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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.


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