Respirocytes
NANOROBOTICS
RESPIROCYTES
Smrithi Sasidharan (Btech 3rd Year, ECE)
Varsha Vasudev(BTech 3rd Year, EB )
Amrita School of Engineering Bangalore, Model Engineering College, Kochi
ABSTRACT
Molecules are the universal basic building blocks of all the elements of nature, whether it be living or non-living. The complex human body with its interdependent physiological subsystems can be scaled down to a collection of various types of molecules. The accessibility to the molecular and atomic components of the body can resolve a variety of constraints faced in the medical field and can provide a tremendous breakthrough for the treatment of a variety of diseases which are considered incurable in the present scenario. Molecular manufacturing deals with the production of micron scaled machines or microcontrolled nanorobots composed of nano scale components which can access each and every molecule in a cell. These nanorobots can be introduced into the human body orally thus eliminating the need for an invasive technique to access the internal body. One type of nanorobot which can be used is the respirocytes.The respirocytes are artificial mechanical red blood cells designed by Robert.A.Fretias. It is a 1000 atm diamondoid pressure vessel designed to deliver oxygen about 236 times more than the natural blood cells per unit cell volume. These respirocytes are provided with mechanical, chemical and pressure sensors and are implanted with an onboard microcomputer. The processor can be remotely controlled by the doctor using acoustic signals thus directing the respirocyte to the specified location and simultaneously monitoring its functioning. The respirocytes can be used in a variety of applications like transfusable blood substitution; partial treatment for anaemia, perinatal/neonatal lung disorders, enhancement of cardiovascular/neurovascular procedures, tumour therapies and diagnostics, prevention of asphyxia and artificial breathing. Eventhough the respirocytes have not been practically implemented wide research is going on for the design of these promising artificial red blood cells. The major problem in the design of these nanorobots is their manufacturing in the nano scale using materials and components which are physically and chemically compatible with the human body with minimum aftereffects. The respirocytes thus give us huge hopes for the elimination of many currently untreatable diseases with added advantages of precise and effective resolution. 1. INTRODUCTION
Robotics is the branch of engineering science dealing with the design of robot, their manufacture and applications. This science can be categorised into three fields : * Electronics * Mechanics * Software Fully autonomous machines started to appear by the start of the twentieth century. The first digitally operated and programmable robot, Unimate, invented in 1961 was used to lift hot pieces of metal from a die casting machine. The robots are designed to accomplish relatively complicated, tedious and dull jobs relative to humans more cheaply, accurately and with utmost reliability. The basic applications of robots are in manufacturing, assembly and packing, transport, earth and space exploration, surgery, lab research and safe and mass production of weaponry. A. Nanorobotics and Nanomedicine
Nanorobotics is the subbranch of Robotics dealing with machines or robots designed in the micron scale of .1 -10 micrometers with nano scale assemblies. As no artificial non – biological nanorobot has been designed till now, it still remains a hypothetical nanotechnology engineering concept. The terms Nanobots, Nanoids, Nanites and Nanomites are synonyms of Nanorobots.
Nanomedicine is the application of nanotechnology in medical field. The approaches to Nanomedicine range from the medical use of nanomaterials, to nanoelectronic biosensors, and even possible future applications of molecular nanotechnology.
Molecular technology has clear implications in the medical field. It allows the physicians to perform precise interventions at the molecular and cellular level. The subassemblies of nanorobots generally include 100nm manipulator arms, 400nm Gigahertz clock computers, 10 nm sorting rotors for molecule by molecule reagent purification and smooth hard surfaces made of atomically flawless diamond.
The major use of nanorobots are in: * gerontological applications * pharmaceutical research, * diagnosis of diseases, * mechanical reversal of artherosclerosis, * supplementing the immune system * Rewriting DNA sequences in-vivo * Repair of brain damage * Reversing cellular insults caused by irreversible processes * Cryogenic storage of biological tissues
2. NATURAL GAS TRANSPORT SYSTEM IN THE BODY
Oxygen and carbon dioxide, the by-products of the combustion of foodstuffs are carried between the lungs and other tissues with the help of the red blood cells. These gases are carried within the red blood cells.
Haemoglobin combines reversibly with oxygen to form oxyhaemoglobin. 95% of oxygen is carried within the body in this form. The rest of the oxygen present is transported dissolved in blood. At normal human body temperature haemoglobin in 1 litre of blood holds 200cm3 of oxygen, which is 87 times more than what the plasma can carry alone which is about 2.3 cm3
Carbon dioxide combines reversibly with amino group of and bicarbonate ions releases hydrogen ions in t to form carbaminohaemoglobin. 25% of total carbon dioxide within the body is transported in this form. 10% is dissolved in plasma and the rest 65% is present within the red blood cells which after hydration is converted to bicarbonate ions.
Creation of carbamino haemoglobin and bicarbonate ions releases hydrogen ions which in the absence of haemoglobin makes venous blood 800 times more acidic than the arterial blood. But this does not happen due to the buffering action of haemoglobin and isohydric carriage monitored by it through the absorption of the excess hydrogen ions mostly within the red blood cells.
The gases are taken and released by haemoglobin according to their local partial pressures. Haemoglobin’s affinity for oxygen is inversely proportional to its affinity for carbon dioxide. High level of oxygen in the lungs aids the release of carbon dioxide which is to be expired. High carbon dioxide level in the other tissues assists the release of oxygen for use by the other tissues.
Tetrameric haemoglobin when freed from the red blood cells loses its effectiveness in three different ways : * It dissociates to dimmers which are rapidly cleared from circulation by mononuclear phagocytic system (10-30 mins half life) and by the kidneys (one hour half life). * It binds oxygen more tightly reducing the deliverability of oxygen during tissue hypoxia. * During storage it’s oxidised to useless methaemoglobin due to absence of the protective enzyme, methemoglobin reductase in the red blood cells.
3. CURRENT BLOOD SUBSTITUTION SYSTEMS
A lot of efforts have thus been put forward to modify haemoglobin to increase its intravascular dwell time. 3.1 Encapsulation
Haemoglobin is cross-linked internally or externally with a macromolecule, polymerised, modified by recombinant DNA techniques and microencapsulated. Encapsulation is a very promising approach as all the vertebrate haemoglobin is contained in cells to maintain its stability, preserve function and to protect the host from toxicity. 3.2 Fluorocarbon Emissions
Fluorocarbon emulsions provide a simpler approach to oxygen transport and delivery. The technique relies on physical solubilisation rather than binding of oxygen molecules. Injectable oxygen carriers which are molecules of eight to ten carbon atoms with a molecular weight of 450-500 grams are prepared using liquid fluorocarbons. They dissolve about 20-25 more times as much oxygen as water delivering optimum volume of oxygen to the tissues as delivered by the equivalent weight of haemoglobin. Mice survive immersion in fluorocarbon through which oxygen is bubbled. Rats breathing 95% oxygen survived total blood replacement.
Fluorocarbons are insoluble in water. They are administered in the form of emulsions of 0.1 – 0.2 micron sized droplets dispersed in a physiologic solution similar to fat emulsions. After opsonisation and phagocytosis of emulsion droplets the fluorocarbons are transferred to lipid carriers in blood and released during passage through pulmonary capillary bed. Thus the fluorocarbons are not metabolised but excreted unchanged by exhalation as a vapour through lungs in 4-12 hours. 3.3 Shortcomings
The current blood substitution systems have the following shortcomings: * Too short a survival time in circulation to be useful in treatment of chronic anaemia. * They are not specifically designed to regulate carbon dioxide to participate in acid or base buffering. * Vaso-constriction * Their use results in reduced tissue oxygenation * Increases the susceptibility to bacterial infection due to blockage of the monocyte-macrophage system * Nephrotoxicity * Free radical induction
4. DESIGN OF RESPIROCYTES
Nobel physicist Richard.P.Feynman first proposed nanotechnology in the year 1959. A Given a future to precisely engineer complex, micron scale machines, it is possible to imagine a complete microscopic chemical factory that avoids the shortcomings of the current blood technology and simulates most major functions of the natural erythrocyte. Respirocytes are the artificial red blood cells or erythrocytes designed according to the principles of nanotechnology. They are basically nanorobots.
4.1. Pressure Vessels
With the goal of oxygen transport from the lungs to other body tissues, the simplest possible design proposed by Robert.A.Fretias is a microscopic pressure vessel, spherical in shape for maximum compactness.
Since one of the necessities for a convenient design is durability, the strongest materials like flawless diamond or sapphire are used and they are constructed with utmost care atom by atom. They have a Young’s modulus of 1012 N/m2 (107 atm) and conservative working stress (~0.2 times tensile strength) of 1010 N/m2 (100,000 atm).
Considering the simplest design, oxygen release will be continuous throughout the body. A slightly more sophisticated design constitutes a system responsive to local oxygen partial pressure, with gas released through one of these methods: * Using a needle valve , controlled by a heme protein that changes conformation in response to hypoxia * Diffusion via low pressure chamber into a densely packed aggregation of heme-like molecules trapped in an external fullerene cage porous to environmental gas and water molecules * Engineering molecular sorting rotors
These proposals have two principal failings: * Once discharged the devices become useless and the discharge time for the presently designed blood substitutes is very short. In the absence of functioning red blood cells the oxygen contained in a 1 cm3 injection of 1000 atm microtanks would be exhausted in 2 minutes. * The proposals involve placement of numerous point source oxygen emitters throughout the capillary bed in conjunction with the existing erythrocyte population. These extra emitters are equivalent to red blood cells with disabled carbon dioxide transport and acid-buffering capabilities. Their inclusion in the blood stream leads to increased carbon dioxide acidity and acidosis especially in patients with respiratory and haemolytic complications.
Neither problem can be overcome by using passive systems alone. A practical and preferable method to extend the duration is to recharge the microvessels with oxygen gas, preferably via the lungs since direct regeneration of oxygen from carbon dioxide is energetically prohibitive. The simplest way to prevent carbon dioxide toxicity is to provide additional tankage for carbon dioxide transport and become active means for gas loading at the tissues and unloading at the lungs as physically stored carbon dioxide makes no net addition to blood acidity. But still respirocytes operating in the absence of red blood cells would generate little carbon dioxide related acidity. Proper blood pH could probably be maintained by the kidneys alone. .2 Molecular Sorting Rotors
Molecular sorting rotors have been proposed for the task of an active method of conveying gas molecules into, and out of the pressurised microvessels which is the key to the successful functioning of the respirocyte. Each rotor has binding site "pockets" along the rim exposed alternately to the blood plasma and interior chamber by the rotation of the disk. Each pocket selectively binds a specific molecule when exposed to the plasma. Once the binding site rotates to expose it to the interior chamber, the bound molecules are forcibly ejected by rods thrust outward by the cam surface. Rotors are fully reversible, so they can be used to load or unload gas storage tanks, depending upon the direction of rotor rotation.
Figure : Molecular sorting rotor
Typical molecular concentrations in the blood for target molecules of interest (O2, CO2, N2 and glucose) are ~10-4, which should be sufficient to ensure at least 90% occupancy of rotor binding sites at the stated rotor speed . Each stage can conservatively provide a concentration factor of 1000, so a multi-stage cascade should ensure storage of virtually pure gases. Since each 12-arm outbound rotor can contain binding sites for 12 different impurity molecules, the number of outbound rotors in the entire system can probably be reduced to a small fraction of the number of inbound rotors.
Figure : Sorting rotor cascade * Sorting Rotor Binding Sites
Receptors should be should be highly sensitive and they should have binding sites only for specific molecules. They should have the additional qualities of reliability, high affinity and should survive long exposures to the aqueous media of blood.
Oxygen transport pigments are a usually coagulated protein that is proteins complexed with another organic molecule or with one or more metal atoms. The main components of the transport pigments are the metal atoms like Cu2+ or Fe3+ which constitutes the binding sites to which oxygen can reversibly attach. Apart from haemoglobin and myoglobin the natural respiratory pigments are hemocyanin, chlorocruorin, hemerythrin and vanadium chromagen. Artificial reversible oxygen-binding molecules have also been studied. Some of them are : * Cobalt based porphyrins such as coboglobin and cobaltohistidine * Simple iron-indigo compounds * Iridium complexes * Nonporphyrin lacunar iron complexes * Heme linked oxidase
Implantable blood oxygen sensors like Medtronics haemodynamic monitor are already in clinical trials. Unlike haemoglobin, the other natural oxygen transport pigments are not susceptible to carbon monoxide poisoning, neither are the respirocytes.
Many proteins and enzymes like haemoglobin, carbonic anhydrase and ribulose biphosphate carboxylase have binding sites for carbon dioxide. A wide variety of molecules like deliquescent crystals, efflorescent minerals, hydrophilic and polar amino acids and numerous enzymes such as carbonic anhydrase, hydrolases and dehydratases bind water reversibly. Binding sites for glucose are common in nature. These include the enzyme hexokinase, the glucose transporter molecule and the glucose binding proteins found in the intestines, liver, kidney and adipose tissue. Implantable glucose sensors have been developed by Becton, Dickinson Incorporation and by the Japans University of Osaka. The enzyme nitrogenase is highly labile in the presence of oxygen but research is concentrated on its highly efficient nitrogen binding sites. Once the required receptor for the transport of the specific gas is selected they are incorporated into the rotors as precisely shaped and charged diamondoid surfaces and cavities, atom by atom, using the manufacturing techniques suggested by Drexler. * Device Scaling
The upper limit for the physical size of the respirocytes can be easily estimated. It cannot be larger than the capillaries which have an average diameter of 8 microns. But these capillaries can be as small as 3.7 microns when the red blood cells have to fold themselves to conveniently pass through them. Smaller cells face greater danger of environmental insults and they encounter potential filtration sites throughout the body. For example the fenestrated endothelium of the glomerular membrane in the kidney filter particles <100 nm from the blood. So these requirements put forward the need for larger device sizes.
The minimum possible respirocyte diameter is driven by operational requirements and by minimum component size. The smallest reasonable computer requires 105 nm3, a 58-nm diameter sphere. Additionally, gas is loaded using molecular sorting rotors mounted on the surface of a spherical tank. In the baseline design (diameter D = 1 micron), 37.28% of tank surface consists of sorting rotors and related subsystems. The number of sorting rotors scales with tank volume or R3; tank surface scales as R2; so the percentage of tank surface in rotors (Rotor/Surface Ratio or RSR) scales linearly with R (RSR ~ qD, q = 0.3728 fractional surface coverage). RSR ~ 1.00 (100%) coverage occurs at D = 2.68 microns, the upper limit. Careful review of the baseline design suggests that the minimum rotor area necessary to achieve all performance specifications while maintaining 10:1 subsystem redundancy is about 17,000 nm2, which implies D = 0.245 micron at RSR = 0.0902 (9.02%). Eliminating all redundancy reduces rotor requirements to 1700 nm2, which implies D = 0.114 micron at RSR = 0.0412 (4.12%). The above considerations suggest a reasonable range for respirocyte diameter of 0.2-2 microns; the present study assumes a spherical respirocyte diameter of ~1 micron. * Buoyancy Control Using Water Ballast
Another factor which comes into picture when operating in an aqueous medium is buoyancy which can be controlled by loading and unloading the water ballast. The smaller the repirocyte, the longer it settles out of suspension according to the Stokes Law. Even a small difference in density between individual red blood cells and blood plasma causes the red blood cells to settle out of suspension at a fast rate depending on haemocrit and degree of red blood cell aggregation. Natural erythrocytes appear unhandicapped by their faster settling rate, so active ballast management for artificial respirocytes is probably unnecessary in normal operations. No other solid blood component can maintain exact neutral buoyancy, hence those other components precipitate outward during gentle centrifugation and are drawn off and added back to filtered plasma on the other side of the apparatus. Meanwhile, after a period of centrifugation, the plasma, containing mostly suspended respirocytes but few other solids, is drawn off through a 1-micron filter, removing the respirocytes. Filtered plasma is recombined with centrifuged solid components and returned undamaged to the patient 's body. The rate of separation is further enhanced either by commanding respirocytes to empty all tanks, lowering net density to 66% of blood plasma density, or by commanding respirocytes to blow a 5-micron O2 gas bubble to which the device may adhere via surface tension, allowing it to rise at 45 mm/hour under normal gravitational acceleration. 5. BASELINE DESIGN
Many specific design issues must be next confronted like tank configuration, rotor and glucose engine replacement, subsystem scaling and redundancy level required to produce acceptable system reliability. The final design represents a compromise among many competing factors. * Power
Onboard power is provided by a mechanochemical engine that exoenergically combines glucose and oxygen to generate mechanical energy to drive molecular sorting rotors and other subsystems, as demonstrated in principle in a variety of biological motor systems. Glucose engine design - possibly involving a ballistic turbine driven by rotor-combustion ejector operating near 1000 atm is a critical research issue. Drexler estimates engines can be designed to operate at efficiency greater than 99%. However, since natural cellular metabolic pathways using the glycolysis and tricarboxylic acid (TCA) cycles achieve only 68% efficiency, we adopt a more conservative 50% efficiency for the present study. Sorting rotors absorb glucose directly from the blood and store it in a fuel tank. Oxygen is tapped from onboard storage. * Communications
The attending physician can broadcast signals to molecular mechanical systems deployed in the human body most conveniently using modulated compressive pressure pulses received by mechanical transducers embedded in the surface of the respirocyte. Converting a pattern of pressure fluctuations into mechanical motions that can serve as input to a mechanical computer requires transducers that function as pressure-driven actuators. Internal communications within the respirocyte may be achieved by impressing modulated low-pressure acoustical spikes on the hydraulic working fluid of the power distribution system, or via simple mechanical rods and couplings. * Sensors
Various sensors are needed to acquire external data essential in regulating gas loading and unloading operations, tank volume management, and other special protocols. Figure : Molecular Concentration Sensor
For instance, sorting rotors can be used to construct quantitative concentration sensors for any molecular species desired. It is also convenient to include internal pressure sensors to monitor O2 and CO2 gas tank loading, (container fullness) sensors for ballast and glucose fuel tanks, and internal/external temperature sensors to help monitor and regulate total system energy output. * Onboard Computation
An onboard computer is necessary to provide precise control of respiratory gas loading and unloading, rotor field and ballast tank management, glucose engine throttling, power distribution, interpretation of sensor data and commands received from the outside, self-diagnosis and activation of failsafe shutdown protocols.
5.5 Baseline configuration
The artificial respirocyte is a spherical nanomedical device 1 micron in diameter consisting of 18 billion precisely arranged structural atoms plus 9 billion temporarily resident molecules when fully loaded. Allocations of device volume and mass were determined by specifying equal O2 and CO2 tank volumes, glucose tank volumes, ballast volume as a variable, and all structural mass as diamondoid in density. Figure.4.Glucose Rotor and Tank,engine assembly
Twelve pumping stations are spaced evenly along an equatorial circle. Each station has its own independent glucose engine, glucose tank, environmental glucose sensors, and glucose sorting rotors. Each station alone can generate sufficient energy to power the entire respirocyte. Detailed reliability simulations will be required to determine whether stations should run at
(1) Peak power on a rotating schedule, (2) Partial power on a continuous basis, or
(3) One at a time until failure, switching to the next backup.
Power is transmitted hydraulically to local station subsystems and also along a dozen independent interstation trunk lines that allow stations to pass hydraulic power among themselves as required, permitting load shifting and balancing.
Computer/mass-memory sets are located at the centre of the device allowing maximum shielding from environmental insults and centralized access to all surface components including communications links, external sensors, and distributed power supply. Any of the computers at the core can receive power or communications directly from any of the pumping stations along hard links in protected utility conduits.
Figure:Pumping station layout
Each pumping station has an array of 3-stage molecular sorting rotor assemblies for pumping O2, CO2, and H2O into and out of the ambient medium. The number of rotor sorters in each array is determined both by performance requirements and by the anticipated concentration of each target molecule in the bloodstream. Any one pumping station, acting alone, can load or discharge any storage tank in 10 sec whether gas, ballast water, or glucose. Gas pumping rotors are arrayed in a noncompact geometry to minimize the possibility of local molecule exhaustion during loading.
Each station also includes three glucose engine flues for discharge of CO2 and H2O combustion waste products, environmental oxygen pressure sensors distributed throughout the O2 sorting rotor array to provide fine control if unusual concentration gradients are encountered, also similar CO2 pressure sensors on the opposite side, 2 external environment temperature sensors (one on each side located as far as possible from the glucose engine to ensure true readings), and 2 fluid pressure transducers for receiving command signals from medical personnel. Figure:Equatorial Cutaway View of Respirocyte
Figure: Polar Cutaway View of Respirocyte
The equatorial pumping station network occupies 50% of respirocyte surface. On the remaining surface, a universal "bar code" consisting of concentric circular patterns of shallow rounded ridges is embossed on each side, centered on the "north pole" and "south pole" of the device. This coding permits easy product identification by an attending physician with a small blood sample and access to an electron microscope, and may also allow rapid reading by other more sophisticated medical nanorobots which might be deployed in the future. 5.6 Tank Chamber Design
Each storage tank is constructed of diamondoid honeycomb or a geodesic grid skeletal framework for maximum strength. Thick diamond bulkheads separate internal tankage volumes. Available structural mass is equivalent to a 10-nm thick (~60 carbon atoms) 2.2 micron x 2.2 micron diamond sheet. Compartment walls are perforated with sufficient holes of varying sizes to allow gas to flow easily between them, with larger compartments nearest the rotors graduating to smaller compartments more distant from the rotors to encourage isobaric entrainment.
The present design includes separate O2 and CO2 chambers. In theory, these gases could be stored mixed in a single chamber. A single chamber design can effectively double the O2-carrying capacity of each respirocyte by allowing the entire gas tank volume to be initially charged with oxygen at 1000 atm. There are four minor drawbacks to this approach: (1) Respiration is controlled by CO2, not O2, levels, requiring maintenance of sizable CO2 inventories at all times, reducing surplus volume available for O2 storage; (2) Respirocytes may be deployed to reverse serious tissue CO2 overloading, requiring significant available storage volume to absorb this gas;
(3) The rate of binding for outbound transport by sorting rotors may be lower for mixed gases, reducing maximum outgassing rate; and (4) Inability to emergency vent pure gas. 6. SAFETY FACTORS Respirocytes should be extremely reliable and usually should have a life of 20 years.
Device overheating: If all the glucose power plants get jammed or refuse to turn off, malfunction occurs while the respirocyte is in your bloodstream, its temperature won 't rise at all. That 's because the 7.3 picowatts of continuous thermal energy the device is generating is easily absorbed by the huge aqueous heat sink, which has a bountiful heat capacity.
Non combustive device explosion: Each device contains up to 0.24 micron3 of oxygen and carbon dioxide gas at 1000 tam pressure, representing 24 picojoules of stored mechanical energy.If the device explodes inside human tissue, the gases may work against the surrounding fluid forming large bubbles.The only plausible respirocyte explosion scenario is dental grinding.A patient with an oral lesion could spread respirocyte-impregnated blood over the teeth can explode thousand of respirocytes at once producing a "fizziness" in the mouth.
Complete structural failure of a respirocyte in vivo is a rare case. A spherical diamondoid shell should resist accelerations up to 108-1010 g 's. Crushing respirocyte-impregnated human tissue in a hydraulic press is unlikely to destroy any devices, as they will simply slide out of the way. 7. RESPIROCYTE CONTROL PROTOCOLS
Respirocyte behaviour is initially governed by a set of default protocols which can be modified at any time by the attending physician.Basic protocols will exist for operating molecular sorting rotors at various speeds and directions in response to sensor data. Gas loading parameters may be precisely specified in an individualized onboard lookup table provided by the physician for his patient, as for instance to adjust for declining arterio-venous oxygen gradient at high altitudes. Respirocytes, like natural haemoglobin, may also participate in the elimination of CO and in NO-mediated vascular control.
Respirocytes can be programmed with more sophisticated behaviours. * Detection of PCO2 < 0.5 mmHg and PO2 > 150 mmHg, indicating direct exposure to atmosphere and a high probability that the device has been bled out of the body, should trigger a prompt gas venting and failsafe device shutdown procedure. * Self-test algorithms monitoring tank filling rates, unaccounted pressure drops (indicating a leak), clutch responses, etc. may detect significant device malfunction, causing the respirocyte to place itself in standby mode ready to respond to an acoustic command to execute the filtration protocol for exfusion. * Out messaging protocols could allow the population of respirocytes to communicate systemwide status directly with the patient by inducing recognizable physiological cues (fever, shivering, gasping), or with the physician by generating subtle respiratory patterns requiring diagnostic equipment to detect, either automatically or in response to an acoustically-transmitted global inquiry initiated by patient or physician. |
8. APPLICATIONS 8.1 Transfusions & Perfusions
Respirocytes may be used as the active oxygen-carrying component of a universally transfusable blood substitute that is free of disease vectors such as hepatitis, venereal disease, malarial parasites or AIDS, storable indefinitely and readily available with no need for cross-matching. In current practice, organs must be transplanted soon after harvest; respirocytes could be used as a long-duration perfusant to preserve living tissue, especially at low temperature, for grafts (kidney, marrow, liver and skin) and organ transplantation. 8.2 Treatment of Anaemia
Oxygenating respirocytes offer complete or partial symptomatic treatment for virtually all forms of anaemia, including acute anaemia caused by a sudden loss of blood after injury or surgical intervention; secondary anaemia’s caused by bleeding typhoid, duodenal or gastric ulcers; chronic, gradual, or post-hemorrhagic anaemia’s from bleeding gastric ulcers , excessive menstrual bleeding, or battle injuries in war zones, hereditary anaemias including haemophilia, leptocytosis and sicklemia chlorosis and hypochromic anaemia, endocrine deficiency anaemia, pernicious and other nutritional anaemias; anaemias resulting from infectious diseases including rheumatism, scarlet fever, tuberculosis, syphilis, chronic renal failure and cancer, or from haemoglobin poisoning such as by carbon monoxide inhalation. * 8.3 Fetal and Child-Related Disorders
Respirocytes may be useful in perinatal medicine, as for example infusions of device suspension to treat fetal anaemia, neonatal hemolytic disease, or in utero asphyxia from partial detachment of the placenta or maternal hypoxia, to restore the oxygen-carrying ability of fetal blood. Asphyxia neonatorum, as from umbilical cord compression during childbirth, may fatally deprive the infant of oxygen; prenatal respirocyte treatment could be preventative. Many cases of Sudden Infant Death Syndrome, the leading cause of neonatal death between 1 week and 1 year of age, and respiratory distress syndrome involve recurrent oxygen deprivation or abnormalities in the automatic control of breathing, both of which could be delethalized using a therapeutic dose of red cell devices. Respirocytes could also aid in the treatment of childhood afflictions such as whooping cough, cystic fibrosis, rheumatic heart disease and rheumatic fever, congenital heart disorders. 8.4 Respiratory Diseases
The devices could provide an effective long-term drug-free symptomatic treatment for asthma, and could assist in the treatment of hemotoxic (pit viper) and neurotoxic (coral) snake bites; hypoxia, stress polycythemia and lung disorders resulting from cigarette smoking and alcoholism; neck goitre and cancer of the lungs, pharynx, or thyroid; pericarditis, coronary thrombosis, hypertension, and even cardiac neurosis; obesity, quinsy, botulism, diphtheria, tertiary syphilis, amyotrophic lateral sclerosis, uraemia, coccidioidomycosis (valley fever), and anaphylactic shock; and Alzheimer 's disease where hypoxia is speeding the development of the condition. 8.5 Cardiovascular and Neurovascular Applications
Respirocyte perfusion could be useful in maintaining tissue oxygenation during anaesthesia, coronary angioplasty, organ transplantation, siamese-twin separation, other aggressive heart and brain surgical procedures, in postsurgical cardiac function recovery, and in cardiopulmonary bypass solutions. The device could help prevent gangrene and cyanosis, for example, during treatment of Raynaud 's Disease. Therapeutic respirocyte dosages can delay brain ischemia under conditions of heart or lung failure, and might be useful in treating senility. 8.6 Tumor Therapy and Diagnostics
Cancer patients are usually anemic. X-rays and many chemotherapeutic agents require oxygen to be maximally cytoxic, so boosting systemic oxygenation levels into the normal range using respirocytes might improve prognosis and treatment outcome. Fluorocarbon emulsions have been used to probe tissue oxygen tension. Respirocytes could be used as reporter devices to map a patient 's whole-body blood pressure or oxygenation profile, storing direct sensor data in each computer along with positional information recorded from a network of precisely positioned acoustic transponders, to be later retrieved by device filtration and data reconstruction . A similar network of acoustic transmitters, making possible respirocyte autotriangulation hence precise internal positional knowledge, could allow preferential superoxygenation of specific tissues, enhancing treatment effectiveness. 8.7 Asphyxia
Respirocytes make breathing possible in oxygen-poor environments, or in cases where normal breathing is physically impossible. Prompt injection with a therapeutic dose, or advance infusion with an augmentation dose, could greatly reduce the number of choking deaths and the use of emergency tracheostomies, artificial respiration in first aid, and mechanical ventilators. The device provides an excellent prophylactic treatment for most forms of asphyxia, including drowning, strangling, electric shock, nerve-blocking paralytic agents, carbon monoxide poisoning, underwater rescue operations, smoke inhalation or firefighting activities, anaesthetic/barbiturate overdose and confinement in airtight spaces. Respirocytes augment the normal physiological responses to hypoxia, which may be mediated by pulmonary neuroepithelial oxygen sensors in the airway mucosa of human and animal lungs. 8.8 Underwater Breathing
Respirocytes could serve as an in vivo SCUBA (Self-Contained Underwater Breathing Apparatus) device. With an augmentation dose or nanolung, the diver holds his breath for 0.2-4 hours, goes about his business underwater, then surfaces, hyperventilates for 6-12 minutes to recharge, and returns to work below.
Respirocytes can relieve the most dangerous hazard of deep sea diving - decompression sickness ("the bends") or caisson disease. 8.9 Other Applications
Respirocytes could permit major new sports records to be achieved, because the devices can deliver oxygen to muscle tissues faster than the lungs can provide, for the duration of the sporting event. This would be especially useful in running, swimming, and other endurance-oriented events, and in competitive sports such as basketball, football and soccer where extended periods of sustained maximum exertion are required.
Artificial blood substitutes may also have wide use in veterinary medicine, especially in cases of vehicular trauma and renal failure where transfusions are required, and in battlefield applications demanding blood replacement or personnel performance enhancement. 9. DEVICE TESTING AND FDA APPROVAL
Since the respirocyte depends for its function on mechanical pumping rather than chemical action, and is not metabolized during the achievement of its purposes, it is clearly a device and not a drug under the Federal Food, Drug, and Cosmetic Act. Devices are regulated under the provisions of the Medical Device Amendments of 1976, the Safe Medical Devices Act of 1990, and the Medical Device Amendments of 1992.
In order for the FDA to approve or license any blood substitute, both efficacy and safety must be established to the satisfaction of the FDA 's Office of Device Evaluation using preclinical and clinical data to support a Premarket Approval Application (PMA). In 1990 the FDA 's Centre for Biologics Evaluation and Research issued points to consider document governing artificial oxygen carriers. The document does not address devices, but many of its suggestions are relevant. The FDA recommends first a program of in vitro biologic assays to characterize the product, including tests for generation of oxygen radicals, activation of triggered enzyme/cell systems such as the complement/kinin/coagulation cascades, macrophage/neutrophil/platelet activation, and mediator release such as histamine, thromboxane metabolites, leukotrienes, and interleukins. This should be followed by animal safety testing to determine effects on microvascular circulation and endothelium, evaluation of nephrotoxicity, blood chemistry assays and hematologic studies. Finally, low-dose human studies could begin, with subjects monitored carefully for circulatory, immune, and other animal-study parameters, as well as for inflammation mediators, specific interactions with human diseases, and comparison of product safety profile with other approved artificial oxygen carriers, and with natural red cells. Since the respirocyte is a purely mechanical 1-micron device, there is no concern with electromagnetic interference. The product liability situation is such that no physician uses any experimental device unless he or she is certain of its effectiveness and safety anyone with insufficient data to demonstrate such is subject to lawsuit, and loss of the right to practice medicine. Clearly a formidable regimen of laboratory, field, and clinical testing lies ahead before the respirocyte could be deemed ready for routine medical use.
10. CONCLUSION
This paper presents a preliminary design for a simple nanomedical device that functions as an artificial erythrocyte, duplicating the oxygen and carbon dioxide transport functions of red cells while largely eliminating the need to manage carbonic acidity because CO2 is carried mechanically, rather than chemically, in the blood. The baseline respirocyte can deliver 236 times more oxygen to the tissues per unit volume than natural red cells, and enjoys a similar advantage in carbon dioxide transport.
The respirocyte is constructed of tough diamondoid material, employs a variety of chemical, thermal and pressure sensors, has an onboard nanocomputer which enables the device to display many complex responses and behaviours, can be remotely reprogrammed via external acoustic signals to modify existing or to install new protocols, and draws power from abundant natural serum glucose supplies, thus is capable of operating intelligently and virtually indefinitely, unlike red cells which have a natural lifespan of four months. This device cannot be built today. However, when future advances in the engineering of molecular machine systems permit its construction, the artificial respirocyte may find dozens of applications in therapeutic and critical care medicine, and elsewhere.
REFERENCES * http://www.kurzweilai.net/meme/frame.html?main=/articles/art0468.html * http://www.foresight.org/nanomedicine/Respirocytes.html * www.wikepedia.com
References: * http://www.kurzweilai.net/meme/frame.html?main=/articles/art0468.html * http://www.foresight.org/nanomedicine/Respirocytes.html * www.wikepedia.com
RESPIROCYTES
Smrithi Sasidharan (Btech 3rd Year, ECE)
Varsha Vasudev(BTech 3rd Year, EB )
Amrita School of Engineering Bangalore, Model Engineering College, Kochi
ABSTRACT
Molecules are the universal basic building blocks of all the elements of nature, whether it be living or non-living. The complex human body with its interdependent physiological subsystems can be scaled down to a collection of various types of molecules. The accessibility to the molecular and atomic components of the body can resolve a variety of constraints faced in the medical field and can provide a tremendous breakthrough for the treatment of a variety of diseases which are considered incurable in the present scenario. Molecular manufacturing deals with the production of micron scaled machines or microcontrolled nanorobots composed of nano scale components which can access each and every molecule in a cell. These nanorobots can be introduced into the human body orally thus eliminating the need for an invasive technique to access the internal body. One type of nanorobot which can be used is the respirocytes.The respirocytes are artificial mechanical red blood cells designed by Robert.A.Fretias. It is a 1000 atm diamondoid pressure vessel designed to deliver oxygen about 236 times more than the natural blood cells per unit cell volume. These respirocytes are provided with mechanical, chemical and pressure sensors and are implanted with an onboard microcomputer. The processor can be remotely controlled by the doctor using acoustic signals thus directing the respirocyte to the specified location and simultaneously monitoring its functioning. The respirocytes can be used in a variety of applications like transfusable blood substitution; partial treatment for anaemia, perinatal/neonatal lung disorders, enhancement of cardiovascular/neurovascular procedures, tumour therapies and diagnostics, prevention of asphyxia and artificial breathing. Eventhough the respirocytes have not been practically implemented wide research is going on for the design of these promising artificial red blood cells. The major problem in the design of these nanorobots is their manufacturing in the nano scale using materials and components which are physically and chemically compatible with the human body with minimum aftereffects. The respirocytes thus give us huge hopes for the elimination of many currently untreatable diseases with added advantages of precise and effective resolution. 1. INTRODUCTION
Robotics is the branch of engineering science dealing with the design of robot, their manufacture and applications. This science can be categorised into three fields : * Electronics * Mechanics * Software Fully autonomous machines started to appear by the start of the twentieth century. The first digitally operated and programmable robot, Unimate, invented in 1961 was used to lift hot pieces of metal from a die casting machine. The robots are designed to accomplish relatively complicated, tedious and dull jobs relative to humans more cheaply, accurately and with utmost reliability. The basic applications of robots are in manufacturing, assembly and packing, transport, earth and space exploration, surgery, lab research and safe and mass production of weaponry. A. Nanorobotics and Nanomedicine
Nanorobotics is the subbranch of Robotics dealing with machines or robots designed in the micron scale of .1 -10 micrometers with nano scale assemblies. As no artificial non – biological nanorobot has been designed till now, it still remains a hypothetical nanotechnology engineering concept. The terms Nanobots, Nanoids, Nanites and Nanomites are synonyms of Nanorobots.
Nanomedicine is the application of nanotechnology in medical field. The approaches to Nanomedicine range from the medical use of nanomaterials, to nanoelectronic biosensors, and even possible future applications of molecular nanotechnology.
Molecular technology has clear implications in the medical field. It allows the physicians to perform precise interventions at the molecular and cellular level. The subassemblies of nanorobots generally include 100nm manipulator arms, 400nm Gigahertz clock computers, 10 nm sorting rotors for molecule by molecule reagent purification and smooth hard surfaces made of atomically flawless diamond.
The major use of nanorobots are in: * gerontological applications * pharmaceutical research, * diagnosis of diseases, * mechanical reversal of artherosclerosis, * supplementing the immune system * Rewriting DNA sequences in-vivo * Repair of brain damage * Reversing cellular insults caused by irreversible processes * Cryogenic storage of biological tissues
2. NATURAL GAS TRANSPORT SYSTEM IN THE BODY
Oxygen and carbon dioxide, the by-products of the combustion of foodstuffs are carried between the lungs and other tissues with the help of the red blood cells. These gases are carried within the red blood cells.
Haemoglobin combines reversibly with oxygen to form oxyhaemoglobin. 95% of oxygen is carried within the body in this form. The rest of the oxygen present is transported dissolved in blood. At normal human body temperature haemoglobin in 1 litre of blood holds 200cm3 of oxygen, which is 87 times more than what the plasma can carry alone which is about 2.3 cm3
Carbon dioxide combines reversibly with amino group of and bicarbonate ions releases hydrogen ions in t to form carbaminohaemoglobin. 25% of total carbon dioxide within the body is transported in this form. 10% is dissolved in plasma and the rest 65% is present within the red blood cells which after hydration is converted to bicarbonate ions.
Creation of carbamino haemoglobin and bicarbonate ions releases hydrogen ions which in the absence of haemoglobin makes venous blood 800 times more acidic than the arterial blood. But this does not happen due to the buffering action of haemoglobin and isohydric carriage monitored by it through the absorption of the excess hydrogen ions mostly within the red blood cells.
The gases are taken and released by haemoglobin according to their local partial pressures. Haemoglobin’s affinity for oxygen is inversely proportional to its affinity for carbon dioxide. High level of oxygen in the lungs aids the release of carbon dioxide which is to be expired. High carbon dioxide level in the other tissues assists the release of oxygen for use by the other tissues.
Tetrameric haemoglobin when freed from the red blood cells loses its effectiveness in three different ways : * It dissociates to dimmers which are rapidly cleared from circulation by mononuclear phagocytic system (10-30 mins half life) and by the kidneys (one hour half life). * It binds oxygen more tightly reducing the deliverability of oxygen during tissue hypoxia. * During storage it’s oxidised to useless methaemoglobin due to absence of the protective enzyme, methemoglobin reductase in the red blood cells.
3. CURRENT BLOOD SUBSTITUTION SYSTEMS
A lot of efforts have thus been put forward to modify haemoglobin to increase its intravascular dwell time. 3.1 Encapsulation
Haemoglobin is cross-linked internally or externally with a macromolecule, polymerised, modified by recombinant DNA techniques and microencapsulated. Encapsulation is a very promising approach as all the vertebrate haemoglobin is contained in cells to maintain its stability, preserve function and to protect the host from toxicity. 3.2 Fluorocarbon Emissions
Fluorocarbon emulsions provide a simpler approach to oxygen transport and delivery. The technique relies on physical solubilisation rather than binding of oxygen molecules. Injectable oxygen carriers which are molecules of eight to ten carbon atoms with a molecular weight of 450-500 grams are prepared using liquid fluorocarbons. They dissolve about 20-25 more times as much oxygen as water delivering optimum volume of oxygen to the tissues as delivered by the equivalent weight of haemoglobin. Mice survive immersion in fluorocarbon through which oxygen is bubbled. Rats breathing 95% oxygen survived total blood replacement.
Fluorocarbons are insoluble in water. They are administered in the form of emulsions of 0.1 – 0.2 micron sized droplets dispersed in a physiologic solution similar to fat emulsions. After opsonisation and phagocytosis of emulsion droplets the fluorocarbons are transferred to lipid carriers in blood and released during passage through pulmonary capillary bed. Thus the fluorocarbons are not metabolised but excreted unchanged by exhalation as a vapour through lungs in 4-12 hours. 3.3 Shortcomings
The current blood substitution systems have the following shortcomings: * Too short a survival time in circulation to be useful in treatment of chronic anaemia. * They are not specifically designed to regulate carbon dioxide to participate in acid or base buffering. * Vaso-constriction * Their use results in reduced tissue oxygenation * Increases the susceptibility to bacterial infection due to blockage of the monocyte-macrophage system * Nephrotoxicity * Free radical induction
4. DESIGN OF RESPIROCYTES
Nobel physicist Richard.P.Feynman first proposed nanotechnology in the year 1959. A Given a future to precisely engineer complex, micron scale machines, it is possible to imagine a complete microscopic chemical factory that avoids the shortcomings of the current blood technology and simulates most major functions of the natural erythrocyte. Respirocytes are the artificial red blood cells or erythrocytes designed according to the principles of nanotechnology. They are basically nanorobots.
4.1. Pressure Vessels
With the goal of oxygen transport from the lungs to other body tissues, the simplest possible design proposed by Robert.A.Fretias is a microscopic pressure vessel, spherical in shape for maximum compactness.
Since one of the necessities for a convenient design is durability, the strongest materials like flawless diamond or sapphire are used and they are constructed with utmost care atom by atom. They have a Young’s modulus of 1012 N/m2 (107 atm) and conservative working stress (~0.2 times tensile strength) of 1010 N/m2 (100,000 atm).
Considering the simplest design, oxygen release will be continuous throughout the body. A slightly more sophisticated design constitutes a system responsive to local oxygen partial pressure, with gas released through one of these methods: * Using a needle valve , controlled by a heme protein that changes conformation in response to hypoxia * Diffusion via low pressure chamber into a densely packed aggregation of heme-like molecules trapped in an external fullerene cage porous to environmental gas and water molecules * Engineering molecular sorting rotors
These proposals have two principal failings: * Once discharged the devices become useless and the discharge time for the presently designed blood substitutes is very short. In the absence of functioning red blood cells the oxygen contained in a 1 cm3 injection of 1000 atm microtanks would be exhausted in 2 minutes. * The proposals involve placement of numerous point source oxygen emitters throughout the capillary bed in conjunction with the existing erythrocyte population. These extra emitters are equivalent to red blood cells with disabled carbon dioxide transport and acid-buffering capabilities. Their inclusion in the blood stream leads to increased carbon dioxide acidity and acidosis especially in patients with respiratory and haemolytic complications.
Neither problem can be overcome by using passive systems alone. A practical and preferable method to extend the duration is to recharge the microvessels with oxygen gas, preferably via the lungs since direct regeneration of oxygen from carbon dioxide is energetically prohibitive. The simplest way to prevent carbon dioxide toxicity is to provide additional tankage for carbon dioxide transport and become active means for gas loading at the tissues and unloading at the lungs as physically stored carbon dioxide makes no net addition to blood acidity. But still respirocytes operating in the absence of red blood cells would generate little carbon dioxide related acidity. Proper blood pH could probably be maintained by the kidneys alone. .2 Molecular Sorting Rotors
Molecular sorting rotors have been proposed for the task of an active method of conveying gas molecules into, and out of the pressurised microvessels which is the key to the successful functioning of the respirocyte. Each rotor has binding site "pockets" along the rim exposed alternately to the blood plasma and interior chamber by the rotation of the disk. Each pocket selectively binds a specific molecule when exposed to the plasma. Once the binding site rotates to expose it to the interior chamber, the bound molecules are forcibly ejected by rods thrust outward by the cam surface. Rotors are fully reversible, so they can be used to load or unload gas storage tanks, depending upon the direction of rotor rotation.
Figure : Molecular sorting rotor
Typical molecular concentrations in the blood for target molecules of interest (O2, CO2, N2 and glucose) are ~10-4, which should be sufficient to ensure at least 90% occupancy of rotor binding sites at the stated rotor speed . Each stage can conservatively provide a concentration factor of 1000, so a multi-stage cascade should ensure storage of virtually pure gases. Since each 12-arm outbound rotor can contain binding sites for 12 different impurity molecules, the number of outbound rotors in the entire system can probably be reduced to a small fraction of the number of inbound rotors.
Figure : Sorting rotor cascade * Sorting Rotor Binding Sites
Receptors should be should be highly sensitive and they should have binding sites only for specific molecules. They should have the additional qualities of reliability, high affinity and should survive long exposures to the aqueous media of blood.
Oxygen transport pigments are a usually coagulated protein that is proteins complexed with another organic molecule or with one or more metal atoms. The main components of the transport pigments are the metal atoms like Cu2+ or Fe3+ which constitutes the binding sites to which oxygen can reversibly attach. Apart from haemoglobin and myoglobin the natural respiratory pigments are hemocyanin, chlorocruorin, hemerythrin and vanadium chromagen. Artificial reversible oxygen-binding molecules have also been studied. Some of them are : * Cobalt based porphyrins such as coboglobin and cobaltohistidine * Simple iron-indigo compounds * Iridium complexes * Nonporphyrin lacunar iron complexes * Heme linked oxidase
Implantable blood oxygen sensors like Medtronics haemodynamic monitor are already in clinical trials. Unlike haemoglobin, the other natural oxygen transport pigments are not susceptible to carbon monoxide poisoning, neither are the respirocytes.
Many proteins and enzymes like haemoglobin, carbonic anhydrase and ribulose biphosphate carboxylase have binding sites for carbon dioxide. A wide variety of molecules like deliquescent crystals, efflorescent minerals, hydrophilic and polar amino acids and numerous enzymes such as carbonic anhydrase, hydrolases and dehydratases bind water reversibly. Binding sites for glucose are common in nature. These include the enzyme hexokinase, the glucose transporter molecule and the glucose binding proteins found in the intestines, liver, kidney and adipose tissue. Implantable glucose sensors have been developed by Becton, Dickinson Incorporation and by the Japans University of Osaka. The enzyme nitrogenase is highly labile in the presence of oxygen but research is concentrated on its highly efficient nitrogen binding sites. Once the required receptor for the transport of the specific gas is selected they are incorporated into the rotors as precisely shaped and charged diamondoid surfaces and cavities, atom by atom, using the manufacturing techniques suggested by Drexler. * Device Scaling
The upper limit for the physical size of the respirocytes can be easily estimated. It cannot be larger than the capillaries which have an average diameter of 8 microns. But these capillaries can be as small as 3.7 microns when the red blood cells have to fold themselves to conveniently pass through them. Smaller cells face greater danger of environmental insults and they encounter potential filtration sites throughout the body. For example the fenestrated endothelium of the glomerular membrane in the kidney filter particles <100 nm from the blood. So these requirements put forward the need for larger device sizes.
The minimum possible respirocyte diameter is driven by operational requirements and by minimum component size. The smallest reasonable computer requires 105 nm3, a 58-nm diameter sphere. Additionally, gas is loaded using molecular sorting rotors mounted on the surface of a spherical tank. In the baseline design (diameter D = 1 micron), 37.28% of tank surface consists of sorting rotors and related subsystems. The number of sorting rotors scales with tank volume or R3; tank surface scales as R2; so the percentage of tank surface in rotors (Rotor/Surface Ratio or RSR) scales linearly with R (RSR ~ qD, q = 0.3728 fractional surface coverage). RSR ~ 1.00 (100%) coverage occurs at D = 2.68 microns, the upper limit. Careful review of the baseline design suggests that the minimum rotor area necessary to achieve all performance specifications while maintaining 10:1 subsystem redundancy is about 17,000 nm2, which implies D = 0.245 micron at RSR = 0.0902 (9.02%). Eliminating all redundancy reduces rotor requirements to 1700 nm2, which implies D = 0.114 micron at RSR = 0.0412 (4.12%). The above considerations suggest a reasonable range for respirocyte diameter of 0.2-2 microns; the present study assumes a spherical respirocyte diameter of ~1 micron. * Buoyancy Control Using Water Ballast
Another factor which comes into picture when operating in an aqueous medium is buoyancy which can be controlled by loading and unloading the water ballast. The smaller the repirocyte, the longer it settles out of suspension according to the Stokes Law. Even a small difference in density between individual red blood cells and blood plasma causes the red blood cells to settle out of suspension at a fast rate depending on haemocrit and degree of red blood cell aggregation. Natural erythrocytes appear unhandicapped by their faster settling rate, so active ballast management for artificial respirocytes is probably unnecessary in normal operations. No other solid blood component can maintain exact neutral buoyancy, hence those other components precipitate outward during gentle centrifugation and are drawn off and added back to filtered plasma on the other side of the apparatus. Meanwhile, after a period of centrifugation, the plasma, containing mostly suspended respirocytes but few other solids, is drawn off through a 1-micron filter, removing the respirocytes. Filtered plasma is recombined with centrifuged solid components and returned undamaged to the patient 's body. The rate of separation is further enhanced either by commanding respirocytes to empty all tanks, lowering net density to 66% of blood plasma density, or by commanding respirocytes to blow a 5-micron O2 gas bubble to which the device may adhere via surface tension, allowing it to rise at 45 mm/hour under normal gravitational acceleration. 5. BASELINE DESIGN
Many specific design issues must be next confronted like tank configuration, rotor and glucose engine replacement, subsystem scaling and redundancy level required to produce acceptable system reliability. The final design represents a compromise among many competing factors. * Power
Onboard power is provided by a mechanochemical engine that exoenergically combines glucose and oxygen to generate mechanical energy to drive molecular sorting rotors and other subsystems, as demonstrated in principle in a variety of biological motor systems. Glucose engine design - possibly involving a ballistic turbine driven by rotor-combustion ejector operating near 1000 atm is a critical research issue. Drexler estimates engines can be designed to operate at efficiency greater than 99%. However, since natural cellular metabolic pathways using the glycolysis and tricarboxylic acid (TCA) cycles achieve only 68% efficiency, we adopt a more conservative 50% efficiency for the present study. Sorting rotors absorb glucose directly from the blood and store it in a fuel tank. Oxygen is tapped from onboard storage. * Communications
The attending physician can broadcast signals to molecular mechanical systems deployed in the human body most conveniently using modulated compressive pressure pulses received by mechanical transducers embedded in the surface of the respirocyte. Converting a pattern of pressure fluctuations into mechanical motions that can serve as input to a mechanical computer requires transducers that function as pressure-driven actuators. Internal communications within the respirocyte may be achieved by impressing modulated low-pressure acoustical spikes on the hydraulic working fluid of the power distribution system, or via simple mechanical rods and couplings. * Sensors
Various sensors are needed to acquire external data essential in regulating gas loading and unloading operations, tank volume management, and other special protocols. Figure : Molecular Concentration Sensor
For instance, sorting rotors can be used to construct quantitative concentration sensors for any molecular species desired. It is also convenient to include internal pressure sensors to monitor O2 and CO2 gas tank loading, (container fullness) sensors for ballast and glucose fuel tanks, and internal/external temperature sensors to help monitor and regulate total system energy output. * Onboard Computation
An onboard computer is necessary to provide precise control of respiratory gas loading and unloading, rotor field and ballast tank management, glucose engine throttling, power distribution, interpretation of sensor data and commands received from the outside, self-diagnosis and activation of failsafe shutdown protocols.
5.5 Baseline configuration
The artificial respirocyte is a spherical nanomedical device 1 micron in diameter consisting of 18 billion precisely arranged structural atoms plus 9 billion temporarily resident molecules when fully loaded. Allocations of device volume and mass were determined by specifying equal O2 and CO2 tank volumes, glucose tank volumes, ballast volume as a variable, and all structural mass as diamondoid in density. Figure.4.Glucose Rotor and Tank,engine assembly
Twelve pumping stations are spaced evenly along an equatorial circle. Each station has its own independent glucose engine, glucose tank, environmental glucose sensors, and glucose sorting rotors. Each station alone can generate sufficient energy to power the entire respirocyte. Detailed reliability simulations will be required to determine whether stations should run at
(1) Peak power on a rotating schedule, (2) Partial power on a continuous basis, or
(3) One at a time until failure, switching to the next backup.
Power is transmitted hydraulically to local station subsystems and also along a dozen independent interstation trunk lines that allow stations to pass hydraulic power among themselves as required, permitting load shifting and balancing.
Computer/mass-memory sets are located at the centre of the device allowing maximum shielding from environmental insults and centralized access to all surface components including communications links, external sensors, and distributed power supply. Any of the computers at the core can receive power or communications directly from any of the pumping stations along hard links in protected utility conduits.
Figure:Pumping station layout
Each pumping station has an array of 3-stage molecular sorting rotor assemblies for pumping O2, CO2, and H2O into and out of the ambient medium. The number of rotor sorters in each array is determined both by performance requirements and by the anticipated concentration of each target molecule in the bloodstream. Any one pumping station, acting alone, can load or discharge any storage tank in 10 sec whether gas, ballast water, or glucose. Gas pumping rotors are arrayed in a noncompact geometry to minimize the possibility of local molecule exhaustion during loading.
Each station also includes three glucose engine flues for discharge of CO2 and H2O combustion waste products, environmental oxygen pressure sensors distributed throughout the O2 sorting rotor array to provide fine control if unusual concentration gradients are encountered, also similar CO2 pressure sensors on the opposite side, 2 external environment temperature sensors (one on each side located as far as possible from the glucose engine to ensure true readings), and 2 fluid pressure transducers for receiving command signals from medical personnel. Figure:Equatorial Cutaway View of Respirocyte
Figure: Polar Cutaway View of Respirocyte
The equatorial pumping station network occupies 50% of respirocyte surface. On the remaining surface, a universal "bar code" consisting of concentric circular patterns of shallow rounded ridges is embossed on each side, centered on the "north pole" and "south pole" of the device. This coding permits easy product identification by an attending physician with a small blood sample and access to an electron microscope, and may also allow rapid reading by other more sophisticated medical nanorobots which might be deployed in the future. 5.6 Tank Chamber Design
Each storage tank is constructed of diamondoid honeycomb or a geodesic grid skeletal framework for maximum strength. Thick diamond bulkheads separate internal tankage volumes. Available structural mass is equivalent to a 10-nm thick (~60 carbon atoms) 2.2 micron x 2.2 micron diamond sheet. Compartment walls are perforated with sufficient holes of varying sizes to allow gas to flow easily between them, with larger compartments nearest the rotors graduating to smaller compartments more distant from the rotors to encourage isobaric entrainment.
The present design includes separate O2 and CO2 chambers. In theory, these gases could be stored mixed in a single chamber. A single chamber design can effectively double the O2-carrying capacity of each respirocyte by allowing the entire gas tank volume to be initially charged with oxygen at 1000 atm. There are four minor drawbacks to this approach: (1) Respiration is controlled by CO2, not O2, levels, requiring maintenance of sizable CO2 inventories at all times, reducing surplus volume available for O2 storage; (2) Respirocytes may be deployed to reverse serious tissue CO2 overloading, requiring significant available storage volume to absorb this gas;
(3) The rate of binding for outbound transport by sorting rotors may be lower for mixed gases, reducing maximum outgassing rate; and (4) Inability to emergency vent pure gas. 6. SAFETY FACTORS Respirocytes should be extremely reliable and usually should have a life of 20 years.
Device overheating: If all the glucose power plants get jammed or refuse to turn off, malfunction occurs while the respirocyte is in your bloodstream, its temperature won 't rise at all. That 's because the 7.3 picowatts of continuous thermal energy the device is generating is easily absorbed by the huge aqueous heat sink, which has a bountiful heat capacity.
Non combustive device explosion: Each device contains up to 0.24 micron3 of oxygen and carbon dioxide gas at 1000 tam pressure, representing 24 picojoules of stored mechanical energy.If the device explodes inside human tissue, the gases may work against the surrounding fluid forming large bubbles.The only plausible respirocyte explosion scenario is dental grinding.A patient with an oral lesion could spread respirocyte-impregnated blood over the teeth can explode thousand of respirocytes at once producing a "fizziness" in the mouth.
Complete structural failure of a respirocyte in vivo is a rare case. A spherical diamondoid shell should resist accelerations up to 108-1010 g 's. Crushing respirocyte-impregnated human tissue in a hydraulic press is unlikely to destroy any devices, as they will simply slide out of the way. 7. RESPIROCYTE CONTROL PROTOCOLS
Respirocyte behaviour is initially governed by a set of default protocols which can be modified at any time by the attending physician.Basic protocols will exist for operating molecular sorting rotors at various speeds and directions in response to sensor data. Gas loading parameters may be precisely specified in an individualized onboard lookup table provided by the physician for his patient, as for instance to adjust for declining arterio-venous oxygen gradient at high altitudes. Respirocytes, like natural haemoglobin, may also participate in the elimination of CO and in NO-mediated vascular control.
Respirocytes can be programmed with more sophisticated behaviours. * Detection of PCO2 < 0.5 mmHg and PO2 > 150 mmHg, indicating direct exposure to atmosphere and a high probability that the device has been bled out of the body, should trigger a prompt gas venting and failsafe device shutdown procedure. * Self-test algorithms monitoring tank filling rates, unaccounted pressure drops (indicating a leak), clutch responses, etc. may detect significant device malfunction, causing the respirocyte to place itself in standby mode ready to respond to an acoustic command to execute the filtration protocol for exfusion. * Out messaging protocols could allow the population of respirocytes to communicate systemwide status directly with the patient by inducing recognizable physiological cues (fever, shivering, gasping), or with the physician by generating subtle respiratory patterns requiring diagnostic equipment to detect, either automatically or in response to an acoustically-transmitted global inquiry initiated by patient or physician. |
8. APPLICATIONS 8.1 Transfusions & Perfusions
Respirocytes may be used as the active oxygen-carrying component of a universally transfusable blood substitute that is free of disease vectors such as hepatitis, venereal disease, malarial parasites or AIDS, storable indefinitely and readily available with no need for cross-matching. In current practice, organs must be transplanted soon after harvest; respirocytes could be used as a long-duration perfusant to preserve living tissue, especially at low temperature, for grafts (kidney, marrow, liver and skin) and organ transplantation. 8.2 Treatment of Anaemia
Oxygenating respirocytes offer complete or partial symptomatic treatment for virtually all forms of anaemia, including acute anaemia caused by a sudden loss of blood after injury or surgical intervention; secondary anaemia’s caused by bleeding typhoid, duodenal or gastric ulcers; chronic, gradual, or post-hemorrhagic anaemia’s from bleeding gastric ulcers , excessive menstrual bleeding, or battle injuries in war zones, hereditary anaemias including haemophilia, leptocytosis and sicklemia chlorosis and hypochromic anaemia, endocrine deficiency anaemia, pernicious and other nutritional anaemias; anaemias resulting from infectious diseases including rheumatism, scarlet fever, tuberculosis, syphilis, chronic renal failure and cancer, or from haemoglobin poisoning such as by carbon monoxide inhalation. * 8.3 Fetal and Child-Related Disorders
Respirocytes may be useful in perinatal medicine, as for example infusions of device suspension to treat fetal anaemia, neonatal hemolytic disease, or in utero asphyxia from partial detachment of the placenta or maternal hypoxia, to restore the oxygen-carrying ability of fetal blood. Asphyxia neonatorum, as from umbilical cord compression during childbirth, may fatally deprive the infant of oxygen; prenatal respirocyte treatment could be preventative. Many cases of Sudden Infant Death Syndrome, the leading cause of neonatal death between 1 week and 1 year of age, and respiratory distress syndrome involve recurrent oxygen deprivation or abnormalities in the automatic control of breathing, both of which could be delethalized using a therapeutic dose of red cell devices. Respirocytes could also aid in the treatment of childhood afflictions such as whooping cough, cystic fibrosis, rheumatic heart disease and rheumatic fever, congenital heart disorders. 8.4 Respiratory Diseases
The devices could provide an effective long-term drug-free symptomatic treatment for asthma, and could assist in the treatment of hemotoxic (pit viper) and neurotoxic (coral) snake bites; hypoxia, stress polycythemia and lung disorders resulting from cigarette smoking and alcoholism; neck goitre and cancer of the lungs, pharynx, or thyroid; pericarditis, coronary thrombosis, hypertension, and even cardiac neurosis; obesity, quinsy, botulism, diphtheria, tertiary syphilis, amyotrophic lateral sclerosis, uraemia, coccidioidomycosis (valley fever), and anaphylactic shock; and Alzheimer 's disease where hypoxia is speeding the development of the condition. 8.5 Cardiovascular and Neurovascular Applications
Respirocyte perfusion could be useful in maintaining tissue oxygenation during anaesthesia, coronary angioplasty, organ transplantation, siamese-twin separation, other aggressive heart and brain surgical procedures, in postsurgical cardiac function recovery, and in cardiopulmonary bypass solutions. The device could help prevent gangrene and cyanosis, for example, during treatment of Raynaud 's Disease. Therapeutic respirocyte dosages can delay brain ischemia under conditions of heart or lung failure, and might be useful in treating senility. 8.6 Tumor Therapy and Diagnostics
Cancer patients are usually anemic. X-rays and many chemotherapeutic agents require oxygen to be maximally cytoxic, so boosting systemic oxygenation levels into the normal range using respirocytes might improve prognosis and treatment outcome. Fluorocarbon emulsions have been used to probe tissue oxygen tension. Respirocytes could be used as reporter devices to map a patient 's whole-body blood pressure or oxygenation profile, storing direct sensor data in each computer along with positional information recorded from a network of precisely positioned acoustic transponders, to be later retrieved by device filtration and data reconstruction . A similar network of acoustic transmitters, making possible respirocyte autotriangulation hence precise internal positional knowledge, could allow preferential superoxygenation of specific tissues, enhancing treatment effectiveness. 8.7 Asphyxia
Respirocytes make breathing possible in oxygen-poor environments, or in cases where normal breathing is physically impossible. Prompt injection with a therapeutic dose, or advance infusion with an augmentation dose, could greatly reduce the number of choking deaths and the use of emergency tracheostomies, artificial respiration in first aid, and mechanical ventilators. The device provides an excellent prophylactic treatment for most forms of asphyxia, including drowning, strangling, electric shock, nerve-blocking paralytic agents, carbon monoxide poisoning, underwater rescue operations, smoke inhalation or firefighting activities, anaesthetic/barbiturate overdose and confinement in airtight spaces. Respirocytes augment the normal physiological responses to hypoxia, which may be mediated by pulmonary neuroepithelial oxygen sensors in the airway mucosa of human and animal lungs. 8.8 Underwater Breathing
Respirocytes could serve as an in vivo SCUBA (Self-Contained Underwater Breathing Apparatus) device. With an augmentation dose or nanolung, the diver holds his breath for 0.2-4 hours, goes about his business underwater, then surfaces, hyperventilates for 6-12 minutes to recharge, and returns to work below.
Respirocytes can relieve the most dangerous hazard of deep sea diving - decompression sickness ("the bends") or caisson disease. 8.9 Other Applications
Respirocytes could permit major new sports records to be achieved, because the devices can deliver oxygen to muscle tissues faster than the lungs can provide, for the duration of the sporting event. This would be especially useful in running, swimming, and other endurance-oriented events, and in competitive sports such as basketball, football and soccer where extended periods of sustained maximum exertion are required.
Artificial blood substitutes may also have wide use in veterinary medicine, especially in cases of vehicular trauma and renal failure where transfusions are required, and in battlefield applications demanding blood replacement or personnel performance enhancement. 9. DEVICE TESTING AND FDA APPROVAL
Since the respirocyte depends for its function on mechanical pumping rather than chemical action, and is not metabolized during the achievement of its purposes, it is clearly a device and not a drug under the Federal Food, Drug, and Cosmetic Act. Devices are regulated under the provisions of the Medical Device Amendments of 1976, the Safe Medical Devices Act of 1990, and the Medical Device Amendments of 1992.
In order for the FDA to approve or license any blood substitute, both efficacy and safety must be established to the satisfaction of the FDA 's Office of Device Evaluation using preclinical and clinical data to support a Premarket Approval Application (PMA). In 1990 the FDA 's Centre for Biologics Evaluation and Research issued points to consider document governing artificial oxygen carriers. The document does not address devices, but many of its suggestions are relevant. The FDA recommends first a program of in vitro biologic assays to characterize the product, including tests for generation of oxygen radicals, activation of triggered enzyme/cell systems such as the complement/kinin/coagulation cascades, macrophage/neutrophil/platelet activation, and mediator release such as histamine, thromboxane metabolites, leukotrienes, and interleukins. This should be followed by animal safety testing to determine effects on microvascular circulation and endothelium, evaluation of nephrotoxicity, blood chemistry assays and hematologic studies. Finally, low-dose human studies could begin, with subjects monitored carefully for circulatory, immune, and other animal-study parameters, as well as for inflammation mediators, specific interactions with human diseases, and comparison of product safety profile with other approved artificial oxygen carriers, and with natural red cells. Since the respirocyte is a purely mechanical 1-micron device, there is no concern with electromagnetic interference. The product liability situation is such that no physician uses any experimental device unless he or she is certain of its effectiveness and safety anyone with insufficient data to demonstrate such is subject to lawsuit, and loss of the right to practice medicine. Clearly a formidable regimen of laboratory, field, and clinical testing lies ahead before the respirocyte could be deemed ready for routine medical use.
10. CONCLUSION
This paper presents a preliminary design for a simple nanomedical device that functions as an artificial erythrocyte, duplicating the oxygen and carbon dioxide transport functions of red cells while largely eliminating the need to manage carbonic acidity because CO2 is carried mechanically, rather than chemically, in the blood. The baseline respirocyte can deliver 236 times more oxygen to the tissues per unit volume than natural red cells, and enjoys a similar advantage in carbon dioxide transport.
The respirocyte is constructed of tough diamondoid material, employs a variety of chemical, thermal and pressure sensors, has an onboard nanocomputer which enables the device to display many complex responses and behaviours, can be remotely reprogrammed via external acoustic signals to modify existing or to install new protocols, and draws power from abundant natural serum glucose supplies, thus is capable of operating intelligently and virtually indefinitely, unlike red cells which have a natural lifespan of four months. This device cannot be built today. However, when future advances in the engineering of molecular machine systems permit its construction, the artificial respirocyte may find dozens of applications in therapeutic and critical care medicine, and elsewhere.
REFERENCES * http://www.kurzweilai.net/meme/frame.html?main=/articles/art0468.html * http://www.foresight.org/nanomedicine/Respirocytes.html * www.wikepedia.com
References: * http://www.kurzweilai.net/meme/frame.html?main=/articles/art0468.html * http://www.foresight.org/nanomedicine/Respirocytes.html * www.wikepedia.com
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