Nanotechnology is a fascinating science for many scientists as it
offers them many challenges. One such challenge is Nanorobots, which once
thought to be a fantasy has come into reality now. The proposed application
of nanorobots can range from common cold to dreadful disease like cancer.
Some such examples can be Pharmacyte, Respirocyte, Microbivores,
Chromallocyte and many more. The study of nanorobots has lead to the field of
Nanomedicine. Nanomedicine offers the prospect of powerful new tools for the treatment
of human diseases and the improvement of human biological systems.
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The present era of Nanotechnology has reached to a stage where
scientists are able to develop programmable and externally controllable
complex machines that are built at molecular level which can work inside the
patient’s body. Nanotechnology will enable engineers to construct
sophisticated nanorobots that can navigate the human body, transport
important molecules, manipulate microscopic objects and communicate with
physicians by way of miniature sensors, motors, manipulators, power
generators and molecular-scale computers. The idea to build a nanorobot comes
from the fact that the body’s natural nanodevices; the neutrophiles,
lymphocytes and white blood cells constantly rove about the body, repairing
damaged tissues, attacking and eating invading microorganisms, and sweeping
up foreign particles for various organs to break down or excrete.
Nanorobotics is emerging as a demanding field dealing with miniscule
things at molecular level. Nanorobots are quintessential
nanoelectromechanical systems designed to perform a specific task with
precision at nanoscale dimensions. Its advantage over conventional medicine
lies on its size. Particle size has effect on serum lifetime and pattern of
deposition. This allows drugs of nanosize to be used in lower concentration
and has an earlier onset of therapeutic action. It also provides materials
for controlled drug delivery by directing carriers to a specific location
[1]. The typical medical nanodevice will probably be a micron-scale robot
assembled from nanoscale parts. These nanorobots can work together in
response to environment stimuli and programmed principles to produce macro
scale results [2].
Carbon will likely be the principal element comprising the bulk of a
medical nanorobot, probably in the form of diamond or diamondoid/fullerene
nanocomposites. Many other light elements such as hydrogen, sulfur, oxygen,
nitrogen, fluorine, silicon, etc. will be used for special purposes in
nanoscale gears and other components [2]. The chemical inertness of diamond
is proved by several experimental studies. One such experiment conducted on mouse
peritoneal macrophages cultured on DLC showed no significant excess release
of lactate dehydrogenase or of the lysosomal enzyme beta
N-acetyl-D-glucosaminidase (an enzyme known to be released from macrophages
during inflammation).
Morphological examination revealed no physical damage to either
fibroblasts or macrophages, and human osteoblast like cells confirming the
biochemical indication that there was no toxicity and that no inflammatory
reaction was elicited in vitro. The smoother and more flawless the diamond
surface, the lesser is the leukocyte activity and fibrinogen adsorption. An
experiment by Tang et al. [41] showed that CVD diamond wafers implanted
intraperitoneally in live mice for 1 week revealed minimal inflammatory response.
Interestingly, on the rougher “polished” surface, a small number of spread
and fused macrophages were present, indicating that some activation had
occurred. The exterior surface with near-nanometer smoothness results in very
low bioactivity. Due to the extremely high surface energy of the passivated
diamond surface and the strong hydrophobicity of the diamond surface, the
diamond exterior is almost completely chemically inert.
Nanorobots will possess full panoply of autonomous subsystems whose
design is derived from biological models. Drexler evidently was the first to
point out, in 1981, that complex devices resemble biological models in their
structural components [42]. The various components in the nanorobot design
may include onboard sensors, motors, manipulators, power supplies, and
molecular computers. Perhaps the best-known biological example of such
molecular machinery is the ribosome the only freely programmable nanoscale
assembler already in existence. The mechanism by which protein binds to the
specific receptor site might be copied to construct the molecular robotic
arm.
The manipulator arm can also be driven by a detailed sequence of
control signals, just as the ribosome needs mRNA to guide its actions. These
control signals are provided by external acoustic, electrical, or chemical
signals that are received by the robot arm via an onboard sensor using a
simple "broadcast architecture"[43, 44, and 45] a technique which
can also be used to import power. the biological cell may be regarded as an
example of a broadcast architecture in which the nucleus of the cell send
signals in the form of mRNA to ribosomes in order to manufacture cellular
proteins.
Assemblers are molecular machine systems that could be described as
systems capable of performing molecular manufacturing at the atomic scale[46]
which require control signals provided by an onboard nanocomputer This
programmable nanocomputer must be able to accept stored instructions which
are sequentially executed to direct the manipulator arm to place the correct
moiety or nanopart in the desired position and orientation, thus giving
precise control over the timing and locations of chemical reactions or
assembly operations [47].
There are two main approaches to building at the nanometer scale:
positional assembly and self-assembly. In positional assembly, investigators
employ some devices such as the arm of a miniature robot or a microscopic set
to pick up molecules one by one and assemble them manually. In contrast,
self-assembly is much less painstaking, because it takes advantage of the
natural tendency of certain molecules to seek one another out. With
self-assembling components, all that investigators have to do is put billions
of them into a beaker and let their natural affinities join them
automatically into the desired configurations. Making complex nanorobotic
systems requires manufacturing techniques that can build a molecular
structure via computational models of diamond mechanosynthesis (DMS) [3, 4].
DMS is the controlled addition of carbon atoms to the growth surface of a
diamond crystal lattice in a vacuum-manufacturing environment. Covalent
chemical bonds are formed one by one as the result of positionally
constrained mechanical forces applied at the tip of a scanning probe
microscope apparatus, following a programmed sequence.
Different molecule types are distinguished by a series of chemotactic
sensors whose binding sites have a different affinity for each kind of
molecule. [6] The control system must ensure a suitable performance. It can
be demonstrated with a determined number of nanorobots responding as fast as
possible for a specific task based scenario. In the 3D workspace the target
has surface chemicals allowing the nanorobots to detect and recognize it [6,
7, and 8]. Manufacturing better sensors and actuators with nanoscale sizes
makes them find the source of release of the chemical. Nanorobot Control Design
(NCD) simulator was developed, which is software for nanorobots in
environments with fluids dominated by Brownian motion and viscous rather than
inertial forces.
First, as a point of comparison, the scientists used the nanorobots’
small Brownian motions to find the target by random search. In a second
method, the nanorobots monitor for chemical concentration significantly above
the background level. After detecting the signal, a nanorobot 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 nanorobots passing within a
few microns of the target are likely to detect the signal.
Thus, we can improve the response by having the nanorobots maintain
positions near the vessel wall instead of floating throughout the volume flow
in the vessel from monitoring the concentration of a signal from others; a
nanorobot can estimate the number of nanorobots at the target. So, the
nanorobot uses this information to determine when enough nanorobots are at
the target, thereby terminating any additional “attractant” signal a
nanorobot may be releasing. It is found that the nanorobots stop attracting
others once enough nanorobots have responded. The amount is considered enough
when the target region is densely covered by nanorobots. Thus these tiny
machines work at the target site accurately and precisely to that extent only
to which it is designed to do [9].
Every medical nanorobot placed inside the human body will encounter
phagocytic cells many times during its mission. Thus all Nanorobots, which
are of a size capable of ingestion by phagocytic cells, must incorporate
physical mechanisms and operational protocols for avoiding and escaping from
phagocytes. The initial strategy for medical nanorobots is first to avoid
phagocytic contact or recognition. To avoid being attacked by the host’s
immune system, the best choice is to have an exterior coating of passive
diamond. The smoother and flawless the coating, the lesser is the reaction
from the body’s immune system. And if this fails then to avoid it’s binding
to the phagocyte surface that leads to phagocytic activation. If trapped, the
medical nanorobot can induce exocytosis of the phagosomal vacuole in which it
is lodged or inhibit both phagolysosomal fusion and phagosome metabolism.
In rare circumstances, it may be necessary to kill the phagocyte or to
blockade the entire phagocytic system. The most direct approach for a fully
functional medical nanorobot is to employ its motility mechanisms to locomote
out of, or away from, the phagocytic cell that is attempting to engulf it.
This may involve reverse cytopenetration, which must be done cautiously
(e.g., the rapid exit of nonenveloped viruses from cells can be cytotoxic).
It is possible that frustrated phagocytosis may induce a localized compensatory
granulomatous reaction. Medical nanorobots therefore may
also need to employ simple but active defensive strategies to forestall
granuloma formation. Metabolizing local glucose and oxygen for energy can do
the powering of the nanorobots. In a clinical environment, another option
would be externally supplied acoustic energy. When the task of the nanorobots
is completed, they can be retrieved by allowing them to exfuse themselves via
the usual human excretory channels or can also be removed by active scavenger
systems [10, 11].
The development of nanorobots may provide remarkable advances for
diagnosis and treatment of cancer. Nanorobots could be a very helpful and
hopeful for the therapy of patients, since current treatments like radiation
therapy and chemotherapy often end 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 (they are different for each type of cell). This is
accomplished by the use of chemotactic sensors keyed to the specific antigens
on the target cells. Another approach uses the innovative methodology to
achieve decentralized control for a distributed collective action in the
combat of cancer. 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 these cells, and only these
cells. The following control methods were considered:
• Random: nanorobots
moving passively with the fluid reaching the target only if they bump into it
due to Brownian motion.
• Follow gradient:
nanorobots monitor concentration intensity for E-cadherin signals, when
detected, measure and follow the gradient until reaching the target. If the
gradient estimate subsequent to signal detection finds no additional signal
in50ms, the nanorobot considers the signal to be a false positive and
continues flowing with the fluid.
• Follow gradient with
attractant: as above, but nanorobots arriving at the target, they release in
addition a different chemical signal used by others to improve their ability
to find the target. Thus, a higher gradient of signal intensity of E-cadherin
is used as chemical parameter identification in guiding nanorobots to
identify malignant tissues. Integrated nanosensors can be utilized for such a
task in order to find intensity of E-cadherin signals. Thus they can be
employed effectively for treating cancer [9].
Pharmacyte is a self-powered, computer controlled medical nanorobot
system capable of digitally precise transport, timing, and targeted-delivery
of pharmaceutical agents to specific cellular and intracellular destinations
within the human body. Pharmacytes escape the phagocytic process as they will
not embolize small blood vessels because the minimum viable human capillary
that allows passage of intact erythrocytes and white cells is 3–4 micronmeter
in diameter, which is larger than the largest proposed Pharmacyte.
Pharmacytes will have many applications in nanomedicine such as
initiation of apoptosis in cancer cells and direct control of cell signaling
processes. Pharmacytes could also tag target cells with biochemical natural
defensive or scavenging systems, a strategy called “phagocytic flagging”
[12]. For example, novel recognition molecules are expressed on the surface
of apoptotic cells. In the case of T lymphocytes, one such molecule is
phosphatidylserine, a lipid that is normally restricted to the inner side of
the plasma membrane [1m] but, after the induction of apoptosis, appears on
the outside [13].
Cells bearing this molecule on their surface can then be recognized
and removed by phagocytic cells. Seeding the outer wall of a target cell with
phosphatidylserine or other molecules with similar action could activate
phagocytic behavior by macrophages, which had mistakenly identified the
target cell as apoptotic substances capable of triggering a reaction by the
body [14] Pharmacytes would be capable of carrying up to approximately
1cubicmeter of pharmaceutical payload stored in onboard tanks that are
mechanically offloaded using molecular sorting pumps operated under the
control of an onboard computer[15,16].
Depending on mission requirements, the payload can be discharged into
the proximate extracellular fluid or delivered directly into the cytosol
using a transmembrane injector mechanism. If needed for a particular
application, deployable mechanical cilia and other locomotive systems can be
added to the Pharmacyte to permit transvascular and transcellular mobility,
thus allowing delivery of pharmaceutical molecules to specific cellular and
even intracellular addresses with negligible error. Pharmacytes, once
depleted of their payloads or having completed their mission, would be
recovered from the patient by conventional excretory pathways. [17] The
nanorobots might then be recharged, reprogrammed and recycled for use in a
second patient who may need a different pharmaceutical agent targeted to
different tissues or cells than in the first patient [27, 28].
Glucose carried through the blood stream is important to maintain the
human metabolism working healthfully, and its correct level is a key issue in
the diagnosis and treatment of diabetes. Intrinsically related to the glucose
molecules, the protein hSGLT3 has an important influence in maintaining
proper gastrointestinal cholinergic nerve and skeletal muscle function
activities, regulating extracellular glucose concentration [18]. The hSGLT3
molecule can serve to define the glucose levels for diabetes patients. The
most interesting aspect of this protein is the fact that it serves as a
sensor to identify glucose [18].
The simulated nanorobot prototype model has embedded Complementary
Metal Oxide semi-conductor (CMOS) nanobioelectronics. It features a size of
~2 micronmeter, which permits it to operate freely inside the body. Whether
the nanorobot is invisible or visible for the immune reactions, it has no
interference for detecting glucose levels in blood stream. Even with the
immune system reaction inside the body, the nanorobot is not attacked by the
white blood cells due biocompatibility [19] For the glucose monitoring the
nanorobot uses embedded chemosensor that involves the modulation of hSGLT3
protein glucosensor activity [20].
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. The image of
the NCD simulator workspace shows the inside view of a venule blood vessel
with grid texture, red blood cells (RBCs) and nanorobots. They flow with the
RBCs through the bloodstream detecting the glucose levels. At a typical
glucose concentration, the nanorobots try to keep the glucose levels ranging
around 130 mg/dl as a target for the Blood Glucose Levels (BGLs). A variation
of 30mg/dl was adopted as a displacement range, though this can be changed
based on medical prescriptions. 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 phone [21].
In the simulation, the nanorobot is programmed also to emit a signal
based on specified lunch times, and to measure the glucose levels in desired
intervals of time. The nanorobot can be programmed to activate sensors and
measure regularly the BGLs early in the morning, before the expected
breakfast time. Levels are measured again each 2 hours after the planned
lunchtime. The same procedures can be programmed for other meals through the
day times. A multiplicity of blood borne nanorobots will allow glucose
monitoring not just at a single site but also in many different locations
simultaneously throughout the body, thus permitting the physician to assemble
a whole-body map of serum glucose concentrations.
Examination of time series data from many locations allows precise
measurement of the rate of change of glucose concentration in the blood that
is passing through specific organs, tissues, capillary beds, and specific
vessels. This will have diagnostic utility in detecting anomalous glucose
uptake rates which may assist in determining which tissues may have suffered
diabetes-related damage, and to what extent. Other onboard sensors can
measure and report diagnostically relevant observations such as patient blood
pressure, early signs of tissue gangrene, or changes in local metabolism that
might be associated with early-stage cancer. Whole-body time series data
collected during various patient activities levels (e.g., resting,
exercising, postprandial, etc.) could have additional diagnostic value in
assessing the course and extent of disease.
This important data may help doctors and specialists to supervise and
improve the patient medication and daily diet. This process using nanorobots
may be more convenient and safe for making feasible an automatic system for
data collection and patient monitoring. It may also avoid eventually
infections due the daily small cuts to collect blood samples, possibly loss
of data, and even avoid patients in a busy week to forget doing some of their
glucose sampling. These Recent developments on nanobioelectronics show how to
integrate system devices and cellular phones to achieve a better control of
glucose levels for patients with diabetes [22].
The artificial mechanical red cell, "Respirocyte" is an
imaginary nanorobot, floats along in the blood stream [23]. These atoms are
mostly carbon atoms arranged as diamond in a porous lattice structure inside
the spherical shell. The Respirocyte is essentially a tiny pressure tank that
can be pumped full of oxygen (O2) and carbon dioxide (CO2)
molecules. Later on, these gases can be released from the tiny tank in a
controlled manner. The gases are stored onboard at pressures up to about 1000
atmospheres. Respirocyte can be rendered completely nonflammable by
constructing the device internally of sapphire, a flameproof material with
chemical and mechanical properties otherwise similar to diamond [24].
There are also gas concentration sensors on the outside of each
device. 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. That is,
CO2 partial
pressure is relatively high and O2 partial
pressure relatively low, so the onboard computer commands the sorting rotors
to release O2and to absorb CO2.Respirocytes mimic the
action of the natural hemoglobin-filled red blood cells. But a Respirocyte
can deliver 236 times more oxygen per unit volume than a natural red cell.
This nanorobot is far more efficient than biology, mainly because its
diamondoid construction permits a much higher operating pressure. So the
injection of a 5 cm3 dose of 50% Respirocyte aqueous
suspension into the bloodstream can exactly replace the entire O2 and
CO2 carrying
capacity of the patient's entire 5,400 cm3 of
blood. Respirocyte will have pressure sensors to receive acoustic signals
from the doctor, who will use an ultrasound-like transmitter device to give
the Respirocyte commands to modify their behavior while they are still inside
the patient's body [25, 27].
A microbivore has been described, whose primary function is to destroy
microbiological pathogens found in the human bloodstream, using the
"digest and discharge" protocol. Nanorobotic artificial
hypothetical phagocytes called ‘‘microbivores’’ could patrol the bloodstream,
seeking out and digesting unwanted pathogens including bacteria, viruses, or
fungi. Microbivores when given intravenously (I.V) would achieve complete
clearance of even the most severe septicemic infections in hours or less.
This is far better than the weeks or months needed for antibiotic-assisted
natural phagocytic defenses. The nanorobots do not increase 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 nanorobot
[26, 27, 28].
Another nanorobot, 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. Chromallocyte is a
hypothetical mobile cell-repair nanorobot capable of limited vascular surface
travel into the capillary bed of the targeted tissue or organ, followed by
extravasation, 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 mission." Inside a cell, a 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 whole cells.
By working along cell-by-cell and tissue-by-tissue, they (aided by larger
devices, where need be) will be able to repair whole organs. By working
through a person organ by organ, they will restore health. Because molecular
machines will be able to build molecules and cells from scratch, they will be
able to repair even cells damaged to the point of complete inactivity. [29,
30, 31]
Nanorobots could be used to maintain tissue oxygenation in the absence
of respiration, repair and recondition the human vascular tree eliminating
heart disease and stroke damage, perform complex nanosurgery on individual
cells, and instantly staunch bleeding after traumatic injury. Monitoring
nutrient concentrations in the human body is a possible application of
nanorobots in medicine. One of interesting nanorobot utilization is also to
assist inflammatory cells (or white cells) in leaving blood vessels to repair
injured tissues [39].
Nanorobots might be used as well to seek and break kidney stones [32].
Nanorobots could also be used to process specific chemical reactions in the
human body as ancillary devices for injured organs [40]. Nanorobots equipped
with nanosensors could be developed to deliver anti-HIV drugs [38]. Another
important capability of medical nanorobots will be the ability to locate
stenosed blood vessels, particularly in the coronary circulation, and treat
them mechanically, chemically, or pharmacologically [33].
To cure skin diseases, a cream containing nanorobots may be used. It
could remove the right amount of dead skin, remove excess oils, add missing
oils, apply the right amounts of natural moisturizing compounds, and even
achieve the elusive goal of 'deep pore cleaning' by actually reaching down
into pores and cleaning them out. The cream could be a smart material with
smooth-on, peel-off convenience.
A mouthwash full of smart nanomachines could identify and destroy
pathogenic bacteria while allowing the harmless flora of the mouth to
flourish in a healthy ecosystem. Further, the devices would identify
particles of food, plaque, or tartar, and lift them from teeth to be rinsed
away. Being suspended in liquid and able to swim about, devices would be able
to reach surfaces beyond reach of toothbrush bristles or the fibers of floss.
As short-lifetime medical nanodevices, they could be built to last only a few
minutes in the body before falling apart into materials of the sort found in
foods.
Medical nanodevices could augment the immune system by finding and
disabling unwanted bacteria and viruses. When an invader is identified, it
can be punctured, letting its contents spill out and ending its
effectiveness. If the contents were known to be hazardous by themselves, then
the immune machine could hold on to it long enough to dismantle it more
completely. Devices working in the bloodstream could nibble away at
arteriosclerotic deposits, widening the affected blood vessels [34]. Cell
herding devices could restore artery walls and artery linings to health, by
ensuring that the right cells and supporting structures are in the right
places. This would prevent most heart attacks [35].
Nanorobots could be used in precision treatment and cell targeted delivery,
in performing nanosurgery, and in treatments for hypoxemia and respiratory
illness, dentistry [36], bacteremic infections, physical trauma, gene therapy
via chromosome replacement therapy and even biological aging. It has been
suggested that a fleet of nanorobots might serve as antibodies or antiviral
agents in patients with compromised immune systems, or in diseases that do
not respond to more conventional measures.
There are numerous other potential medical applications, including
repair of damaged tissue, unblocking of arteries affected by plaques, and
perhaps the construction of complete replacement body organs. Nanoscale
systems can also operate much faster than their larger counterparts because
displacements are smaller; this allows mechanical and electrical events to
occur in less time at a given speed [37].
Nanotechnology as a diagnostic and treatment tool for patients with
cancer and diabetes showed how actual developments in new manufacturing
technologies are enabling innovative works which may help in constructing and
employing nanorobots most effectively for biomedical problems. Nanorobots
applied to medicine hold a wealth of promise from eradicating disease to
reversing the aging process (wrinkles, loss of bone mass and age-related
conditions are all treatable at the cellular level); nanorobots are also
candidates for industrial applications. 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.
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18. Wright, E.M., Sampedro, A.D.,
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Thursday 6 March 2014
Prospects for Medical Robots
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