The authors declare no competing financial interest. 2018 Oct 23;9(11):540. doi: 10.3390/mi9110540. (C) (a) Transport from ref (289). (A) Schematic image of Purcells scallop presenting fish-like nanoswimmer under an oscillating magnetic field. Art & Collectibles. microswimmers by laser ablation. Reproduced with permission from ref (39). Chen XZ, Jang B, Ahmed D, Hu C, De Marco C, Hoop M, Mushtaq F, Nelson BJ, Pan S. Adv Mater. Grider J. S., Manchikanti L., Carayannopoulos A., Sharma M. L., Balog C. C., Harned M. E., et al.. (2016). Lead manipulation is optimized when MNS are combined with variable stiffness catheters that consist of multiple segments with independent stiffness control (Figure 2B) (Chautems et al., 2017). All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Download Download PDF. Accessibility (B) Cell biopsy from a cell cluster using a magnetically of a hybrid MagRobot with flexible DNA flagella via DNA self-assembly Biocompatible encapsulation of CMOS based chemical sensors. Fiber-optic force sensors for MRI-guided interventions and rehabilitation: a review. and transmitted securely. (C) Sperm-based MagRobots capable of delivering Sep 2019 - Present3 years 5 months. For the latter, in our experience, manual control of the lead can be challenging, especially in presence of scar tissue, and may be associated with prolonged operating room (OR) time, patient discomfort, increased cost, and potential complications. cells using superparamagnetic/Pt Janus micromotors via bubble propulsion SP acknowledges the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (Grant agreement No. / Nelson, Bradley J. 2023 Jan 11;14(1):163. doi: 10.1038/s41467-023-35905-6. Reproduced with permission from ref (173). (D) Magnetic manipulation of Si/Ni/Au nanospears Wu J, Jang B, Harduf Y, Chapnik Z, Avci B, Chen X, Puigmart-Luis J, Ergeneman O, Nelson BJ, Or Y, Pan S. Adv Sci (Weinh). Gazelka H. M., Freeman E. D., Hooten W. M., Eldrige J. S., Hoelzer B. C., Mauck W. D., et al.. (2015). However, when navigating within the spinal epidural space, support from surrounding tissue does not exist and the catheter body can move relatively freely within the space. Singer A., Dutta S., Lewis E., Chen Z., Chen J. C., Verma N., et al.. (2020). The remaining surgery would proceed in the traditional sense. Verbal feedback can be given by the patient regarding the location of the induced paresthesia while being awake and in a comfortable position. Manipulation and navigation of micro and nanoswimmers in different fluid environments can be achieved by chemicals, external fields, or even motile cells. (A) Fabrication steps of Fe, Schematic illustrations of representative 2022 Dec 9;24:1-19. doi: 10.1016/j.bioactmat.2022.12.002. Reproduced with permission from (2013). For semi-automated procedures, haptic feedback devices could be linked with FBGs signals to provide a sense of touch to the surgeons' hand (El Rassi and El Rassi, 2020). 2022 Feb 10;2022:9824057. doi: 10.34133/2022/9824057. Reproduced 10.1002/adfm.201502248. 3D-printed soft magnetoelectric microswimmers for delivery and differentiation of neuron-like cells. No use, distribution or reproduction is permitted which does not comply with these terms. Such radii extend the reachable workspace and allow for greater accuracy (Ilami et al., 2020). experimental image (inset) of rolled-up magnetic microdrillers with JLFS/E-402/18, the ITF Projects under Projects MRP/036/18X and ITS/374/18FP funded by the HKSAR Innovation and Technology Commission (ITC), the Hong Kong Croucher Foundation project under Ref. Schematic illustrations would like to thank the financial support from the Hong Kong Research Grants Council (RGC) under Project No. Recent progress on magnetically driven micro- and nanorobots is delivered. In contrast to navigating a probe through cortical tissue, the spinal epidural space is a relatively empty cavity with connective adipose tissue and blood vessels (Newell, 1999; Grady et al., 2000). a nonreciprocal Magnetically controlled probes could be the precursor of untethered magnetic devices. Journal: Chemical Reviews. Yuan S., Holmqvist F., Kongstad O., Jensen S. M., Wang L., Ljungstrm E., et al.. (2017). This work reports a new type of magnetic nanorobot, a symmetric multilinked two-arm nanoswimmer, capable of efficient "freestyle" swimming at low Reynolds numbers, and demonstrates for the first time that the nonplanar propulsion gait due to the cooperative "Freestyle" stroke of the two magnetic arms can be powered by a plane oscillatory magnetic field. Reproduced with permission from ref (129). Magnetic needle guidance for neurosurgery: initial design and proof of concept, 2016 IEEE International Conference on Robotics and Automation (ICRA). Magnetically driven mobile micro/nanorobots have a significant influence on the application and development of intelligent targeted drug delivery. ref (128). Author information. motion of an AuAgNi nanowire. dynamically swarming spore@Fe, (A) Helical Di Natali C., Beccani M., Simaan N., Valdastri P. (2016). Magnetically controlled probes could be the precursor of untethered magnetic devices. Publisher Copyright: {\textcopyright} 2021 American Chemical Society. The goal of this perspective article is to review conventional SCS implantation techniques together with their related complications and limitations, and to reflect on how magnetically steered leads and untethered micro- and nanorobots could be implemented to improve the existing standard. 2019 The Royal Society of Chemistry. The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s. Verlag GmbH and Co. KGaA, Weinheim. Copyright In addition to tethered electrode steering, we discuss the navigation of untethered micro- and nanorobots for wireless and remote neuromodulation. Reproduced with permission from ref (210). . This is an open access article distributed under the terms sharp end penetrating into a pig liver after drilling motion. Magnetically Driven Micro and Nanorobots. Z., Ferrari A., Mushtaq F., Ghazaryan G., Tervoort T., et al.. (2017). 3D path planning for flexible needle steering in neurosurgery. (A). L.Z. These concepts are discussed to describe the interactions between micro/nanorobots and magnetic fields. UR - http://www.scopus.com/inward/record.url?scp=85104965511&partnerID=8YFLogxK, UR - http://www.scopus.com/inward/citedby.url?scp=85104965511&partnerID=8YFLogxK. (F) Fabrication of helical microrobots with hollow structures with Careers, Edited by: Paolo Motto Ros, Politecnico di Torino, Italy, Reviewed by: Ganesan Baranidharan, University of Leeds, United Kingdom; Kyungsik Eom, Pusan National University, South Korea. The https:// ensures that you are connecting to the 121 4999-5041 . 37 Full PDFs related to this paper. Magnetically Driven Micro and Nanorobots Chemical Reviews ( IF 72.087 ) Pub Date: 2021-03-31 , DOI: 10.1021/acs.chemrev.0c01234 Huaijuan Zhou, Carmen C. Mayorga-Martinez, Salvador Pan, Li Zhang, Martin Pumera This Paper. of suspended fibroblast cells captured by the microgripper. The use of MNS allows correction of the trajectory in real time during advancement of the electrode and offers the surgeon a yet unidentified degree of flexibility to adjust the surgical probe to follow the desired trajectory. 2. This review introduces fundamental concepts and advantages of magnetic micro/nanorobots (termed here as "MagRobots") as well as basic knowledge of magnetic fields and magnetic materials, setups for magnetic manipulation, magnetic field configurations, and symmetry-breaking strategies for effective movement. Publisher Copyright: exclusive licensee American Association for the Advancement of Science. Recent developments in magnetically driven micro- and nanorobots. Cortical mapping in conventional and high dose spinal cord stimulation: an exploratory power spectrum and functional connectivity analysis with electroencephalography. . MNS also allow for steering control at longer distances, e.g., the lead could be inserted at the thoraco-lumbar level (which is safer than more cranial insertion points) and guided to the cervical level, or a combined cervical and thoracic lead could be guided through a single entry and navigated to both targets. Proving the suitability of magnetoelectric stimuli for tissue engineering applications. Hybrid helical magnetic microrobots obtained by 3D template-assisted electrodeposition. with permission from ref (159). The portal can access those files and use them to remember the user's data, such as their chosen settings (screen view, interface language, etc. difference, causes the self-propulsion of a Janus particle. MagRobots for cell manipulation. They have been successfully applied in endovascular cardiovascular interventions (Ali et al., 2016). Copyright 2020 American Chemical Society. N1 - Funding Information: Reproduced with permission from ref (201). (D) Magnetically powered microspirals for the delivery Abstract. Adv. Copyright 2019 WILEY-VCH Verlag GmbH and Co. Copyright 2016 The Authors. Applications of MagRobots in targeted drug/gene delivery, cell manipulation, minimally invasive surgery, biopsy, biofilm disruption/eradication, imaging-guided delivery/therapy/surgery, pollution removal for environmental remediation, and (bio)sensing are also reviewed. spin-coating sacrificial layer and PPF/DEF solution, (ii) cross-linking 2021, 121, 4999 5041 Recent advances in the design, fabrication, and operation of micro/nanorobots have greatly enhanced their power, function, and versatility. Bio-inspired magnetic-driven folded diaphragm for biomimetic robot. Copyright The contrast can be enhanced by increasing the concentration of the contrast medium and . Candidates who have satisfactory results during the trial stage undergo permanent implantation of an implantable pulse generator (IPG), which is placed subcutaneously or subfascial in the gluteal or abdominal region (Rock et al., 2019). This work was supported by grants from the Heidi Demetriades Foundation, the ETH Zurich Foundation, and the Henan Provincial People's Hospital Outstanding Talents Founding Grant Project to AZ. A highly efficient NiFe nanorod-based magnetic miniature swimmer that can be manipulated in 3D spaces using two pairs of coils placed in the x-y horizontal plane and is able to perform incision operations as a minimally invasive microsurgical tool is described. Both MRI and MPI are magnetic-based imaging techniques. Magnetically guided ultrasound-powered nanowire motors, functionalized with bioreceptors and a drug-loaded . from ref (158). Yu H, Tang W, Mu G, Wang H, Chang X, Dong H, Qi L, Zhang G, Li T. Micromachines (Basel). This process could be time-consuming until optimal lead placement is achieved and it creates positional discomfort for the patients since they are awake and in the prone position. Applications of MagRobots in targeted drug/gene delivery, cell manipulation, minimally . A force to be reckoned with: a review of synthetic microswimmers powered by ultrasound. LLC 2013. Chemical Society. about navigating our updated article layout. Care Pain. Hu X., Chen A., Luo Y., Zhang C., Zhang E. (2018). of the representative fabrication processes Copyright 2019 Elsevier Ltd. (D) Preparation of liquid metal MagRobots. Reproduced with permission Yue K., Guduru R., Hong J., Liang P., Nair M., Khizroev S. (2012). Micro- or nanorobots are small-scale devices designed to perform minimally-invasive interventions and are powered by external power sources (Colberg et al., 2014; Zeeshan et al., 2014; Rao et al., 2015; Chen et al., 2017a; Soto et al., 2021). of T47D cancer In particular, the locomotion of these micro/nanorobots, as well as the requirement of biocompatibility, transportation efficiency, and controllable motion for . 2019 American Chemical Society. Here we report a new class of artificial nanomachine, named magneto-acoustic hybrid nanomotor, which displays efficient propulsion in the presence of either magnetic or . Nat Commun. (2019). While 30 mm radii have been precisely followed in the brain (Petruska et al., 2016), the steering radius of the tip in SCS is closer to 15 mm, which has to be tested in in vivo environments. Recent developments in magnetically driven micro- and nanorobots. Reproduced with permission from Publications . Flagellar-based propulsion mechanisms. When the adipose tissue is fibrotic and too dense, the catheter can be deflected, and the surgeon must adjust the tip to redirect the catheter to the desired path. Reproduced with permission from ref (269). 2019 American Chemical Society. Superparamagnetic nanoparticles are widely used to construct magnetic micro/nanorobots and can be used as T2 contrast agents. (2010). Spinal cord stimulation for very advanced parkinson's disease: a 1-year prospective trial. Annual Review of Control, Robotics, and Autonomous Systems. Th A selection of 2019 articles Copyright 2014, Brumley et Zeeshan M. A., Grisch R., Pellicer E., Sivaraman K. M., Peyer K. E., Sort J., et al.. (2014). 2021 American Chemical Society. N2 - Manipulation and navigation of micro and nanoswimmers in different fluid environments can be achieved by chemicals, external fields, or even motile cells. Reproduced with permission from ref (160). HHS Vulnerability Disclosure, Help and magnetoelectric applications. The information regarding microrobots that appears in this study is applicable to nanorobots as well. Chen X., Liu J.-H., Mei D., Mller L., Chatzipirpiridis G., Hu C., et al.. (2019). The present review is dedicated to novel. Copyright 2005 Nature Publishing Group. A) Magnetic control methods and techniques. the assistance of coiled flow template. Prodromakis T., Michelakis K., Zoumpoulidis T., Dekker R., Toumazou C. (2009). (E) Alignment of magnetic moment of microrobots with an external magnetic field. with permission from ref (222). from ref (296). A flexible beam or a sheet can be magnetically actuated when it is fixed to a magnetic head [80,81]. Reproduced with permission from ref (348). from ref (3). Nelson B. J., Kaliakatsos I. K., Abbott J. J. 2015, 25, 53335342. or eradication using Mater. (A) Diagram, Classifications and configurations of magnetic. Reproduced with permission Due to friction between microrobot and dura mater, the microrobot will advance in the epidural space tumbling over the surface and approaching the target location. nanorobot, spinal cord stimulation, magnetic steering, neurorobotics, microrobot. Highly Efficient Freestyle Magnetic Nanoswimmer. In recent years, there has been explosive growth in the number of investigations devoted to the development and study of biomimetic micro- and nanorobots. Verlag GmbH and Co. KGaA, Weinheim. Chemical Society. Copyright 2016 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim. In some cases, a repeat surgery to adjust the electrode lead(s) is needed to determine ideal lead placement. Go to reference in article; Crossref; Google Scholar [6] Loget G and Kuhn A 2011 Electric field . The magnetic field-induced actuation of colloidal nanoparticles has enabled tremendous recent progress towards microrobots, suitable for a variety of applications including targeted drug delivery. Chen X-Z., Marcus H., Fajer M., Erdem S., Chengzhi H., Bradley N. J., et al.. (2017a). of a driller working in a 3D vascular network and experiment result 2020 American Chemical Society. An official website of the United States government. SCS implantation is typically divided into two stages. Zhou, H., Mayorga-Martinez, C. C., Pan, S., Zhang, L. Zhou, Huaijuan ; Mayorga-Martinez, Carmen C. ; Pan, Salvador et al. Christiansen M. G., Senko A. W., Anikeeva P. (2019). Recent strides in micro and nanofabrication technologies have enabled researchers to design and develop micro and nanoscale robotic systems with enhanced power, functionality, and versatility. (A) However, these magnets are not biocompatible and must be shielded from the body to avoid inflammatory reactions by means of biocompatible enclosures with Parylene (Evans and McDonald, 1995; Prodromakis et al., 2009). 28, pp. (C) Reproduced with permission Reproduced with permission from ref (238). It covers several areas of micro and nanorobotics including robotics, materials science, and . Magnetically actuated micro/nanorobots have attracted considerable research interests and have been developed rapidly in recent years because of their advantages, such as untouched control, insensitivity to biological substances, and precise positioning [23-26].Under the dominance of the magnetic fields, many investigators employed the micro/nanomachines assembled by DNA origami frameworks . Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Go to citation Crossref Google Scholar. its end-effector and a robotic arm. Hong A., Boehler Q., Moser R., Zemmar A., Stieglitz L., Nelson B. J. Strong lateral tissue forces may require relatively high magnetic field strengths to hold the electrode tip on the pre-planned trajectory. Copyright 2014 Macmillan Publishers combining active flagella-containing cells such as (G) bacterium, Soto F., Wang J., Ahmed R., Demirci U. (E) Released drugs from hydrogel-based Fe-coated camptothecin-loaded magnetic biotube for killing HeLa cells. Peyer K. E., Zhang L., Nelson B. J. (A) Manipulation of T47D cancer cells using superparamagnetic/Pt Janus, MagRobots for minimally invasive surgery., MagRobots for minimally invasive surgery. The integrated magnets in the tip must be arranged and designed to comply with current surgical access methods through Tuohy needles. and Modulation of neuroglial interactions using differential target multiplexed spinal cord stimulation in an animal model of neuropathic pain. was supported by Ministry of Education, Youth and Sports (Czech Republic) Grant No. Reproduced with permission from heparin-loaded liposomes through flowing blood. Neurological Disease and Therapy. @article{6381a5d9200445a7a315ac8ddb10a5bb. biotinstreptavidin interaction under a magnetic field. (A) Directional Many researchers have selected magnetic fields as the active external actuation source based on the advantageous features of this actuation strategy such as remote and spatiotemporal control, fuel-free, high degree of reconfigurability, programmability, recyclability, and versatility. Steerable catheters for minimally invasive surgery: a review and future directions, A review of magnetic actuation systems and magnetically actuated guidewire- and catheter-based microrobots for vascular interventions. Navigation, release, anchoring, and biocompatibility of these small-scale devices are further open challenges that require proof-of-concept studies and in vivo verification. Fabrication Encapsulated magnetoelectric composites for wirelessly powered brain implantable devices, 2020 27th IEEE International Conference on Electronics, Circuits and Systems (ICECS). Many researchers have selected magnetic fields as the active external actuation source based on the advantageous features of this actuation strategy such as remote and spatiotemporal control, fuel-free, high degree of . S5 is reproduced with permission from refs ( and 140). Today 9, 37-48. S.P. from ref (402). Together they form a unique fingerprint. Magnetic steering provides improved dexterity, precision, and safety of implantation over manual steering. In general, when designing a magnetic catheter, one is faced with the challenge of catheter flexibility and the necessary amount of a magnetic volume to bend the tip and catheter rigidity for prevention of buckling during catheter advancement (Carey et al., 2006; Chautems et al., 2020). Since neuronal stimulation in the brain has already been demonstrated (Yue et al., 2012; McGlynn et al., 2020; Singer et al., 2020; Kozielski et al., 2021), this can serve as an intriguing technology for SCS. -, Ying Y.; Pourrahimi A. M.; Sofer Z.; Matejkov S.; Pumera M. Radioactive Uranium Preconcentration via Self-Propelled Autonomous Microrobots Based on Metal-Organic Frameworks. A. Aziz, J. Holthof, S. Meyer, O.G. By continuing you agree to the use of cookies. with permission from ref (342). Cheng C., Tietjen G., Saucier-Sawyer J., Mark Saltzman W. (2015). Representative examples of biohybrid MagRobots Reproduced with permission from ref (270). A bioinspired magnetically powered microswimmer is designed and experimentally demonstrated by mimicking the morphology of annelid worms, displaying efficient propulsion under an oscillating magnetic field and able to transport microparticles toward a predefined destination. of PVDF-Ppy-Ni nanoeels. SCS has recently also gained interest for improving locomotion (Pinto de Souza et al., 2017; Rohani et al., 2017; Wagner et al., 2018; Courtine and Sofroniew, 2019; Goudman et al., 2020; Prasad et al., 2020). This article is distributed under the terms of the Creative Commons The choice of composite materials must be carefully considered as they need to fulfill all safety criteria for permanently implantable devices (Soto et al., 2020, 2021). Actuation mechanisms of flagella-inspired MagRobots (i.e., corkscrew-like motion and traveling-wave locomotion/ciliary stroke motion) and surface walkers (i.e., surface-assisted motion), applications of magnetic fields in other propulsion approaches, and magnetic stimulation of micro/nanorobots beyond motion are provided followed by fabrication techniques for (quasi-)spherical, helical, flexible, wire-like, and biohybrid MagRobots. Alignment could be achieved by magnetic fields in the range of 50100 mT. Clipboard, Search History, and several other advanced features are temporarily unavailable. Development of a sperm-flagella driven micro . For SCS, this technology harbors several benefits, including (i) enhanced flexibility to navigate the SCS electrode to the target location during its placement, (ii) reduced procedure time and cost in the operating room, and (iii) non-invasive ability to adjust the SCS electrode post-operatively. government site. HHS Vulnerability Disclosure, Help 10.1021/acs.chemrev.0c00535. LL2002 under ERC-CZ program. Grady M. S., Howard M. A., Dacey R. G., Blume W., Lawson M., Werp P., et al.. (2000). (2020). This setting would enhance the comfort for the patient and the surgeon. of the Creative Commons CC BY license. FOIA (A) Schematic process of removing A pre-operative magnetic resonance imaging (MRI) could assist in plotting a pre-defined trajectory for the MNS. abstract = "Manipulation and navigation of micro and nanoswimmers in different fluid environments can be achieved by chemicals, external fields, or even motile cells. (2020). Actuation mechanisms of flagella-inspired MagRobots (i.e., corkscrew-like motion and traveling-wave locomotion/ciliary stroke motion) and surface walkers (i.e., surface-assisted motion), applications of magnetic fields in other propulsion approaches, and magnetic stimulation of micro/nanorobots beyond motion are provided followed by fabrication techniques for (quasi-)spherical, helical, flexible, wire-like, and biohybrid MagRobots. The traditional SCS system includes the SCS lead(s), the implantable pulse generator (IPG), and the extension wire(s), which connect(s) the lead(s) to the IPG (Figure 1A). official website and that any information you provide is encrypted using two-photon polymerization. PMC They may therefore represent a potent alternative to traditional neuromodulation with the advantage that they could be placed with less invasive procedures and would obviate the need for placement and replacement of pulse generators (Christiansen et al., 2019). However, early results in deep brain stimulation with multiferroics demonstrate a beneficial effect, which is promising for application in the spinal cord (Singer et al., 2020; Kozielski et al., 2021). Micro- and nanodevices have the potential for remote neurostimulation without requiring a stimulation lead and implantation or replacement of an IPG, which saves additional surgeries for the patient (Nan et al., 2008; Armin et al., 2012). sharing sensitive information, make sure youre on a federal Copyright Reproduced with permission B) Magnetic control targets. (F) Electromagnetic actuation system using a stationary The achievements of manufacturing micro- and nanorobots by incorporating different magnetic nanoparticles, such as diamagnetic, paramagnetic, and ferromagnetic materials, are discussed in detail, highlighting the importance of a rational use of magnetic materials. Reproduced with permission from ref (106). S.P. 08705 - Gruppe Pan Vidal. to the motion of MagRobots. JLFS/E-402/18, the ITF Projects under Projects MRP/036/18X and ITS/374/18FP funded by the HKSAR Innovation and Technology Commission (ITC), the Hong Kong Croucher Foundation project under Ref. Chautems C., Tonazzini A., Boehler Q., Jeong S. H., Floreano D., Nelson B. J. Bookshelf A holistic approach to targeting disease with polymeric nanoparticles. Copyright To be considered for neurostimulation, micro- and nanorobots must be able to generate an electrical field. acknowledges the support from the project Advanced Functional Nanorobots (Reg. Vallejo R., Kelley C. A., Gupta A., Smith W. J., Vallejo A., Cedeo D. L. (2020). By clicking accept or continuing to use the site, you agree to the terms outlined in our. (A) Manipulation Pane S, Zhang L and Pumera M 2021 Magnetically driven micro and nanorobots Chem. Copyright 2019 The Royal Zhang Z, Sukhov A, Harting J, Malgaretti P, Ahmed D. Nat Commun. This optimization problem is particularly difficult in the epidural space, as connective tissue, open cavities, and long insertion depths generally require a stiff catheter design. MagRobots for minimally invasive surgery. In this review, four types of propulsionmagnetically, acoustically, chemically/optically and hybrid drivenand their corresponding features have been outlined and categorized. CAS20403, the Research Sustainability of Major RGC Funding Schemes, and the Direct Grant from CUHK, as well as support from the Multiscale Medical Robotics Center (MRC), InnoHK, at the Hong Kong Science Park. Received 2021 Jul 28; Accepted 2021 Sep 10. and magnetic stimulation of micro/nanorobots beyond motion are provided followed by fabrication techniques for (quasi-)spherical, helical, flexible, wire-like, and biohybrid MagRobots. When piezoelectric materials are exposed to mechanical strain and deformation, electrical surface charges can be generated. (2004). hyperthermia, thermophoresis, Manipulation and navigation of micro and nanoswimmers in different fluid environments can be achieved by chemicals, external fields, or even motile cells. (B) Graphene Quantum (C) microalgae, or (D) sperm as templates. All authors contributed to the article and approved the submitted version. 10.1016/j.apmt.2017.04.006 . Copyright This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).
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