Robotic system for magnetic resonance imaging‐guided focused ultrasound treatment of thyroid nodules

Herein, a robotic system offering Magnetic Resonance‐guided Focused Ultrasound (MRgFUS) therapy of thyroid nodules was developed.

guidelines and grading systems for determining thyroid nodule malignancy based on sonographic features, thus differently deciding on the need for biopsy and any further therapeutic management.
However, since the majority of the recorded nodules are benign these do not induce symptoms and therefore treatment other than surveillance with ultrasound (US) imaging at specific timeframes after diagnosis is not usually followed. 7,10 However, it has been evidenced that over a 5-year period, approximately 15% of the benign nodules increase over 20% in size, 10 and therefore induce significant symptoms such as pain, pressure, dyspnoea, 2,11 hyperthyroidism 2,12 and cosmetic problems. 2 As a result, different therapeutic modalities have been available for the treatment of large-sized symptomatic benign nodules as well as malignant thyroid nodules. 13 Thyroidectomy is the mainstay of treatments for malignant nodules 7 as well as benign nodules with a diameter larger than 3-4 cm 7,14 and offers immediate relief of symptoms 11,15 with a low percentage of permanent complications. 16 Nevertheless, most commonly, treatable hypocalcaemia and temporary or permanent vocal cord paresis (VCP), hypoparathyroidism 16,17 and voice changes 18 are recorded, while the invasive nature of the procedure leaves visible scar marks. 7 Furthermore, post-operative infections and haemorrhages might occur to a lesser extent, 16,17 while a lifelong administration of thyroid hormonal medication is required so that patients maintain a normal thyroid function. 7,19 Radioactive iodine (RAI) is another conventional non-surgical treatment for either malignant 20 or toxic benign thyroid nodules 14 with significant results seen within 1 year. 21 RAI is preferred due to its relatively lower cost compared to surgery, 2 while its radioactive nature induces several early and late side effects including nausea, damage to the DNA, 21 and development of secondary cancers. 22 Additionally, RAI is contraindicated for pregnant women, 12 it can cause hypothyroidism thereby requiring life-long medication, 23,24 while the radioactive nature of the treatment induces reluctance to the patients. 25 Several US-guided minimally invasive modalities such as ethanol ablation (EA) or thermal ablation techniques have emerged over the years as alternatives to surgical resection or RAI treatment 14,26 improving the quality of life of individuals who are contraindicated for or refuse surgery. 15 EA is considered the most effective and mainstay method for benign nodules with a cystic compartment 14,27 achieving over 70% nodule volume reduction (NVR) 28,29 and euthyroidism in over 80% of the treated patients. 28,29 Nevertheless, while EA can also successfully treat malignant thyroid nodules achieving significant NVR with no major adverse effects, 30 its routine clinical employment is currently contraindicated. 14,20 Thermal ablation techniques such as laser, radiofrequency (RF), microwave (MW) and high-intensity focused ultrasound (HIFU) locally increase tissue temperature to over 65°C so as to induce coagulative necrosis of the selected tissue cells, with tissue necrosis observed as hyperechoic changes on US images acquired during treatment. 18,27 The feasibility of laser ablation for the treatment of benign thyroid nodules was performed in 2002 on 16 patients 31 and since then has been used in a single-session approach for the treatment of both benign [32][33][34] and malignant thyroid nodules, 35,36 achieving significant NVR and immediate symptom improvement with results remaining up to 3-years of follow-up. 33, 34

RF was introduced in 2006
for the treatment of thyroid nodules, achieving symptom improvement in the majority of the patients and gradual NVR over a 6-month follow-up. 37 Its safety and efficacy have since been extensively proven for treating both benign 38,39 and malignant nodules 40,41 with long-term results. MW for benign nodules was assessed later than the other techniques, in 2012, in a pilot study by Feng et al. 42 where ablation in 11 patients resulted in an average NVR of 46% and improved cosmetic symptoms. Later studies achieved a mean NVR of approximately 90% in both benign nodules at 12 months follow-up 43 and malignant nodules at 18 months 44 with no tumour recurrences observed up to 11 months post-ablation. 45 Overall, laser, RF and MW are generally perceived as safe procedures inducing side effects such as voice changes, 32,35,38,39,44,45 mild pain during and after the procedure 32,33,38,39 and skin burns 32,38,39 with the latter two preventable by utilising cooled probes. 12,46 These thermal techniques are increasingly preferred for managing small symptomatic benign thyroid nodules 47,48 with RF, MW, and laser recently recommended for potential use on malignant thyroid nodules. 20 Among thermal therapies, HIFU is the sole modality that is completely non-invasive since it focuses on energy within a millimetre-sized area of the tissue using extracorporeal applicators 49 and has thus emerged as a clinical treatment for benign thyroid nodules 15 due to its convenient use. 50 The ECHOPULSE (Theraclion, Paris, France) is the only commercially available HIFU system offering US-guided ablation of thyroid nodules and plays a dominant role in clinical studies assessing the efficacy of HIFU on benign thyroid nodules, 13,18,51,52 however, its effect on malignant thyroid nodules is yet to be assessed. The system is equipped with a robotised treatment head featuring two ultrasonic transducers: one therapeutic transducer and one imaging transducer operating at frequencies of 3 and 7.5 MHz, 13,51,53 with the imaging transducer integrated at the centre of the therapeutic probe so that during treatment the focus is always imaged on the centre of the US image. 51 Moreover, the probe is equipped with a cooling device that minimises skin burns 13,51 and a laser sensor that interrupts treatment upon minor patient movement. 13 Additionally, the system features a treatment planning software that automatically sections the nodule into subunits, 13,51 while it adds safety distances between the focus and the trachea, carotid artery and oesophagus. 51 HIFU is considered equally effective for all types of benign nodules 54 except cystic, 14 while multiple nodules can be sequentially treated in the same session. 55 During treatments, patients experience only minor complications such as moderate pain that subsides shortly after treatment 18,52,[54][55][56] along with skin redness and swelling. 18,52,53,57,58 To a lesser extent, major complications such as Horner's syndrome 57,59 and VCP 13,18,57-60 occur, subsiding a few months after treatment; however, these can be prevented by maintaining specific distances between the focus and the tracheoesophageal groove. 58 Moreover, small nodules can be treated with no anaesthesia without compromising patient comfort, 61 while employing general anaesthesia results in lower pain scores and increased NVR, albeit with higher rates of adverse effects 62 and diminishing the ambulatory nature of the treatment. 56 US-guided HIFU treatments with the ECHOPULSE system often start at specific energy values that are progressively increased until hyperechoic marks, indicative of successful tissue heating, are shown on the US image. 13,18,53,60 However, Kovatcheva et al. 53 showed that the presence of hyperechoic marks did not correlate with successful NVR at 6-months post-ablation, while a more recent larger cohort study by Lang et al. 60 reported that treatments where hyperechoic marks were present resulted in significantly increased NVR at 6 months with their presence a significant indicator of treatment success. Nevertheless, the presence of hyperechoic marks has been associated with lower Body Mass Index (BMI) 53,60 and increased HIFU power, 60 with the treatment less efficient in patients with higher BMI. 53,60 However, no correlation of BMI with applied HIFU power has been indicated, 53 with the presence of hyperechoic marks and better treatment efficacy in lower BMI patients possibly attributed to reduced attenuation of the ultrasonic beam potentially due to a thinner fat tissue layer in the neck. 53,60 In contrast, employment of Magnetic Resonance Imaging (MRI) as a guidance modality for HIFU treatments does not rely on the presence of hyperechoic marks on the image for assessing successful tissue ablation. MRI guidance utilises Magnetic Resonance (MR) thermometry that provides direct quantitative feedback of the in situ increase in tissue temperature in real-time. 63 As a result, MRI-guided focused ultrasound (MRgFUS) treatments are considered more effective in adequately reaching necrotic levels of temperatures, while simultaneously providing higher image resolution of the tissue anatomy. 64 MRgFUS systems were first introduced in 1993 65 and have thenceforth gained a significant share as non-invasive therapies in the clinical oncological settings. 66 Due to the increasing interest HIFU ablation of thyroid nodules has gained over the last decade, herein, we propose an MRIguided system for HIFU ablation of thyroid nodules, designed to be placed on the MRI table with the patient in the supine position. In contrast to the US-guided ECHOPULSE system, the proposed prototype can exploit MR thermometry to result in safer treatments.
Additionally, since HIFU ablation of thyroid nodules results in adverse side effects such as VCP due to unnecessary heating of adjacent nerves, 58 the MRI guidance proposed with the current prototype could provide added feedback on the heating of nearby nerves, thereby promptly urging operators to alter treatment parameters in order to result in safer treatments that potentially spare the onset of major adverse effects. The developed system features robotic motion in two linear stages, thereby being able to accurately ablate large areas on both benign and malignant thyroid nodules.

| Robotic system design and configuration
A Computer Aided Design (CAD) software (Inventor, Autodesk, San Rafael, California, USA) was utilised for designing the robotic system.
The robotic system was designed with mechanisms that offer linear PC-controlled motion in two stages (X and Z). The X and Z motion stages of the robotic system correspond to motion along the X and Z imaging planes of the MRI, respectively. The robotic system was developed with MRI-compatible non-ferromagnetic materials for proper functioning inside the MRI environment. In this manner, additive manufacturing was employed for the development of the ro- Motion in the two stages is actuated using a similar concept as shown in Figure 1. The positioning mechanisms of the Z-stage are assembled within the Z-frame that is in turn attached and secured to the mechanism enclosure as shown in Figure 1A. The Z-jackscrew attaches to the shaft of the Z-motor that is in turn positioned at the rear end of the Z-frame. Brass screws are employed to secure the jackscrew on the Z-motor shaft, resulting in accurate displacement.
Accordingly, the jackscrew is coupled to the Z-plate through the developed inner jackscrew guide slots (not visible in Figure 1 Figure 1B. Nevertheless, the X-frame is not secured on the mechanism enclosure. In fact, the rear end of the X-frame attaches to the Zplate through couplings and secures with two brass screws, resulting in unrestricted motion of the X-frame in forward and reverse directions according to the displacement of the Z-plate. Moreover, the X-motor attaches to the X-frame and is covered and secured with the X-frame cover. The X-jackscrew is identical to the Z-jackscrew and provides the same stable displacement (2.34 mm) to the X-plate for each complete rotation of the X-motor shaft. Left to right motion accuracy of the X-plate is ensured with the optical encoder that mounts to the X-plate (not visible in Figure 1). The X-stage transfers the motion to the ultrasonic transducer. The transducer shaft attaches with two brass screws on the X-plate, securing the shaft, thus offering an alignment of the shaft with the positioning mechanisms and stability during robotic movement. The transducer holder couples to the transducer shaft via couplings. The transducer holder FILIPPOU ET AL. extends the transducer, via an arm, to a water container that attaches and secures to the mechanism enclosure. On the side of the mechanism enclosure, a C-arm coupling exists, mounting the device on a C-arm that in turn attaches to the table of the MRI scanner. Figure  Accordingly, if a smaller space is required between the patient and the coupling point of the robotic system, a mattress having an appropriate thickness can be added between the patient and the MRI table. Furthermore, as seen in Figure  positioning mechanism enclosure (i.e., to the side proximal with the MRI bore), thus achieving increased safety and decreased discomfort to the patient.

| High intensity focused ultrasound system
A single-element spherically focused ultrasonic transducer integrated in the robotic system was developed in-house using MRI-compatible materials. The custom transducer was developed using a piezocer- Consequently, treatment planning can be performed, with the motion of the robotic system executed along the defined trajectory, relative to the MRI imaging coordinates, and with the position of the transducer continuously monitored on MR images during the procedure.

| MRI compatibility
The complete system was assessed after full assembly inside the environment of a clinical MRI scanner for evaluating its MRI compatibility by assessing the Signal to Noise Ratio (SNR). The employed method is based on SNR calculations performed for a series of identical MRI images sequentially acquired under different activation states of the various components of the system that require electricity for operation, namely the robotic device and the integrated transducer.
For the purposes of SNR calculations, an agar-based phantom was imaged. The phantom was developed with 6% weight per volume (w/v) agar (10164, Merck KGaA) and 2% w/v silicon dioxide (S5631, Sigma-Aldrich) following a preparation procedure mentioned in the literature. 68 The specific phantom was employed since it has previously been shown to exhibit homogeneity in MR images and similar MRI signal with certain human tissues. 69 The SNR was calculated for each image by measuring the average signal intensity in a region of interest (ROI) set within the agar-based phantom and in a ROI set in the background, and substituting in the following equation: where the SI phantom represents the signal intensity measured in the phantom ROI, while σ noise is the standard deviation of the signal intensity measurements in the background ROI.

| Laboratory ablations on excised tissue
The heating performance of the robotic system was evaluated during bench-top ablations executed on excised pork tissue in a laboratory setting. Freshly excised pork tissue, acquired from a butchery, was placed under the acoustic window of the robotic system and was sonicated using high acoustic power to assess the ability of the FILIPPOU ET AL.
where γ is the gyromagnetic ratio, α is the PRF temperature change tissue coefficient (−0.01 ppm/°C), Β ο is the local magnetic field strength and ΤΕ is the echo time of the employed MR imaging sequence.

MRI sonications on a homogeneous agar-based phantom
Initially, sonications were performed with the robotic system on the abovementioned homogeneous agar-based phantom doped with silicon dioxide (6% w/v agar and 2% w/v silicon dioxide) by applying an  CAD design of the thyroid gland was then utilised for designing a thyroid model mould. The thyroid model mould was designed, using the CAD software (Inventor, Autodesk), with seven separate parts that are easily assembled together as shown in Figure 3B. Specifically, the 3D model of the human thyroid gland was employed for designing inner and outer enclosures for the left and right thyroid gland lobes as shown in Figure 3B. After the development of all three moulds, the thyroid phantom was developed using a 6% w/v agar (10164, Merck KGaA) and 4% w/ v silicon dioxide (S5631, Sigma-Aldrich) mixture that was prepared according to the method in the literature 68 and was poured in the thyroid mould to solidify. Upon solidification, the 6% w/v agar and 4% w/v silicon dioxide thyroid phantom was placed around the sealed ABS air-filled trachea phantom, and both parts were accommodated in the rectangular mould that was filled with an agar-based mixture consisting of 6% w/v agar (10164, Merck KGaA) which was prepared according to the previously described procedure. 68 Figure 4B shows

| Laboratory ablations on excised tissue
Sonications (45 W for 20 s) on freshly excised tissue in a grid manner (2 � 3) with a 10 mm spatial step resulted in the formation of six discrete well-demarcated lesions. After sonications, the tissue was vertically sliced on a plane parallel to the ultrasonic beam, revealing the shape of the formed lesions. Figure 6A shows the three discrete lesions formed by resulting sonications on the first grid row, while Figure 6B shows

| MRI sonications on an agar-based thyroid phantom
A T2-W FSE image of the thyroid phantom acquired for targeting before sonications is shown in Figure 9. The thyroid agar-based phantom (6% w/v agar and 4% w/v silicon dioxide) was clearly demarcated from the air-filled ABS trachea phantom and the sur-  Figure 10A shows the coronal thermal maps generated at different timepoints during ultrasonic exposures on the agar-based thyroid phantom, showing the evolution of thermal heating in a specific ROI set in the thyroid agarbased model. At the targeted ROI within the thyroid phantom, a maximum temperature of 72°C was recorded in a plane perpendicular to the ultrasonic beam propagation (coronal) as shown in Figure 10B. Accordingly, Figure 11A shows    Although the simple design of the device is based on previously proposed systems developed by our group, 71,74,[76][77][78]80 with one such recent system offering the potential for top to bottom MRgFUS therapy of thyroid tumours, 76 the herein system offers advanced characteristics. The current prototype has been designed for use on thyroid tumours and not on multiple, potentially deeper, targets as the previously developed system. 76 This allows for the incorporation of only two motion stages with a specific motion range (30 mm for each stage) for sufficient ablation of the human thyroid. This design configuration results in a more cost-effective device compared to the previous system. 76 Additionally, the current device has been designed with a proper size to allow direct coupling with the human neck, thus achieving easier and quicker coupling without requiring motion in the Y-axis (i.e., the Y imaging axis of the MRI). 76 Furthermore, this system attaches to the MRI table with a single C-arm structure, thus allowing more space for the patient than the previously proposed system. 76 Moreover, contrary to the previously proposed device, 76  Overall, the proposed system is MRI compatible and offers proper coupling with the target for ultrasound delivery with excellent thermal heating capabilities. Although the current system has been evaluated only ex-vivo, further evaluation in-vivo should be performed for assessing the efficacy of the device, ultimately employing the prototype for clinical use for MRgFUS treatment of thyroid nodules. Advantageously, considering the dimensions of the device, the herein system can also be applied for other shallow targets such as superficial neck tumours or sarcoma in extremities.