Erratum: Publisher's Note: "Contrast-enhanced ultrasound tracking of helical propellers with acoustic phase analysis and comparison with color Doppler" [APL Bioeng. 6, 036102 (2022)].

[This corrects the article DOI: 10.1063/5.0097145.].

Contrast-enhanced ultrasound tracking of helical propellers with acoustic phase analysis and comparison with color Doppler.

Medical microrobots (MRs) hold the potential to radically transform several interventional procedures. However, to guarantee therapy success when operating in hard-to-reach body districts, a precise and robust imaging strategy is required for monitoring and controlling MRs in real-time. Ultrasound (US) may represent a powerful technology, but MRs' visibility with US needs to be improved, especially when targeting echogenic tissues. In this context, motions of MRs have been exploited to enhance their contrast, e.g., by Doppler imaging. To exploit a more selective contrast-enhancement mechanism, in this study, we analyze in detail the characteristic motions of one of the most widely adopted MR concepts, i.e., the helical propeller, with a particular focus on its interactions with the backscattered US waves. We combine a kinematic analysis of the propeller 3D motion with an US acoustic phase analysis (APA) performed on the raw radio frequency US data in order to improve imaging and tracking in bio-mimicking environments. We validated our US-APA approach in diverse scenarios, aimed at simulating realistic in vivo conditions, and compared the results to those obtained with standard US Doppler. Overall, our technique provided a precise and stable feedback to visualize and track helical propellers in echogenic tissues (chicken breast), tissue-mimicking phantoms with bifurcated lumina, and in the presence of different motion disturbances (e.g., physiological flows and tissue motions), where standard Doppler showed poor performance. Furthermore, the proposed US-APA technique allowed for real-time estimation of MR velocity, where standard Doppler failed.

A Reusable Thermochromic Phantom for Testing High Intensity Focused Ultrasound Technologies.

High Intensity Focused Ultrasound (HIFU) surgery is a promising technology for the treatment of several pathologies, including cancer. Testing is a fundamental step for verifying treatment efficacy and safety. Ex-vivo tissues represent the most common solution for replicating the properties of human tissues in the HIFU operative scenario. However, they constitute an avoidable waste of resources. Thus, tissue mimicking phantoms have been investigated as a more sustainable and reliable alternative. In this scenario, we proposed a reusable silicone-based thermochromic phantom. It is cost-effective and can be rapidly fabricated. The acoustic, mechanical, and thermal characterization of the phantom are reported. The phantom usability was evaluated with a HIFU robotic platform. 18 different working conditions were tested by varying both sonication power and duration. Temperature and simulated lesions' size were quantified for all testing conditions. An accordance between temperature and lesion dimension trend over time was found. The proposed phantom results a valid alternative to ex-vivo tissues, especially in the early stages of developing novel HIFU treatment paradigms.

A Pilot Study for a Quantitative Evaluation of Acoustic Coupling in US-guided Focused Ultrasound Surgery.

In Ultrasound-guided High Intensity Focused Ultrasound (USgHIFU) surgery, the verification of the acoustic coupling correctness between the HIFU transducer and the patient's body is a fundamental step for an efficient and safe therapy. Nowadays, clinicians perform this check by qualitative inspecting Ultrasound images. The aim of this study is the introduction of an objective index to quantitively evaluate the coupling on the base of the radiofrequency echo signals acquired during a low-energy HIFU shot. The experimental session involved a tissue mimicking phantom and a robotic system composed by a HIFU therapeutic transducer and a 2D confocal Ultrasound probe. 15 different coupling conditions between the phantom and the transducer were tested: in each of them, the maximum absolute value of the Fourier Transform of the echo signals was computed and employed to determine an Acoustic Coupling (AC) coefficient.This metrics showed a sigmoidal trend between AC coefficient and coupling increase. This curve can be employed as a calibration tool to quantitatively assess the correctness of the therapeutic set-up before starting the HIFU treatment.

Ex Vivo Assessment of Multiple Parameters in High Intensity Focused Ultrasound.

High Intensity Focused Ultrasound (HIFU) is a very promising technology for a non-invasive treatment of several pathologies, especially in oncology. However, optimizing the stimulation parameters for better tuning the induced lethal effects (thermal and/or mechanical) in the targeted area is not trivial and it has not been achieved yet. The aim of this study is to present the results of a combined analysis of temperature, acoustic cavitation and lesion geometry induced in ex vivo tissues during HIFU procedures by varying power, sonication time and duty cycle. Temperature rise was analyzed using a thin wire thermocouple embedded in the sonicated tissue; stable and inertial cavitation were measured using a passive cavitation detector (PCD), and lesion volume was assessed using both ultrasound imaging and optical visualization. The obtained results may represent an important guideline for clinical treatments, providing useful nformation for better tuning HIFU operational parameters to induce a desired type of ablation (i.e. thermal, mechanical or a combination of both).

Ultrasound Acoustic Radiation Force Impulse imaging for High Intensity Focused Ultrasound focal spot localization.

Focal spot precise localization highly contributes to the accuracy and safety of High Intensity Focused Ultrasound (HIFU) therapies, and it is usually performed by means of Magnetic Resonance-Acoustic Radiation Force Impulse imaging (MR-ARFI). Acoustic Radiation Force Impulse imaging using ultrasound (US-ARFI) is herein proposed as a valid alternative to MR-ARFI for an accurate and non-destructive detection of the focal spot position during the pre-treatment phase. To this aim, a system composed of a HIFU transducer for generating the acoustic radiation force and a 2D confocal ultrasound probe for measuring the induced micro-displacement have been used. Then, an algorithm based on the Normalized Cross Correlation was implemented for the creation of a displacement map in which the highest displacement area, corresponding to the focal spot region, is unequivocally visualized. The feasibility of the proposed USARFI method for HIFU focal spot localization was successfully demonstrated in a tissue mimicking phantom model.

Motion compensation with skin contact control for high intensity focused ultrasound surgery in moving organs.

High intensity focused ultrasound (HIFU) is an emerging therapeutic solution that enables non-invasive treatment of several pathologies, mainly in oncology. On the other hand, accurate targeting of moving abdominal organs (e.g. liver, kidney, pancreas) is still an open challenge. This paper proposes a novel method to compensate the physiological respiratory motion of organs during HIFU procedures, by exploiting a robotic platform for ultrasound-guided HIFU surgery provided with a therapeutic annular phased array transducer. The proposed method enables us to keep the same contact point between the transducer and the patient's skin during the whole procedure, thus minimizing the modification of the acoustic window during the breathing phases. The motion of the target point is compensated through the rotation of the transducer around a virtual pivot point, while the focal depth is continuously adjusted thanks to the axial electronically steering capabilities of the HIFU transducer. The feasibility of the angular motion compensation strategy has been demonstrated in a simulated respiratory-induced organ motion environment. Based on the experimental results, the proposed method appears to be significantly accurate (i.e. the maximum compensation error is always under 1 mm), thus paving the way for the potential use of this technique for in vivo treatment of moving organs, and therefore enabling a wide use of HIFU in clinics.

Flexible nanofilms coated with aligned piezoelectric microfibers preserve the contractility of cardiomyocytes.

The use of engineered cardiac tissue for high-throughput drug screening/toxicology assessment remains largely unexplored. Here we propose a scaffold that mimics aspects of cardiac extracellular matrix while preserving the contractility of cardiomyocytes. The scaffold is based on a poly(caprolactone) (PCL) nanofilm with magnetic properties (MNF, standing for magnetic nanofilm) coated with a layer of piezoelectric (PIEZO) microfibers of poly(vinylidene fluoride-trifluoroethylene) (MNF+PIEZO). The nanofilm creates a flexible support for cell contraction and the aligned PIEZO microfibers deposited on top of the nanofilm creates conditions for cell alignment and electrical stimulation of the seeded cells. Our results indicate that MNF+PIEZO scaffold promotes rat and human cardiac cell attachment and alignment, maintains the ratio of cell populations overtime, promotes cell-cell communication and metabolic maturation, and preserves cardiomyocyte (CM) contractility for at least 12 days. The engineered cardiac construct showed high toxicity against doxorubicin, a cardiotoxic molecule, and responded to compounds that modulate CM contraction such as epinephrine, propranolol and heptanol.

Magnetically Controlled Endourethral Artificial Urinary Sphincter.

Urinary incontinence is a largely spread disfunction that affects more than 300 million people worldwide. At present, no technological solutions are able to restore continence in a minimally invasive and effective way. In this article the authors report the design, fabrication, and testing of a novel artificial endourethral urinary sphincter able to fully restore continence. The device can be inserted/retracted in a minimally invasive fashion without hospital admission, does not alter the body scheme and can be applied to both women and men. The device core is a unidirectional polymeric valve and a magnetically activated system able to modulate its opening pressure. Bench tests and ex vivo tests on a human cadaver demonstrated that the device is able to fully restore continence and to allow urination when desired. Overall, the proposed system shows a high potential as a technological solution able to restore a normal daily life in patients affected by urinary incontinence.

Tuning acoustic and mechanical properties of materials for ultrasound phantoms and smart substrates for cell cultures.

Materials with tailored acoustic properties are of great interest for both the development of tissue-mimicking phantoms for ultrasound tests and smart scaffolds for ultrasound mediated tissue engineering and regenerative medicine. In this study, we assessed the acoustic properties (speed of sound, acoustic impedance and attenuation coefficient) of three different materials (agarose, polyacrylamide and polydimethylsiloxane) at different concentrations or cross-linking levels and doped with different concentrations of barium titanate ceramic nanoparticles. The selected materials, besides different mechanical features (stiffness from few kPa to 1.6MPa), showed a wide range of acoustic properties (speed of sound from 1022 to 1555m/s, acoustic impedance from 1.02 to 1.67MRayl and attenuation coefficient from 0.2 to 36.5dB/cm), corresponding to ranges in which natural soft tissues can fall. We demonstrated that this knowledge can be used to build tissue-mimicking phantoms for ultrasound-based medical procedures and that the mentioned measurements enable to stimulate cells with a highly controlled ultrasound dose, taking into account the attenuation due to the cell-supporting scaffold. Finally, we were able to correlate for the first time the bioeffect on human fibroblasts, triggered by piezoelectric barium titanate nanoparticles activated by low-intensity pulsed ultrasound, with a precise ultrasound dose delivered. These results may open new avenues for the development of both tissue-mimicking materials for ultrasound phantoms and smart triggerable scaffolds for tissue engineering and regenerative medicine. STATEMENT OF SIGNIFICANCE: This study reports for the first time the results of a systematic acoustic characterization of agarose, polyacrylamide and polydimethylsiloxane at different concentrations and cross-linking extents and doped with different concentrations of barium titanate nanoparticles. These results can be used to build tissue-mimicking phantoms, useful for many ultrasound-based medical procedures, and to fabricate smart materials for stimulating cells with a highly controlled ultrasound dose. Thanks to this knowledge, we correlated for the first time a bioeffect (the proliferation increase) on human fibroblasts, triggered by piezoelectric nanoparticles, with a precise US dose delivered. These results may open new avenues for the development of both tissue-mimicking phantoms and smart triggerable scaffolds for tissue engineering and regenerative medicine.

Speed of sound in rubber-based materials for ultrasonic phantoms.

PURPOSE: In this work we provide measurements of speed of sound (SoS) and acoustic impedance (Z) of some doped/non-doped rubber-based materials dedicated to the development of ultrasound phantoms. These data are expected to be useful for speeding-up the preparation of multi-organ phantoms which show similar echogenicity to real tissues. METHODS: Different silicones (Ecoflex, Dragon-Skin Medium) and polyurethane rubbers with different liquid (glycerol, commercial detergent, N-propanol) and solid (aluminum oxide, graphene, steel, silicon powder) inclusions were prepared. SoS of materials under investigation was measured in an experimental setup and Z was obtained by multiplying the density and the SoS of each material. Finally, an anatomically realistic liver phantom has been fabricated selecting some of the tested materials. RESULTS: SoS and Z evaluation for different rubber materials and formulations are reported. The presence of liquid additives appears to increase the SoS, while solid inclusions generally reduce the SoS. The ultrasound images of realized custom fabricated heterogeneous liver phantom and a real liver show remarkable similarities. CONCLUSIONS: The development of new materials' formulations and the knowledge of acoustic properties, such as speed of sound and acoustic impedance, could improve and speed-up the development of phantoms for simulations of ultrasound medical procedures.

Frontiers of robotic endoscopic capsules: a review.

Digestive diseases are a major burden for society and healthcare systems, and with an aging population, the importance of their effective management will become critical. Healthcare systems worldwide already struggle to insure quality and affordability of healthcare delivery and this will be a significant challenge in the midterm future. Wireless capsule endoscopy (WCE), introduced in 2000 by Given Imaging Ltd., is an example of disruptive technology and represents an attractive alternative to traditional diagnostic techniques. WCE overcomes conventional endoscopy enabling inspection of the digestive system without discomfort or the need for sedation. Thus, it has the advantage of encouraging patients to undergo gastrointestinal (GI) tract examinations and of facilitating mass screening programmes. With the integration of further capabilities based on microrobotics, e.g. active locomotion and embedded therapeutic modules, WCE could become the key-technology for GI diagnosis and treatment. This review presents a research update on WCE and describes the state-of-the-art of current endoscopic devices with a focus on research-oriented robotic capsule endoscopes enabled by microsystem technologies. The article also presents a visionary perspective on WCE potential for screening, diagnostic and therapeutic endoscopic procedures.

Polydimethylsiloxane films doped with NdFeB powder: magnetic characterization and potential applications in biomedical engineering and microrobotics.

This work reports the fabrication, magnetic characterization and controlled navigation of film-shaped microrobots consisting of a polydimethylsiloxane-NdFeB powder composite material. The fabrication process relies on spin-coating deposition, powder orientation and permanent magnetization. Films with different powder concentrations (10 %, 30 %, 50 % and 70 % w/w) were fabricated and characterized in terms of magnetic properties and magnetic navigation performances (by exploiting an electromagnet-based platform). Standardized data are provided, thus enabling the exploitation of these composite materials in a wide range of applications, from MEMS/microrobot development to biomedical systems. Finally, the possibility to microfabricate free-standing polymeric structures and the biocompatibility of the proposed composite materials is demonstrated.

Self-assembly of polydimethylsiloxane structures from 2D to 3D for bio-hybrid actuation.

This work aims to demonstrate the feasibility of a novel approach for the development of 3D self-assembled polydimethylsiloxane structures, to be used as engineered flexible matrices for bio-hybrid actuation. We described the fabrication of engineered bilayers, organized in a 3D architecture by means of a stress-induced rolling membrane technique. Such structures were provided with ad hoc surface topographies, for both cell alignment and cell survival after membrane rolling. We reported the results of advanced finite element model simulations, predicting the system behavior in terms of overall contraction, induced by the contractile activity of muscle cells seeded on the membrane. Then, we tested in vitro the structure with primary cardiomyocytes to evaluate the real bio-actuator contraction, thus validating the simulation results. At a later stage, we provided the samples with a stable fibronectin coating, by covalently binding the protein on the polymer surface, thus enabling long-term cultures with C2C12 skeletal muscle cells, a more controllable cell type. These tests revealed cell viability and alignment on the rolled structures, but also the ability of cells to differentiate and to form multinucleated and oriented myotubes on the polymer surface, also supported by a fibroblast feeder layer. Our results highlighted the possibility of developing 3D rolled PDMS structures, characterized by different mechanical properties, as novel bio-hybrid actuators.

A bioinspired soft manipulator for minimally invasive surgery.

This paper introduces a novel, bioinspired manipulator for minimally invasive surgery (MIS). The manipulator is entirely composed of soft materials, and it has been designed to provide similar motion capabilities as the octopus's arm in order to reach the surgical target while exploiting its whole length to actively interact with the biological structures. The manipulator is composed of two identical modules (each of them can be controlled independently) with multi-directional bending and stiffening capabilities, like an octopus arm. In the authors' previous works, the design of the single module has been addressed. Here a two-module manipulator is presented, with the final aim of demonstrating the enhanced capabilities that such a structure can have in comparison with rigid surgical tools currently employed in MIS. The performances in terms of workspace, stiffening capabilities, and generated forces are characterized through experimental tests. The combination of stiffening capabilities and manipulation tasks is also addressed to confirm the manipulator potential employment in a real surgical scenario.

Magnetically driven microrobotic system for cancer cell manipulation.

Lab-on-a-chip applications, such as single cell manipulation and targeted delivery of chemicals, could greatly benefit from mobile untethered microdevices able to move in fluidic environments by using magnetic fields. In this paper a magnetically driven microrobotic system enabling the controlled locomotion of objects placed at the air/liquid interface is proposed and exploited for cell manipulation. In particular authors report the design, fabrication and testing of a polymeric thin film-based magnetic microrobot (called "FilmBot") used as a support for navigating cancer cells. By finely controlling magnetic film locomotion, it is possible to navigate the cells by exploiting their adhesion to the film without affecting their integrity. Preliminary in vitro tests demonstrated that the magnetic thin film is able to act as substrate for T24 bladder cancer cells without affecting their viability and that film locomotion can be magnetically controlled (with a magnetic field and a gradient of 6 mT and 0.6 T/m, respectively) along specific directions, with a mean speed of about 3 mm/s.

Design, development and characterization of a modular end effector for MIS procedures.

The Minimally Invasive Surgery (MIS) paradigm is well established in modern surgical procedures. Although MIS is successful from the patient's viewpoint, the use of rigid instruments inserted through small skin incisions leads to dexterity constraints and loss of degree of motion. Robotics has been introduced as support for augmenting dexterity during interventions, restoring hand-eye coordination and providing tools with enhanced degrees of motion. However, surgical robots have high costs and large footprint, pushing the research towards the development of modular robots to be used in Naturally Orifice Trans-luminal Endoscopic Surgery (NOTES) procedures. The main need of having simple and cheap tools able to be interchanged during the surgical procedure became crucial. In this paper an innovative modular end-effector based on a compliant soft actuation system able to provide up to 5.78 N gripping forces is presented.

A novel robotic platform for laser-assisted transurethral surgery of the prostate.

Benign prostatic hyperplasia (BPH) is the most common pathology afflicting ageing men. The gold standard for the surgical treatment of BPH is transurethral resection of the prostate. The laser-assisted transurethral surgical treatment of BPH is recently emerging as a valid clinical alternative. Despite this, there are still some issues that hinder the outcome of laser surgery, e.g., distal dexterity is strongly reduced by the current endoscopic instrumentation and contact between laser and prostatic tissue cannot be monitored and optimized. This paper presents a novel robotic platform for laser-assisted transurethral surgery of BPH. The system, designed to be compatible with the traditional endoscopic instrumentation, is composed of a catheter-like robot provided with a fiber optic-based sensing system and a cable-driven actuation mechanism. The sensing system allows contact monitoring between the laser and the hypertrophic tissue. The actuation mechanism allows steering of the laser fiber inside the prostatic urethra of the patient, when contact must be reached. The design of the proposed robotic platform along with its preliminary testing and evaluation is presented in this paper. The actuation mechanism is tested in in vitro experiments to prove laser steering performances according to the clinical requirements. The sensing system is calibrated in experiments aimed to evaluate the capability of discriminating the contact forces, between the laser tip and the prostatic tissue, from the pulling forces exerted on the cables, during laser steering. These results have been validated demonstrating the robot's capability of detecting sub-Newton contact forces even in combination with actuation.

A computer-assisted robotic platform for Focused Ultrasound Surgery: Assessment of high intensity focused ultrasound delivery.

In the last century, medicine showed considerable advancements in terms of new technologies, devices and diagnostic/therapeutic strategies. Those advantages led to a significant reduction of invasiveness and an improvement of surgical outcomes. In this framework, a computer-assisted surgical robotic platform able to perform non-invasive Focused Ultrasound Surgery (FUS) - the FUTURA platform - has the ambitious goal to improve accuracy, safety and flexibility of the treatment, with respect to current FUS procedures. Aim of this work is to present the current implementation of the robotic platform and the preliminary results about high intensity focused ultrasound (HIFU) delivery in in-vitro conditions, under 3D ultrasound identification and monitoring. Tests demonstrated that the average accuracy of the HIFU delivery is lower than 0.7 mm in both X and Y radial directions and 3.7 mm in the axial direction (Z) with respect to the HIFU transducer active surface.

Analysis of a dielectric EAP as smart component for a neonatal respiratory simulator.

Nowadays, respiratory syndrome represents the most common neonatal pathology. Nevertheless, being respiratory assistance in newborns a great challenge for neonatologists and nurses, use of simulation-based training is quickly becoming a valid meaning of clinical education for an optimal therapy outcome. Commercially available simulators, are, however, not able to represent complex breathing patterns and to evaluate specific alterations. The purpose of this work has been to develop a smart, lightweight, compliant system with variable rigidity able to replicate the anatomical behavior of the neonatal lung, with the final aim to integrate such system into an innovative mechatronic simulator device. A smart material based-system has been proposed and validated: Dielectric Electro Active Polymers (DEAP), coupled to a purposely shaped silicone camera, has been investigated as active element for a compliance change simulator able to replicate both physiological and pathological lung properties. Two different tests have been performed by using a bi-components camera (silicone shape coupled to PolyPower film) both as an isolated system and connected to an infant ventilator. By means of a pressure sensor held on the silicon structure, pressure values have been collected and compared for active and passive PolyPower working configuration. The obtained results confirm a slight pressure decrease in active configuration, that is in agreement with the film stiffness reduction under activation and demonstrates the real potentiality of DEAP for active volume changing of the proposed system.