Development and evaluation of a titanium-based planar ultrasonic scalpel for precision surgery.

This paper introduces a titanium-based planar ultrasonic microscalpel. The concept of silicon-based planar ultrasonic transducers has already been proven, but they are not yet suitable for clinical use due to material failure. The main objective of this work was to develop a smaller, lighter, and more cost-effective ultrasonic scalpel that could be used as an alternative or supplementary device to current surgical instruments. Various prototypes were fabricated and characterized, differing in bonding by three epoxy adhesives and two solder pastes as well as three variations in tip design. The instruments were designed to operate in the frequency range of commercial instruments and to generate a longitudinal displacement amplitude. The electro-mechanical characterization through impedance analysis and vibration measurements was complemented by an in vitro cutting trial and an acute in vivo animal experiment in comparison to commercial ultrasonic and electrosurgical devices. The operating frequency was around 40 kHz and 48 kHz depending on whether matched or unmatched operation was used. Unmatched operation turned out to be more suitable, achieving displacement amplitudes of 25.3 µm and associated velocity amplitudes of up to 7.9 m/s at an electrical power of 10.2 W. The cutting ability was demonstrated in vivo by successful dissection even under anticoagulation. The geometry of the instrument tip was found to have a major influence on cutting performance by affecting the resonance behaviour and tissue penetration.

Extended high-frequency bone conduction audiometry Calibration of bone conductor transducers in the conventional and extended high-frequency range.

OBJECTIVE: To monitor ototoxicity, air conduction (AC) extended high frequency (EHF) thresholds can be measured up to 16 kHz. However, conductive hearing loss might influence these results. This is unfortunate because the EHF thresholds are important to follow the impact of ototoxic medication during therapy. Therefore a suitable bone conduction (BC) transducer and norm values for EHF BC measurements are needed. DESIGN: In this study three different BC transducers were used: the B71 (Radioear), the KH70 (Präcitronic), and the KLH96 (Westra). Hearing thresholds were measured from 0.125 to 16 kHz using AC transducers (Telephonics TDH39, Sennheiser HDA200), and BC thresholds from 0.25 to 8 kHz with the B71, and from 0.25 to 16 kHz with the KLH96 and KH70. STUDY SAMPLE: 60 ears of 30 normal hearing subjects were measured. RESULTS: The KLH96 showed the highest output for the high frequencies, and distortion measurements were similar to the KH70. The results show that EHF measurements are possible using the KLH96 and KH70 bone conductors. CONCLUSION: EHF BC measurements are reliable when using the KLH96 and KH70 bone conductors. The extended force sensitivity of the used artificial mastoid should be determined for a proper EHF BC calibration.

Evaluation of the dual-frequency transducer for controlling thermal ablation morphology using frequency shift keying signal.

PURPOSE: The catheter-based ultrasound (CBUS) can reach the target tissue directly and achieve rapid treatment. The frequency shift keying (FSK) signal is proposed to regulate and evaluate tumor ablation by a miniaturized dual-frequency transducer. METHODS: A dual-frequency transducer prototype (3 × 7 × 0.4 mm) was designed and fabricated for the CBUS applicator (OD: 3.8 mm) based on the fundamental frequency of 5.21 MHz and the third harmonic frequency of 16.88 MHz. Then, the acoustic fields and temperature field distributions using the FSK signals (with 0, 25, 50, 75, and 100% third harmonic frequency duty ratios) were simulated by finite element analysis. Finally, tissue ablation and temperature monitoring were performed in phantom and ex vivo tissue, respectively. RESULTS: At the same input electrical power (20 W), the output acoustic power of the fundamental frequency of the transducer was 10.03 W (electroacoustic efficiencies: 50.1%), and that of the third harmonic frequency was 6.19 W (30.6%). As the third harmonic frequency duty ratios increased, the shape of thermal lesions varied from strip to droplet in simulated and phantom experimental results. The same trend was observed in ex vivo tests. CONCLUSION: Dual-frequency transducers excited by the FSK signal can control the morphology of lesions. SIGNIFICANCE: The acoustic power deposition of CBUS was optimized to achieve precise ablation.

Calibration of Ultrasonic Transducer Based on Ultrasonic Logging Instrument for Shaft Sinking.

High-precision logging equipment is critical for measuring the borehole diameter and drilling offset in coal mining and petroleum drilling. We propose a module composition and positioning principle for an ultrasonic transducer based on an ultrasonic logging instrument for shaft sinking by drilling (ULISSD) for calculating the reflection distance. The logging distance, which is the primary performance index of a logging system, is determined by using the self-reception sensitivity and error of the ultrasonic transducer in a downhole system. To measure the error between the piezoelectric element of the transducer and the rubber seal of the borehole logging system, we developed an ultrasonic-transducer error-calibration device and a calibration method for a central-air-return-shaft-drilling project. This calibration device can eliminate the inherent error of the transducer and calculate the rate of propagation with high accuracy. The measurement error is reduced by approximately 1.5 mm; thus, the ULISSD measurement accuracy can be effectively improved in central-air-return-shaft drilling.

Dark Current Modeling for a Polyimide-Amorphous Lead Oxide-Based Direct Conversion X-ray Detector.

The reduction of the dark current (DC) to a tolerable level in amorphous selenium (a-Se) X-ray photoconductors was one of the key factors that led to the successful commercialization of a-Se-based direct conversion flat panel X-ray imagers (FPXIs) and their widespread clinical use. Here, we discuss the origin of DC in another X-ray photoconductive structure that utilizes amorphous lead oxide (a-PbO) as an X-ray-to-charge transducer and polyimide (PI) as a blocking layer. The transient DC in a PI/a-PbO detector is measured at different applied electric fields (5-20 V/µm). The experimental results are used to develop a theoretical model describing the electric field-dependent transient behavior of DC. The results of the DC kinetics modeling show that the DC, shortly after the bias application, is primarily controlled by the injection of holes from the positively biased electrode and gradually decays with time to a steady-state value. DC decays by the overarching mechanism of an electric field redistribution, caused by the accumulation of trapped holes in deep localized states within the bulk of PI. Thermal generation and subsequent multiple-trapping (MT) controlled transport of holes within the a-PbO layer governs the steady-state value at all the applied fields investigated here, except for the largest applied field of 20 V/µm. This suggests that a thicker layer of PI would be more optimal to suppress DC in the PI/a-PbO detector presented here. The model can be used to find an approximate optimal thickness of PI for future iterations of PI/a-PbO detectors without the need for time and labor-intensive experimental trial and error. In addition, we show that accounting for the field-induced charge carrier release from traps, enhanced by charge hopping transitions between the traps, yields an excellent fit between the experimental and simulated results, thus, clarifying the dynamic process of reaching a steady-state occupancy level of the deep localized states in the PI. Practically, the electric field redistribution causes the internal field to increase in magnitude in the a-PbO layer, thus improving charge collection efficiency and temporal performance over time, as confirmed by experimental results. The electric field redistribution can be implemented as a warm-up time for a-PbO-based detectors.

Exploring Low-Loss Surface Acoustic Wave Devices on Heterogeneous Substrates.

This article presents shear horizontal surface acoustic wave (SH-SAW) devices with excellent temperature stability and low loss on ultrathin Y42-cut lithium tantalate film on sapphire substrate (LiTaO3-on-sapphire, LTOS). The demonstrated resonators exhibit scalable resonances from 1.76 to 3.17 GHz, effective electromechanical coupling coefficients between 5.1% and 7.6%, and quality factors (Bode-Q) between 419 and 3019. The filter with a center frequency of 3.26 GHz features a suppressed spurious passband, a 3-dB fractional bandwidth (FBW) of 3%, and a minimum insertion loss (IL) of 2.39 dB. In addition, coplanar waveguides (CPWs) and SH-SAW resonators built on LTOS and LiTaO3-on-insulator (LTOI) substrates were compared over a temperature range of 25 °C-150 °C. Due to the extremely high resistivity of the sapphire and the excellent thermal stability of the LiTaO3/sapphire interface, the IL of the CPW and the impedance ratio (in addition to Bode-Q) of the SH-SAW on the LTOS are maintained well even at 150 °C, while those on the LTOI seriously deteriorate. Of these, the impedance attenuation of LTOS-SAW at the antiresonant frequency is only 3.7 dB at 150 °C, whereas that of LTOI-SAW reaches 9.6 dB, demonstrating excellent temperature stability of the LTOS substrate's radio frequency (RF) performance. Overall, the SAW devices on LTOS substrates show great potential for temperature-sensitive and low-loss applications in RF wireless communications.

Feasibility of ultrasound tomography-guided localized mild hyperthermia using a ring transducer: Ex vivo and in silico studies.

BACKGROUND: As of 2022, breast cancer continues to be the most diagnosed cancer worldwide. This problem persists within the United States as well, as the American Cancer Society has reported that ∼12.5% of women will be diagnosed with invasive breast cancer over the course of their lifetime. Therefore, a clinical need continues to exist to address this disease from a treatment and therapeutic perspective. Current treatments for breast cancer and cancers more broadly include surgery, radiation, and chemotherapy. Adjuncts to these methods have been developed to improve the clinical outcomes for patients. One such adjunctive treatment is mild hyperthermia therapy (MHTh), which has been shown to be successful in the treatment of cancers by increasing effectiveness and reduced dosage requirements for radiation and chemotherapies. MHTh-assisted treatments can be performed with invasive thermal devices, noninvasive microwave induction, heating and recirculation of extracted patient blood, or whole-body hyperthermia with hot blankets. PURPOSE: One common method for inducing MHTh is by using microwave for heat induction and magnetic resonance imaging for temperature monitoring. However, this leads to a complex, expensive, and inaccessible therapy platform. Therefore, in this work we aim to show the feasibility of a novel all-acoustic MHTh system that uses focused ultrasound (US) to induce heating while also using US tomography (UST) to provide temperature estimates. Changes in sound speed (SS) have been shown to be strongly correlated with temperature changes and can therefore be used to indirectly monitor heating throughout the therapy. Additionally, these SS estimates allow for heterogeneous SS-corrected phase delays when heating complex and heterogeneous tissue structures. METHODS: Feasibility to induce localized heat in tissue was investigated in silico with a simulated breast model, including an embedded tumor using continuous wave US. Here, both heterogenous acoustic and thermal properties were modeled in addition to blood perfusion. We further demonstrate, with ex vivo tissue phantoms, the feasibility of using ring-based UST to monitor temperature by tracking changes in SS. Two phantoms (lamb tissue and human abdominal fat) with latex tubes containing varied temperature flowing water were imaged. The measured SS of the water at each temperature were compared against values that are reported in literature. RESULTS: Results from ex vivo tissue studies indicate successful tracking of temperature under various phantom configurations and ranges of water temperature. The results of in silico studies show that the proposed system can heat an acoustically and thermally heterogenous breast model to the clinically relevant temperature of 42°C while accounting for a reasonable time needed to image the current cross section (200 ms). Further, we have performed an initial in silico study demonstrating the feasibility of adjusting the transmit waveform frequency to modify the effective heating height at the focused region. Lastly, we have shown in a simpler 2D breast model that MHTh level temperatures can be maintained by adjusting the transmit pressure intensity of the US ring. CONCLUSIONS: This work has demonstrated the feasibility of using a 256-element ring array transducer for temperature monitoring; however, future work will investigate minimizing the difference between measured SS and the values shown in literature. A hypothesis attributes this bias to potential volumetric average artifacts from the ray-based SS inversion algorithm that was used, and that moving to a waveform-based SS inversion algorithm will greatly improve the SS estimates. Additionally, we have shown that an all-acoustic MHTh system is feasible via in silico studies. These studies have indicated that the proposed system can heat a tumor within a heterogenous breast model to 42°C within a narrow time frame. This holds great promise for increasing the accessibility and reducing the complexity of a future all-acoustic MHTh system.

Dedicated Photoacoustic Imaging Instrument for Human Periphery Blood Vessels: A New Paradigm for Understanding the Vascular Health.

A novel photoacoustic imaging system based on a semi-ring transducer array is proposed to image peripheral blood vessels. The system's penetration depth is deep (∼15 mm) with high spatial (∼200 µm) and temporal resolution. In a clinical study, volumetric photoacoustic data of limbs were obtained within the 50s (for a FOV of 15 cm × 4 cm) with the volunteers in the standing and sitting posture. Compared to the previous studies, our system has many advantages, including (1) Larger field of view; (2) Finer elevational and in-plane resolutions; (3) Enhanced 3D visualization of peripheral vascular networks; (4) Compact size and better portability. The 3D visualization and cross-sectional images of five healthy volunteers clearly show the vascular network and the system's ability to image submillimeter blood vessels. This high-resolution PA system has great potential for imaging human periphery vasculatures noninvasively in clinical research.

Deployable ultrasound applicators for endoluminal delivery of volumetric hyperthermia.

PURPOSE: To investigate the design of an endoluminal deployable ultrasound applicator for delivering volumetric hyperthermia to deep tissue sites as a possible adjunct to radiation and chemotherapy. METHOD: This study considers an ultrasound applicator consisting of two tubular transducers situated at the end of a catheter assembly, encased within a distensible conical shaped balloon-based reflector that redirects acoustic energy distally into the tissue. The applicator assembly can be inserted endoluminally or laparoscopically in a compact form and expanded after delivery to the target site. Comprehensive acoustic and biothermal simulations and parametric studies were employed in generalized 3D and patient-specific pancreatic head and body tumor models to characterize the acoustic performance and evaluate heating capabilities of the applicator by investigating the device at a range of operating frequencies, tissue acoustic and thermal properties, transducer configurations, power modulation, applicator positioning, and by analyzing the resultant 40, 41, and 43 °C isothermal volumes and penetration depth of the heating volume. Intensity distributions and volumetric temperature contours were calculated to define moderate hyperthermia boundaries. RESULTS: Parametric studies demonstrated the frequency selection to control volume and depth of therapeutic heating from 62 to 22 cm3 and 4 to 2.6 cm as frequency ranges from 1 MHz to 4.7 MHz, respectively. Width of the heating profile tracks closely with the aperture. Water cooling within the reflector balloon was effective in controlling temperature to 37 °C maximum within the luminal wall. Patient-specific studies indicated that applicators with extended OD in the range of 3.6-6.2 cm with 0.5-1 cm long and 1 cm OD transducers can heat volumes of 1.1-7 cm3, 3-26 cm3, and 3.3-37.4 cm3 of pancreatic body and head tumors above 43, 41, and 40 °C, respectively. CONCLUSION: In silico studies demonstrated the feasibility of combining endoluminal ultrasound with an integrated expandable balloon reflector for delivering volumetric hyperthermia in regions adjacent to body lumens and cavities.

[Full-information Force Sensor for Pulse Condition Diagnose].

According to the collection principles and characteristics of the pulse physiological signals of traditional Chinese medicine, combined with the international standard requirements of the pulse graph force transducer (ISO 19614:2017-05), a special force sensor component that can be used for a complete and objective collection of pulse signals has been developed, this sensor meets the requirements of industrialization. The sensor can measure the pulse amplitude and width signals of the cunpart of the human body. In addition, three sensors can be placed at the cun, guan, chi part at the same time, so that the "three body parts and nine pulse-taking sites" can be realized synchronously. After the sensor has been verified, the results meet the relevant requirements of international standard. The consistency of the result can be reached to 92.3% compared with the diagnosis result of clinical TCM experts.

Full-information Force Sensor for Pulse Condition Diagnose / 中国医疗器械杂志

According to the collection principles and characteristics of the pulse physiological signals of traditional Chinese medicine, combined with the international standard requirements of the pulse graph force transducer (ISO 19614:2017-05), a special force sensor component that can be used for a complete and objective collection of pulse signals has been developed, this sensor meets the requirements of industrialization. The sensor can measure the pulse amplitude and width signals of the cunpart of the human body. In addition, three sensors can be placed at the cun, guan, chi part at the same time, so that the "three body parts and nine pulse-taking sites" can be realized synchronously. After the sensor has been verified, the results meet the relevant requirements of international standard. The consistency of the result can be reached to 92.3% compared with the diagnosis result of clinical TCM experts.

Combined radiotherapy and concurrent tumor treating fields (TTFields) for glioblastoma: Dosimetric consequences on non-coplanar IMRT as initial results from a phase I trial.

BACKGROUND: Glioblastoma is a rapidly proliferating tumor. Patients bear an inferior prognosis with a median survival time of 14-16 months. Proliferation and repopulation are a major resistance promoting factor for conventionally fractionated radiotherapy. Tumor-Treating-Fields (TTFields) are an antimitotic modality applying low-intensity (1-3 V/cm), intermediate-frequency (100-300 kHz) alternating electric-fields. More recently interference of TTFields with DNA-damage-repair and synergistic effects with radiotherapy were reported in the preclinical setting. This study aims at examining the dosimetric consequences of TTFields applied during the course of radiochemotherapy. METHODS: Cone-beam-computed-tomography (CBCT)-data from the first seven patients of the PriCoTTF-phase-I-trial were used in a predefined way for dosimetric verification and dose-accumulation of the non-coplanar-intensity-modulated-radiotherapy (IMRT)-treatment-plans as well as geometric analysis of the transducer-arrays by which TTFields are applied throughout the course of treatment. Transducer-array-position and contours were obtained from the low-dose CBCT's routinely made for image-guidance. Material-composition of the electrodes was determined and a respective Hounsfield-unit was assigned to the electrodes. After 6D-fusion with the planning-CT, the dose-distribution was recalculated using a Boltzmann-equation-solver (Acuros XB) and a Monte-Carlo-dose-calculation-engine. RESULTS: Overdosage in the scalp in comparison to the treatment plan without electrodes stayed below 8.5% of the prescribed dose in the first 2 mm below and also in deeper layers outside 1cm2 at highest dose as obtained from dose-volume-histogram comparisons. In the clinical target volume (CTV), underdosage was limited to 2.0% due to dose attenuation by the electrodes in terms of D95 and the effective-uniform-dose. Principal-component-analysis (PCA) showed that the first principal-position-component of the variation of repeated array-placement in the direction of the largest variations and the perpendicular second-component spanning a tangential plane on the skull had a standard deviation of 1.06 cm, 1.23 cm, 0.96 cm, and 1.11 cm for the frontal, occipital, left and right arrays for the first and 0.70 cm, 0.71 cm, 0.79 cm, and 0.68 cm, respectively for the second-principal-component. The variations did not differ from patient-to-patient (p > 0.8, Kruskal-Wallis-tests). This motion led to a diminution of the dosimetric effects of the electrodes. CONCLUSION: From a dosimetric point of view, dose deviations in the CTV due to transducer-arrays were not clinically significant in the first 7 patients and confirmed feasibility of combined adjuvant radiochemotherapy and concurrent TTFields. PriCoTTF Trial: A phase I/II trial of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma. DRKS-ID: DRKS00016667. Date of Registration in DRKS: 2019/02/26. Investigator Sponsored/Initiated Trial (IST/IIT): yes. Ethics Approval/Approval of the Ethics Committee: Approved. (leading) Ethics Committee Nr.: 18-8316-MF, Ethik-Kommission der Medizinischen. Fakultät der Universität Duisburg-Essen. EUDAMED-No. (for studies acc. to Medical Devices act): CIV-18-08-025247.

GHz Ultrasonic Chip-Scale Device Induces Ion Channel Stimulation in Human Neural Cells.

Emergent trends in the device development for neural prosthetics have focused on establishing stimulus localization, improving longevity through immune compatibility, reducing energy re-quirements, and embedding active control in the devices. Ultrasound stimulation can single-handedly address several of these challenges. Ultrasonic stimulus of neurons has been studied extensively from 100 kHz to 10 MHz, with high penetration but less localization. In this paper, a chip-scale device consisting of piezoelectric Aluminum Nitride ultrasonic transducers was engineered to deliver gigahertz (GHz) ultrasonic stimulus to the human neural cells. These devices provide a path towards complementary metal oxide semiconductor (CMOS) integration towards fully controllable neural devices. At GHz frequencies, ultrasonic wavelengths in water are a few microns and have an absorption depth of 10-20 µm. This confinement of energy can be used to control stimulation volume within a single neuron. This paper is the first proof-of-concept study to demonstrate that GHz ultrasound can stimulate neurons in vitro. By utilizing optical calcium imaging, which records calcium ion flux indicating occurrence of an action potential, this paper demonstrates that an application of a nontoxic dosage of GHz ultrasonic waves [Formula: see text] caused an average normalized fluorescence intensity recordings >1.40 for the calcium transients. Electrical effects due to chip-scale ultrasound delivery was discounted as the sole mechanism in stimulation, with effects tested at α = 0.01 statistical significance amongst all intensities and con-trol groups. Ionic transients recorded optically were confirmed to be mediated by ion channels and experimental data suggests an insignificant thermal contributions to stimulation, with a predicted increase of 0.03 oC for [Formula: see text] This paper paves the experimental framework to further explore chip-scale axon and neuron specific neural stimulation, with future applications in neural prosthetics, chip scale neural engineering, and extensions to different tissue and cell types.

A Soft Housing Needle Ultrasonic Transducer for Focal Stimulation to Small Animal Brain.

Conventional acoustic brain stimulators that transmit low frequency (< 1 MHz) bursts in a pulse repetition frequency with large-sized transducers are barely compatible with small animal models because of broad beam width, possible stimulation of auditory pathways, and blocking of field-of-view for in vivo imaging of brain hemodynamics and neuronal activities. A miniaturized ultrasound stimulator with higher stimulation frequencies will enhance spatial specificity and enable simultaneous eliciting and monitoring brain activities. Moreover, the use of non-periodic pulse sequences may reduce unintended stimulations on auditory cortex, which might be caused by transmitting periodic bursting patterns. A platform for ultrasound brain stimulations for small animal models, including a soft housing 10 MHz needle transducer with a beam size of 680 µm, random transmission sequences, and optical imaging systems, was developed. The platform can deliver focal stimulations to the visual and barrel cortex of mice and monitor subsequent brain activities. The stimulated sites in both the visual and primary somatosensory cortices (S1) showed approximately two to three times higher neuronal calcium signal levels than those in peripheral regions. Activities in the auditory cortex were elicited by periodic sequence stimulation, while it was reduced by 67 and 35% for barrel and visual cortex stimulation with the random sequence, respectively.

Nanoplatforms with Remarkably Enhanced Absorption in the Second Biological Window for Effective Tumor Thermoradiotherapy.

Thermoradiotherapy acts as an important antitumor modality because heating can increase the blood flow and improve the oxygen level in tumor, thus remission of hypoxia-associated resistance for radiotherapy (RT). However, most agents for thermoradiotherapy are used either in the first near-infrared biological window or low photothermal conversion efficiency. Here, a facile method to prepare CuxS/Au nanocomposites via reduction methods from CuxS templates in mild synthetic conditions (i.e., aqueous solution and room temperature) is presented. After the growth of Au nanoparticles, the CuxS/Au nanocomposites have greater benefits for photothermal efficiency than that of CuxS nanoparticles due to the enhanced absorbance in the second near-infrared window. Moreover, biocompatibility and stability of these nanocomposites are greatly improved by lipoic acid poly(ethylene glycol). After the tumors were irradiated with a 1064 nm laser, their oxygenation status is subsequently improved, and the combination of photothermal therapy and RT achieves remarkable synergistic therapeutic effects. This work provides a novel idea to design a new-generation nanomedicine for tumor thermoradiotherapy.

Multifrequency Analysis of Single Inductive Coil Measurements Across a Gel Phantom Simulation of Internal Bleeding in the Brain.

The present study is part of an ongoing effort to develop a simple diagnostic technology for detecting internal bleeding in the brain, which can be used in lieu or in support of medical imaging and thereby reduce the cost of diagnostics in general, and in particular, would make diagnostics accessible to economically disadvantaged populations. The study deals with a single coil inductive device to be used for detecting cerebral hemorrhage. It presents a first-order experimental study that examines the predictions of our recently published theoretical study. The experimental model employs a homogeneous cylindrical phantom in which internal head bleeding was simulated by way of a fluid inclusion. We measured the changes in amplitude and phase across the coil with a network vector analyzer as a function of frequency (100-1,000 MHz), volume of blood simulating fluid, and the site of the fluid injection. We have developed a new mathematical model to statistically analyze the complex data produced in this experiment. We determined that the resolution for the fluid volume increase following fluid injection is strongly dependent on frequency as well as the location of liquid accumulation. The experimental data obtained in this study supports the predictions of our previous theoretical study, and the statistical analysis shows that the simple single coil device is sensitive enough to detect changes due to fluid volume alteration of two milliliters. Bioelectromagnetics. 2020;41:21-33 © 2019 Bioelectromagnetics Society.

Temperature control in TTFields therapy of GBM: impact on the duty cycle and tissue temperature.

In TTFields therapy, Optune® is used to deliver the electric field to the tumor via 4 transducer arrays. This device monitors the temperature of the transducers and reduces the current whenever a transducer reaches 41 °C. Our aim is to quantify Optune's duty cycle and to predict the steady-state temperature distribution in the head during GBM treatment. We used a realistic head model and the finite element method to solve Pennes equation and to simulate how Optune operates considering that current reduces to zero when the thermal limit is reached. The thermal impact was evaluated considering the maximum temperature reached by each tissue and using the CEM 43 °C metric. We observed that Optune switches the current on and off intermittently. In our model, one transducer reached the temperature limit quicker than the others and consequently it was the one that controlled current injection. This led to different duty cycles for the anterior-posterior and left-right array pairs. The thermal analysis indicated that the highest temperature in the model, 41.7 °C, was reached on the scalp under a transducer. However, TTFields may lead to significant changes only at the brain level such as BBB permeability increase, cerebral blood flow variation and changes in the concentration of some neurotransmitters. The duty cycle may be increased, e.g. by controlling the current at the transducer level. These predictions should be validated by comparison with experimental data and reconciled with the lack of evidence of thermal impact in clinical trials.

Functionalized erythrocyte-derived optical nanoparticles to target ephrin-B2 ligands.

Over- or under-expression of erythropoietin-production human hepatocellular receptors (Eph) and their ligands are associated with various diseases. Therefore, these molecular biomarkers can potentially be used as binding targets for the delivery of therapeutic and/or imaging agents to cells characterized by such irregular expressions. We have engineered nanoparticles derived from erythrocytes and doped with the near-infrared (NIR) FDA-approved dye, indocyanine green. We refer to these nanoparticles as NIR erythrocyte-derived transducers (NETs). We functionalized the NETs with the ligand-binding domain of a particular Eph receptor, EphB1, to target the genetically modified human dermal microvascular endothelial cells (hDMVECs) with coexpression of EphB1 receptor and its ligand ephrin-B2. This cell model mimics the pathological phenotypes of lesional endothelial cells (ECs) in port wine stains (PWSs). Our quantitative fluorescence imaging results demonstrate that such functionalized NETs bind to the ephrin-B2 ligands on these hDMVECs in a dose-dependent manner that varies sigmoidally with the number density of the particles. These nanoparticles may potentially serve as agents to target PWS lesional ECs and other diseases characterized with over-expression of Eph receptors or their associated ligands to mediate phototherapy.

RESTORE-Cognitive functional therapy with or without movement sensor biofeedback versus usual care for chronic, disabling low back pain: study protocol for a randomised controlled trial.

INTRODUCTION: Low back pain (LBP) is the leading cause of disability globally and its costs exceed those of cancer and diabetes combined. Recent evidence suggests that individualised cognitive and movement rehabilitation combined with lifestyle advice (cognitive functional therapy (CFT)) may produce larger and more sustained effects than traditional approaches, and movement sensor biofeedback may enhance outcomes. Therefore, this three-arm randomised controlled trial (RCT) aims to compare the clinical effectiveness and economic efficiency of individualised CFT delivered with or without movement sensor biofeedback, with usual care for patients with chronic, disabling LBP. METHODS AND ANALYSIS: Pragmatic, three-arm, randomised, parallel group, superiority RCT comparing usual care (n=164) with CFT (n=164) and CFT-plus-movement-sensor-biofeedback (n=164). Inclusion criteria include: adults with a current episode of LBP >3 months; sought primary care ≥6 weeks ago for this episode of LBP; average LBP intensity of ≥4 (0-10 scale); at least moderate pain-related interference with work or daily activities. The CFT-only and CFT-plus-movement-sensor-biofeedback participants will receive seven treatment sessions over 12 weeks plus a 'booster' session at 26 weeks. All participants will be assessed at baseline, 3, 6, 13, 26, 40 and 52 weeks. The primary outcome is pain-related physical activity limitation (Roland Morris Disability Questionnaire). Linear mixed models will be used to assess the effect of treatment on physical activity limitation across all time points, with the primary comparison being a formal test of adjusted mean differences between groups at 13 weeks. For the economic (cost-utility) analysis, the primary outcome of clinical effect will be quality-adjusted life years measured across the 12-month follow-up using the EuroQol EQ-5D-5L . ETHICS AND DISSEMINATION: Approved by Curtin University Human Research Ethics Committee (HRE2018-0062, 6 Feb 2018). Study findings will be disseminated through publication in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12618001396213).

The dielectric properties of skin and their influence on the delivery of tumor treating fields to the torso: a study combining in vivo measurements with numerical simulations.

The study of the dielectric properties of tissues plays a key role in understanding the interaction between electromagnetic energy and the human body, for safety assessments of human exposure to electromagnetic fields, as well as for numerous biomedical applications such as tumor treating fields (TTFields). TTFields are low-intensity alternating electric fields in the 100-500 kHz frequency range, which have an antimitotic effect on cancerous cells. TTFields are delivered to the body through pairs of transducer arrays placed on a patient's skin in close proximity to the tumor. Therefore, it is essential to understand how the skin's dielectric properties affect TTFields delivery in clinical settings. In this paper, we present a study combining in vivo measurements with numerical simulations that elucidate how different layers of the skin influence TTFields distribution in the body. The dielectric properties of the skin were measured on volunteers using a setup that ensured skin conditions resembled those when TTFields are delivered to patients. The measured properties were incorporated into a realistic human computational phantom and delivery of TTFields to the phantom's abdomen was simulated. The total impedance of the simulated model was within the mid-range of impedance values measured in patients with pancreatic cancer treated with TTFields. A computational study investigating model sensitivity to the dielectric properties of the skin and subcutaneous adipose tissue (SAT) showed that when skin conductivity increased above a threshold value, the total impedance of the model was largely insensitive to changes in the conductivity of these tissues. Furthermore, for a given current, the field intensity within the internal organs was mostly unaffected by skin properties but was highly sensitive to the conductivity of the organ itself. This study provides a new insight into the role of skin in determining the distribution of TTFields within the body.