Andrea Cafarelli

Advanced Micro-Nano-Bio Systems for Future Targeted Therapies

This article aims at highlighting the most recent and promising research trends, the open challenges and the possible routes to follow in the field of targeted therapy. A highly interdisciplinary viewpoint has been used, trying to evidence and discuss the different opportunities deriving from recent evolutions of nanotechnology, polymer science, robotics and biotechnology. The most used vectors for nanomedicine applications are described, together with the different action strategies reported in the literature, such as passive targeting, site-directed targeting and remotely triggerable drug delivery. Special emphasis is given to magnetically triggered systems and ultrasound-responsive materials, identified as the most promising paradigms. Key competences and system integration strategies derived from robotics are also introduced, focusing the attention on the crucial issue of achieving high controllability of the vector at the microand nano-scale. Finally, biocomponents are described, highlighting their potential as functional sensing elements or smart mechanisms to be integrated on board of advanced micro-nano therapeutic devices. The conclusion aims at depicting the importance of novel and improved targeted therapy strategies, to be coupled with the emerging world of predicting and personalized medicine. To this aim, a real merging of skills and approaches, derived from the aforementioned research fields, is recognized as highly desirable and rich of opportunities.

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

AbstractPurposeIn 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.MethodsDifferent 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.ResultsSoS 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.ConclusionsThe 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.SommarioScopoIn questo lavoro sono riportati i valori di velocità del suono (SoS) e impedenza acustica (Z) di alcune gomme nella loro formulazione originale o con l’aggiunta di sostanze droganti (liquide o solide). Le gomme analizzate sono pensate per lo sviluppo di fantocci (phantom) per tecniche ad ultrasuoni. La conoscenza di questi dati può essere utile per accelerare la preparazione di phantom multi-organo che mostrano ecogenicità simili a quelle dei tessuti reali.MetodiDifferenti siliconi (Ecoflex, Dragon-Skin Medium) e gomme poliuretaniche con diversi dopaggi liquidi (Glicerolo, detergente commerciale, N-Propanolo) e inclusioni solide (Ossido di Alluminio, Grafene, Acciaio, Polvere di Silicio) sono stati preparati. La velocità del suono è stata misurata in un banco di prova sperimentale e l’impedenza acustica (Z) è stata ottenuta moltiplicando la densità e la SoS di ogni materiale. Infine, è stato fabbricato un phantom anatomicamente realistico, inteso a riprodurre un fegato ed alcune sue caratteristiche, selezionando alcuni dei materiali testati.RisultatiLe misure della SoS e di Z di diverse gomme a differenti formulazioni sono riportate. In generale, la presenza di additivi liquidi aumenta la SoS, mentre le inclusioni metalliche la riducono. Le immagini ecografiche del phantom e di un fegato reale mostrano somiglianze significative.ConclusioniLa realizzazione di nuovi materiali e la conoscenza delle proprietà acustiche quali la velocità del suono e l’impedenza acustica può dare un importante contributo per quanto riguarda la realizzazione di phantom per simulazioni di procedure mediche che utilizzano ultrasuoni.

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.

Feedback control of microbubble cavitation for ultrasound-mediated blood–brain barrier disruption in non-human primates under magnetic resonance guidance:

Focused ultrasound (FUS) in combination with microbubbles is capable of noninvasive, site-targeted delivery of drugs through the blood–brain barrier (BBB). Although acoustic parameters are reproducible in small animals, their control remains challenging in primates due to skull heterogeneity. This study describes a 7-T magnetic resonance (MR)-guided FUS system designed for BBB disruption in non-human primates (NHP) with a robust feedback control based on passive cavitation detection (PCD). Contrast enhanced T1-weighted MR images confirmed the BBB opening in NHP sonicated during 2 min with 500-kHz frequency, pulse length of 10 ms, and pulse repetition frequency of 5 Hz. The safe acoustic pressure range from 185 ± 22 kPa to 266 ± 4 kPa in one representative case was estimated from combining data from the acoustic beam profile with the BBB opening and hemorrhage profiles obtained from MR images. A maximum amount of MR contrast agent at focus was observed at 30 min after sonication with a relative contrast enhancement of 67% ± 15% (in comparison to that found in muscles). The feedback control based on PCD using relative spectra was shown to be robust, allowing comparisons across animals and experimental sessions. Finally, we also demonstrated that PCD can test acoustic coupling conditions, which improves the efficacy and safety of ultrasound transmission into the brain.

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 patients 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.

Robotic Platform for High-Intensity Focused Ultrasound Surgery Under Ultrasound Tracking: The FUTURA Platform

Focused Ultrasound Therapy Using Robotic Approaches (FUTURA) is a European seventh research framework programme project aimed at creating an innovative platform for Focused Ultrasound Surgery (FUS). Merging robotics together with noninvasive ultrasound monitoring and therapy has the goal to improve flexibility, precision and accuracy of the intervention, thus enabling a large use of FUS for the treatment of different pathologies. The FUTURA platform, based on FUS therapy under US tracking, has been set up with the first clinical target of kidney cancer treatment. Experiments for assessing the accuracy of the FUS delivery with the FUTURA platform have been carried out under in vitro static conditions and presented here as preliminary outcomes of this study.