Micro/Nanorobots for Medical Diagnosis and Disease Treatment: History
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Micro/nanorobots are functional devices in microns, at nanoscale, which enable efficient propulsion through chemical reactions or external physical field, including ultrasonic, optical, magnetic, and other external fields, as well as microorganisms. Compared with traditional robots, micro/nanorobots can perform various tasks on the micro/nanoscale, which has the advantages of high precision, strong flexibility, and wide adaptability. In addition, such robots can also perform tasks in a cluster manner.

  • micro/nanorobots
  • driving mechanism
  • medical diagnosis
  • disease treatment

1. Introduction

The emergence of micro/nanorobots promotes the development of a precision medicine, which is an important direction of modern biomedical development. Micro/nanorobots refers to the functional devices that can realize motion at micron and nanoscale, driven by a light field, magnetic field, and sound field [1]. Richard Phillips Feynman first suggested that micro/nanorobots can be used in biomedical applications, and he predicted that the micro-machines can achieve microscopic treatment [2]. Professor Toshio Fukuda, the father of micro/nanorobots in the early 2000s, pioneered the world’s first nanorobot operating system for single-cell analysis and manipulation [3]. However, due to the difficulty of manufacturing micro/nanomaterials with complex structures of different physical properties, the development of micro/nanorobots faces great challenges. In recent years, through top-down and bottom-up methods, the artificially synthesized micro/nanorobots have not only achieved a breakthrough from centimeter level to micro/nano level but also developed micro/nanorobots with various materials and structures, such as tubular, linear, rod, yin-yang spherical, spiral, peanut, and sea urchin micro/nanorobots. Due to its small structure and controlled navigation ability, micro/nanorobots have been widely used in many fields, including drug targeting delivery, cell capture and separation, minimally invasive surgery, analysis and detection, environmental purification, and nano printing [4,5]. With the deepening of research, the motion control methods for micro/nanorobots are also developing. For example, the navigation motion of micro/nanorobots can be realized by using an electric field, magnetic field, ultrasound, and light field.

2. Micro/Nanorobots in Medical Diagnosis

2.1. Sensing Detection

Micro/nanorobots can mix with fluids and induce target receptors to interact, providing the possibility for medical diagnosis. Micro/nanorobots can selectively identify metal ions, bacterial toxins, proteins, cells, etc., offering accurate pre-treatment analysis for disease treatment. Accurate detection of metal ions in the blood can prevent excessive ion concentration to protect human health [7,35,36]. For example, a new type of magnetic mesoporous silica/ZnS·Mn/gold/tetraethylenepentamine/heparin (MMS/ZM/Au/T/Hep) micromotors can directly detect and remove excess copper from the blood. The micro/nanorobot accelerated the spread of solute and fully mixed with the target, and its magnetic meconium silica microtube provided a rich load space for the adsorption of tetramethylene pentaamine (TEPA), thus showing good adsorption ability and short processing time for Cu2+. Due to the synergy of mesoporous structure, adsorption function group, and good mobility, the removal rate of blood copper ions was as high as 74.1%. At the same time, the micro/nanorobot selectively monitored the concentration of copper ions in the blood based on changes in fluorescent signals after separation from the blood. The entire self-mixing process can be achieved by autonomous motion of the micro/nanorobot without stirring or ultrasound. The magnetic Fe3O4 enables the micro/nanorobot to quickly separate after removing Cu2+ from the blood. This research result provided some support for the integration of toxin detection and removal in the blood, as well as solved the problem of long treatment cycle, high cost, separation of diagnosis and treatment, and limited therapeutic effect of traditional treatment methods.
To diagnose sepsis early on, Molinero-Fernández et al. developed a fluorescent immunoassay based on micro/nanorobot and used it for the determination of calcitonin-lowering protones (PCT). The polypyrrole (PPy) layer of this micro/nanorobot has high binding specific antibodies that actively identify PCT antigens through magnetic guidance and catalyzing the push of bubbles. Within the clinically relevant concentration range, the assay can be used with a small number of samples to measure PCT levels in clinical samples of low-weight newborns suspected of sepsis [36].
In addition, micro/nanorobots, serving as biosensors, have great potential in intelligent sensing and drive systems. Kong et al. [37] have introduced an Mg/Pt Janus miniature robot capable of self-renewing the surface. With the aid of the Mg/Pt Janus micro/nanorobot, the electrochemical detection of glucose in human serum can be improved without the need for additional toxic fuels or surfactants. The study showed that the rapid movement of the Mg/Pt Janus micro/nanorobot enhanced the current signal, as well as the current signal increased with the increase of introduced micro/nanorobots, and the addition of micro/nanorobots established great linear relationship between the current signal and the glucose concentration. Compared to synthetic sensors, red blood cell biosensors and micro/nanorobots are highly biocompatible, flexible, and noninvasive in biological systems.

2.2. Imaging of Medical Micro/Nanorobots

A key clinical application of medical micro/nanorobots is to rely on individuals or groups for monitoring. They can be easily located and guided in the body, and even send signals to induce trigger release, so the potential for medical imaging cannot be ignored. For example, the micro/nanorobot is well detected in the in vivo environment at a penetration depth of 2 mm, and its real-time position in a mouse vein is monitored using optical coherence tomography imaging to provide feedback on the movement of the micro/nanorobot in vivo [40]. Another way is to design a living intestinal micro/nanorobots guided by a photoacoustic computed tomography (PACT) as an imaging contrast agent and a controlled drug carrier. Among them, the micro/nanorobot has a multi-layer functional coating, and its Au layer enhanced the optical absorption and improved the propulsion rate, gelatin hydrogel layer expanded the load capacity of different functional components, and polyethylene layer maintained the robot’s geometry in the process of propulsion. Because of its high space-time resolution, noninvasiveness, high molecular contrast, and strong depth penetration, the migration of micro/nanorobots capsules to the target area can be observed in real-time [41]. In addition, Iacovacci et al. [42] have proposed a magnetically-driven therapeutic microbot made of thermally responding double-layer hydrogels. The tiny robot contains magnetic nanoparticles and radioactive compounds that act as imaging agents in a hydrogel frame. Magnetic nanoparticles can be used to remotely drive and trigger shape changes in micro-devices, while imaging agents can monitor micro/nanorobots in the body. The epithelial imaging of the mouse was followed by a single-photon emission tomography scan, and the micro/nanorobots were detected in the mouse’s abdomen. For the first time, the study showed that imaging of a single micro/nanorobot can be performed using hydrogel structures as low as 100 μm in diameter, laying the foundation for the future development of single-robot closed-loop control. In addition to photoacoustic imaging, micro/nanorobots can also use magnetic resonance imaging.

3. Micro/Nanorobots in Disease Treatment

3.1. Drug Carriers

Therapeutic effects of drugs are usually affected by various factors. Under traditional treatments, the general approach may repeat the drug in high doses if the desired therapeutic effect is achieved, but this is likely to increase toxicity and side effects. The precise delivery potential of micro/nanorobots in the target area is expected to solve the toxicity problem caused by excessive drug use [44]. A drug-loaded micro/nanorobot for the treatment of gastric bacterial infection is made of Mg particles with an average size of about 20 μm. It has the ability of efficient propulsion, and the average velocity tested in vitro simulated gastric juice (pH = 1.3) is about 120 μm/s. In vitro bactericidal activity test of Helicobacter pylori (H. pylori) showed that the drug-loaded robot demonstrated similar bactericidal activity to free drug solution, and the micro/nanorobot could be effectively promoted and distributed throughout the stomach of live mice, thereby significantly reducing the number of H. pylori. In vivo toxicity studies have demonstrated the safety of micro/nanorobots in the treatment of mouse models. Propulsion of the carrier Mg-microbot in the gastric medium allows for more efficient delivery of antibiotics than passive drug carriers. In addition, the acid-Mg reaction required for autonomous propulsion also consumes protons in the stomach fluid, neutralizing the pH of the stomach [45]. Similarly, another Zn-based micro/nanorobot in gastric drug delivery also has high power propulsion, high load capacity, payload self-release, and non-toxic self-degradation, compared with oral administration of ordinary passive diffusion and dispersion, and its payload retention in the stomach wall has been significantly improved [21]. In addition, the metal-organic framework (MOF) controls drug release through pH response, enabling magnetic movement in cell cultures, drug delivery, and degradation of all its components. Further, a new catalytic micro/nanorobot based on the porous zeolite meth salt skeleton-67 (ZIF-67) is synthetically prepared at room temperature by ultrasonic-assisted wet chemistry [46]. These porous microbots show effective autonomous motion and a long-lasting motion life of up to 90 min in H2O2. When combined with doxorubicin (DOX), the load can be up to 682 μg/mg. The micro/nanorobot shows excellent drug delivery performance under an external magnetic field due to its porous nature, high surface area, and dual stimulation based on the catalytic reaction of H2O2 and the effect of H2O solvent. Compared with the traditional porous membrane carrier based on the pH response release mechanism, the drug release of the double stimulation-induced porous ZIF-67 microbot is more direct and timelier.
Magnetic fields can precisely control magnetic micro/nanorobots, but the harmfulness of magnetic materials, such as Ni, limits their use in drug delivery. Based on this, Park et al. have developed a biodegradable thermotherapy microbot with a 3D spiral structure and used it to actively control drug delivery, release, and thermotherapy [47]. The microbot is made of poly (ethylene glycol) diacrylate (PEGDA) and pentaerythritol triacrylate (PETA), containing magnetic Fe3O4 nanoparticles and the cancer drug 5-fluorouracil (5-FU). Under the remote precise control of the rotating magnetic field generated by the electromagnetic drive system, the 5-FU can be released from the micro/nanorobot. Further research on this type of robot found that it responds more to sound energy and releases the drug under ultrasound, as shown in Figure 4b. By changing the condition of the ultrasound beam, it was found that the robot released three modes, natural release, explosive mode release, and constant release of the drug, and the in vitro test results showed that each release mode had different therapeutic results. Among them, in the outbreak and constant release mode, the survival of cancer cells was significantly reduced, confirming that the ultrasound can enhance the treatment effect by increasing drug concentrations and acoustic holes. Ultrasound-mediated therapy can reduce the side effects of the drug because the microrobot can be precisely manipulated to the target position, and the loaded drug can be selectively released by ultrasound focus. Even if some drug transport proteins are offset during operation, drug losses can be minimized by using focused ultrasound active release drugs only at the target location [48]. Based on the excellent magnetism of Fe3O4, Zhong et al. [49] used a hybrid microbiological nanofiltration robot, using microalgae as living scaffolds, to “wear” magnetic coating coat, and target them to tumor tissue, which successfully improved the hypoxic microenvironment of tumors and effectively realized the diagnosis and treatment of tumor under the guidance of three modes of medical imaging: magnetic resonance, fluorescence, and photoacoustic. The photosynthetic biological hybrid micro/nano-swimming body system (PBNs) is to evenly coat superparamagnetic Fe3O4 nanoparticles to the surface of photosynthetic microalgae Spirulina platensis through the dip coating process to obtain biological hybrid magnetized micro nano-swimming bodies. This hybrid system maintains the efficient oxygen production activity of microalgae and the directional magnetic drive ability of Fe3O4 nanoparticles. Magnetic engineered PBNs can target and accumulate to the tumor under the control of external magnetic field, and produce oxygen in situ through photosynthesis to reduce the degree of hypoxia in the tumor, so as to improve the efficiency of radiotherapy. At the same time, the chlorophyll released by PBNs after radiation treatment can be used as a photosensitizer to produce cytotoxic reactive oxygen species under laser irradiation to realize collaborative photodynamic therapy. In the mouse orthotopic breast cancer model, enhanced combination therapy showed significant tumor growth inhibition. In addition, PBNs have not only excellent T2 mode magnetic resonance imaging function brought by Fe3O4 coating but also chlorophyll-based natural fluorescence and photoacoustic imaging functions, which can noninvasively monitor tumor treatment and changes in tumor microenvironment. More importantly, the micro nano-swimming body can be effectively degraded in vivo, which provides a transformation prospect for the application of biological hybrid materials in targeted delivery and biomedicine in vivo. Micro/nanorobots can also transport biological agents (e.g., viral vaccines) to treat metastatic tumors in the abdominal cavity (e.g., ovarian cancer). In vitro cell studies have shown that micro/nano-machines can prolong the interaction time between nanoparticles and macrophages, thus more effectively activating macrophages, causing an increase in immune stimulation, which, in turn, improves survival in mice. This solves the problem of passive therapy requiring multiple injections due to large peritoneal space and rapid excretion. In the direction of immunotherapy, active delivery has broad prospects in the treatment of different types of primary and metastatic peritoneal cavity tumors [50]. Multimodal treatment strategies that are more conducive to the diagnosis and precise treatment of diseases have received widespread attention from researchers. Xing et al. [51] selected marine magnetotactic bacteria (AMB-1) as a template and loaded nano photosensitizers on the bacterial surface by Michael addition reaction to construct an intelligent micro/nano biological robot. Through magnetic/optical sequential manipulation, magnetic navigation, tumor penetration, and photothermal ablation were realized in mice. The results show that micro-nanorobots, under the control of magnetic field, realize the precise migration control of single or group at micron scale and track it in real time through fluorescence and magnetic resonance dual-mode imaging. Using the magnetic and hypoxic integrated target of a micro-na biobot, breaking through the complex physiological barrier with photosensitive agent into the tumor, using remote near-infrared laser trigger to produce local high temperature, the visual precision treatment of tumor is realized.
The use of micro/nanorobots to transport live cells directly to the target area can improve their retention and survival. Thus, spherical and spiral magnetic micro/nanorobots have been developed for 3D culture and precise delivery of in vitro, discrete, and in vivo stem cells. These miniature robots are manufactured by 3D printing technology and exhibit rolling and spiral motion under the condition of an applied rotating magnetic field, which is more propulsion efficient and more suitable for biofluid than robots driven by magnetic field gradients. Hippocell neural stem cells proliferate on them and differentiate into astrocytes, protrusion glial cells, and neurons. In addition, micro/nanorobots can transfer rectal cancer cells in vitro to tumor microsomic tissue on the microchip of liver tumors. These results show that it is feasible for micro/nanorobots to carry out targeted stem cell transport and transplantation in various in vitro, exosome, and in vivo physiological fluid environments [52]. In addition, a super-magnetic/catalytic micro/nanorobot can move as a single robot and “team up” under the influence of a weak magnetic field to form a chain-shaped spherical structure that can effectively load and transport cancer cells. After loading DOX, they accurately capture breast cancer cells while releasing the drug through diffusion [53]. In addition to stem cell transplantation, micro/nanorobots can also be used as sperm carriers to assist in the fertilization process. For some sperm cells that are low or unable to move due to defective activity, Medina-Sánchez et al. have designed metal-coated-polymer micro-helix robots to transport sperm cells with motion disorders to help them achieve natural fertilization. Fluid channels simulate physiological conditions in which individual inactive living sperm is captured, transported, and released, and individual sperm cells are successfully transported to the cell walls of oocytes. Except for helical microbots, tubular microbots were also designed to capture transport sperm [54]. The advantage of this innovative fertilization method is its potential in vivo applicability, and, if it can target fertilization in the natural environment of oocytes, there is no need to transplant and replace oocytes. However, artificially transporting sperm to oocytes fertilization seems to have a long way to go.

3.2. Surgery Tool

Traditional surgical tools without micro/nanoscale surgical tools limit the ability to operate on such small scales. Miniaturized micro/nanorobots that can be used as surgical tools will have a clear advantage in reaching areas that are not accessible to catheters and blades. It is also possible to reduce the risk of infection, shorten recovery time, and improve the accuracy and control of surgery.
Using the external physical field and the characteristics of the material itself, micro/nanorobots can directly locate the focus to achieve disease treatment. Chen et al. manipulated magnetic bacteria-microrobots by focusing magnetic fields to target to kill pathogens [55]. The researchers first guided the magnetotactic bacteria-microrobot in the microfluidic chip, and then manipulated the microrobot to target and attach to Staphylococcus aureus. When the microrobot combined with Staphylococcus aureus, the oscillating magnetic field could significantly reduce the viability of Staphylococcus aureus. Although magnetic targeting device can kill Staphylococcus aureus, simple mixtures or solutions containing only Staphylococcus aureus cannot be killed. These results show that the use of magnetic targeting device is a promising method of targeted therapy of micro/nanorobots. In future research, it is necessary to explore the effects of pulsating blood flow, red blood cells, friction on magnetic bacteria-microrobot control, and the safety of magnetic bacteria in the human body. Resistance to bacteria can also rely on the action of microrobots themselves, such as the use of Ga/Zn micro/nanorobot degradation-produced Ga cations, as built-in antibiotics. Compared with passively used Ga particles, this method enhanced the diffusion of Ga ions and significantly improved the antibacterial efficiency of anti-H. pylori [56]. Cancer cells are more sensitive to heat than normal cells and suffer irreversible thermal damage in environments greater than 40 °C, with temperatures of 42 to 45 °C being enough to kill cancer cells. Therefore, it is possible to use biodegradable thermotherapy micro/nanorobots to convert electromagnetic energy into thermal energy under the action of alternating magnetic fields, as well as to reduce the viability of cancer cells by raising the temperature. The use of cancer cell lines in vitro has demonstrated the feasibility of this mediated targeted thermal therapy, which kills cancer cells in a way that minimizes damage to the body [47].
The application of injection therapy method in a glass body is expected to promote the development of ophthalmology. The traditional delivery methods rely on the random and passive diffusion of molecules, and they cannot quickly deliver concentrated drugs to the limited area behind the eyes. Most tissues, including vitreous ones, have a close macromolecular matrix as a barrier to prevent the penetration of particles. However, magnetically-driven spiral micro/nanorobots can actively reach the retina through vitreous humor. However, magnetically-driven spiral micro/nanorobots can actively pass-through glass body fluids to reach the retina. Among them, the diameter of the spiral is equivalent to the mesh size of the vitreous biopolymer network, and the surface coating is functionalized with perfluorocarbon. The coating minimizes the interaction between the spiral and the biopolymer (including the collagen bundle in the vitreous) and decreases the adhesion to the surrounding biopolymer network. With wireless excitation from the external magnetic field, large groups of spiral micro/nanorobots can be driven a few centimeters through the eyeball and can reach the retina within 30 min, reducing the delivery time to 1/10 of the original. The entire system is scanned using standard optical coherent faults. Complete operating procedures include glass in vivo injection, remote self-propelled, and noninvasive monitoring [57]. To improve the biocompatibility of micro/nanorobots and minimize the inflammatory response of micro/nanorobots when they enter the eye, Pokki et al. studied polypyrrole (PPy)’s application in gold-coated cobalt-nickel microrobots [58]. They used PPy, which has good long-term biocompatibility with a variety of cells, as a microstructure-protected functional coating and injected a coating-coated microrobot into the rabbit’s eye. The results showed that the biocompatibility of micro/nanorobots was enhanced by the use of PPy coating, and the inflammatory response was minimal compared to the controls not coated with PPy coating. All in all, microbots show potential suitability in drug delivery and retinal prefrontal peeling operations that block retinal veins.
Venous thrombosis, which has a high incidence worldwide, can often be life-threatening. At present, there are obvious shortcomings in the treatment of venous thrombosis, such as short half-life of thrombosis drug treatment, frequent large doses of systemic administration, which brings high medical costs and bleeding, body allergy, and blood pressure instability, and other side effects. Micro/nanobots can load drugs and, with their unique motor ability, release drugs in a controlled manner after deep blood clots, thereby significantly improving the therapeutic effect. Wan et al. have developed a platelet membrane modification, self-moving multi-stage hole nanorobot, used to treat venous thrombosis continuous targeted administration for short-term thrombosis and long-term anticoagulant purposes [59]. At the same time, the micro/nanobots has also made outstanding contributions to the common gastrointestinal problems and gastric wall injury. Bioprinting technology, which delivers new cells directly to the injured site to repair tissue, provides a potentially useful method for the treatment of this problem. The difficulty is that the current bioprinting technology is concentrated outside the human body, and the bioprinter is usually large. Without invasive surgery, it cannot provide enough space for internal tissue repair for printing operation. In order to overcome this problem, Zhao et al. developed a microrobot, which enters the human body through an endoscope for tissue repair in the body. Human gastric epithelial cells and human gastric smooth muscle cells were used as biological ink to simulate the anatomical structure of the stomach. The printed cells still maintained high viability and stable proliferation after 10 days of culture, which showed that the cells had good biological functions in the printed tissue scaffold. This work shows innovative progress not only in the field of biological micro/nanorobots but also in the field of clinical science [60].

This entry is adapted from the peer-reviewed paper 10.3390/mi13050648

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