Nanotechnological proposal of artificial rbc
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Molecular manufacturing promises precise control of matter at the atomic and molecular level, allowing the construction of micron-scale machines comprised of nanometer-scale components.
Medical nanomachines will be among the earliest applications. The artificial red blood cell or "respirocyte" proposed here is a bloodborne spherical 1-micron diamondoid 1000-atm pressure vessel with active pumping able to deliver 236 times more oxygen to the tissues per unit volume than natural red cells and to manage carbonic acidity. An onboard nanocomputer and numerous chemical and pressure sensors enable complex device behaviors remotely reprogrammable by the physician via externally applied acoustic signals.
Primary applications will include transfusable blood substitution; partial treatment for anemia, perinatal/neonatal and lung disorders; enhancement of cardiovascular/neurovascular procedures, tumor therapies and diagnostics; prevention of asphyxia; artificial breathing; and a variety of sports, veterinary, battlefield and other uses.
INTRODUCTIONMolecular manufacturing promises precise control of matter at the atomic and molecular level. One major implication of this realization is that in the next 10-30 years it may become possible to construct machines on the micron scale, comprised of parts on the nanometer scale. Subassemblies of such devices may include such useful robotic components as 100-nm manipulator arms, 400-nm mechanical GHz-clock computers, 10-nm sorting rotors for molecule-by-molecule reagent purification, and smooth superhard surfaces made of atomically flawless diamond.
Such technology has clear medical implications. It would allow physicians to perform precise interventions at the cellular and molecular level. Medical nanorobots have been proposed for gerontological applications, in pharmaceutical research, and to diagnose diseases ,mechanically reverse atherosclerosis, supplement the immune system, rewrite DNA sequences in vivo, repair brain damage, and reverse cellular insults caused by "irreversible" processes or by cryogenic storage of biological tissues. The goal of the present paper is to present one such preliminary design for a specific medical nanodevice that would achieve a useful result: An artificial mechanical erythrocyte (red blood cell, RBC), or "respirocyte."
The biochemistry of respiratory gas transport in the blood is well understood in brief that oxygen and carbon dioxide are carried between the lungs and the other tissues, mostly within the red blood cells. Hemoglobin, the principal protein in the red blood cell, combines reversibly with oxygen, forming oxyhemoglobin. About 95% of the O2 is carried in this form, the rest being dissolved in the blood. At human body temperature, the hemoglobin in 1 liter of blood holds 200 cm3 of oxygen, 87 times more than plasma alone (2.3 cm3) can carry.
Carbon dioxide also combines reversibly with the amino groups of hemoglobin, forming carbamino hemoglobin. About 25% of the CO2 produced during cellular metabolism is carried in this form, with another 10% dissolved in blood plasma and the remaining 65% transported inside the red cells after hydration of CO2 to bicarbonate ion. The creation of carbamino hemoglobin and bicarbonate ion releases hydrogen ions which, in the absence of hemoglobin, would make venous blood 800 times more acidic than the arterial. This does not happen because buffering action and isohydric carriage by hemoglobin reversibly absorbs the excess hydrogen ions, mostly within the red blood cells.
Respiratory gases are taken up or released by hemoglobin according to their local partial pressure. There is a reciprocal relation between hemoglobin's affinity for oxygen and carbon dioxide. The relatively high level of O2 in the lungs aids the release of CO2, which is to be expired, and the high CO2 level in other tissues aids the release of O2 for use by those tissues.
EXISTING ARTIFICIAL RESPIRATORY GAS CARRIERS
Current blood substitutes are either hemoglobin formulations or fluorocarbon emulsions.
When tetrameric hemoglobin is freed from the red cell it loses effectiveness in three ways.
1. It dissociates to dimers that are rapidly cleared from circulation by the mononuclear phagocytic system (10-30 minute half life) and by the kidneys (1 hour half life).
2. It binds O2 more tightly, reducing deliverability of O2 during tissue hypoxia.
3. During storage, hemoglobin may be oxidized to useless methemoglobin due to the absence of the protective enzyme methemoglobin reductase normally present in red cells.
Efforts to modify hemoglobin to increase intravascular dwell time have followed many pathways. Hemoglobin (in solution) has been cross-linked (either internally or with a macromolecule), polymerized, modified by recombinant DNA techniques, or microencapsulated. Encapsulation is most promising, given that all vertebrate hemoglobin is contained in cells to maintain its stability, preserve function, and protect the host from toxicity.
Fluorocarbons offer a simpler approach to oxygen transport and delivery that relies on physical solubilization rather than binding of the oxygen molecules. Liquid fluorocarbons selected for the preparation of injectable oxygen carriers are typically molecules of 8-10 carbon atoms with molecular weights in the 450-500 range, dissolving 20-25 times as much O2 as water and delivering about the volume of oxygen to the tissues as an equal weight of hemoglobin.
Because they are insoluble in water, fluorocarbons are administered in the form of emulsions of 0.1-0.2 micron droplets dispersed in a physiologic solution similar to fat emulsions routinely used for parenteral nutrition. After opsonization and phagocytosis of the emulsion droplets, the fluorocarbon is transferred to lipid carriers in the blood and released during passage through the pulmonary capillary bed. Thus fluorocarbons are not metabolized but are excreted unchanged by exhalation as a vapor through the lungs, typically in 4-12 hours for the present emulsions
SHORTCOMINGS OF CURRENT TECHNOLOGY
Most of the red cell substitutes under trial at present have far too short a survival time in the circulation to be useful in the treatment of chronic anemia, and are not specifically designed to regulate carbon dioxide or to participate in acid/base buffering. Several cell-free hemoglobin preparations evidently cause vasoconstriction, decreasing tissue oxygenation, and there are reports of increased susceptibility to bacterial infection due to blockade of the monocyte-macrophage system, complement activation, free-radical induction, and nephrotoxicity.
NANOTECHNOLOGICAL DESIGN OF RESPIRATORY GAS CARRIERS
A Scanning Tunneling Microscope was used in 1989 to spell out "IBM" using 35 individual xenon atoms on a nickel surface . Atomic Force Microscopes (AFMs) have performed nanomachining operations on planar MoO3 crystals: applying 100 nanonewtons at the tip, two rectangular slots and a 50-nm rectangular sliding member were milled from a crystal, then the member was slid repeatedly from one slot to the other, making a reversible mechanical latch 10-nm features can be milled with AFMs. Individual nucleotides have been distinguished and manipulated on stretched DNA strands using AFMs
A large number of potentially useful rigid nanoparts including molecular-scale rods, rings, springs, cubes, spheres, tetrahedrons, hollow tubes, propellors, and tongs, and wire-frame nanostructures of many shapes made of polymerized DNA were built and self-assembling multi-nanopart assemblies such as rotaxane "molecular shuttles" which move back and forth ~500 times/sec like a molecular abacus, and N-catenanes were manufactured.
In future with micron-scale machines, it is possible to imagine a complete microscopic chemical factory that avoids the shortcomings of current artificial blood technologies and simulates most major biochemical functions of the natural erythrocyte.
Given the goal of oxygen transport from the lungs to other body tissues, the simplest possible design for an artificial respirocyte is a microscopic pressure vessel, spherical in shape for maximum compactness. Most proposals for durable nanostructures employ the strongest materials, such as flawless diamond or sapphire constructed atom by atom, with Young's modulus 1012 N/m2 and conservative working stress of 1010 N/m2 . Tank storage capacity is given by Van der Waals equation which takes account of the finite size of tightly packed molecules and the intermolecular forces at higher packing densities. Rupture risk and explosive energy rise with pressure, so a standard 1000 atm peak operating pressure appears optimum, providing high packing density with an extremely conservative 100-fold structural safety margin.
In the simplest case, oxygen release could be continuous throughout the body. Slightly more sophisticated is a system responsive to local O2 partial pressure, with gas released either through a needle valve controlled by a heme protein that changes conformation in response to hypoxia, or by 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, or by molecular sorting rotors .These simple proposals have two principal failings
1. First, once discharged the devices become useless. As with current blood substitutes, discharge time is too short. In the absence of functioning red cells the O2 contained in a 1 cm3 injection of 1000 atm microtanks would be exhausted in 2 minutes. .
2. The proposals involve placement of numerous point source O2 emitters throughout the capillary bed in conjunction with the existing erythrocyte population. These extra emitters are functionally equivalent to red blood cells whose CO2 transport and acid-buffering capabilities have been selectively disabled. Their addition to the blood pushes respiratory gas equilibrium toward higher CO2 tension and elevated hydrogen ion concentration, which could lead to carbon dioxide toxicity and acidosis (hypercapnia), especially in anemic, nonrespiratory, or ischemic patients, and to hyperoxic hemolysis and other complications.
Neither problem may be overcome using passive systems alone. The easiest way to extend duration is to provide for recharging the microvessels with oxygen gas, preferably via the lungs.The easiest way to prevent carbon dioxide toxicity is to provide additional tankage for CO2 transport and some active means for gas loading at the tissues and unloading at the lungs. Note that physically stored CO2 makes no net addition to blood acidity. Respirocytes operating in the absence of red cells would generate little CO2-related acidity. Proper blood pH could probably be maintained by the kidneys alone.
MOLECULAR SORTING ROTORS
The key to successful respirocyte function is an active means of conveying gas molecules into, and out of, pressurized microvessels and it can be done by Molecular sorting rotor .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.
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