrane of S. cerevisiae, including the increase of membrane permeability, and the loss of membrane potential and integrity. MPCO2 and carvacrol in combination also aggravated the mitochondrial depolarization of S. cerevisiae and reduced intracellular ATP and protein content. This study suggests the potential of carvacrol and pressurized CO2 as an alternative technology for food pasteurization.

A time variant uncertainty propagation method for high-dimensional dynamic structural system via K-L expansion and Bayesian deep neural network.

In this paper, a time variant uncertainty propagation (TUP) method for dynamic structural system with high-dimensional input variables is proposed. Firstly, an arbitrary stochastic process simulation (ASPS) method based on Karhunen-Loève (K-L) expansion and numerical integration is developed, expressing the stochastic process as the combination of its marginal distributions and eigen functions at several discrete time points. Secondly, the iterative sorting method is implemented to the statistic samples of marginal distributions for matching the constraints of covariance function. Since marginal distributions are directly used to express the stochastic process, the proposed ASPS is suitable for stationary or non-stationary stochastic processes with arbitrary marginal distributions. Thirdly, the high-dimensional TUP problem is converted into several high-dimensional static uncertainty propagation (UP) problems after implementing ASPS. Then, the Bayesian deep neural network based UP method is used to compute the marginal distributions as well as the eigen functions of dynamic system response, the high-dimensional TUP problem can thus be solved. Finally, several numerical examples are used to validate the effectiveness of the proposed method. This article is part of the theme issue 'Physics-informed machine learning and its structural integrity applications (Part 1)'.

A Scholte wave approach for ultrasonic surface acoustic wave elastography.

BACKGROUND: Pathological changes in tissues are often related to changes in tissue mechanical properties, making elastography an important tool for medical applications. Among the existing elastography methods, ultrasound elastography is of great interest due to the inherent advantages of ultrasound imaging technology, such as low cost, portability, safety, and wide availability. Although ultrasonic shear wave elastography, as a platform technology, can potentially quantify the elasticity of tissue at any depth, its current implementation cannot assess superficial tissue but can only image deep tissue. PURPOSE: To address this challenge, we proposed an ultrasonic Scholte-wave-based approach for imaging the elasticity of superficial tissue. METHODS: The feasibility of the proposed technique was tested using a gelatin phantom with a cylindrical inclusion. To generate Scholte wave in the superficial region of the phantom, we proposed a new experimental configuration in which a liquid layer was introduced between an ultrasound imaging transducer and the tissue-mimicking phantom. We utilized an acoustic radiation force impulse to excite the tissue-mimicking phantom, analyzed the properties of the generated Scholte waves, and applied the waves for elasticity imaging. RESULTS: In this study, we first reported the observation that Scholte (surface) waves and shear (bulk) waves were simultaneously generated, and they propagated in the superficial and deeper regions of the phantom, respectively. Then, we presented some important properties of the generated Scholte waves. For a 5w/v% gelatin phantom, the generated Scholte waves have a speed of around 0.9 m/s, a frequency of about 186 Hz, and thus a wavelength of about 4.8 mm. The speed ratio between the simultaneously generated Scholte wave and shear wave is about 0.717, which is 15% lower than the theoretical expectation. And we further demonstrated the feasibility of Scholte wave as a mechanism for imaging superficial tissue elasticity. Together with the simultaneously generated shear wave, the Scholte wave was shown to be able to quantitatively image both the background and the cylindrical inclusion (4 mm in diameter) of the tissue-mimicking gelatin phantom. CONCLUSIONS: This work shows that the elasticity of superficial tissue can be evaluated by utilizing the generated Scholte wave alone, and it also shows that a comprehensive elasticity imaging of the tissue extending from the superficial to deep regions can be achieved by combining the proposed Scholte wave technique and the conventional shear wave technique.

Noninvasive ultrasound assessment of tissue internal pressure using dual mode elasticity imaging: a phantom study.

Objective.Tissue internal pressure, such as interstitial fluid pressure in solid tumors and intramuscular pressure in compartment syndrome, is closely related to the pathological state of tissues. It is of great diagnostic value to measure and/or monitor the internal pressure of targeted tissues. Because most of the current methods for measuring tissue pressure are invasive, noninvasive methods are highly desired. In this study, we developed a noninvasive method for qualitative assessment of tissue internal pressure based on a combination of two ultrasound elasticity imaging methods: strain imaging and shear wave elasticity imaging.Approach.The method was verified through experimental investigation using two tissue-mimicking phantoms each having an inclusion confined by a membrane, in which hydrostatic pressures can be applied and maintained. To examine the sensitivity of the elasticity imaging methods to pressure variation, strain ratio and shear modulus ratio (SMR) between the inclusion and background of phantom were obtained.Main results.The results first experimentally prove that pressure, in addition to elasticity, is a contrast mechanism of strain imaging, and further demonstrate that a comparative analysis of strain ratio and SMR is an effective method for noninvasive tissue internal pressure detection.Significance.This work provides a new perspective in interpreting the strain ratio data in medical diagnosis, and it also provides a noninvasive alternative for assessing tissue internal pressure, which could be valuable for the diagnosis of pressure-related diseases.

Effect of Combined Treatment with Cinnamon Oil and petit-High Pressure CO2 against Saccharomyces cerevisiae.

This study investigated the effects of the combined treatment with cinnamon oil (CIN) and petit-high pressure CO2 (p-HPCO2) against Saccharomyces cerevisiae. The results showed that CIN and p-HPCO2 exhibited a synergistic antifungal effect against S. cerevisiae. After being treated by CIN at a final concentration of 0.02% and p-HPCO2 under 1.3 MPa at 25 °C for 2 h, the S. cerevisiae population decreased by 3.35 log10 CFU/mL, which was significantly (p < 0.05) higher than that of CIN (1.11 log10 CFU/mL) or p-HPCO2 (0.31 log10 CFU/mL). Through scanning electron microscopy, fluorescence staining, and other approaches, a disorder of the structure and function of the cell membrane was observed after the CIN + p-HPCO2 treatment, such as severe morphological changes, increased membrane permeability, decreased cell membrane potential, and loss of membrane integrity. CIN + p-HPCO2 also induced mitochondrial membrane depolarization in S. cerevisiae cells, which could be associated with the decrease in intracellular ATP observed in this study. Moreover, the expression of genes involved in ergosterol synthesis in S. cerevisiae was up-regulated after exposure to CIN + p-HPCO2, which might be an adaptive response to membrane damage. This work demonstrates the potential of CIN and p-HPCO2 in combination as an alternative pasteurization technique for use in the food industry.

Enzyme-instructed and mitochondria-targeting peptide self-assembly to efficiently induce immunogenic cell death.

Immunogenic cell death (ICD) plays a major role in cancer immunotherapy by stimulating specific T cell responses and restoring the antitumor immune system. However, effective type II ICD inducers without biotoxicity are still very limited. Herein, a tentative drug- or photosensitizer-free strategy was developed by employing enzymatic self-assembly of the peptide F-pY-T to induce mitochondrial oxidative stress in cancer cells. Upon dephosphorylation catalyzed by alkaline phosphatase overexpressed on cancer cells, the peptide F-pY-T self-assembled to form nanoparticles, which were subsequently internalized. These affected the morphology of mitochondria and induced serious reactive oxygen species production, causing the ICD characterized by the release of danger-associated molecular patterns (DAMPs). DAMPs enhanced specific immune responses by promoting the maturation of DCs and the intratumoral infiltration of tumor-specific T cells to eradicate tumor cells. The dramatic immunotherapeutic capacity could be enhanced further by combination therapy of F-pY-T and anti-PD-L1 agents without visible biotoxicity in the main organs. Thus, our results revealed an alternative strategy to induce efficient ICD by physically promoting mitochondrial oxidative stress.

Peptide OM-LV20 promotes structural and functional recovery of spinal cord injury in rats.

At present, there are no satisfactory therapeutic drugs for the functional recovery of spinal cord injury (SCI). We previously identified a novel peptide (OM-LV20) that accelerated the regeneration of injured skin tissues of mice and exerts neuroprotective effects against cerebral ischemia/reperfusion injury in rats. Here, the intraperitoneal injection of OM-LV20 (1 µg/kg) markedly improved motor function recovery in the hind limbs of rats with traumatic SCI, and further enhanced spinal cord repair. Administration of OM-LV20 increased the number of surviving neuron bodies, as well as the expression levels of brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB). In the acute stage of SCI, OM-LV20 treatment also increased superoxide dismutase and glutathione content but decreased the levels of malonaldehyde and nitric oxide. Thus, OM-LV20 significantly promoted structural and functional recovery of SCI in adult rats by increasing neuronal survival and BDNF and TrkB expression, and thereby regulating the balance of oxidative stress. Based on our knowledge, this research is the first report on the effects of amphibian-derived peptide on the recovery of SCI and our results highlight the potential of peptide OM-LV20 administration in the acceleration of the recovery of SCI.

Tandem molecular self-assembly for selective lung cancer therapy with an increase in efficiency by two orders of magnitude.

In situ self-assembly of prodrug molecules into nanomedicine can elevate the therapeutic efficacy of anticancer medications by enhancing the targeting and enrichment of anticancer drugs at tumor sites. However, the disassembly and biodegradation of nanomedicine after enrichment prevents the further improvement of the efficiency, and avoiding such disassembly and biodegradation remains a challenge. Herein, we rationally designed a tandem molecular self-assembling prodrug that could selectively improve the therapeutic efficacy of HCPT against lung cancer by two orders of magnitude. The tandem molecular self-assembly utilized an elevated level of alkaline phosphatase and reductase in lung cancer cells. The prodrug first self-assembled into nanofibers by alkaline phosphatase catalysis and was internalized more efficiently by lung cancer cells than free HCPT. The resulting nanofiber was next catalyzed by intracellular reductase to form a more hydrophobic nanofiber that prevented the disassembly and biodegradation, which further significantly improved the efficacy of HCPT against lung cancer both in vitro and in vivo.

Correction: Sonodynamic therapy induces oxidative stress, DNA damage and apoptosis in glioma cells.

[This corrects the article DOI: 10.1039/C8RA07099G.].

Bifunctional supramolecular nanofiber inhibits atherosclerosis by enhancing plaque stability and anti-inflammation in apoE-/- mice.

Background and Purpose: Atherosclerosis is vascular disease of chronic inflammation and lipid disorder, which is a major cause of coronary heart disease. Foam cell formation is key progress during the atherosclerosis development. Insulin-like growth factor (IGF)-1 is a growth hormone that plays a crucial role in growth, metabolism, and homeostasis. Previous studies have demonstrated that increase in circulating IGF-1 can reduce atherosclerotic burden. However, active IGF-1 is characterized with poor tissue retention and is at a very low level in circulation system. Therefore, supplementation of exogenous IGF-1 to restore the physiological level is a promising approach to inhibit atherosclerosis. In this study, we develop a self-assembling, anti-inflammatory drug-modified peptide derived from IGF-1 to mimic IGF-1 bioactivity and simultaneously with an anti-inflammatory property for the treatment of atherosclerosis. Methods: ApoE-/- mice were subcutaneously (s.c.) injected with the different hydrogels or natural IGF-1 protein solution per week and simultaneously fed a high-fat diet for 16 weeks. Atherosclerotic lesion formation and stability were assessed after treatment. Moreover, peritoneal macrophage and serum samples were collected to determine lipid profile and inflammatory cytokines. Concurrently, we determined the effect of bifunctional supramolecular nanofibers/hydrogel on cholesterol efflux, foam cell formation, phenotypic transformation of VSMC to macrophage-like cells, and macrophage polarization in vitro or in vivo. Results: Bifunctional supramolecular nanofibers/hydrogel for the treatment of atherosclerosis was formed by a short peptide consisting of a tetrapeptide SSSR from C-region of growth factor IGF-1, an anti-inflammatory drug naproxen (Npx), and a powerful self-assembling D-peptide DFDF. The resulting hydrogel of Npx-DFDFGSSSR (Hydrogel 1, H1) possessed both the anti-inflammatory and IGF-1 mimicking properties, and it efficiently promoted the expression of ABCA1 and ABCG1, thereby significantly reducing cholesterol accumulation in macrophages and preventing foam cell formation. Moreover, H1 markedly inhibited the transformation of vascular smooth muscle cells (VSMCs) into macrophage-like cells which also contributed to foam cell formation. In addition, H1 significantly reduced the inflammatory response in vitro and in vivo. Most importantly, the IGF-1 mimetic peptide showed comparable performance to IGF-1 in vivo and inhibited atherosclerosis by markedly reducing lesion area and enhancing plaque stability. Conclusions: Our study provides a novel supramolecular nanomaterial to inhibit pathological progress of atherosclerosis through regulating cholesterol efflux and inflammation, which may contribute to the development of a promising nanomedicine for the treatment of atherosclerosis in the clinic.

Ultrafast ultrasound imaging of surface acoustic waves induced by laser excitation compared with acoustic radiation force.

Two generation mechanisms-optical perturbation and acoustic radiation force (ARF)-were investigated where high frame rate ultrasound imaging was used to track the propagation of induced SAWs. We compared ARF-induced SAWs with laser-induced SAWs generated by laser beam irradiation of the uniformly absorbing tissue-like viscoelastic phantom, where light was preferentially absorbed at the surface. We also compared the frequency content of SAWs generated by ARF versus pulsed laser light, using the same duration of excitation. Differences in the SAW bandwidth were expected because, in general, laser light can be focused into a smaller area. Finally, we compared wave generation and propagation when the wave's origin was below the surface. We also investigated the relationship between shear wave amplitude and optical fluence. The investigation reported here can potentially extend the applications of laser-induced SAW generation and imaging in life sciences and other applications.

Sonodynamic therapy induces oxidative stress, DNA damage and apoptosis in glioma cells.

Malignant glioma remains one of the most challenging diseases to treat because of the invasive growth of glioma cells and the existence of the blood-brain barrier (BBB), which blocks drug delivery to the brain. New strategies are urgently needed to overcome these shortcomings and improve the outcomes. Ultrasound represents a promising noninvasive and reversible BBB opening approach and the related sonodynamic therapy (SDT) is rapidly emerging. This study aims to explore the ultrasound parameters for BBB opening and the cell killing effect of SDT in human glioma U373 cells by using a recently reported sonosensitizer, sinoporphyrin sodium (DVDMS). The in vitro BBB model indicated that SDT caused a time-dependent permeability increase, which peaked at 2 h post treatment and then recovered gradually. The results of toxicology tests showed significant U373 cell viability loss and apoptosis increase after DVDMS-SDT, accompanied by enhanced cleaved-caspase-3 level and DNA fragmentation, in which reactive oxygen species (ROS) were a major triggering intermediate during DVDMS-SDT. Furthermore, DVDMS-SDT produced DNA damage and the underlying mechanisms were evaluated, in order to provide a fundamental basis for DVDMS-SDT application in glioma therapy. The findings indicated that the DNA molecules could be temporarily regulated by SDT and DNA double-strand breaks (DSBs), which increased the difficulty of cellular self-repair, thus aggravating cell apoptosis and inhibiting glioma cell invasive growth. Therefore, this study supports the use of SDT as an alternative approach for glioma therapy.

Effects of fluoride on morphology, growth, development, and thyroid hormone of Chinese toad (Bufo gargarizans) embryos.

Excessive fluoride in natural water ecosystem has the potential to detrimentally affect amphibians, but little is known of such effects or underlying mechanisms in Bufo gargarizans embryos. In the present study, the effects of fluoride exposure on B. gargarizans embryos were investigated. First, fluoride teratogenic experiment showed that the 9 days EC50 of fluoride on B. gargarizans embryos was 177.62 mg/L. Then, we studied the sublethal effects of fluoride on B. gargarizans embryos at control, 0.7, 4.1, 19.6, 41.9, and 62.7 mg/L fluoride concentration. Malformation, growth, and development of embryos were monitored, and type 2 and 3 iodothyronine deiodinase (Dio2 and Dio3), thyroid hormone receptors (TRα and TRß) mRNA levels were measured. Our results showed the morphological malformations, such as tail curvature (lordosis), edema, cuticularized ciliated cells, and hyperplasia were occurred during fluoride exposure. Growth and development were all inhibited at 19.5, 41.9, and 62.7 mg/L fluoride-treated groups after 9 days' exposure. According to real-time PCR results, exposure to fluoride upregulated Dio3 and TRß mRNA expression and downregulated Dio2 and TRα mRNA level. All above indicated that excessive fluoride could induce morphology malformations, inhibit embryonic growth and development, and disrupt the normal function of maternal thyroid hormone in B. gargarizans embryos. Environ. Mol. Mutagen. 59:123-133, 2018. © 2017 Wiley Periodicals, Inc.

Supersonic transient magnetic resonance elastography for quantitative assessment of tissue elasticity.

Non-invasive, quantitative methods to assess the properties of biological tissues are needed for many therapeutic and tissue engineering applications. Magnetic resonance elastography (MRE) has historically relied on external vibration to generate periodic shear waves. In order to focally assess a biomaterial or to monitor the response to ablative therapy, the interrogation of a specific region of interest by a focused beam is desirable and transient MRE (t-MRE) techniques have previously been developed to accomplish this goal. Also, strategies employing a series of discrete ultrasound pulses directed to increasing depths along a single line-of-sight have been designed to generate a quasi-planar shear wave. Such 'supersonic' excitations have been applied for ultrasound elasticity measurements. The resulting shear wave is higher in amplitude than that generated from a single excitation and the properties of the media are simply visualized and quantified due to the quasi-planar wave geometry and the opportunity to generate the wave at the site of interest. Here for the first time, we extend the application of supersonic methods by developing a protocol for supersonic transient magnetic resonance elastography (sst-MRE) using an MR-guided focused ultrasound system capable of therapeutic ablation. We apply the new protocol to quantify tissue elasticity in vitro using biologically-relevant inclusions and tissue-mimicking phantoms, compare the results with elasticity maps acquired with ultrasound shear wave elasticity imaging (US-SWEI), and validate both methods with mechanical testing. We found that a modified time-of-flight (TOF) method efficiently quantified shear modulus from sst-MRE data, and both the TOF and local inversion methods result in similar maps based on US-SWEI. With a three-pulse excitation, the proposed sst-MRE protocol was capable of visualizing quasi-planar shear waves propagating away from the excitation location and detecting differences in shear modulus of 1 kPa. The techniques demonstrated here have potential application in real-time in vivo lesion detection and monitoring, with particular significance for image-guided interventions.

In vitro characterization and in vivo ultrasound molecular imaging of nucleolin-targeted microbubbles.

Nucleolin (NCL) plays an important role in tumor vascular development. An increased endothelial expression level of NCL has been related to cancer aggressiveness and prognosis and has been detected clinically in advanced tumors. Here, with a peptide targeted to NCL (F3 peptide), we created an NCL-targeted microbubble (MB) and compared the performance of F3-conjugated MBs with non-targeted (NT) MBs both in vitro and in vivo. In an in vitro study, F3-conjugated MBs bound 433 times more than NT MBs to an NCL-expressing cell line, while pretreating cells with 0.5 mM free F3 peptide reduced the binding of F3-conjugated MBs by 84%, n = 4, p < 0.001. We then set out to create a method to extract both the tumor wash-in and wash-out kinetics and tumor accumulation following a single injection of targeted MBs. In order to accomplish this, a series of ultrasound frames (a clip) was recorded at the time of injection and subsequent time points. Each pixel within this clip was analyzed for the minimum intensity projection (MinIP) and average intensity projection (AvgIP). We found that the MinIP robustly demonstrates enhanced accumulation of F3-conjugated MBs over the range of tumor diameters evaluated here (2-8 mm), and the difference between the AvgIP and the MinIP quantifies inflow and kinetics. The inflow and clearance were similar for unbound F3-conjugated MBs, control (non-targeted) and scrambled control agents. Targeted agent accumulation was confirmed by a high amplitude pulse and by a two-dimensional Fourier Transform technique. In summary, F3-conjugated MBs provide a new imaging agent for ultrasound molecular imaging of cancer vasculature, and we have validated metrics to assess performance using low mechanical index strategies that have potential for use in human molecular imaging studies.

Pulsed ultrasonic comb filtering effect and its applications in the measurement of sound velocity and thickness of thin plates.

An analytical and experimental study of the pulsed ultrasonic comb filtering effect is presented in this work intending to provide a fundamental tool for data analysis and phenomenon understanding in pulsed ultrasonics. The basic types of comb filter, feedforward and feedback filters, are numerically simulated and demonstrated. The characteristic features of comb filters, which include the formula for determining the locations of the spectral peaks or notches and the relationship between its temporal characteristics (relative time delay between constituent pulses) and its spectral characteristics (frequency interval between peaks or notches), are theoretically derived. To demonstrate the applicability of the comb filtering effect, it is applied to measuring the sound velocities and thickness of a thin plate sample. It is proven that the comb filtering effect based method not only is capable of accurate measurements, but also has advantages over the conventional time-of-flight based method in thin plate measurements. Furthermore, the principles developed in this study have potential applications in any pulsed ultrasonic cases where the output signal shows comb filter features.

Development of a spherically focused phased array transducer for ultrasonic image-guided hyperthermia.

A 1.5 MHz prolate spheroidal therapeutic array with 128 circular elements was designed to accommodate standard imaging arrays for ultrasonic image-guided hyperthermia. The implementation of this dual-array system integrates real-time therapeutic and imaging functions with a single ultrasound system (Vantage 256, Verasonics). To facilitate applications involving small animal imaging and therapy the array was designed to have a beam depth of field smaller than 3.5 mm and to electronically steer over distances greater than 1 cm in both the axial and lateral directions. In order to achieve the required f number of 0.69, 1-3 piezocomposite modules were mated within the transducer housing. The performance of the prototype array was experimentally evaluated with excellent agreement with numerical simulation. A focal volume (2.70 mm (axial) × 0.65 mm (transverse) × 0.35 mm (transverse)) defined by the -6 dB focal intensity was obtained to address the dimensions needed for small animal therapy. An electronic beam steering range defined by the -3 dB focal peak intensity (17 mm (axial) × 14 mm (transverse) × 12 mm (transverse)) and -8 dB lateral grating lobes (24 mm (axial) × 18 mm (transverse) × 16 mm (transverse)) was achieved. The combined testing of imaging and therapeutic functions confirmed well-controlled local heating generation and imaging in a tissue mimicking phantom. This dual-array implementation offers a practical means to achieve hyperthermia and ablation in small animal models and can be incorporated within protocols for ultrasound-mediated drug delivery.