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Respirocytes

A Mechanical Artificial Red Cell:
Exploratory Design in Medical Nanotechnology

by Robert A. Freitas Jr.

Research Fellow, Institute for Molecular Manufacturing (IMM)
Palo Alto, California USA

© Copyright 1996-1999, Robert A. Freitas Jr.
All rights reserved.

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6. Applications

The artificial respirocyte is a simple nanotechnological device whose primary applications include transfusable blood substitution; treatment for anemia, perinatal and neonatal disorders, and a variety of lung diseases and conditions; contribution to the success of certain aggressive cardiovascular and neurovascular procedures, tumor therapies and diagnostics; prevention of asphyxia; maintenance of artificial breathing in adverse environments; and a variety of sports, veterinary, battlefield and other applications.

6.1 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. Mechanical red cells, like other artificial blood substitutes, may permit treatment of devout Jehovah's Witness patients and others who refuse transfusion of natural blood products on religious grounds [42,150]. 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.

6.2 Treatment of Anemia

Oxygenating respirocytes offer complete or partial symptomatic treatment for virtually all forms of anemia, including acute anemia caused by a sudden loss of blood after injury or surgical intervention; secondary anemias caused by bleeding typhoid, duodenal or gastric ulcers; chronic, gradual, or post-hemorrhagic anemias from bleeding gastric ulcers (including ulcers caused by hookworm), hemorrhoids, excessive menstrual bleeding, or battle injuries in war zones; hereditary anemias including hemophilia, leptocytosis and sicklemia, thalassemia, hemolytic jaundice and congenital methemoglobinemia; chlorosis and hypochromic anemia, endocrine deficiency anemia, pernicious and other nutritional anemias; anemias resulting from infectious diseases including rheumatism, scarlet fever, tuberculosis, syphilis, chronic renal failure and cancer, or from hemoglobin poisoning such as by carbon monoxide inhalation; hemolytic anemias including chemical hemolysis (including malarial, snake bite, etc.), paroxysmal hemoglobinuria, and chronic hemolytic anemia from hypersplenism due to cirrhosis of the liver; leukemia and other idiopathic or toxic aplastic anemias caused by chemicals, radiation, or various antimetabolic agents; and diseases involving excessive red cell production such as polycythemia.

6.3 Fetal and Child-Related Disorders

Respirocytes may be useful in perinatal medicine, as for example infusions of device suspension to treat fetal anemia (erythroblastosis fetalis), 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 (SIDS) or crib death, the leading cause of neonatal death between 1 week and 1 year of age (~5000/yr in the U.S.), and respiratory distress syndrome (~3000 deaths/yr) 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 and laryngotracheobronchitis (croup).

6.4 Respiratory Diseases

Current treatments for a variety of respiratory viruses and diseases, including pneumonia, bronchopneumonia and pleuropneumonia; pneumoconiosis including asbestosis, silicosis and berylliosis; emphysema, empyema, abscess, pulmonary edema and pleurisy; epidemic pleurodynia; diaphragm diseases such as diaphragmatic hernia, tetanus, and hiccups; blood flooding in lungs (hemoptysis, tuberculosis, chronic histoplasmosis, and bronchial tube rupture); bronchitis and bronchiectasis; atelectasis and pneumothorax; chronic obstructive lung disease; arterial chest aneurysm; influenza, dyspneas, and even laryngitis, snoring, pharyngitis, hay fever and colds could be improved using respirocytes to reduce the need for strong, regular breathing.

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 goiter 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, uremia, coccidioidomycosis (valley fever), and anaphylactic shock; and Alzheimer's disease where hypoxia is speeding the development of the condition.

Respirocytes could also be used to treat conditions of low oxygen availability to nerve tissue, as occurs in advanced atherosclerotic narrowing of arteries, strokes, diseased or injured reticular formation in the medulla oblongata (controlling autonomic respiration), birth traumas leading to cerebral palsy, and low blood-flow conditions seen in most organs of people as they age. Even poliomyelitis, which still occurs in unvaccinated Third World populations, could be treated with respirocytes and a diaphragmatic pacemaker.

6.5 Cardiovascular and Neurovascular Applications

Respirocyte perfusion could be useful in maintaining tissue oxygenation during anesthesia, coronary angioplasty [151], organ transplantation, siamese-twin separation, other aggressive heart and brain surgical procedures [152-153], in postsurgical cardiac function recovery, and in cardiopulmonary bypass solutions [154]. The device could help prevent gangrene and cyanosis, for example, during treatment of Raynaud's Disease, a condition in which spasms in the superficial blood vessels of the extremities cause fingers and toes to become cyanotic, then white and numb. Therapeutic respirocyte dosages can delay brain ischemia under conditions of heart or lung failure, and might be useful in treating senility, which has apparently been temporarily reversed in patients treated with hyperbaric oxygen [155-156].


Respirocytes Table of Contents

 

6.6 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 [157-158]. Fluorocarbon emulsions (Section 2.1.2) have been used to probe tissue oxygen tension [159]; similarly, respirocytes could be used as reporter devices to map a patient's whole-body blood pressure (Section 4.3) 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 [9]. 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.

6.7 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 (~3200 deaths/yr in U.S.) 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 (respirocytes are purely mechanical), nerve-blocking paralytic agents, carbon monoxide poisoning, underwater rescue operations, smoke inhalation or firefighting activities, anaesthetic/barbiturate overdose, confinement in airtight spaces (refrigerators, closets, bank vaults, mines, submarines), and obstruction of breathing by a chunk of meat or a plug of chewing tobacco lodged in the larynx, by inhalation of vomitus, or by a plastic bag pulled over the head of a child. 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 [79].

A design alternative to augmentation infusions is a therapeutic population of respirocytes that loads and unloads at an artificial nanolung, implanted in the chest, which exchanges gases directly with the natural lungs or with exogenous gas supplies. (An intravascular oxygenator using a bundle of hollow fiber membranes inserted into the vena caval bloodstream (which functions as an "artificial lung") is in clinical trials [160].) Assuming 80% storage volume at ~1000 atm, an unobtrusive 250 cm3 nanolung could provide 0.3-7 hours O2 supply, depending on exertion level. By sacrificing one natural lung to make room in the thorax, a 3250 cm3 nanolung extends intracorporeal oxygen supply to 4-87 hours, plus an additional 40% if operating pressure is increased to 10,000 atm.

6.8 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. (Similar considerations apply in space exploration scenarios.)

Respirocytes can relieve the most dangerous hazard of deep sea diving -- decompression sickness ("the bends") or caisson disease, the formation of nitrogen bubbles in blood as a diver rises to the surface, from gas previously dissolved in the blood at higher pressure at greater depths. Safe decompression procedures normally require up to several hours. At full saturation, a human diver breathing pressurized air contains about ~(d - d0) x 1021 molecules N2, where d is diving depth in meters and d0 is the maximum safe diving depth for which decompression is not required, ~10 meters. A therapeutic dose of respirocytes reconfigured to absorb N2 instead of O2/CO2 could allow complete decompression of an N2-saturated human body from a depth of 26 meters (86 feet) in as little as 1 second, although in practice full relief will require ~60 sec approximating the circulation time of the blood. Each additional therapeutic dose relieves excess N2 accumulated from another 16 meters of depth. Since full saturation requires 6-24 hours at depth, normal decompression illness cases present tissues far from saturation, hence relief will normally be achieved with much smaller dosages. The same device can be used for temporary relief from nitrogen narcosis while diving, since N2 has an anesthetic effect beyond 100 feet of depth.

Direct water-breathing, even with the help of respirocytes, is problematic for several reasons: (1) Seawater contains at most one-thirtieth of the oxygen per lungful as air, so a person must breathe at least 30 times more lungfuls of water than air to absorb the same volume of respiratory oxygen; lungs full of water weigh nearly three times more than lungs full of air, so a person could hyperventilate water only about one-third as fast as the same volume of air. As a result, a water-breathing human can absorb at most 1%-10% of the oxygen needed to sustain life and physical activity. (2) Deep bodies of water may have low oxygen concentrations because oxygen is only slowly distributed by diffusion; in swamps or below the thermocline of lakes, circulation is poor and oxygen concentrations are low, a situation aggravated by the presence of any oxygen-consuming bottom dwellers or by oxidative processes involving bottom detritus, pollution, or algal growth. (3) Both the diving reflex and the presence of fluids in the larynx inhibit respiration and cause closure of the glottis, and inhaled waterborne microflora and microfauna such as protozoa, diatoms, dinoflagellates, zooplankton and larvae could establish (harmful) residence in lung tissue.

6.9 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. (Blood doping [161] and erythropoietin (rhEPO) injection [112-113,162], though illegal, are common among athletes to increase tissue oxygenation, hence performance.) Aerobic capacity in men declines with age, from ~6.9 kg O2/day at age 25 to ~3.7 kg O2/day at age 75 [163], so respirocytes could improve geriatric sports participation.

Hyperbaric oxygenation by respirocytes could help treat anaerobic [164] and aerobic [165] infections such as clostridial myonecrosis, chronic refractory osteomyelitis, and necrotizing soft tissue infections including cutaneous ulcers, and could assist in burn recovery by reducing fluid requirements, improving microcirculation, and reducing the need for grafting [165].

Artificial blood substitutes may also have wide use in veterinary medicine [166-167], especially in cases of vehicular trauma and renal failure where transfusions are required, and in battlefield applications demanding blood replacement or personnel performance enhancement. Swallowed in pill form, respirocytes could be an effective, though temporary, cure for flatulence, which gas is largely swallowed air and CO2 generated by fermentation in the stomach. With suitable modifications, respirocyte technology could provide a precisely metered ingestible or injectable drug delivery system, or could assist in the management of serum glycerides, fatty acids or lipoproteins, diabetic ketosis and gestational diabetes, and other dietary conditions.

6.10 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 (21 U.S.C. §321(h)) [168]. 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 [169].

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 [169] to support a Premarket Approval Application (PMA). In 1990 the FDA's Center for Biologics Evaluation and Research issued a Points to Consider document governing artificial oxygen carriers [170]. 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 [171].

Currently it is extremely difficult to obtain an Investigational Device Exemption (IDE) for clinical applications of new devices; the cost of a device that can be produced at $100 can easily exceed $1000 [172]. FDA does have a policy of expedited review for devices deemed medically significant [169], but each different proposed use must have separate field and clinical trials. Also, the product liability situation in the U.S. 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, multiple penalties up to $1 million [173], 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.


Respirocytes Table of Contents

 

7. Summary and Conclusions

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 behaviors, 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 4 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.

 

8. Acknowledgments

The author thanks Ralph C. Merkle and four unnamed referees for helpful comments on an earlier version of this manuscript.

 

9. References

1. Drexler KE. Molecular engineering: an approach to the development of general capabilities for molecular manipulation. Proc. NAS USA 1981; 78:5275-5278.

2. Drexler KE. Nanosystems: Molecular Machinery, Manufacturing, and Computation. New York: John Wiley & Sons, 1992.

3. Fahy GM. Short-term and long-term possibilities for interventive gerontology. Mt Sinai J Med 1991; 58:328-340.

4. Fahy GM. Molecular nanotechnology. Clin Chem 1993; 39:2011-2016.

5. Fahy GM. Molecular nanotechnology and its possible pharmaceutical implications. In: Bezold C, Halperin JA, Eng JL, eds. 2020 Visions: Health Care Information Standards and Technologies. Rockville MD: U.S. Pharmacopeial Convention, 1993:152-159.

6. Lampton C. Nanotechnology promises to revolutionize the diagnosis and treatment of diseases. Genetic Eng News, 1 Apr 1995:4,23.

7. Freitas RA Jr. The future of computers. Analog (Mar 1996); 116:57-73.

8. Dewdney AK. Nanotechnology -- wherein molecular computers control tiny circulatory submarines. Sci Am (Jan 1988); 258:100-103.

9. Merkle RC. Nanotechnology and medicine. In: Klatz RM, ed. Advances in Anti-Aging Medicine, Vol. 1, Liebert Press, 1996:277-286. (http://nano.xerox.com/nanotech/nanotechAndMedicine.html)

10. Drexler KE. Engines of Creation: The Coming Era of Nanotechnology. New York: Anchor Press/Doubleday, 1986.

11. Merkle RC. The molecular repair of the brain. Cryonics (Jan 1994):16-31 (Part I); (Apr, 1994):20-32 (Part II).

12. Fahy GM. Possible medical applications of nanotechnology. In: Crandall BC, Lewis J, eds. Nanotechnology: Research and Perspectives, Cambridge MA: MIT Press, 1992:251-267.

13. Merkle RC. The technical feasibility of cryonics. Med Hypoth 1992; 39:6-16.

14. Fahy GM. A realistic scenario for nanotechnological repair of the frozen human brain. In: Alcor Life Extension Foundation. Cryonics: Reaching for Tomorrow, Appendix B. Scottsdale AZ: Alcor Foundation, 1993.

15. Wowk B. Cell repair technology. Cryonics (July 1988).

16. Devlin TM, ed. Textbook of Biochemistry with Clinical Correlations. New York: John Wiley & Sons, 1986.

17. Sellards AM, Minot GR. Injection of haemoglobin in man and its relation to blood destruction, with special reference to the anemias. J Med Res 1916; 34:496-594.

18. Hodgson J. Substitutes for human blood. Biotechnology 1991; 9:69.

19. Eastaugh SR. Valuation of the benefits of risk-free blood. Intl J Technol Assess Health Care 1991; 7:51-57.

20. Jones JA. Red blood cell substitutes: current status. Brit J Anaesthes 1995; 74:697-703.

21. Zuck TF, Riess JG. Current status of injectable oxygen carriers. Crit Rev Clin Lab Sci 1994; 31:295-324.

22. Chang TMS, Geyer R, eds. Blood Substitutes. New York: Marcel Dekker, 1988; and Chang TMS, ed. Blood Substitutes II. New York: Marcel Dekker, 1992.

23. Tsuchida E, Komatsu T. Synthetic hemes. Meth Enzymol 1994; 231:167-193,685-687.

24. Chang TMS. Artificial cells: 35 years. Art Organs 1992; 16:8-12.

25. Hunt CA, Burnette RR, MacGregor RD, Strubbe AE, Lau DT, Taylor N, Kawada H. Synthesis and evaluation of a prototypal artificial red cell. Science 1985; 230:1165-1168.

26. Rudolph AS, Cliff RO. Dry storage of liposome-encapsulated hemoglobin: a blood substitute. Cryobiology 1990; 27:585-590.

27. Rudolph AS, Stratton LP, Goins B, Ligler F. Liposome-encapsulated hemoglobin: efficacy and stabilization. In: The Red Cell: Seventh Ann Arbor Conference. New York: Alan R. Liss, 1989:435-455.

28. Service RF. Small spheres lead to big ideas. Science 1995; 267:327-329.

29. Clark JC Jr, Gollan F. Survival of mammals breathing organic liquids equilibrated with oxygen at atmospheric pressure. Science 1966; 152:1755-1757.

30. Geyer RP. Bloodless rats through the use of artificial blood substitutes. Fed Proc 1975; 34:1499-1505.

31. Marwick C. More than a trickle of interest in blood substitutes. JAMA 1994; 271:895.

32. Griffiths E, Cortes A, Gilbert N, Stevenson P, MacDonald S, Pepper D. Haemoglobin-based blood substitutes and sepsis. Lancet 1995; 345:158-160.

33. Litwin MS, Walter CW, Ejarque P, Reynolds ES. Synergistic toxicity of Gram-negative bacteria and free colloidal hemoglobin. Annals Surg 1963; 157:485-493.

34. Bornside GH, Cohn I. Hemoglobin as a bacterial virulence-enhancing factor in fluids produced in strangulated intestinal obstruction," Am Surg 1968; 34:63-67.

35. Marks DH, Patressi J, Chaudry IH. Effects of pyridoxylated stabilized stroma-free hemoglobin solution on the clearance of intravascular lipid by the reticuloendothelial system. Circ Shock 1985; 16:165-172.

36. Feola M, Simoni J, Dobke M, et al. Complement activation and the toxicity of stroma-free hemoglobin solutions in primates. Circ Shock 1988; 25:275-290.

37. Alayash AI, Brockner Ryan BA, Fratantoni JC, et al. Redox reactivity of modified hemoglobins with hydrogen peroxide and nitric oxide: toxicological implications. Blood Subst Art Cells Immobil Biotech 1994; 22:373-386.

38. Vercellotti GM, Balla G, Balla J, et al. Heme and the vasculature: an oxidative hazard that induces antioxidant defenses in the endothelium. Blood Subst Art Cells Immobil Biotech 1994; 22:207-213.

39. Rabiner SF, O'Brien K, Peskin GM, Friedman LH. Further studies on stroma-free hemoglobin solution," Annals Surg 1970; 171:615-622.

40. Savitsky JP, Doczi J, Black J, Arnold JD. A clinical safety trial of stroma-free hemoglobin. Clin Pharmacol Therapeut 1978; 23:73-80.

41. Simoni J, Tran R, Feola M, Buckner M, Canizaro PC. Macrophage reactions to hemoglobin solution. Biomaterials Art Cells Art Organs 1989; 17:700.

42. Kale PB, Sklar GE, Wesolowicz LA, DiLisio RE. Fluosol: therapeutic failure in severe anemia. Annals Pharmacotherapy 1993; 27:1452-1454.

43. Feynman RP. There's plenty of room at the bottom. Eng. and Sci. 1960; 23:22-36.

44. Regis E. Nano: The Emerging Science of Nanotechnology. New York: Little, Brown & Company, 1995.

45. Foresight Update, No. 24, 1996:1-2

46. Eigler DM, Schweizer EK. Positioning single atoms with a scanning tunneling microscope. Nature 1990; 344:524.

47. Sheehan PE, Lieber CM. Nanotribology and nanofabrication of MoO3 structures by atomic force microscopy. Science 1996; 272:1158-1161.

48. Lee GU, Chrisey LA, Colton RJ. Direct measurement of the forces between complementary strands of DNA. Science 1994; 266:771-773.

49. Boland T, Ratner BD. Direct measurement of hydrogen bonding in DNA nucleotide bases by atomic force microscopy. Proc. Natl. Acad. Sci. USA 1995; 92:5297-5301.

50. Ball P. Designing the Molecular World: Chemistry at the Frontier. Princeton NJ: Princeton University Press, 1994.

51. Zhang Y, Seeman NC. Construction of a DNA-truncated octahedron. J. Amer. Chem. Soc. 1994; 116:1661-1669.

52. Seeman NC. Molecular craftwork with DNA. The Chemical Intelligencer, July 1995:38-47.

53. Pease R. Nanoworlds are made of this. New Scientist, June 1995; 146:26-29.

54. Ashton PR, Bissell RA, Spencer N, Stoddart JF, Tolley MS. Towards controllable molecular shuttles. Synlett 1992:914-926

55. Stoddart F. Making molecules to order. Chemistry in Britain 1991; 27:714-718.

56. Lehn J-M. Supramolecular Chemistry: Concepts and Perspectives. New York: VCH, 1995.

57. Kim CJ, Pisano AP, Muller RS, Lim MG. Design fabrication and testing of a polysilicon microgripper. Microstructures, Sensors, and Actuators (ASME, New York) 1990; (DSC-19):99-109.

58. Teshigahara A, Watanabe M, Kawahara N, Ohtsuka Y, Hattori T. Performance of a 7-mm microfabricated car. J. Microelectromechanical Systems 1995; 4:76-80.

59. Bard AJ. Integrated Chemical Systems: A Chemical Approach to Nanotechnology. New York: John Wiley & Sons, 1994.

60. Ralph C. Merkle, Computer Science Lab, Xerox Corporation, 3333 Coyote Hill Road, Palo Alto, CA 94304; private communication, 1995.

61. Porter DI, Goldberg WA. Regulation of erythropoietin production. Exp Hematol 1993; 21:399-404.

62. Redmond JR. The respiratory function of hemocyanin in crustacea. J Cell Comp Physiol 1955; 46:209-242.

63. Mill PJ. Respiration in the Invertebrates. New York: St. Martin's Press, 1972.

64. Wolvekamp HP. The evolution of oxygen transport. In: Macfarlane RG, Robb-Smith AHT, eds. Functions of the Blood. New York: Academic Press, 1961:1-72.

65. Carlisle DB. Vanadium and other metals in ascidians. Proc. Royal Soc B 1968; 171:31-42.

66. Baldwin E. An Introduction to Comparative Biochemistry, 4th Edition. Cambridge University Press, 1964.

67. Hearon JZ, Burke D, Schade AL. Physicochemical studies of reversible and irreversible complexes of cobalt, histidine, and molecular oxygen. J Natl Cancer Inst 1949; 9:337-377.

68. Hoffman BM, Petering DH. Coboglobins: oxygen-carrying cobalt-reconstituted hemoglobin and myoglobin. Proc. NAS 1970; 67:637-643.

69. Martell AE, Calvin M. Chemistry of the Metal Chelate Compounds. New York: Prentice-Hall, 1952.

70. Michaelis L. Molecular oxygen as a ligand in metal porphyrins and other metal-complex compounds. Fed Proc 1948; 7:509-514.

71. De Sanctis G et al. Mini-myoglobin: electron paramagnetic resonance and reversible oxygenation of the cobalt derivative. J Mol Biol 1991; 222:637-643.

72. Lapidot A, Irving CS. The electronic structure of coordinated oxygen. In: Hayaishi O, ed. Molecular Oxygen in Biology: Topics in Molecular Oxygen Research. New York: American Elsevier, 1974.

73. Falk JE. Porphyrins and Metalloporphyrins. New York: Elsevier Publishing, 1964.

74. Kunz K. Berliner 1927; 60:367.

75. Vaska L. Oxygen-carrying properties of a simple synthetic system. Science 1963; 140:809-810.

76. Vaska L, Chen S, Senoff CV. Oxygen-carrying iridium complexes: kinetics, mechanism, and thermodynamics. Science 1971; 174:587-589.

77. Kellerman R, Hutta PJ, Klier K. Reversible oxygen binding by divalent chromium (II) ion exchanged molecular sieve. J Amer Chem Soc 1974; 96:5946-5947.

78. Busch D. J Amer Chem Soc 1983; 105:298.

79. Youngson C, Nurse C, Yeger H, Cutz E. Oxygen sensing in airway chemoreceptors. Nature 1993; 365:153-155.

80. Zubay G. Biochemistry, Second Edition. New York: Macmillan, 1988.

81. Baldwin SA, Lienhard GE. Purification and reconstitution of glucose transporter from human erythrocytes. Methods Enzymol 1989; 174:39-50.

82. Simpson IA, Cushman SW. Hormonal regulation of mammalian glucose transport. Ann Rev Biochem 1986; 55:1059-1089.

83. Burton AC. The mechanics of the red cell in relation to its carrier function. In: Wolstenholme GEW, Knight J, eds. Circulatory and Respiratory Mass Transport. Boston: Little, Brown and Company, 1969:67-81.

84. Evans E, Fung YC. Improved measurements of the erythrocyte geometry. Microvasc. Res. 1972; 4:335-347.

85. Wisse E. Ultrastructure and function of Kupffer cells and other sinusoidal cells in the liver. In: Wisse E, Knook DL, eds. Kupffer Cells and Other Liver Sinusoidal Cells. New York: Elsevier/North-Holland Biomedical Press, 1977:33-60.

86. Berg HC, Purcell EM. Physics of chemoreception. Biophys Y 1977; 20:193-219.

87. Wilson JA, Principles of Animal Physiology. New York: Macmillan, 1972.

88. Ter Haar GR. Biological effects of ultrasound in clinical applications. In: Suslick KS, ed. Ultrasound: Its Chemical, Physical and Biological Effects. New York: VCH Publishers, 1988.

89. Ayers E. An automatic chemical plant. Sci Am 1952; 187:82-88.

90. Luke HD. Automation for Productivity. New York: John Wiley & Sons, 1972.

91. Merkle RC. Reversible electronic logic using switches. Nanotechnology 1993; 4:21-40.

92. Nunn JF. Nunn's Applied Respiratory Physiology, 4th Edition. London: Butterworth-Heinemann Ltd., 1993.

93. Hardy JD. Temperature regulation, exposure to heat and cold, and effects of hypothermia. In: Lehmann JF, ed. Therapeutic Heat and Cold, Third Edition. Baltimore: Williams & Wilkins, 1982:172-198.

94. Lee GR, Bithell TC, Foerster J, Athens JW, Lukens JN, eds. Wintrobe's Clinical Hematology, Ninth Edition. Philadelphia: Lea & Febiger, 1993.

95. Weihe WH, ed. Physiological Effects of High Altitude. New York: Macmillan, 1964.

96. Erslev AJ. Secondary polycythemia (erythrocytosis). In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, eds. Williams Hematology, Fifth Edition. New York: McGraw-Hill, 1995:714-726.

97. Hillman RS. Acute blood loss anemia. In Ernest Beutler E, Lichtman MA, Coller BS, Kipps TJ, eds. Williams Hematology, Fifth Edition. New York: McGraw-Hill, 1995:704-708.

98. Modell JH, Moya F. Effects of volume of aspirated fluid during chlorinated water fresh water drowning. Anesthesiol 1966; 27:662-672.

99. Drexler KE, Peterson C, Pergamit G. Unbounding the Future: The Nanotechnology Revolution. New York: William Morrow, 1991.

100. Goldsmith HL, Turitto VT. Rheological aspects of thrombosis and haemostasis: basic principles and applications. Thromb Haemostasis 1986; 55:415-435.

101. Fishbein M. Popular Illustrated Medical Encyclopedia. New York: Doubleday, 1979.

102. Jia L, Bonaventura C, Bonaventura J, Stamler JS. S-nitrosohaemoglobin: a dynamic activity of blood involved in vascular control. Nature 1996; 380:221-226.

103. Smit MH, Cass AEG. Cyanide detection using a substrate-regenerating, peroxidase-based biosensor. Analytic Chem 1990; 62:2429-2436.

104. Yanagida Y, Fujiwara S, Mizoi Y. Differences in the intercranial pressure caused by a blow and/or a fall -- an experimental study using physical models of the head and neck. Forensic Sci Intl 1989; 41:135-145.

105. Allen ME, Weir-Jones I, Motiuk DR, Flewin KR, Goring RD, Kobetitch R, Broadhurst A. Acceleration perturbations of daily living: a comparison to whiplash. Spine 1994; 19:1285-1290.

106. Erslev AJ. In vitro production of erythropoietin by kidneys perfused with a serum-free solution. Blood 1974; 44:77-85.

107. Erslev AJ, Beutler E. Production and destruction of erythrocytes. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, eds., Williams Hematology, Fifth Edition. New York: McGraw-Hill, 1995:425-441.

108. Denny WF, Flanigan WJ, Zukoski CF III. Serial erythropoietin studies in patients undergoing renal homotransplanation. J Lab Clin Med 1966; 67:386-397.

109. Hallberg L, Magnusson B. The etiology of sports anemia. Acta Medica Scand 1984; 216:145-148.

110. Mengel CE, Kann HE Jr., Heyman A, Metz E. Effects of in vivo hyperoxia on erythrocytes. II. Hemolysis in a human after exposure to oxygen under high pressure. Blood 1965; 25:822-829.

111. Tavassoli M. Anemia of spaceflight. Blood 1982; 60:1059-1067.

112. Ekblom B, Berglund B. Effect of erythropoietin administration on maximal aerobic power. Scand J Med Sci Sports 1991; 1:88-93.

113. Berglund B, Ekblom B. Effect of recombinant human erythropoietin treatment on blood pressure and some haematological parameters in healthy men. J Internal Med 1991; 229:125-130.

114. Bowling RA. A theoretical review of particle adhesion. In: Mittal KL, ed. Particles on Surfaces I. Detection, Adhesion, and Removal. New York: Plenum Press, 1988:129-142.

115. Baier RE. Selected methods of investigation for blood-contact surfaces. In: Leonard EF, Turitto VT, Vroman L, eds. Blood in Contact with Natural and Artificial Surfaces. Annals of the New York Academy of Sciences 1987; 516:68-77.

116. Ware JA, Coller BS. Platelet morphology, biochemistry, and function. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, eds. Williams Hematology, Fifth Edition. New York: McGraw-Hill, 1995:1161-1201.

117. Ruggeri ZM. Mechanisms of shear-induced platelet adhesion and aggregation. Thromb Haemostasis 1993; 70:119-123.

118. Kroll MH, Hellums JD, Guo Z, Durante W, Razdan K, Hrbolich JK, Schafer AI. Protein kinase C is activated in platelets subjected to pathological shear stress. J Biol Chem 1993; 268:3520-3524.

119. Ikeda Y, Handa M, Kawano K, Kamata T, Murata M, Araki Y, Anbo H, Kawai Y, Watanabe K, Sakai K, Ruggeri ZM. The role of von Willebrand factor and fibrinogen in platelet aggregation under varying shear stress. J Clin Invest 1991; 87:1234-1240.

120. Ikeda Y, Murata M, Araki Y, Watanabe K, Ando Y, Itagaki I, Mori Y, Ichitani M, Sakai K. Importance of fibrinogen and platelet membrane glycoprotein IIb/IIIa in shear-induced platelet aggregation. Thromb Res 1988; 51:157-163.

121. Moake JL, Turner NA, Stathopoulos NA, Nolasco L, Hellums JD. Shear-induced platelet aggregation can be mediated by vWF released from platelets, as well as by exogenous large or unusually large vWF multimers, requires adenosine diphosphate, and is resistant to aspirin. Blood 1988; 71:1366-1374.

122. Moake JL, Turner NA, Stathopoulos NA, Nolasco LH, Hellums JD. Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear stress-induced platelet aggregation. J Clin Invest 1986; 78:1456-1461.

123. National Materials Advisory Board. Status and Applications of Diamond and Diamond-Like Materials: An Emerging Technology, Report of the Committee on Superhard Materials, NMAB-445, National Academy Press, 1990.

124. De Robertis EDP, De Robertis EMF. Cell and Molecular Biology, Eighth Edition. Philadelphia: Lea & Febiger, 1987.

125. Chien S. Shear dependence of effective cell volume as a determinant of blood viscosity. Science 1970; 168:977-979.

126. Pitt WG, Park K, Cooper SL. Sequential protein adsorption and thrombus deposition on polymeric biomaterials. J. Colloid Interface Sci. 1986; 111:343-362.

127. Anderson JW, Bonfield TL, Ziats NP. Protein adsorption and cellular adhesion and activation on biomedical polymers. Intl J Art Organs 1990; 13:375-382.

128. Sevastianov VL. Role of protein adsorption in blood compatibility of polymer. CRC Crit Rev Biocompat 1988; 4:109-154.

129. Shinoda BA, Mason RC. Reaction of blood with artificial surfaces of hemodialyzers: studies of human blood with platelet defects or coagulation factor deficiencies. Biomaterials Med Dev Art Organs 1978; 6:305-329.

130. Roohk HV, Nakamura M, Hill RL, Hung EK, Bartlett RH. A thrombogenic index for blood contact materials. Trans Am Soc Art Internal Organs 1977; 23:152-161.

131. Weiss HJ, Rogers J. Fibrinogen and platelets in the primary arrest of bleeding. New Eng J Med 1971; 285:369-374.

132. Tang L, Eaton JM. Adsorbed fibrinogen triggers acute inflammatory responses to biomaterials. J Exp Med 1993; 178:2147-2156.

133. Tang L, Lucas AH, Eaton JW. Inflammatory responses to implanted polymeric biomaterials: role of surface-adsorbed immunoglobin G. J Lab Clin Med 1993; 122:292-300.

134. Salzman EW, Linden J, McManama G, Ware JA. Role of fibrinogen in activation of platelets by artificial surfaces. Annals NY Acad Sci 1987; 516:184-195.

135. Tang L, Tsai C, Gerberich WW, Kruckeberg L, Kania DR. Biocompatibility of chemical-vapor-deposited diamond. Biomaterials 1995; 16:483-488.

136. Yoder MN. Diamond properties and applications. In: Davis RF, ed. Diamond Films and Coatings: Development, Properties, and Applications. New Jersey: Noyes Publications, 1993:1-30.

137. Yoder MN. Diamond: what, when, and where. In: Purdes AJ, Angus JC, Davis RF, Meyerson BM, Spear KE, Yoder M, eds. Proceedings of the Second International Symposium on Diamond Materials, Volume 91-8. New Jersey: The Electrochemical Society, 1991:513-519.

138. Hoffman AS. Modification of material surfaces to affect how they interact with blood. Annals NY Acad Sci 1987; 516:96-101.

139. Noishiki Y, Miyata T. A simple method to heparinize biological materials. J Biomed Materials 1986; 20:337-346.

140. Beena MS, Chandy T, Sharma CP. Heparin immobilized chitosan -- poly ethylene glycol interpenetrating network: antithrombogenicity. Art Cells Blood Subst Immobil Biotech 1995; 23:175-192.

141. MacGregor RD, Hunt CA. Artificial red cells: a link between the membrane skeleton and RES detectability? Biomaterials Art Cells Art Organs 1990; 18:329-343.

142. Thomson JA, Law FC, Rushton N, Franks J. Biocompatibility of diamond-like carbon coating. Biomaterials 1991; 12:37-40.

143. Lettington AH. Application of DLC films to optical windows and tools. In: Tzeng Y, Yoshikawa M, Murakawa M, Feldman A, eds. Applications of Diamond Films and Related Materials, Materials Science Monographs No.73. New York: Elsevier, 1991:703-710.

144. Chang TMS. Artificial cell including blood substitute and biomicroencapsulation: from ideas to applications. Art Cells Blood Subst Immobil Biotech 1994; 22:vii-xiv.

145. Jones EA, Summerfield JA. Kupffer cells. In: Arias IM, Jakoby WB, Popper H, Schachter D, Shafritz DA, eds. The Liver: Biology and Pathobiology, Second Edition. New York: Raven Press, 1988:683-704.

146. Portnoy DA. Innate immunity to a facultative intracellular bacterial pathogen. Curr Opin Immun 1992; 4:20-24.

147. Bloch EH, McCuskey RS. Biodynamics of phagocytosis: an analysis of the dynamics of phagocytosis in the liver by in vivo microscopy. In: Wisse E, Knook DL, eds. Kupffer Cells and Other Liver Sinusoidal Cells. New York: Elsevier/North-Holland Biomedical Press, 1977:21-32.

148. Athens JW. The reticuloendothelial (mononuclear phagocyte) system and the spleen. In: Lee GR, Bithell TC, Foerster J, Athens JW, Lukens JN, eds. Wintrobe's Clinical Hematology, Ninth Edition. Philadelphia: Lea & Febiger, 1993:311-325.

149. Peacock EE Jr. Wound Repair, Third Edition. Philadelphia: W.B. Saunders Company, 1984.

150. Marelli TR. Use of a hemoglobin substitute in the anemic Jehovah's Witness patient. Crit Care Nursing 1994; 14:31-38.

151. Robalino BD, Marwick T, LaFont A, Vaska K, Whitlow PL. Protection against ischemia during prolonged balloon inflation by distal coronary perfusion with use of an autoperfusion catheter or fluosol. J Amer Coll Cardiol 1992; 20:1378-1384.

152. Spence RK. The status of bloodless surgery. Transfusion Med Rev 1991; 5:274-286.

153. Spence RK, Cernaianu AC. Pharmacological agents as adjuncts to bloodless vascular surgery. Seminars Vascul Surg 1994; 7:114-120.

154. Holman WL, McGiffin DC, Walter VAV, et al. Use of current generation perfluorocarbon emulsions in cardiac surgery. Blood Subst Art Cells Immobil Biotech 1994; 22:979-990.

155. Hoffer A, Walker M. Smart Nutrients. Garden City Park NY: Avery Publishing Group, 1994.

156. Pearson D, Shaw S. Life Extension: A Practical Scientific Approach. New York: Warner Books, 1983.

157. Teicher BA. Use of perfluorochemical emulsions in cancer therapy. Biomaterials Art Cells Immobil Biotech 1992; 20:875-882.

158. Rockwell S. Perfluorochemical emulsions and radiation therapy, Blood Subst Art Cells Immobil Biotech 1994; 22:1097-1108.

159. Mason RP, Shukla H, Antich PP. Oxygent: a novel probe of tissue oxygen tension. Biomaterials Art Cells Immobil Biotech 1992; 20:929-932.

160. Mortensen JD. Intravascular oxygenator: a new alternative method for augmenting blood gas transfer in patients with acute respiratory failure. Art Organs 1992; 16:75-82.

161. Eichner ER. Blood doping: results and consequences from the laboratory and the field. Phys. Sports Med 1987; 15:121-129.

162. Eichner ER. Better dead than second. J Lab Clin Med 1992; 120:359-360.

163. Costill DL. Endurance performance and aging. Sports Med Digest 1990; 12:7-10.

164. Brummelkamp WH. Reflections on hyperbaric oxygen therapy at 2 atmospheres absolute for Clostridium welchii infections. In: Ledingham I, ed. Hyperbaric Oxygenation. London: Churchill Livingstone, 1965.

165. Thom SR. Hyperbaric oxygen therapy. J Int Care Med 1989; 4:58-63.

166. Rentko VT. Red blood cell substitutes. Prob Veterinary Med 1992; 4:647-651.

167. Dodds WJ. Blood substitutes. Adv Veterinary Sci Comp Med 1991; 36:257-290.

168. Fiedler FA, Reynolds GH. Legal problems of nanotechnology: an overview. S Calif Interdisc Law J 1994; 3:593-629.

169. Kessler DA. FDA's revitalization of medical device review and regulation. Biomed Instrum Technol 1994; 28:220-226.

170. Fratantoni JC. Points to consider in the safety evaluation of hemoglobin-based oxygen carriers. Transfusion 1991; 31:369-371.

171. Electromagnetic interference may cause problems with some medical devices. FDA Med Bull (Sep 1994) 24:5-6.

172. Nose Y. No government overregulation on the development of new medical devices. Art Organs 1993; 17:673-674.

173. Loob WH. The Safe Medical Devices Act of 1990: are hospitals ready to deal with the FDA? J Clin Eng 1991; 16:35-48.

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