News from November 2017
Research ArticleMEDICAL ROBOTS
Multifunctional biohybrid magnetite microrobots for imaging-guided therapy
1. Xiaohui Yan1,
2. Qi Zhou2,
3. Melissa Vincent3,
4. Yan Deng4,
5. Jiangfan Yu1,
6. Jianbin Xu5,
7. Tiantian Xu1,
8. Tao Tang4,
9. Liming Bian1,5,
10. Yi-Xiang J. Wang6,
11. Kostas Kostarelos3 and
12. Li Zhang1,*
See all authors and affiliations
Science Robotics 22 Nov 2017:
Vol. 2, Issue 12, eaaq1155
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Magnetic microrobots and nanorobots can be remotely controlled to propel in complex biological fluids with high precision by using magnetic fields. Their potential for controlled navigation in hard-to-reach cavities of the human body makes them promising miniaturized robotic tools to diagnose and treat diseases in a minimally invasive manner. However, critical issues, such as motion tracking, biocompatibility, biodegradation, and diagnostic/therapeutic effects, need to be resolved to allow preclinical in vivo development and clinical trials. We report biohybrid magnetic robots endowed with multifunctional capabilities by integrating desired structural and functional attributes from a biological matrix and an engineered coating. Helical microswimmers were fabricated from Spirulina microalgae via a facile dip-coating process in magnetite (Fe3O4) suspensions, superparamagnetic, and equipped with robust navigation capability in various biofluids. The innate properties of the microalgae allowed in vivo fluorescence imaging and remote diagnostic sensing without the need for any surface modification. Furthermore, in vivo magnetic resonance imaging tracked a swarm of microswimmers inside rodent stomachs, a deep organ where fluorescence-based imaging ceased to work because of its penetration limitation. Meanwhile, the microswimmers were able to degrade and exhibited selective cytotoxicity to cancer cell lines, subject to the thickness of the Fe3O4 coating, which could be tailored via the dip-coating process. The biohybrid microrobots reported herein represent a microrobotic platform that could be further developed for in vivo imaging–guided therapy and a proof of concept for the engineering of multifunctional microrobotic and nanorobotic devices.
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Scaling down of microrobots and nanorobots able to be navigated into hard-to-reach tissues and other human body cavities currently inaccessible to available devices can offer miniaturized medical tools for biomedical applications such as disease monitoring, targeted drug delivery, minimally invasive surgery, and so on (1–6). However, miniaturization also brings fundamental engineering challenges such as power sourcing, precise actuation, integration of multifunctionality, and capability of post-injection recovery or biodegradation. To date, several strategies have been reported to address actuation and motion control, including application of external fields (e.g., magnetic, ultrasound, and light) (7–9), use of biological motors (10, 11), addition of chemical fuel (2, 12), or combinations of the above (13, 14). Among them, magnetic actuation has attracted particular attention because magnetic fields can continuously transmit power to the robotic devices in a wireless manner with high penetrating capacity through the human body harmlessly even at relatively high field strengths (1, 3–6, 15), which has been well justified by the widespread use of magnetic resonance (MR) imaging.
To enable magnetic actuation at the microscale and/or nanoscale, magnetic robots of various structures—such as rigid-flexible nanowires (13, 16, 17), microspheres (18, 19), ellipsoids (20, 21), helices (7, 22–25), filaments (26), and even arbitrary shapes (27, 28)—have been developed. Powered by an externally applied magnetic field of certain form (e.g., gradient, oscillating, rotating, or periodically varying), they can be remotely controlled to navigate a variety of complex geometries filled with biological media such as water, blood, serum, and mucus (1, 3–5, 7, 14, 16, 20–31). Furthermore, they have the ability to manipulate cellular or subcellular components in either a contact or noncontact fashion (7, 16, 19, 21, 26, 29). To be applied as versatile tools for in vivo applications, microrobots and nanorobots need to be equipped with further functionalities, such as traceability, biodegradability, and bioactivity. These can be realized with multiple engineering strategies, such as surface decoration, selection of chemical composition, structural design, or a combination of the above (7, 18, 22–24, 29–32). Among all functionalities, of particular interest are absence of cytotoxic response, biodegradability, chemical stability, noninvasive in vivo tracking, targeted drug release, and stimulus-responsive release (1–5, 7, 18, 22, 24, 29–32).
Nature offers a rich database of answers to scientific challenges and can inspire solutions. Through natural selection, organisms in real life have evolved sophisticated biological materials featuring not only diverse structures but also a wealth of functionalities, among others, including hydrophobicity/hydrophilicity, reversible adhesion, biodegradability, renewability, magnetotaxis, bioimpedance, fracture resistance, light weight, anti-reflection, and autofluorescence (33–41). Such nature-abundant functionalities provide interesting options for the engineering of navigable robotic devices (6, 10, 11, 42, 43). We hypothesized that magnetization of biological entities with certain specifications could allow fabrication of magnetic microrobots that incorporate the morphological and functional features from a biological matrix. The fabricated biohybrid agents could be considered essentially composite materials, benefiting from both the biological organic matter and the integrated magnetic component. Furthermore, the inherited functionalities could be tailored for designated applications by controlling the thickness of the magnetic coating during the magnetization process. Hereafter, we refer to this type of robotic agents as biohybrid magnetic robots (BMRs).
We report BMRs successfully fabricated from microalgae organisms, exhibiting intrinsic fluorescence (see section S1 and figs. S1 to S3), MR signals, natural degradability, and desirable cytotoxicity. These are all critical features in the design of imaging-guided microrobots for therapeutic inventions (1–5). First, to accomplish navigation in complex biological environments via feedback control, the motion of the microrobots and nanorobots needs to be tracked in vivo and monitored in real time, for which noninvasive multimodal imaging is an effective means. Second, such tiny robots should eventually either degrade themselves to be excreted or be removed without causing undesired side effects. Third, during navigation inside the body, they should not cause hazard to normal cells and, preferably, can inhibit the function of abnormal cells (e.g., malignant).
Microalgae, organisms with several million distinct species on Earth, have been widely studied and commercialized for their abundance of valuable chemical compositions, for example, pharmaceutically active compounds, high-quality proteins, and natural pigments (40, 44). To fabricate BMRs, an essential step is to magnetize microalgae while preserving their structural features and intrinsic functionalities. For that purpose, we used a facile dip-coating method that bonds Fe3O4 nanoparticles (NPs) onto biological surfaces (41, 45). We chose Fe3O4 NPs as the magnetic component for their MR contrast, agglomeration-free colloidal suspension, facile surface functionalization, and low cytotoxicity, which means negligible physiological effect on cell or tissue viability (5, 31, 46).
Previously, we have used Spirulina platensis (a microalgae subspecies that features helical shapes) as a biotemplate to fabricate magnetic microswimmers via three steps: deposition of magnetite precursors, annealing, and reduction (31). That work only harnessed the structural features of S. platensis to build a porous hollow microhelix suitable for cargo loading (the S. platensis in the core was removed during the annealing process). Here, we aimed to develop magnetic microrobots with integrated functionalities envisioned for imaging-guided therapy. Simply by coating the biological matrix S. platensis with Fe3O4 NPs in a controlled fashion, large quantities of such microrobots can be fabricated via a single cost-effective step, without the need of any functionalization processing (although further expansion of the microrobots’ functionalities are also possible owing to the easy functionalization nature of Fe3O4 NPs).
Figure 1A demonstrates the dip-coating process of S. platensis in Fe3O4 NP suspensions. The deposited Fe3O4 NPs firmly bonded to the surface of S. platensis and gradually formed a magnetite coating. For the mechanism and characterization of this process, refer to the Supplementary Materials (section S2, figs. S4 to S8, and table S1). As the field-emission scanning electron microscopy (FESEM) images in Fig. 1A show, the deposition of Fe3O4 NPs and therefore the coating thickness on S. platensis could be controlled by adjusting the dipping time. Consequently, the magnetic property of the microalgae BMR was also tailored (fig. S7), as were properties of the inherited functionalities such as autofluorescence, MR contrast, biodegradation, and bioactivity. Owing to the easy functionalization feature of Fe3O4, further extension of the BMR’s functions or designated loading of drugs is also possible by chemically decorating the Fe3O4 NPs through functional ligands (5, 31, 32, 46).
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