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  In this article
 »  Abstract
 » Introduction
 »  Nanorobots: What...
 »  Proposed Nanorob...
 »  Chemical Signals...
 »  System Implement...
 » Nanorobot Simulation
 » Disadvantages
 » Conclusions
 »  The Architecture...
 »  References
 »  Article Figures

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  Table of Contents  
REVIEW ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 2  |  Page : 236-241
 

Design, architecture and application of nanorobotics in oncology


1 Departments of Oral and Maxillo-Facial Pathology, Seema Dental College and Hospital, Rishikesh, Uttarakhand, India
2 Departments of Oral Medicine and Radiology, Subharthi Dental College and Hospital, Meerut, Uttar Pradesh, India

Date of Web Publication5-Feb-2016

Correspondence Address:
S Saxena
Departments of Oral and Maxillo-Facial Pathology, Seema Dental College and Hospital, Rishikesh, Uttarakhand
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.175805

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 » Abstract 

Oncologists all over the globe, relentlessly research on methodologies for detection of cancer and precise localization of cancer therapeutics with minimal adverse effects on healthy tissues. Since the previous decade, the fast growing research in nanotechnology has shown promising possibilities for achieving this dream of every oncologist.Nanorobots (or nanobots) are typical devices ranging in size from 0.1 to 10 μm and constructed of nanoscale or molecular components. Robots will augment the surgeon's motor performance, diagnostic capability and sensations with haptics and augmented reality. The article here aims in briefly describing the architecture of the nanorobots and their role in oncotherapy. Although, research into nanorobots is still in its preliminary stages, the promise of such technology is endless.


Keywords: Cancer, nanorobots, nanotechnology, oncotherapy


How to cite this article:
Saxena S, Pramod B J, Dayananda B C, Nagaraju K. Design, architecture and application of nanorobotics in oncology. Indian J Cancer 2015;52:236-41

How to cite this URL:
Saxena S, Pramod B J, Dayananda B C, Nagaraju K. Design, architecture and application of nanorobotics in oncology. Indian J Cancer [serial online] 2015 [cited 2019 Oct 18];52:236-41. Available from: http://www.indianjcancer.com/text.asp?2015/52/2/236/175805



 » Introduction Top


Nanotechnology is popularly known as the science of the small or scientifically described as the technology to develop materials and structures of the size range from 1 to 10 nm. Oncologists all over the globe, relentlessly research on methodologies for detection of cancer and precise localization of cancer therapeutics with minimal adverse effects on healthy tissues. Since the previous decade, the fast growing research in nanotechnology has shown promising possibilities for achieving this dream of every oncologist.[1]

Burgeoning interest in the medical applications of nanotechnology has led to the emergence of a new field called nanomedicine.[2],[3],[4] Most broadly, nanomedicine is the process of diagnosing, treating and preventing disease and traumatic injury, of relieving pain and of preserving and improving human health, using the molecular tools and molecular knowledge of the human body.[2],[5]

Nanorobotics is the technology of creating machines or robots at or close to the microscopic scale of nanometers (10−9).[3]

More specifically nanorobotics, refers to the still largely theoretical nanotechnology engineering discipline of designing and building nanorobots. Nanorobots (or nanobots) are typical devices ranging in size from 0.1 to 10 µm and constructed of nanoscale or molecular components. As no biological nanorobots have so far been created they remain a hypothetical concept at this time. Another definition sometimes used is a robot, which allows precision interactions with nanoscale objects, or can manipulate with nanoscale resolution. Following this definition even a large apparatus such as an Atomic force microscope (AFM) can be considered a nanorobotic instrument when configured to perform nanomanipulation. Furthermore, macroscale robots or microrobots, which can move with nanoscale precision can also be considered nanorobots.[6]

Molecular nanotechnology (MNT) or nanorobotics [2],[7],[8] takes as its purview the engineering of complex nanomechanical systems for medical applications. Just as biotechnology extends the range and efficacy of treatment options available from nanomaterials, the advent of MNT will again expand enormously the effectiveness, precision and speed of future medical treatments while at the same time significantly reducing their risk, cost and invasiveness. MNT will allow doctors to perform direct in vivo surgery on individual human cells. The ability to design, construct and deploy large numbers of microscopic medical nanorobots will make this possible.[9]

Nanorobots are expected to provide advances in medicine through the miniaturization from microelectronics to nanoelectronics.[10] The aim of this article is to present the future use of nanorobots to combat cancer. Cancer can be successfully treated with current stages of medical technologies and therapy tools. However, a decisive factor to determine the chances for a patient with cancer to survive is: How earlier it was diagnosed; what means, if possible, cancer should be detected at least before the metastasis has begun. Another important aspect to achieve a successful treatment for patients is the development of efficient targeted drug delivery to decrease the side-effects from chemotherapy. Considering the properties of nanorobots to navigate as blood-borne devices, they can help on such extremely important aspects of cancer therapy.[10] Nanorobots with embedded chemical biosensors can be used to perform detection of tumor cells in early stages of development inside the patient's body.[11],[12] Integrated nanosensors can be utilized for such a task in order to find intensity of E-cadherin signals.[13] According to current theories, nanorobots will possess at least rudimentary two-way communication; will respond to acoustic signals and will be able to receive power or even reprogramming instructions from an external source through sound waves. A network of special stationary nanorobots might be strategically positioned throughout the body, logging each active nanorobot as it passes and then reporting those results, allowing an interface to keep track of all devices in the body. A doctor could not only monitor a patient's progress, but change the instructions of the nanorobots in vivo to progress to another stage of healing. When the task is completed, the nanorobots would be flushed from the body.[14] Here, we aim to describe the use of nanorobots in oncology and also their hardware architecture based on nanobioelectronics.

Historical perspective

In his remarkably prescient 1959 talk “There's Plenty of Room at the Bottom,” the late Nobel physicist Richard P. Feynman proposed employing machine tools to make smaller machine tools, these to be used in turn to make still smaller machine tools and so on all the way down to the atomic level.[15] Feynman was clearly aware of the potential medical applications of the new technology he was proposing. He said, “A friend of mine (Albert R. Hibbs) suggests a very interesting possibility for relatively small machines. He says that, although it is a very wild idea, it would be interesting in surgery if you could swallow the surgeon. You put the mechanical surgeon inside the blood vessel and it goes into the heart and looks around (Of course the information has to be fed out). It finds out which valve is the faulty one and takes a little knife and slices it out. Other small machines might be permanently incorporated in the body to assist some inadequately functioning organ.” Later in his historic lecture in 1959, Feynman considered the possibility, in connection with biological cells, “that we can manufacture an object that maneuvers at that level!” The vision behind Feynman's remarks became a serious area of inquiry two decades later, when Eric Drexler, published a technical paper [15] suggesting that it might be possible to construct, from biological parts, nanodevices that could inspect the cells of a living human being and carry on repairs within them. This was followed a decade later by Drexler's seminal technical book [8] laying the foundations for molecular machine systems and molecular manufacturing and subsequently by Freita's technical books on medical nanorobotics.[9]


 » Nanorobots: What Are They? Top


Nanorobots are theoretical microscopic devices measured on the scale of nanometers (1 nm equals 1 millionth of 1 mm). When fully realized from the hypothetical stage, they would work at the atomic, molecular and cellular level to perform tasks in both the medical and industrial fields that have until now been the stuff of science fiction. Nanomedicine's nanorobots are so tiny that they can easily traverse the human body. Scientists report the exterior of a nanorobot will likely be constructed of carbon atoms in a diamondoid structure because of its inert properties and strength. Super-smooth surfaces will lessen the likelihood of triggering the body's immune system, allowing the nanorobots to go about their business unimpeded. Glucose or natural body sugars and oxygen might be a source for propulsion and the nanorobot will have other biochemical or molecular parts depending on its task. Nanomachines are largely in the research and-development phase,[16] but some primitive molecular machines have been tested. An example is a sensor having a switch approximately 1.5 nm across, capable of counting specific molecules in a chemical sample. The first useful applications of nanomachines, might be in medical technology, where they might be used to identify cancer cells and destroy them.[17]


 » Proposed Nanorobotic Theory Top


Since nanorobots would be microscopic in size, it would probably be necessary for very large numbers of them to work together to perform microscopic and macroscopic tasks. These nanorobot swarms, both those which are incapable of replication and those which are capable of unconstrained replication in the natural environment. The word “nanobot” (also “nanite,” “nanogene,” or “nanoant”) is an informal or even pejorative term used to refer to the engineering concept of nanorobots. The word nanorobot is the correct technical term in the nonfictional context of serious engineering studies. Some proponents of nanorobotics, hold the view that nanorobots capable of replication outside of a restricted factory environment do not form a necessary part of a purported productive nanotechnology and that the process of self-replication, if it were ever to be developed, could be made inherently safe. They further assert that free-foraging replicators are in fact absent from their current plans for developing and using molecular manufacturing.[17]


 » The Architecture of Nanorobot Top


The architecture is based on two criteria, which are means of nanorobot navigation and methods to attach to the cancerous cells. The way a nanorobot moves in a liquid environment is the main consideration during the design. It is important that the device is able to have a smooth trajectory path while navigating in the blood environment and at the same time does not cause any damage to other cells. The tentacles need to have a very high responsive rate in order to move its tentacles forward just in time to capture the cancerous cell once it is detected. On the other hand, a microcomputer consisting of a miniature processor might be needed to provide a “brain” to the nanorobot.[18]

The body of the nanorobot will be constructed from carbon nanotube due to its intrinsic property where they tend to absorb near infrared light waves, which pass harmlessly through human cells. Ultrasonic sensors are attached around the body of the nanorobot for collision avoidance purposes. This is to prevent nanorobot from knocking onto each other as well as other cells in the blood vessels. Folate materials on the body of the nanorobot act as an agent that will cause the attraction of the nanorobot to the cancerous cells, which is also known as the folate-receptor cells. For modeling purposes, the folate material is modeled as an object attached to the nanorobot, rather than a coating so that the viewer can have a better visualization of the treatment process. The flagella provide the movement the nanorobot in the blood environment. It is powered by flagella motors, which is a set of rotary motor that is able to generate an impressive torque, driving a long, thin, helical filament that extends several cell bodies into the external medium. These are necessary to help the cell decide which way to go, depending on the change of concentration of nutrients in the surroundings.[18]

The rotary motion imparted to the flagella needs to be modulated to ensure the cell is moving in the proper direction as well as all flagella of the given nanorobot are providing a concerted effort toward it. When the motors rotate the flagella in a counterclockwise direction as viewed along the flagella filament from outside, the helical flagella create a wave away from the cell body. Adjacent flagella subsequently intertwine in a propulsive corkscrew manner and propel the nanorobot. When the motor rotates clockwise, the flagella fly apart, causing the bacteria to tumble, or change its direction. The flagella motors allow the nanorobot to move at speed as much as 25 μm/s with directional reversals occurring approximately 1/s. The assembled nanorobot is roughly approximate to be within the range of 0.5 microns to 0.8 microns, taking into consideration the size of the smallest blood vessels, which is the capillary. The size of a capillary is found to be around 5-10 μm in diameter. Having to design a nanorobot within that range, the nanorobot can definitely navigates in the blood stream [18] [Figure 1].
Figure 1: Architecture and design of a nanorobot (Courtesy of picture: Nanotechnology News Network. Author: Analyst Svidinenko Yuriy)

Click here to view


Manufacturing technology

The ability to manufacture nanorobots may result from current trends and new methodologies in fabrication, computation, transducers and manipulation. Depending on the case, different gradients on temperature, concentration of chemicals in the bloodstream and electromagnetic signature are some of the relevant parameters for diagnostic purposes.[19] Complementary metal oxide semiconductor (CMOS) very large scale integration systems design using deep ultraviolet lithography provide high precision and a commercial way for manufacturing early nanodevices and nanoelectronics systems. The CMOS industry may successfully drive the pathway for the assembly processes needed to manufacture nanorobots, where the joint use of nanophotonic and nanotubes may even accelerate further the actual levels of resolution ranging from 248 nm to 157 nm devices.[20]

Chemical sensor

Chemical nanosensors can be embedded in the nanorobot to monitor E-cadherin gradients. Thus, nanorobots programmed for such a task can make a detailed screening of the patient whole body. In various medical nanorobotic architecture, the mobile phone is applied to retrieve information about the patient conditions. For that, it uses electromagnetic waves to command and detect the current status of nanorobots inside the patient.[21],[22]


 » Chemical Signals Inside the Body Top


Chemical signals and interaction with the bloodstream is a key aspect to address the application of nanorobots for cancer therapy. The nanorobot sensing for the simulated architecture in detecting gradient changes on E-cadherin signals is examined. To improve the response and bio-sensing capabilities, the nanorobots maintain positions near the vessel wall instead of floating throughout the volume flow in the vessel an important choice in chemical signaling is the measurement time and detection threshold at which the signal is considered to be received. Due to background concentration, some detection occurs even without the target signal. After the first nanorobot has detected a tumor for medical treatment, it can be programmed to attach on it. Then, beyond attracting a predefined number of other nanorobots to help for incisive chemotherapeutic action with precise drug delivery above the tumor, the architecture permits it to use wireless communication to send accurate position for the doctors informing that a tumor was found.[23]

Power supply

The use of CMOS for active telemetry and power supply is the most effective and secure way to ensure energy as long as necessary to keep the nanorobot in operation. The same technique is also appropriate for other purposes like digital bit encoded data transfer from inside a human body.[24] Thus, nanocircuits with resonant electric properties can operate as a chip providing electromagnetic energy supplying 1.7 mA at 3.3 V for power, allowing the operation of many tasks with few or no significant losses during transmission.[25] Radio frequency (RF)-based telemetry procedures have demonstrated good results in patient monitoring and power transmission with the use of inductive coupling using well-established techniques already widely used in commercial applications of radio frequency identification (RFID). The energy received can be also saved in ranges of ~1 μW while the nanorobot stays in inactive modes, just becoming active when signal patterns require it to do so.[26]

Data transmission

The application of devices and sensors implanted inside the human body to transmit data about the health of patients can provide great advantages in continuous medical monitoring.[10] Most recently, the use of RFID for in vivo data collecting and transmission was successfully tested for electroencephalograms (EEG).[25] For communication in liquid workspaces, depending on the application, acoustic, light, RF and chemical signals may be considered as possible choices for communication and data transmission.[27] Chemical signaling is quite useful for nearby communication among nanorobots for some teamwork coordination.[10] Using integrated sensors for data transfer is the better answer to read and write data in implanted devices. Teams of nanorobots may be equipped with single chip RFID CMOS based sensors.[28] CMOS with sub-micron SoC design could be used for extremely low power consumption with nanorobots communicating collectively for longer distances through acoustic sensors. For the nanorobot active sonar communication frequencies may reach up to 20 μW 8 Hz at resonance rates with 3 V supply.[29]


 » System Implementation Top


The nanorobot architecture includes integrated nanoelectronics.[10] The nanorobot architecture involves the use of mobile phones for, e.g., the early diagnosis of E-cadherin levels for smart chemotherapy drug delivery and new cancer tumor detection for cancer treatments.[21] The nanorobot uses a RFID CMOS transponder system for in vivo positioning [2],[26] using well-established communication protocols, which allow track information about the nanorobot position.[21] This information may help doctors on detecting tiny malignant tissues even in initial stages of development. The nanorobot exterior shape consists of a diamondoid material [30] to which may be attached an artificial glycocalyx surface that minimizes fibrinogen (and other blood proteins) adsorption and bioactivity, ensuring sufficient biocompatibility to avoid immune system attack.[2] Different molecule types are distinguished by a series of chemotactic biosensors whose binding sites have a different affinity for each kind of molecule.[2] These sensors can also detect obstacles which might require new trajectory planning.[31] A variety of sensors are possible.[32] For instance, chemical detection can be very selective, e.g. for identifying various types of cells by markers.[2] Acoustic sensing is another possibility, using different frequencies to have wavelengths comparable to the object sizes of interest.[28]


 » Nanorobot Simulation Top


As a result from the advances on nanoelectronics, nanorobots may be considered a promising new technology to help with new treatments for medicine. The nanorobots are inside the vessel, they can be either observed in 3D real time with or without the visualization of red blood cell. Glucose carried through the blood stream is important to maintain the human metabolism working healthfully. The simulated nanorobot prototype model has embedded Complementary Metal Oxide semi- conductor [CMOS] bioelectronics. The nanorobot computation is performed through embedded nanosensor; for pervasive computing, performance requires low energy consumption. The nanorobot is not attacked by the white blood cells due to biocompatibility. In the medical nanorobot architecture,the significant measured data can be then transferred automatically to the mobile phone.[33]

Nanorobots in cancer detection and treatment

The development of nanorobots may provide remarkable advances for diagnosis and treatment of cancer. Nanoparticles (NPs) play a key role in developing new methods for detecting cancer. Detection of cancer in an early stage is a critical step in improving cancer treatment. Various NPs used are cantilever, nanopores, nanotubes and quantum dots. These are being briefly described here in the literature.[34]

Cantilever

As cancer cells secrete its molecular products, the antibodies coated on the cantilever fingers selectively bind to these secreted proteins. The physical properties of the cantilever change in real time and provide information about the presence and also the concentration of different molecular expressions.[34]

Nanopore

Another interesting device is nanopore. Improved methods of reading the genetic code will help researchers in detecting errors in gene that may contribute to cancer. Nanopores contain a tiny hole that allows deoxyribonucleic acid (DNA) to pass through one stand at a time making DNA sequencing more efficient.[34]

Nanotubes

Nanotubes carbon rods about half the diameter of a molecule of DNA will not only detect the presence of altered genes, but also pinpoint the exact location of those changes. A multidisciplinary team oat the Massachusetts institute of technology has developed carbon nanotubes (CNT) that can be used as sensors for cancer drugs and other DNA damaging agents inside living cells.[34]

Quantum dots

Quantum dots are tiny crystals that glow when they are stimulated by ultraviolet light. When injected into the body, they would drift around until encountering cancerous tissue. The deadly cells would latch onto a special coating on the glowing dots. The light particles would serve as a beacon to show doctors where the disease has spread.[34] Nanorobot could be very helpful for therapy of patients, since current treatments like radiation therapy and chemotherapy often land up destroying more healthy cells than cancerous ones. From this point of view, it provides a non-depressed therapy for cancer patients. The nanorobots will be able to distinguish between different cell types that is the malignant and the normal cells by checking their surface antigens this can be accomplished by the use of chemotactic sensors keyed to the specific antigens on the target cells. Using chemical sensors they can be programmed to detect different levels of E-cadherin and beta-catenin in primary and metastatic phases. Medical nanorobots will then destroy only the cancerous cells.[35] There are ongoing attempts to build micro-electromechanical system [MEMS]-based microrobots intended for in-vivo use. For example, the “MR – Sub” project of the nanorobotics Laboratory of Ecole Polytechnique in Montreal will use a magnetic resonance imaging system as a means of propulsion for a microrobot in the blood vessels. Application of the first generation prototype might include targeted drug release, the reopening of blocked arteries, or taking biopsies. The project is gathering the necessary information to define design rules for this type of microrobot, with a long-term goal “to further miniaturize the system and to create a robot made up of nanometric parts,” making it possible to carry out procedures in the blood vessels which are still inaccessible.[9] Gorden's group at the University of Manitoba have also proposed magnetically controlled “cytobots” and “karyobots” for performing wireless intracellular and intranuclear surgery, respectively.[34]

The nanorobots may enable drug delivery and are loaded with therapeutic chemicals avoiding the cancer to advance further. Dendrimer and nanoshells, liposomes, NPs, micelles are used for drug delivery.[34],[36]

Dendrimers

These are spherical, highly branched and synthetic macromolecules with adjustable size and shape.[36] A single dendrimer can carry a molecule that recognizes cancer cell, a therapeutic agent to kill those cells, a molecule that recognizes the signal of cell death. Dendrimer NPs have shown promise as drug delivery vehicles capable of targeting tumors with large doses of anti-cancer drugs.[34]

Nanoshells

Nanoshells have a core of silica and a metallic outer layer. By manipulating the thickness of the layer, scientist can design beads to absorb near infra-red light, creating an intense heat that is lethal to cancer cells. The physical selectivity to cancer lesion site occurs through a phenomenon called enhanced permeation retention.[34]

Liposomes

Liposomes have a long history as drug carrier systems because of their easy preparation, acceptable toxicity and biodegradability profiles. Drug loading in liposomes can be achieved through: (1) Liposome formation in an aqueous solution saturated with soluble drug; (2) the use of organic solvents and solvent exchange mechanisms; (3) the use of lipophilic drugs; and (4) pH gradient methods.[36]

Polymeric NPs

These are delivery devices made from biodegradable polymers and are an attractive option as carriers of therapeutic drugs in cancer therapy. Polymeric NPs, which include nanospheres and nanocapsules, are solid carriers ranging from 10 to 1000 nm in diameter made of natural or artificial polymers which are generally biodegradable and in which therapeutic drugs can be adsorbed, dissolved, entrapped, encapsulated or covalently linked to the polymer backbone by means of a simple ester or amide bond that can be hydrolyzed in vivo through a change of pH. When systemically administered, NPs are generally more stable than liposome, but are limited by poor pharmacokinetic properties that is, uptake by the Reticulo-Endothelial system [RES]. As with liposomes, the surface of NPs can be coated with molecules or intercalated into their structure to increase pharmacokinetics and even enable targeting for delivery and imaging purpose.[37]

Micelles

Polymeric micelles are biodegradable spherical nano-carriers with a usual size range of 10-200 nm. Micelles are considered ideal drug delivery vehicles because they provide a set of important advantages. The hydrophobic core can be used to carry pharmaceuticals, especially lipophilic drugs, which are solubilized and physically entrapped in the inner region with high loading capacity. Polymeric micelles can simultaneously co-deliver two or more therapeutic agents and are capable of releasing drugs in a regulated manner. The encapsulated drugs can be released through erosion of the biodegradable polymers, diffusion of the drug through the polymer matrix, or polymer swelling followed by drug diffusion. External conditions such as change of pH and temperature can also induce drug release from micelles. Moreover, the surface modification of micelles with ligands such as antibodies, peptides, or other small molecules can be used for targeted delivery and uptake of these nano-carriers, thereby reducing their systemic toxicity and improving their specificity and efficacy.[38]

Pictorial representation of the various drug delivery systems in cancer detection and therapy [Figure 2].[34]
Figure 1: Various Nano drug delivery systems in cancer detection and therapy

Click here to view


Though nanorobots may prove to be a boon to developing medical technology but at the same time there are certain disadvantages associated with it.


 » Disadvantages Top






  • The initial design cost is very high
  • The design of the nanorobot is a very complicated one
  • Electrical systems can create stray fields which may activate bioelectric-based molecular recognition systems in biology
  • Electrical nanorobots are susceptible to electrical interference from external sources such as RF or electric fields, electromagnetic pulse and stray fields from other in vivo electrical devices
  • Hard to interface, customize and design, complex
  • Nanorobots can cause a brutal risk in the field of terrorism. The terrorism and anti-groups can make use of nanorobots as a new form of torturing the communities as nanotechnology also has the capability of destructing the human body at the molecular level
  • Privacy is the other potential risk involved with Nanorobots. As Nanorobots deals with the designing of compact and minute devices, there are chances for more eavesdropping than that already exists.[17]



 » Conclusions Top


  • 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 and also by providing combined action – drugs marketed with diagnostics, imaging agents acting as drugs, surgery with instant diagnostic feedback
  • The advent of MNT 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 health-care, to treat disease in future. It opens up new ways for vast, abundant research work in oncotherapy
  • We are at the dawn of a new era in which many disciplines will merge, including robotics, mechanical, chemical and biomedical engineering, chemistry, biology, physics and mathematics, so that a fully functional system will be developed.


 
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    Figures

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