INTRODUCTION:

nanotechnology provides a wide range of new technologies for optimizing the drug delivery of pharmaceutical products. Nanotechnology raises hopes for the patients that suffer from chronic diseases like cancer, multiple sclerosis, cardiovascular diseases etc.

Nanotechnology is a part of applied science whose theme is to control the matter on atomic and molecular scale. Nanomedicine is a subfield of nanotechnology referred to the repair, construction and control of human biological systems using devices built upon nanotechnology standards.¹The full potential of nanomedicine is unlikely to arrive until after complex, high-sophisticated, medically programmable nanomachines and nanorobots are developed. Nanomedicine would make use of these nanorobots introduced into the body, to repair or detect damages and infections.²

Nanotechnology is a field of applied science focused on the design, synthesis, characterization and application of materials and devices on the nanoscale. The application of nanotechnology within medicine has the ability to revolutionize the cure, alleviation and prevention of disease drastically, and ultimately reinforce the restoration and preservation of health through the design, characterization, production and application of nano sized, intelligent materials. The nanorobots or nanoparticles are made with a mixture of a polymer and a protein called transferrin which has the capacity of detecting tumor cells because of its molecular particularities. Once they are in the cells the chemical sensor gives the order to dissolve; and when nanoparticles are dissolved they let free some substances which actuate on the RNA of each cell disabling the gene responsible of the cancer. Specifically, what the nanoparticles deactivate is the ribonucleic reductasa, the protein associated with the cancer growth which is fabricated by the disabled gene. 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, a cancer should be detected at least before the metastasis has began. 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 bloodborne devices, they can help on such extremely important aspects of cancer therapy. Nanorobots with embedded chemical biosensors can be used to perform detection of tumor cells in early stages of development inside the patient's body. Integrated nanosensors can be utilized for such a task in order to find intensity of E-cadherin signals. Therefore a hardware architecture based on nanobioelectronics is described for the application of nanorobots for cancer therapy. Analyses and conclusions for the proposed model is obtained through real time 3D simulation.³

History of Nanorobots:

1980’s by Nobel Prize laureate Richard Smalley. Smalley has extended his vision to carbon nanotubes, discovered by Sumio Iijima, which he envisions as the next super interconnection for ultra small electronics. The term nanotechnology has evolved to mean the manipulation of the elements to create unique and hopefully useful structures,⁴

· December 29, 1959: Richard Feynman gives the famous “There’s Plenty of Room at the Bottom” talk. - First use of the concepts of nanotechnology. Describes an individual atoms and molecules can be manipulated.

· 1974: Professor Norio Taniguchi defines nanotechnology as “the processing of, separation, consolidation, and deformation of materials by atom / molecule.”

· 1980’s: Dr. Eric Drexler publishes several scientific articles promoting nanoscale phenomena and devices.

· 1986: The book Engines of Creation: The Coming Era of Nanotechnology by Dr. Eric Drexler is published. He envisioned nanorobots as self replicating. A first book on nanotechnology.

Beginnings:

· 1981: Gerd Binnig and Heinrich Rohrer of IBM Zürich. Invented of the Scanning Tunneling Microscope (STM). By Used for imaging surfaces at the atomic level and identifying some properties (i.e. energy).

· 1985: Discovery of fullerenes (molecules composed entirely of carbon). They have many applications in materials science, electronics, and nanotechnology.

· 1991: discovering Carbon nano tubes (cylindrical fullerenes) as direct result of the fullerenes. – Exhibit high tensile strength, unique electrical properties, and efficient thermal conductivity. Their electrical properties make them ideal circuit components (i.e. transistors and ultra capacitors).

· Recently, researched chemical and biomedical engineering have used carbon nano tubes as a vessel for delivering drugs into the body.⁵

Contents:

· 1991: Invention of atomic force microscope (AFM).One of the foremost tools for imaging, measuring and manipulating matter at the nanoscale. It performs its functions by feeling the surface with mechanical probe. Since it allows for precision interaction with materials on the nanoscale, it is considered a nanorobot.

· 2000: United States National Nanotechnology Initiative is founded to coordinate federal research and development in nanotechnology. Marks the start of a serious effort in nanotechnology research.

· 2000: The company Nanofactory Collaboration is founded. Developing a research agenda for building a nanofactory capable of building nanorobots for medical purposes.

· Currently, DNA machines(nucleic acid robots) are being developed. Performs mechanical-like movements, such as switching, in response to certain stimuli(inputs).

· Molecular size robots and machines paved the way for nanotechnology by creating smaller and smaller machines and robots.

IDEAL CHARACTERISTICS:

· 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.

· After the completion of the task, it can be retrieved by allowing it to exfuse themselves via the usual human excretory channels or can also be removed by active scavenger systems.

· Nanorobots must have size between 0.5 to 3 microns large with 1-100 nm parts.

· It will prevent itself, from being attacked by the immune system by having a passive, diamond exterior⁶.

ADVANTAGES OF NANOROBOT:

· “Nanotechnology enables us to create functional materials, devices, and systems by controlling matter at the atomic and molecular scales, and to exploit novel properties and phenomena.

· Cost Benefit ration is great

· Environmentally friendly

o Little pollution from production

o No wasted materials

· Very durable

· Can complete work faster than larger robots

· Nanorobots can be programmed to self‐replicate.

· As the nanorobot do not generate any harmful activities there is no side effect. It operates at specific site only.

· It has no side affect

DISADVANTAGES:

· The initial design cost is very high⁷.

· 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, EMP pulses, 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 NANOROBOTS,

· The nanorobot should be very accurate, otherwise Harmful effects may occur.

Approaches in Nanorobotics: ⁸

Biochip:

The joint use of nanoelectronics, photolithography, and new biomaterials provides a possible approach to manufacturing nanorobots for common medical applications, such as for surgical instrumentation, diagnosis and drug delivery⁹.Biochips not only consist of immobilized bio molecules spatially addressed on planar surfaces, but also contain bio molecules fixed in micro channels or microcells or on an array of beads or sensors. Nanotechnology has made biochips more applicable for commercialization purpose where biochips could be implanted inside body to dynamically transmit the information and monitor any biological changes in vivo¹⁰.

Nubots:

Nubot is an abbreviation for "nucleic acid robot." They are organic molecular machines¹¹. DNA structure can provide means to assemble 2D and 3D nanomechanical devices. DNA based machines can be activated using small molecules, proteins and other molecules of DNA¹². Nubots have DNA structure used for targeting drug delivery as a carrier.

Bacteria-based:

This approach proposes the use of biological microorganisms, like the bacterium Escherichia coli. Thus the model uses a flagellum for propulsion purposes. Electromagnetic fields normally control the motion of this kind of biological integrated device.

Open Technology:

A document with a proposal on nanobiotech development using open technology approaches has been addressed to the United Nations General Assembly. According to the document sent to the UN, in the same way that Open Source has in recent years accelerated the development of computer systems, a similar approach should benefit the society at large and accelerate nanorobotics development.

Nanobearing and Nanogears:

In order to establish the feasibility of molecular manufacturing, it is first necessary to create and to analyze possible designs for nanoscale mechanical parts that could, in principle, be manufactured.¹³ “ ability to model molecular machines (systems and devices) of specific kinds, designed in part for ease of modeling, has far outrun our ability to make them. Design calculations and computational experiments enable the theoretical studies of these devices, independent of the technologies needed to implement them.” Simple structure and operation of molecular bearings makes it the most convenient class of components to be designed. One of the simplest examples is Drexler’s overlap-repulsion bearing design.

Medical Nanorobot Architecture:

The main parameters used for the medical nanorobot architecture and its control activation, as well as the required technology background that may lead to manufacturing hardware for molecular machines, are described next.

1. 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 relevant parameters for diagnostic purposes¹⁴. CMOS VLSI (Very Large Scale Integration) Systems design using deep ultraviolet lithography provides high precision and a commercial way for manufacturing early nanodevices and nanoelectronics systems. The CMOS (Complementary Meta Oxide Semiconductor) 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 248nm to 157nm devices¹⁵. To validate designs and to achieve a successful implementation, the use of VHDL (Verification Hardware Description Language) has become the most common methodology utilized in the integrated circuit manufacturing industry¹⁶.

2. Chemical Sensor:

Manufacturing silicon-based chemical- and motion-sensor arrays using a two-level system architecture hierarchy has been successfully conducted in the last 15 years. Applications range from autmotive and chemical industry with detection of air to water element pattern recognition through embedded software programming, and biomedical uses. Through the use of nanowires, existing significant costs of energy demand for data transfer and circuit operation can be decreased by up to 60%. CMOS-based biosensors using nanowires as material for circuit assembly can achieve maximal efficiency for applications regarding chemical changes, enabling new medical treatments¹⁷. Chemical nanosensors can be embedded in the nanorobot to monitor E-cadherin gradients. Thus, nanorobots programmed for such task can make a detailed screening of the patient whole body. In our medical nanorobotic architecture, the mobile phone is applied to retrieve information about the patient conditions^18,19. For that, it uses electromagnetic waves to command and detect the current status of nanorobots inside the patient. New materials such as strained channel with relaxed SiGe layer can reduce self-heating and improve performance. Recent developments in 3D circuits and FinFETs double-gates have achieved astonishing results and according to the semiconductor roadmap should improve even more²⁰. To further advance manufacturing techniques, Silicon-On-Insulator (SOI) technology has been used to assemble high-performance logic sub 90nm circuits. Circuit design approaches to solve problems with bipolar effect and hysteretic variations based on SOI structures has been demonstrated successfully²¹. Thus, already-feasible 90nm and 45nm CMOS devices represent breakthrough technology devices that are already being utilized in products.

3. 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 (Fig. 1). The same technique is also appropriate for other purposes like digital bit encoded data transfer from inside a human body²².Thus, nanocircuits with resonant electric properties can operate as a chip providing electromagnetic energy supplying 1.7 mAat 3.3V for power, allowing the operation of many tasks with few or no significant losses during transmission²³. RF-based telemetry procedures have demonstrated good results in patient monitoring and power transmission with the use of inductive coupling²⁴using well established techniques already widely used in commercial applications of RFID²⁵.The energy received can be also saved in ranges of ~1μW while the nanorobot stays in inactive modes, just becoming active when signal patterns require it to do so. Some typical nanorobotic tasks may require the device only to spend low power amounts, once it has been strategically activated. For communication, sending RF signals ~1mW is required. A practical way to achieve easy implementation of this architecture will obtain both energy and data transfer capabilities for nanorobots by employing mobile phone in such process²⁶. The mobile phone should be uploaded with the control software that includes the communication and energy transfer protocols.

4. 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 monitoring²⁷. Most recently, the use of RFID for in vivo data collecting and transmission was successfully tested for electroencephalograms. 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. Chemical signaling is quite useful for nearby communication among nanorobots for some teamwork coordination²⁸. Work with RFID (Radio Frequency Identification Device) has been developed as an integrated circuit device for medicine^29,30 .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. CMOS with submicron SoC design could be used for extremely low power longer distances through acoustic sensors. For the nanorobot active sonar communication frequencies may reach up to 20μW@8Hz at resonance rates with 3V supply³¹. In our molecular machine architecture, to successfully set an embedded antenna with 200nm size for the nanorobot RF communication, a small loop planar device is adopted as an electromagnetic pick-up having a good matching on Low Noise Amplifier; it is based on gold nanocrystal with 1.4nm, CMOS and nanoelectronic circuit technologies³². Frequencies ranging from 1 to 20MHz can be successfully used for biomedical applications without any damage.

Fig. No.1 All the nanorobots swim near the wall to detect cancer signals. Vein internal view without the red cells. The tumour cell is the target represented by the pink sphere located left at the wall.

Target Site and Their Communication with the Machines³³ :

The nanorobot design includes integrated nanoelectronics which involves use of mobile phones. It uses RFID (radio frequency identification device) CMOS (complementary metal oxide semiconductor) transponder system for in vivo positioning, using well established communication protocol which allows track information about its positioning. There are three approaches to recognize the target site-First, as a point of comparison; the scientists use nanorobots small Brownian motions to find the target by random search. In a second method, it monitors for chemical concentration significantly above the background level. After detecting the signal, it estimates the concentration gradient and moves toward higher concentrations until it reaches the target. In the third approach, nanorobots at the target release another chemical, which others use as an additional guiding signal to the target. With these signal concentrations, only it passes within a few microns of the target is likely to detect the signal. Most recently, the use of RFID for in vivo data collecting and transmission was successfully tested for electroencephalograms. 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. One of the simplest ways to send broadcast-type messages into the body, to be received by in vivo nanorobots, is aural messaging. A device similar to an ultrasound probe would encode messages on aural carrier waves at frequencies between 1-10 MHz. Thus the supervising physician can easily send new commands or parameters to nanorobots already at work inside the body. Each nanorobot has its own power supply, computer, and sensorium, thus can receive the physician's messages via aural sensors, then compute and implement the appropriate response. The other half of the process is getting messages back out of the body, from the working nanodevices out to the physician³⁴.

Applications- Diagnosis and Treatment: ³⁵

Medical nanorobots can perform a vast array of diagnostic, testing and monitoring functions, both in tissues and in the bloodstream. These devices could continuously record and report all vital signs including temperature, pressure, chemical composition, and immune system activity, from all different parts of the body.

Cancer Therapy:

Nanorobots with embedded chemical biosensors can be used to perform detection of tumor cells in early stages of development inside the patient's body. These nanorobots would search out and identify the cancer affected cells using certain molecular as they could be introduced into the blood stream. Medical nanorobots would then destroy these cells. Nanorobots with chemical nanobiosensors can be programmed to detect different levels of E-cadherin and beta-catenin as medical targets in primary and metastatic phases, helping target identification and drug delivery. Integrated nanosensors can be utilized for such a job in order to find intensity of E-cadherin signals. Nanorobots could also carry the chemicals used in chemotherapy to treat the cancer directly at the site³⁶.

Diabetes:

The protein hSGLT3 has an important influence in maintaining proper gastrointestinal cholinergic nerve and skeletal muscle function activities, regulating extra cellular glucose concentration. The hSGLT3 molecule can serve to define the glucose levels and serves as a sensor to identify glucose for diabetes patients. For the glucose monitoring the nanorobot uses embedded chemosensor that involves the modulation of hSGLT3 protein glucosensor activity. Through its onboard chemical sensor, the nanorobot can thus effectively determine if the patient needs to inject insulin or take any further action, such as any medication clinically prescribed. They flow with the RBCs through the bloodstream detecting the glucose levels. In the medical nanorobot architecture, the significant measured data can be then transferred automatically through the RF signals to the mobile phone carried by the patient. At any time, if the glucose achieves critical levels, the nanorobot emits an alarm through the mobile phone³⁷.

Surgery:

Surgical nanorobots could be introduced into the body through the vascular system or at the ends of catheters into various vessels and other cavities in the human body. A surgical nanorobot, programmed or guided by a human surgeon, could act as a semiautonomous on-site surgeon inside the human body. It performs various functions such as searching for pathology and then diagnosing and correcting lesions by nanomanipulation, coordinated by an on-board computer while maintaining contact with the supervising surgeon via coded ultrasound signals. The earliest forms of cellular nanosurgery are already being explored today³⁸.

As a Artificial Oxygen Carrier:

The artificial mechanical red cell, "Respirocyte" is an imaginary nanorobot, floats all along in the blood stream. The Respirocyte is basically a tiny pressure tank that can be pumped full of oxygen (O2) and carbon dioxide (CO2) molecules. These gases can be released from the tiny tank in a controlled manner. When the nanorobot passes through the lung capillaries, O2 partial pressure is high and CO2 partial pressure is low, so the onboard computer tells the sorting rotors to load the tanks with oxygen and to dump the CO2. When the device later finds itself in the oxygen-starved peripheral tissues, the sensor readings are reversed. CO2 partial pressure is relatively high and O2 partial pressure relatively low, so the onboard computer commands the sorting rotors to release O2 and to absorb CO2. Respirocytes mimic the action of the natural haemoglobin-filled red blood cells and can deliver 236 times more oxygen per unit volume than a natural red cell³⁹.

As Artificial Phagocyte (Microbivore):

Microbivore is an artificial mechanical phagocyte of microscopic size whose primary function is to destroy microbiological pathogens found in the human bloodstream, using the "digest and discharge" protocol. The chief function of microbivore is to wipe out microbiological pathogens found in the human bloodstream, using the "digest and discharge" procedure. Microbivores upon given intravenously (I.V) would achieve complete clearance of the most severe septicemic infections in hours or less, far better than the weeks or months needed for antibiotic-assisted natural phagocytic defenses. The nanorobots do not boost the risk of sepsis or septic shock because the pathogens are completely digested into harmless simple sugars, monoresidue amino acids, mononucleotides, free fatty acids and glycerol, which are the biologically inactive effluents from the nanorobot⁴⁰.

As Artificial Neurons:

Nanorobots can be employed in replacing every neuron in one’s brain with nanorobot which is designed to function just like normal, everyday, natural neurons. The nanotech neurons are functionally equivalent. They connect to the same synapses of the original neuron, and they perform the same functional roles⁴¹.

Atherosclerosis:

Medical nanorobots have the ability to locate atherosclerotic lesions in blood vessels, mainly in the coronary circulation, and treat them either mechanically, chemically or pharmacologically⁴².

Cell Repair and Lysis:

An interesting utilization of nanorobots may be their attachment to transmigrating inflammatory cells or white blood cells, to reach swollen tissues and assist in their healing process. Mobile cell-repair nanorobot capable of limited vascular surface travel into the capillary bed of the targeted tissue or organ, followed by extravasations, histonatation, cytopenetration, and complete chromatin replacement in the nucleus of one target cell, and ending with a return to the bloodstream and subsequent extraction of the device from the body, completing the cell repair mission⁴³.

Hemophilia:

One particular kind of nanorobot is the clottocyte or artificial platelet. The clottocyte carries a small mesh net that dissolves into a sticky membrane upon contact with blood plasma. According to Robert A. Freitas, Jr., the man who designed the clottocyte, clotting could be up to 1,000 times faster than the body's natural clotting mechanism⁴⁴.

Gout:

Gout is a situation where the kidneys lose the ability to remove waste from the breakdown of fats from the bloodstream. This waste sometimes crystallizes at points near joints like the knees and ankles. A nanorobot could break up the crystalline structures at the joints, providing relief from the symptoms, though it wouldn't be able to reverse the state permanently.

Kidney Stones:

Kidney stones can be intensely painful the larger the stone the more difficult it is to pass. A nanorobot could break up kidney stones using a small laser.

Cleaning Wounds:

Nanorobots could help remove debris from wounds, decreasing the likelihood of infection. They would be particularly useful in cases of puncture wounds, where it can be difficult to treat using more conventional methods.

Gene Therapy:

Medical nanorobots can readily treat genetic diseases by comparing the molecular structures of both DNA and proteins found in the cell to known or desired reference structures. Any irregularities can then be corrected, or desired modifications can be edited in place. In some cases, chromosomal replacement therapy is more efficient than in cytorepair.

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Received on 20.06.2016 Accepted on 30.07.2016

Asian J. Pharm. Res. 2016; 6(4): 217-224.

DOI: 10.5958/2231-5691.2016.00030.7