INTRODUCTION:

Nanorobots are essentially Nano Electro Mechanical Systems (NEMS). These nanorobotic devices are comparable to biological cells and organelles in size. The technology of design, fabrication, and programming of these nanorobotics known as Nanorobotics¹. It is a multidisciplinary field requiring advanced level input from different areas of science and technology including, physics, chemistry, biology, medicine, pharmaceutical sciences, engineering, biotechnology and other biomedical sciences. Richard Feynman, Nobel laureate and a scientist predicted nanomachines to be devices of the future. The concept of medical nanodevices traveling in the human body was first viewed in the movie Fantastic Voyage (Twentieth Century Fox, winner of the 1966 Oscar for best visual effects).

Since then, Nano mechanics have become the matter of scientific or technical curiosity and debate for researchers. It is predicted that nanorobotics would deliver precedent results in medicine and drug delivery applications. These systems would be useful for drug targeting, controlled drug release, tumor diagnosis, cellular as well as genetic repair in the biological system². Specifically in medical nanorobotics, it appears that there exist two schools of thought concerning the practical feasibility of nanorobots. Apart from the general view of the scientific community, which considers it theoretically acceptable but actually impractical, there exists a pool of scientists working in molecular nanotechnology and mechanic synthesis for nanorobotic applications. Eminent scientists including Feynman, Merkle, Drexler and Freitas have contributed significantly in the Nanorobots applied to medicine hold a wealth of promise from eradicating disease to reversing the aging process. They will provide personalized treatments with improved efficacy and reduced side effects that are not available today. They will provide combined action drugs marketed with diagnostics, imaging agents acting as drugs, surgery with instant diagnostic feedback. The advent of molecular nanotechnology will again expand enormously the effectiveness, comfort and speed of future medical treatments while at the same time significantly reducing their risk, cost, and invasiveness. This science might sound like a fiction now, but nanorobotics has strong potential to revolutionize healthcare, to treat diseases in future³.

Nanorobots are mainly the nano-devices that are used for providing protection or treatment against pathogens in humans. They are designed to perform a particular task or sometimes tasks with precision at nanoscale dimensions of 1-100 nm. They are expected to work at atomic, molecular, and cellular levels in both medical and industrial fields. Advance in the areas of robotics, nano structuring, medicine, bioinformatics, and computers can lead to the development of the nanorobot drug delivery system. Some of the examples are reciprocate nanorobots, microbivore nanorobots, surgical nanorobots, and cellular repair nanorobots⁴. They have a diameter of about 0.5 to 3 microns and the main element used in nanorobots is carbon because of its inertness and strength in the form of diamond and fullerene. Techniques like Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM) are being employed to understand the molecular structure of the nanoscale devices. Such as quantum mechanics, thermal motions and friction, has been considered and resolved and discussions about the manufacturing of nano devices is growing up. The names nanobots, nanocides, nanites or nano mites have also been used to describe these hypothetical devices. The word "nanobot" is often used to indicate this fictional context and is an informal or even pejorative term to refer to the engineering concept of nanorobots. Bionanorobots are designed by harnessing properties of biological materials (peptides, DNAs), their designs and functionalities. This colossal array of potential applications in environmental watching for microorganisms and in health care as an example, imagine artificial cells (nanorobots) that patrol the cardiovascular system, notice tiny concentrations of pathogens, and destroy them. This might quantity to a programmable system, and may need sweeping implications in medication, inflicting a paradigm shift from treatment to bar⁵.

Ideal characteristics of Nanorobots⁶

· Nanorobots must have size in between 0.5 to 3 microns large with 10 nm parts.

· Nanorobots of larger size than the above will block capillary flow.

· It will prevent itself, from being attacked by the immune system by have passive, diamond exterior.

· It will communicate with the doctor by encoding messages to acoustic signals at carrier wave frequencies of 1-100 MHz.

· It might produce multiple copies of it to replace worn-out units, a process called self-replication.

Composition of nanorobots⁷

Biochip:

The combined use of nanoelectronics, photography and new biomaterials can be considered as a best possible way to enable the required manufacturing technology towards nanorobots for common medical applications, like surgical instrumentation, diagnosis and drug delivery so, practical nanorobots should be integrated as nanoelectronics devices, which will allow teleoperation and advanced capabilities for medical instrumentation⁸.

Bacteria Based:

This approach proposes the use biological micro-organisms, like Escherichia coli bacteria. Hence, the model uses a flagellum for propulsion purposes. The use of electromagnetic fields is normally applied to control the motion of this kind of biological integrated device, although his limited applications.

Nubots:

Nubot is an abbreviation for “nucleic acid robot”. They are organic molecular machines at the nanoscale. Biological circuit gates are based on DNA materials, which have been engineered as molecular machines to allow in-vitro drug delivery for the targeted region.

Positional Nano Assembly:

Nano factory collaboration 8, founded by Robert Freitas and Ralph Werkle in 2000, is a focused ongoing effort that is developing positionally- controlled diamond mecha-nosynthesis and diamondoid nano factory that would have the capability of building diamondoid medical nanorobots.

Figure 1: Composition of nanorobots

Advantages of Nanorobots^9,10

· The speed and durability of the bots are its main advantages.

· Nanorobot drug delivery systems with increased bioavailability

· As drug molecules are carried by nanorobots and released where needed the advantages of large interfacial area during mass transfer can be realized;

· Drug inactive in areas where therapy not needed minimizing undesired side effects.

· The upper limit of the size of nanorobot is 3 microns so that it can easily flow in the body without blocking the capillary flow.

· Manufacturing by batch processing reduces the cost even if the initial cost of development is high (if mass produced).

· As it is minimally invasive technique, therefore less post treatment care is required.

· Rapid elimination of disease.

· The major advantage of nanorobots is thought to be their durability, in theory, they can remain operational for years, decades or centuries.

· It has the ability to deliver payloads such as drugs, or healthy cells to the specific site.

· It minimizes surgeon mistakes.

· Nanorobot is that they can be used to kill infections that takes place in the body and grows without our knowledge.

Limitations of Nanorobots¹¹

· When different nanorobots are inserted to cure different diseases, the clusters may be formed inside the body.

· Installation cost is quite high.

· The nanorobot should be very accurate otherwise harmful events may occur.

· The design of thus robot is very complicated.

· Regulatory issues.

· Each nanorobot have different qualities and features, thus their effect also differs and thus might prove very dangerous to human health.

· Nanorobots, if misused by terrorists, could even be used as bio-weapons and may become a threat to the society.

· If nanobacteria that are present in our body can cause serious effects in our body, so can nanobots which are foreign to us. Hence, care has to be taken to overcome this drawback.

· If nanobots self-replicate, a harmful version of the bots could be created.

· Risk of Cancer.

· Biocompatibility.

· Difficulty of communicating with organic system.

· Must carry own (Limited) payload.

Types of Nanorobots:

1. Pharmacyte: It is a medical nanorobot having a size of 1-2 μm able to carrying up 1 μm a given drug in the tanks. They are controlled using mechanical systems for sorting pumps. They are provided with a molecular markers or chemotactic sensors that guarantee full targeting accuracy. Glucose and oxygen extracted from the local environments such as blood, intestinal fluid and cytosol are the onboard power supply (Figure 2). After the nanorobot completing task they can be removed or recovered by centrifuge nana pheresis¹².

Figure 2: Fictitious Pharmacyte

2. Respirocyte:

It is an Artificial Oxygen Carrier nanorobot which is about an artificial red blood cell. The power is obtained by endogenous serum glucose. This artificial cell is able to give 236 times more oxygen to the tissues per unit volume than RBCs (Red Blood Cells) and to administer acidity¹³. When the respirocyte passes through the lung capillaries, O2 partial pressure will be high and CO2 partial pressure will be low, therefore the onboard nano computer commands the sorting rotors to load in oxygen and release the carbon dioxide molecules (Figure 3). The respirocyte works as an artificial erythrocyte by mimicking the oxygen and carbon dioxide transport functions.

Figure 3: Respirocytes

3. Clottocytes:

This is a type of nanorobot, with a unique biological capability: “instant” hemostasis using clottocytes, or artificial mechanical platelets. It is known that platelets are roughly spheroidal nucleus-free blood cells measuring approximately 2 μm in diameter. Platelets join at a place of bleeding. Where they are activated, becoming tacky and lumping together to form a tampon that aid stamps the blood vessel and stop the bleeding¹⁴. They also delivery substances that help promote coagulating. The clotting function by clottocyte is essentially equivalent to that of natural platelets at about 1/10,000^th the concentration in the blood stream i.e. 20 clottocytes per cubic milimeter of blood. The theoretically designed clottocyte describes artificial mechanical platelet or clottocyte that would complete hemostasis in approximately 1 sec. fiber mesh that is compactly folded onboard. The response time of clottocyte is 100-1000 times faster than the natural hemostatic system. The fiber mesh would be biodegradable and upon release, a soluble film coating of the mesh would dissolve in contact with the plasma to expose sticky mesh. Reliable communication protocols would be required to control the coordinated mesh release from neighboring clottocytes and also to regulate multi-device activation radius within the local clottocyte population. As clottocyte-rich blood enters the injured blood vessel, the onboard sensors of clottocyte rapidly detects the change in partial pressure, often indicating that it is bled out of body (Figure 4).

Figure 4: Clottocytes

4. Chromallocyte:

The Chromallocyte would replace entire chromosomes in individual cells thus reversing the effects of genetic disease and other accumulated damage to our genes, preventing aging. Inside a cell, repair machine will first size up the situation by examining the cell’s contents and activity, and then take action by working along molecule-by-molecule and structure-by structure; repair machines will be able to repair the whole cell¹⁵.

Figure 5: Chromallocyte

5. Cellular repair nanorobots:

These little guys could be built to perform surgical procedures more precisely. By working at the cellular level, such nanorobots could prevent much of the damage caused by the comparatively clumsy scalpel¹⁶.

Figure 6: Diamondoid Cell-Repair Nanorobot

Medical Application of Nanorobots:

Nanorobots are expected to enable new treatments for patients suffering from different diseases and will result in a remarkable advance in the history of medicine. The use of nanorobots may advance biomedical intervention with minimally invasive surgeries and help patients who need constant body functions monitoring, or ever improve treatment efficiency through early diagnosis of possible serious diseases¹⁷.

The ability to guide nanorobots directly into diseased tissue could serve as a dynamic platform for the delivery of diverse types of cargoes for example pharmaceutical drugs, biologics, living cells, and inorganic therapeutics. Moreover, the stimuli that propel and guide micromotors can be used to improve drug targeting by inducing trigger the release of the therapeutic payload when the micromotor reaches a specific location. Nanorobots use diverse methods to carry therapeutic agents, including the use electrostatic or covalent interactions to entrapping them directly on their surface, or by embedding them inside responsive materials. The subsequent release of the therapeutic cargoes is based on diverse mechanisms, including autonomous release induced by a change in environment (changes in pH or temperature) and the use of triggered release induced by application of external fields (near infrared, ultrasound field). In both cases regardless of the loading methodology, either local or external stimuli can result in the change of surface proprieties or degradation of a material that entails the release of the loaded therapeutic cargo¹⁸.

1. Pharmaceutical Drugs:

Pharmaceutical drugs consist mostly of small synthetic chemicals designed to treat and prevent diseases. Regardless of the type of administration, the efficacy of drug formulations is often compromised by poor pharmacokinetic proprieties of pharmaceutical drugs, such as short half-life, limited biodistribution, and rapid clearance from the body. Therefore, repeated administrations in high dosages are inevitable to induce the desired therapeutic effect, which could lead to increased toxicity and side effects (e.g., cardiotoxicity). In this direction, micro/nanorobots have the potential to overcome this challenge by offering amotile platform capable of delivering a precise dosage in the target area rather than relying on the systemic release of large therapeutic dosages. One of the first examples of micro/nanorobots for delivery of pharmaceuticals was reported a decade ago, where a catalytic nanowire nanorobot was used as a nanoshuttle to pick up, transport,and release doxorubicin/iron oxide loaded poly D,L-lacticco- glycolic acid (PLGA) liposomes. The microrobot contained a nickel segment that served as both a magnetic navigation guide and anchor for PLGA liposomes through weak magnetic interaction. The rapid change of direction resulted in the dislodging of the PLGA liposome due to the increased drag force imposed on the particle. A similar approach was reported using a flexible magnetic microrobot composed of a nickel head and a flexible silver tail. The use of nickel/titanium helical microrobots was reported to load calcein loaded liposomes. The vesicles were adsorbed over the TiO₂ surfaces of the microrobot via electrostatic interaction. Superparamagnetic microengines arranged in a train-like structure have also been used to capture cells and simultaneously release doxorubicin by diffusion. In this work, the micro/nanorobot was functionalized with to groups on its outer surface, which served to bind cancer cells through their surface and load drugs such as doxorubicin¹⁹.

Figure 7: Ultrasound propelled nanowires for near-IR triggered delivery of doxorubicin.

Pharmaceutical agents have also been entrapped directly on the surface of micro/nanorobots by using electrostatic interactions. The use of electrostatic forces was reported to load the positively charged brilliant green antiseptic drug into a negatively charged polypyrrole–polystyrene sulfonate segment of an ultrasound propelled nanorobot. The electrostatic interaction was stable at pH 7. On the other hand, when the environmental Ph became relatively acidic (pH 4) the polypyrrole–polystyrene material segment was protonated, resulting in a triggered release of the loaded Brilliant green drug molecule. In another example, reduced graphene oxide/platinum microrockets were used to transport doxorubicin. The reduced graphene oxide served to load the pharmaceutical drug via 𝜋–𝜋 interactions. This method presented a unique trigger-release mechanism based on electrochemical stimuli that disrupt the interactions between the doxorubicin and the graphene surface of the micro/nanomotor. Moreover, the use of an electrochemical stimuli as a release mechanism was further expanded by using bismuth coatings to load the therapeutic payload²⁰. The injection of electrons into the motor surface caused electrostatic repulsions and the loading of doxorubicin. Ultrasound propelled porous nanowire surface was functionalized with an anionic coating that permitted the electrostatic loading of doxorubicin into the micro/nanorobot structure. The porous segment was responsible for increasing the drug loading capacity and for facilitating the release by photothermal effect upon radiation of near-infrared light (Figure 7). Similarly, mesoporous chemically propelled Janus microrobots were used for near-infrared triggered delivery. The use of pH-sensitive polymers is potentially ideal for autonomous and trigger-release of pharmaceutical drugs next to cancer sites, as the byproducts of cancer cell metabolites result in a local acidic environment. Another concept for drug delivery relies on inducing drug release based on mechanical rotation. Amicrorobot powered by rotating and alternating currents was used to deliver Nile blue loaded onto the nanorobot via weak electrostatic interactions. The release of this model drug was controlled by modulating the mechanical rotation rate of the nanorobot. Moreover, the use of urea powered nanorobots was reported to enhance doxorubicin release kinetics. A mesoporous silica shell was loaded via electrostatic interactions with a pharmaceutical, doxorubicin, and urease, a biocatalytic enzyme capable of decomposing urea and harnessing the chemical energy into fluid mixing. The limitation of electrostatic loading is that multiple environmental factors can result in dislodging of the loaded pharmaceutical due to the weak binding of the therapeutic cargo with the micro/nanorobot surface²¹.

Figure 8: Magnesium powered microrobot for stomach pH neutralization and sustain drug release.

The use of magnesium powered microengines has been used toward targeted drug delivery inside the gastrointestinal tract, using biofluids as fuel. Magnesium microengines coated with a poly (N-isopropylacrylamide) have been used to induce temperature-controlled delivery of fluorescein isothiocyanate as a model drug in simulated body fluids or blood plasma. The use of acid-driven micromotors was reported based on Mg coated with a cargo-containing pH-responsive polymer, to neutralize gastric acid in a mouse model. The consumption of the magnesium core by the acidic environment in the gut led to the depletion of hydrogen protons from the gastric environment, thus raising the pH to a neutral environment without the requirement of a proton pump inhibitor. The increase in pH resulted in the degradation of the pH sensitive polymer containing the loaded drug model (Figure 8). Taking advantage of this principle, further work demonstrated the first in vivo micro/nanorobot therapeutic application by delivering clarithromycin, loaded into a PLGA layer over the magnesium propellant, as a model antibiotic to treat Helicobacter pylori infection inside a mouse stomach. More recently, magnesium microrobots loaded with ampicillin were reported for bacterial treatment. Another animal study used a zinc/iron engine toward gastrointestinal delivery tool of doxorubicin. The use of magnesium-based micromotor was reported to enhance therapeutic efficacy doxorubicin by a synergistic effect on site hydrogen generation²².

Figure 9: Biohybrid micromotor consisting of a magneto-tactic bacterium transporting liposomes.

Biotemplated chemically propelled micro/nanorobots have also been used as carriers for different pharmaceuticals. Platinum-coated plant virus capsules, including brome mosaic virus and cowpea chlorotic mottle virus, were used as nanotemplates for the delivery of tamoxifen, loaded inside their hollow interior. When the virus was internalized inside a cell, its structure denaturalized due to a lower pH environment, which resulted in the autonomous release of the drug. Another type of biotemplate was fabricated by turning red blood cells into microrobots. This biorobot was fabricated by incorporating quantum dots, doxorubicin, and magnetic nanoparticles into red blood cell micromotors. The fluorescent emission of both quantum dots and doxorubicin provided direct visualization of their loading inside the red blood cell motors at two distinct wavelengths. They demonstrated that these red blood cell micromotors could transport imaging and therapeutic agents at high speed and spatial precision through a complex microchannel network. Pollen structures were used to obtain different microengine proprieties by taking advantage of their resilient outer layer and hollow interior. More recently, a fully organic microrobot consisting of urease-powered Janus platelet micromotor was engineered by immobilizing enzyme onto the surface of natural platelet cells toward selective adhesion to cancer cells and subsequent delivery of doxorubicin. Microorganism-driven micro/nanorobots have also been used as targeted drug delivery systems. Motile sperm loaded with doxorubicin were integrated into a 3D-printed magnetic tubular microstructure that permitted magnetic guidance and assistance to push against the tumor site. The use of electrostatic self-assembly was used to fabricate biohybrid sperms and Chlamydomonas Reinhardtian based microrobots carrying magnetic nanoparticles and therapeutic loads. In another example, Escherichia coli (E. coli) was captured with drug-loaded polyelectrolyte multilayer microparticles containing magnetic nanoparticles, and doxorubicin. This work reported in vitro magnetic guided delivery of doxorubicin encapsulated in the multilayer microparticle toward 4T1 breast cancer cells. The use of magneto tactic bacteria was used to carry drug-loaded nanoliposomes (Figure 9)²³. An external magnetic field was used to guide the biohybrids toward cancer cells. Another advantage of the use of biohybrids as motile carriers relies on their build-in sensing capabilities because microorganisms can detect chemical cues in their environment to find food or avoid danger. Thus, hybrid neutrophil micromotors were loaded with therapeutic cargoes. Neutrophils can detect chemoattractant gradients produced in inflammatory sites and move eliminating pathogens. Doxorubicin-loaded biohybrid sperm have also shown a chemotactic movement to a “sperm activating and attracting factor” molecule. The biohybrid platform was tested in vivo for the targeted delivery of doxorubicin into human ovarian cancer cells. These contributions are of great interest as they use biodegradable materials to transport the therapeutic payloads, leaving nontoxic by products behind²⁴.

2. Biologics:

Another relevant area of research has been focused on the micro/nanorobot delivery of biological components, such as proteins, tissue plasminogen activator for thrombolysis, viral vaccines, or antibodies. In contrast to synthetic pharmaceutical drugs, biologics are therapeutic agents that are commonly produced by living systems, including proteins or small segments of a biological component. For example, The recombinant tissue plasminogen activator (rtPA or tPA), a protein used to break the cross-linked fibrins that provide blood clot structure, has been a highly studied target for micro/ nanomotors in the precision medicine tools for delivery²⁵. While t-PA is a Food and Drug Administration (FDA) approved biological, there is an important risk of side effects, such as symptomatic intracranial haemorrhages. Therefore, this protein requires control of the dosage as well as effective delivery to the blood clot to reduce secondary risks associated with stroke treatment. The first targeted delivery methods for this biological consisted of micro and nanocarriers transporting a small dose of tPA with magnetic nanoparticles coated on a biodegradable polymeric matrix driven to the blood clot via external magnetic fields. Taking advantage of the shear stress caused by the constriction in a vessel, a passive diffusion strategy for tPA delivery was developed. Coated tPA-based microaggregates of PLGA nanoparticles, similar in size to natural platelets, were naturally targeted to the blood clot where tPA induced rapid dissolution of the obstruction and allowed normal flow dynamics²⁶.

Figure 10: Accelerated catalytic reactivity of tissue plasminogen activator (t-PA) mediated blood clot degradation by magnetically powered microrobots.

An active strategy using rotating nickel-based magnetic nanorobots to improve the local mass transport of t-PA at the blood clot interface has also been reported. The robots were used along with free t-PA to act as an independent input for efficiency. Using a polydimethylsiloxane fluidic channel model to mimic blood vessels, they directed the motor to the clot, produced active motion of the nanorobot, and enhanced the thrombolysis by hydrodynamic convection (Figure 10). The clinical application of these nickel-based robots was limited because of the toxicity of the material. Therefore, other groups attempted using biocompatible magnetic micromotors, based on superparamagnetic iron oxide (Fe3O4). The tPA was covalently loaded onto the Fe3O4 nanomaterials. Iron oxide nanobots loaded with tPA targeted clots in the brain under magnetic guidance. The application of a rotational magnetic field allowed performing enough mechanical force to perforate the clot and release the tPA within 30 min into the clot. This approach enabled the plasminogen to reach new binding sites and enhanced the susceptibility of the clots to lysis. However, a limitation of this ferromagnetic Fe3O4 nanorods t is the tendency of these structures to aggregate. New works have tested the capabilities of porous superparamagnetic Fe3O4–C nanorobots that encapsulate tPA to deliver this biological in a target area. After the injection of a solution containing the robots near the brain, they target the blood clot occluded in the middle cerebral artery in the mice. The microrobots were guided by an external magnet, located in proximity to the blood clot. In this case, the clot was dissolved via both tPA (chemical lysis) and rotating nanorobots (mechanical lysis) with the aid of an external rotating magnetic field. More importantly, the microcarriers did not cause liver or kidney damage and could be discharged from the kidney and collected in urine with a magnet or from the biliary system since they were found in bile tracts. More recently, the use of microgel spherical microrobots embedded with aligned magnetic nanoparticles toward thrombolysis by tPA were reported²⁷.

3. Living cells:

Recent developments in the use of micro/nanorobots as cell carriers offer a unique opportunity for regenerative medicine. The ability to deliver cells directly into the target tissue or stem cell could increase their retention rate and survival. Additionally, it could help address some of the significant challenges of regenerative cell transplantation. Taking advantage of the large loading capacity of micro/nanorobots, they can be engineered with various types of cells and possess different biological features. One strategy consists of using their microrobot surface as a cell culture scaffold, serving as a mechanical support for the cells to grow over a motile structure. SU-8 microcages, coated with nickel for magnetic response and titanium for compatibility, were used to grow human embryonic kidney 293 cells and subsequently controlled by external magnetic fields. Microrobotic cell scaffolds made of programable materials were used for inducing biochemical and biophysical cues that regulated cell fate before and during their targeted delivery. The motile scaffold consisted of a hollow magnetic cylinder wrapped by a double helix. The inner cavity walls comprised of diverse niche components, including collagen, hyaluronan heparin, and fibronectin, entrapped in a gelatin matrix. This inner wall served to increase the adhesive stability of a transported cell, protect it from undergoing differentiation during transport, and directing it toward the desired lineage²⁸. The stem cell loaded microrobot could move along predetermined trajectories under external rotating magnetic fields (Figure 11) Moreover, the microrobot scaffold demonstrated the ability to induce preosteogenic differentiation of transported stem cells by including bone morphogenetic protein-2 embedded inside the inner matrix. Larger functionalized hydrogel-based robots have been used as cell carriers with the advantage of generating assemblies of different types of cells.

Figure 11: Microrobot carrier with programable surfaces to control cell differentiation

4. Inorganic therapies²⁹

Large-scale surgical tools do not have analogousmicro/nanoscale counterparts, hindering the ability to operate at this small scale and resulting in minimal tissue penetration. Miniaturization of surgical tools could provide distinct advantages due to their small size and ability to access places where catheters and blades cannot. Micro/nanorobotics could serve as surgical tools, aiming to penetrate or retrieve cellular tissues directly. These untethered minimally invasive systems would provide access to regions of the body that their large-scale robotics counterparts are not able to reach. Besides, they will have the potential to reduce the risk of infection and recovery time. Indeed, micro/nanorobot could complement current surgical robotics tools, aiming to increase the precision and control of human surgeons³⁰.

Biopsy/Sample collection:

Researchers have illustrated micro/nanorobotic devices that collect tissue samples and bacteria for reduction of damage to tissue, via lowering invasive surgery, and advancing diagnosis. The milli-meter size range permits to integrate builtin communication electronics into the motile robotic pills. However, further miniaturization from these devices would allow sampling even smaller regions. For instance, star-shaped grippers that are capable of responding to diverse environmental stimuli to close down and capture tissue have been reported (Figure 12a). These tiny medical devices have been evaluated using animal models, demonstrating the ability to excise tissue from a pig bile duct. Biocompatible designs made of responsive hydrogels embedded with magnetic alginate microbeads were magnetically guided and presented infrared light-induced gripping (Figure 12b)³¹.

Micro/nanorobotics were also explored to collect bacteria inside the body. The use of motile robotic collectors could help expand the understanding of the biome. Deployable microtraps were used for sequestering motile bacteria from a liquid environment. The device consisted of micro engineered funnels that confine bacteria into subdivision trap chambers. More recently, motile microtraps, consisting of an onion inspired multilayer structure, were used to collect motile pathogens. The depletion of the magnesium engine core resulted in a hollow structure that served as a structural trap. Moreover, the inner layer released a chemoattractant (serine) that served to attract nearby motile microorganisms and capture E. coli within the microtrap structure (Figure 12c). These examples demonstrate the potential of micro robotic devices for biopsy and sample collection. However, the main challenge that these applications face is the ability to preserve the specimen and avoid contamination. Moreover, motile micro/nanorobots could be used to collect diverse biomarkers, such as exosomes (small vesicles excreted from cells) and disease markers³².

Figure 12: Microrobot based biopsy and sampling. (a) Star-shaped griper collecting tissue (b) Star gripper collecting red blood cells (c) Motile microtrap collecting pathogens.

Tissue Penetration:

The micro-bullet consisted of a hollow tube (5 μm diameter) filled with perfluorocarbon emulsions electrostatically interacting with the interior surface of the hollow structure. The application of high intensity focused ultrasound pulse directed at the micro-bullet, vaporized the perfluorocarbon emulsion, rapidly changing its state from liquid to gas, serving as a propellant. Such remarkable speed provided enough thrusts for deep tissue penetration, ablation, and destruction (Figure 13). A modified version of this design results in a functional microscale cannon, where the hollow conical structure was filled with a hydrogel containing 1 μm nano-bullets or fluorescent microspheres, and perfluorocarbon emulsion. The application of the focused ultrasound field resulted in the spontaneous vaporization of the perfluorocarbon emulsion, resulting in the rapid ejection of the nano-bullets at high speed in the minute of meters per second. The acoustic micro-cannons were able to deliver nanoparticles into phantom tissue, reaching penetration lengths 20 μm. Arrays of micro-cannons have also been translated into transdermal patches, consisting of hundreds of micropores loaded with the therapeutic payload and the perfluorocarbon emulsion. The release kinetics was tested using phantom tissues and pigskin. The use of acoustic droplet vaporization micro-ballistic delivery resulted in enhanced delivery of the anesthetic agent lidocaine when compared to passive diffusion or the use of ultrasound pulses by themselves.

Figure 13: Ultrasound powered microbullet for tissue penetration and cleaving.

Financial and Market Challenges:

When analyzing the technology readiness of micro/nanorobots as an emerging technology, their clinical translation potential is still in the early stages. The maturity of the field will progress based on its commercialization outlook. Therefore, one of the major barriers to their clinical translation involves securing the cost of funding early developments in university and private research. No dilute funding is available but is quite competitive. Therefore, novel technologies could benefit from academic-industry partnerships. The main financial cost that should be considered involves scientific staff, cost of equipment and materials, regulatory costs, and intellectual property. Universities offer a unique setting for developing technological innovation as multiple fields of study (engineering, medicine, business, law) are under the same institution³³. Researchers in the field should expand their patenting, as technological developments without proper intellectual property protection are unlikely to secure funding from the private sector. Commercial enterprises are also essential to advance the field of robotics, as profits could be reinvested into research and development of new micro/nanorobotic technology. Finally, there is the market risk. Although nanorobots have shown promising results in in-vitro and in-vivo studies, they currently lack proof of concept application that offers a distinct potential advantage over the state of the art. In order to achieve lab to market transition, commercial enterprises in micro/nanorobotics should identify unmet needs that could validate the market of medical microrobots. Initial micro/nanorobotic commercial ventures should focus on complementing existing medical devices. Although there is a long road ahead, once micro/ nanomotors have initial proof of concept in human subjects, leveraging micro/nanorobots in precision medicine will improve diagnosis and treatments, which could lead to improve patient’s life^34.

Future Scope³⁵

In the present world most of the treatment which is required for curing problems inside the human body is done through surgical operations. Thus the use of nanorobots helps us to cure all those problems without surgery. Comparing with the surgical methods, using nanorobots provides more controlled medical treatment. In the case of cancer treatment using nanorobots to destroy the cancer cells helps in replacing chemotherapy. As the future scope, medical nanorobots can be utilized in the area of eye surgery. The nanorobots will make surgical procedures and medical treatments safe for all the patients and will be an effective tool for targeting the source of dreadful diseases. The dimensions of nanorobots are made smaller to prevent the damages caused to the tissues. Another future scope of nanorobotics in the field of biotechnology where it’s mainly focuse on information delivery not on the medicine. It will be programmed in such a way that it will deliver the data to the brain. Dr. Richard Thompson, a former professor of ethics, has written about the ethical implications of nanotechnology. He says the most important tool is communication, and that it's pivotal for communities, medical organizations and the government to talk about nanotechnology now, while the industry is still in its infancy. Will we one day have thousands of microscopic robots rushing around in our veins, making corrections and healing our cuts, bruises and illnesses? With nanotechnology, it seems like anything is possible. nanorobot technology is to re- engineer our bodies to become resistant to disease, increase our strength or even improve our intelligence. Some believe that semiautonomous nanorobots are right around the corner doctors would implant robots able to patrol a human's body, reacting to any problems that popup³⁶.

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Received on 29.04.2022 Modified on 09.10.2022

Asian J. Res. Pharm. Sci. 2023; 13(1):19-28.

DOI: 10.52711/2231-5659.2023.00004