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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.
What are Nanorobots
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].
Elements of Nanorobots
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.
The Constituents and Design of Nanorobots
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].
Approaches for the Construction of Nanorobots
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.
Recognition of Target Site by Nanorobots
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].
Strategies Employed by Nanorobots for Evading the Immune System
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].
Nanorobots in Cancer Detection and Treatment
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].
Practical Example of Nanorobots Approach for Cancer Detection and Treatment
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].
Nanorobots in the Diagnosis and Treatment of Diabetes
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].
Controlling Glucose Level using Nanorobots
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].
Respirocyte - An Artificial Oxygen Carrier Nanorobot
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 O2 and 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].
Artificial Phagocytes – Microbivores Nanorobots
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].
Chromallocyte: A Hypothetical Mobile Cell-Repair Nanorobot
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]
Further Applications of Nanorobots
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].
Conclusion
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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1. Chan V.S.W., Nanomedicine: An unresolved regulatory issue. Science direct.
2. Freitas R., http://www.foresight.org
3. Drexler K.E., Nanosystems: molecular machinery, manufacturing and computation. New York: John Wiley & Sons; 1992.
4. Merkle R.C., Freitas Jr. R.A., Theoretical analysis of a carbone carbon dimer placement tool for diamond mechano synthesis Nanosci Nanotechnol 2003; 3:319e24.
5. Drexler K.E., Nanosystems: Molecular Machinery, Manufacturing, and Computation, John Wiley & Sons, 1992.
6. Curtis A.S.G., Dalby M., Gadegaard N., Cell signaling arising from nanotopography: implications for nanomedical devices”, Nanomedicine Journal, Future Medicine, vol. 1, no. 1, pp. 67-72, June 2006.
7. Wasielewski R., Rhein A., Werner M., Scheumann G.F., Dralle H., Potter E., Brabant G., Georgii A., Immunohistochemical detection of Ecadherin in differentiated thyroid carcinomas correlates with clinical outcome, Cancer Research, Vol 57, Issue 12 2501-2507, American Association for Cancer Research, 1997.
8. Hazana R.B., Phillipsa G.R., Qiaoa R.F., Nortonb L., Aaronsona S.A., Exogenous Expression of N-Cadherin in Breast Cancer Cells Induces Cell Migration, Invasion, and Metastasis, The Journal of Cell Biology, Volume 148, Number 4, 779-790, Feb. 2000.
9. Nanorobot Communication Techniques: A Comprehensive Tutorial.
10. How Nanorobots Can Avoid Phagocytosis by White Cells, Part I, By Robert A. Freitas Jr., Research Scientist, Zyvex Corp.
11. Freitas Jr. R.A., Nanomedicine, Volume IIA: Biocompatibility, Landes Bioscience, and Georgetown, TX, 2003.
12. Freitas, Jr. R.A., Nanomedicine, Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX (1999); Sections (k) 10.4.1.2.
13. Fadok V.A., Voelker D.R., Campbell P.A., Cohen J.J., Bratton D.L., Henson P.M., J. Immunol. 148, 2207 (1992).
14. Grakoui A., Bromley S.K., Sumen C., Da Vis M.M., Shaw A.S., Allen P.M., Dustin M.L., Science 285, 221 (1999).
15. Freitas, Jr. R.A., Nanomedicine, Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX (1999); Sections (a) 3.4.2.
16. Drexler K.E., “Nanosystems: Molecular Machinery, Manufacturing, and Computation,” John Wiley & Sons, New York (1992).
17. Freitas, Jr. R.A., Nanomedicine, Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX (1999); Sections (i) 10.3.6.
18. Wright, E.M., Sampedro, A.D., Hirayama, B.A., Koepsell, H., Gorboulev, V., Osswald, C.: US20050267154 (2005).
19. Marchant, R.E., Zhang, T., Qiu, Y., Ruegsegger, M.A.: US6759388 (1999).
20. Human Chromosome 22 Project Overview, Trust Sanger Institute,
21. www.nanorobotdesign.com
22. Cavalcanti A., Shirinzadeh B., Freitas Jr. R.A., Kretly L.C., Medical Nanorobot Architecture Based on Nanobioelectronics.
23. Freitas Jr RA. Exploratory design in medical nanotechnology: a mechanical artificial red cell. Artif Cells Blood Substit Immobil Biotechnol 1998; 26:411e30.
24. Nanosystems: Molecular Machinery, Manufacturing and Computation. By K. Eric Drexler (xx + 556 pp., 200+ illustrations. John Wiley & Sons, Inc.: New York, Chichester, Brisbane, Toronto, and Singapore. 1992) Page 374.
25. Quoted from Robert A. Freitas Jr., "Exploratory Design in Medical Nanotechnology: A Mechanical Artificial Red Cell," Artificial Cells, Volume 26, 1998, pp. 411-430. This paper is apparently the first detailed design study of a specific medical nanodevice (of the general type proposed by Drexler in Nanosystems) that has been published. See earlier description in: Robert A. Freitas Jr., "Respirocytes: High Performance Artificial Nanotechnology Red Blood Cells," Nanotechnology Magazine, Volume 2, October 1996, pp. 1, 8-13.).
26. Freitas Jr RA. Microbivores: artificial mechanical phagocytes using digest and discharge protocol. J Evol Technol 2005 Apr: 14:1e52.
27. Freitas Jr R.A., Nanomedicine, Volume I: Basic Capabilities Landes Bioscience, Georgetown, TX, 1999
28. Nanomedicine Volume II: Biocompatibility Landes Bioscience, Georgetown, TX, 2003
29. Wright, E.M., Sampedro, A.D., Hirayama, B.A., Koepsell, H., Gorboulev, V., Osswald, C.: US20050267154 (2005).
30. Marchant, R.E., Zhang, T., Qiu, Y., Ruegsegger, M.A.: US6759388 (1999).
31. Human Chromosome 22 Project Overview, Trust Sanger Institute, and https://www.sanger.ac.uk/.
32. Cavalcanti A. and Freitas Jr. R.A., “Autonomous Multi-Robot Sensor-Based Cooperation for Nanomedicine”, Int’l J. Nonlinear Science Numerical Simulation.
33. Freitas Jr. R.A., “Nanomedicine, Vol. I: Basic Capabilities”, Landes Bioscience, 1999.
34. Yamamoto H., Uemura S., Tomoda Y., Fujimoto S., Hashimoto T., and Okuchi K., “Transcardiac Gradient of Soluble Adhesion Molecules Predicts Progression of Coronary Artery Disease”, International Journal of Cardiology, 84(2-3):249-257, Aug. 2002.
35. https://www.ieee.org/
36. Freitas Jr R.A., Nanodentistry.
37. www.wikipedia.org
38. Menezes A.J., Kapoor V.J., Goel V.K., Cameron B.D., Lu J.Y., Within a Nanometer of your Life, Mechanical Engineering Magazine, August 2001,
39. Casal A., Hogg T., Cavalcanti A., Nanorobots as Cellular Assistants in Inflammatory Responses, IEEE BCATS Biomedical Computation at Stanford 2003 Symposium, IEEE Computer Society, Stanford CA, October 2003.
40. Cavalcanti A., Assembly Automation with Evolutionary Nanorobots and Sensor-Based Control applied to Nanomedicine, IEEE Transactions on Nanotechnology, 2(2), pp. 82-87, June2003, www.nanorobotdesign.com
41. IMM Report Number 12, Nanomedicine: Is Diamond Biocompatible With Living Cells? By Robert A. Freitas Jr., IMM Research Fellow.
42. Eric Drexler K., Molecular Engineering: An Approach to the Development of General Capabilities for Molecular Manipulation, Proc. National Academy of Sciences (USA) 78(September 1981):5275-5278.
43. Eric Drexler K., Nanosystems: Molecular Machinery, Manufacturing, and Computation, John Wiley & Sons, NY, 1992.
44. Merkle R.C., Design-Ahead for Nanotechnology, in Markus Krummenacker, James Lewis, eds., Prospects in Nanotechnology: Toward Molecular Manufacturing, John Wiley & Sons, New York, 1995, pp. 23-52.
45. Merkle R.C., Self-replicating systems and low cost manufacturing, in M.E. Welland, J.K. Gimzewski, eds., The Ultimate Limits of Fabrication and Measurement, Kluwer, Dordrecht, 1994, pp. 25-32.
46. Cavalcanti, A. Assembly Automation with Evolutionary Nanorobots and Sensor-Based Control Applied to Nanomedicine.
47. Bryson J.W., et al., "Protein Design: A Hierarchic Approach," Science 270(1995):935-941.
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