IMM Report Number 22: Nanomedicine
In conjunction with Foresight Update 43
By Robert A. Freitas Jr.
Research Scientist, Zyvex Corp.
|Robert A. Freitas Jr.|
When considering the biocompatibility of medical nanorobots , an important concern is whether such devices may inadvertently act as “pyrogens” — agents causing systemic body temperature suddenly to rise, mimicking the effects of an infection. To understand this potential medical risk and its possible resolution, we must first examine how body temperature is normally controlled.
Human core temperature is tightly regulated through the preoptic nucleus of the anterior hypothalamus  to a mean “set point” of 37o C with circadian variations around this mean rarely exceeding 0.6o C. An array of thermoregulatory mechanisms ensures that the hypothalamic thermal set point temperature is maintained to within a natural “load error” of 0.2-0.5o C. Thermal deviations exceeding the load error provoke a natural counteractive response to restore core temperature back to the set point.
Abnormal elevation of systemic body temperature (called “pyrexia”) can occur in one of two ways: hyperthermia or fever .
In hyperthermia, thermal control mechanisms are overwhelmed, so that heat production exceeds heat dissipation. Hyperthermia may develop during periods of intense physical exertion, dehydration, immersion in hot fluids, or from waste heat thrown off by energy-consuming nanorobots in vivo . In each case the body’s thermoregulatory mechanisms are fully engaged, attempting to cope with the departure from homeostasis. In some situations, thermoregulatory disorders such as heatstroke, hypothalamic insult (caused by drugs, infection or tumor), malignant hyperthermia of anesthesia, or thyroid storm, can cause extreme pyrexia with temperature rising to 41.1o C or higher. Heating blood above 47o C rapidly produces visible damage to erythrocytes ; heat-damaged cells show morphologic changes, increases in osmotic and mechanical fragility, and are removed rapidly after reinjection into the circulation. Similarly, an increase of ~6.5-10o C in tooth pulp temperature for > 30-45 seconds (e.g., due to overactive dental nanorobots ) can permanently damage the pulp . If nanorobots are the cause of hyperthermia, it is because local or systemic thermogenic limits  are being exceeded. Obeying these operational limits should avoid the problem.
In fever, the second cause of pyrexia and the primary topic of this paper, the hypothalamic thermal set point is shifted higher. Fever is a natural self-defense mechanism (produced by substrate cycling in skeletal muscle) intended to make the host less hospitable to microscopic invaders. The intact control mechanisms of thermoregulation act to raise body temperature up to the new set point, then maintain the elevated systemic temperature. Thus fever is not equivalent to an elevated core temperature, but rather represents an elevated set point . Fever is triggered by the release of endogenous pyrogen (a fever-producing substance) from cells of the immune system into the bloodstream. Mononuclear phagocytes are the main source of endogenous pyrogens, and a variety of these substances, often categorized as monokines and lymphokines, or collectively, as cytokines, also mediate the acute-phase response to infection and inflammation. Pyrogenic cytokines act as hormones in that they are carried by the circulation from the local inflammatory site of production to the central nervous system, where they bind with high affinity to 80 kDa receptors present on vascular endothelial cells within the hypothalamus. This elicits phospholipases which in turn cause release of arachidonic acids from membrane phospholipids, as a result of which prostaglandin levels rise, resetting the hypothalamic regulatory center to a new set point; the cytokines may also interact directly with neural tissues .
The most important of the pyrogenic cytokines are interleukin-1 (IL-1), tumor necrosis factor (TNF), interleukin-6 (IL-6), interferon alpha, beta and gamma, interleukin-8 (IL-8), macrophage inflammatory protein (MIP-1 alpha, MIP-1 beta), and possibly platelet-derived growth factor (PDGF).
IL-1 (17.4 kDa) comes mainly from monocytes and macrophages, though it can also be produced by neutrophils, B and T cells, endothelial cells, and virtually all other nucleated cells . IL-1 production may be stimulated by the presence of microorganisms, exposure to endotoxin and other bacterial toxins or microbial products, phagocytosis, antigen-antibody immune complexes, and various forms of tissue injury , and IL-1 induces additional IL-1 production and additional IL-1 receptor expression on certain target cells. IL-1 also stimulates immune cells thus enhancing host defense mechanisms, stimulates lactoferrin release by neutrophils (which have ~1700 IL-1 receptors per cell) reducing serum iron levels during many bacterial infections thus retarding bacterial growth, acts on the central nervous system to induce sleep, and has numerous other biologic properties.
TNF is another pyrogenic cytokine that acts directly on the hypothalamus to elevate the thermal set point, and also causes fever by stimulating IL-1 production. Macrophages are the main source of TNF, along with monocytes and NK cells. TNF production is stimulated most potently by endotoxin, but also by certain parasites, viruses, enterotoxins (including toxic-shock syndrome toxin-1), and IL-1. Peak serum levels occur in 90 minutes, but TNF is cleared from the circulation in ~3 hours . TNF binds to different receptors than IL-1 — these are found in the CNS, on vascular endothelium, adipose tissue, and on liver, kidney and lung tissues . TNF has other biological properties besides pyrogenicity, including increasing resistance to infection, inhibition of ACTH release, induction of sleep, and mediation of septic shock.
Can nanorobots act as pyrogens, inducing systemic fever (nanopyrexia)? Certainly, any external organic coatings on nanorobots should be verified as nonpyrogenic. For example, phagocytosed latex particles do not stimulate pyrogen production in macrophages . Fever occurs in about one-third of all hospital patients, 67% of these due to infection but 12%-18% due to “fever of unknown origin” or FUO that is nonetheless almost certainly biochemically mediated. FUO is usually ascribed to infections, neoplasms, collagen vascular disease, granulomatous diseases (including starch peritonitis, a febrile granulomatous response to starch introduced on surgical gloves), chronic liver disease and IBD, pulmonary emboli and atelectasis, and very rarely certain drugs such as Dilantin. Fever can also be produced by mechanical tissue disturbance such as a thoracic esophageal perforation , excision of Teflon particulate masses , knee and hip arthroplasty, or shock wave lithotripsy , confirming the need for cautious nanosurgery.
As of 2000, there are no reports of pyrogenicity for anticipated nanorobot simple building materials such as diamond, fullerenes, or graphite. Carbon powder has been used in nasal provocation tests without eliciting fever, though there are rare cases of fever from amorphous carbon particles in India ink . With rare exception, bulk Teflon appears nonpyrogenic in vivo, although perfluorocarbon emulsion can cause cutaneous flushing and fever at low doses and “polymer fume fever”  or “Teflon fever” results when Teflon combustion products are inhaled.
No pyrogenicity of monocrystal sapphire has been reported. However, there is one case of fever possibly caused by alumina powder inhalation . Additionally, while ceramics appear generally nonpyrogenic, macrophages exposed to particulate alumina ceramic release TNF, increasingly with size and concentration of particles .
Other particulates are less inert. Metal fume fever (due to zinc oxide inhalation) is well-known and excess trace elements such as copper and zinc can induce fever. Phagocytosed silica crystals do elicit pyrogen [16, 17] and various low-solubility substances that crystallize in the human body can trigger fever once the crystals have formed. For example, monosodium urate monohydrate crystals [16-18] which are deposited in synovial fluid during gout, causing fever, stimulate IL-1, TNF, and IL-6 production in monocytes or synoviocytes, with smaller 10-40 micron crystals less pyrogenic than the larger aggregates . Calcium pyrophosphate dihydrate (CPPD) deposited in the fibrocartilage during chondrocalcinosis (aka CPPD crystal deposition disease) is pyrogenic , and CPPD crystals increase IL-6 production by monocytes and synoviocytes in vitro . Fever has been reported from nephrolithiasis (kidney stones), from crystalluria with calcium oxalate or phosphate in urolithiasis (bladder stones), from calcified lymph-node stones in broncholithiasis, from calcified salivary gland stones in sialolithiasis, and from precipitated crystals in the pulmonary microvasculature in a patient receiving total parenteral nutrition. Cholesterol crystals deposited as gallstones during cholelithiasis may be pyrogenic, as are cholesterol crystal emboli in the blood . A systematic assessment of pyrogenicity should be undertaken for all crystalline and ceramic materials likely to be employed in the construction of medical nanorobots.
If inherent nanodevice surface pyrogenicity cannot be avoided, the pyrogenic pathway is readily controlled by in vivo medical nanorobots because only a small number of critical mediators are involved. For instance, the cytokine IL-4 suppresses production of the endogenous pyrogens IL-1, TNF and IL-6 , and NSAID prostaglandin inhibitors like aspirin or ibuprofen are also effective antipyretic agents that block prostaglandin synthase (cyclooxygenase) enzyme activity and thus block prostaglandin production. Antagonists of the IL-1 receptor have been identified . Glucocorticoids inhibit the production of IL-1, TNF and IL-6, and other inhibitors of TNF are known such as the anti-TNF monoclonal antibody Etanercept currently used in rheumatoid arthritis patients with excellent results. Nonsteroidal anti-inflammatory antipyretic drugs are used for treatment of gout and other crystal-induced arthropathies . Nanorobots may release these (or similar) inhibitors, antagonists or down-regulators in a targeted fashion to interrupt the pyrogenic pathway, or may use molecular rotors to selectively absorb the endogenous pyrogens, chemically modify them, then release them back into the body in a harmless inactivated form.
For example, typical bloodstream concentrations are ~10 pg/cm3 for IL-1 beta  and ~100 pg/cm3 for TNF , or ~0.0003-0.003 molecules/micron3 assuming a molecular weight of ~17.4 kDa for either molecule . If there are 2-20 x 1012 molecules of these cytokines in the entire circulation, then a fleet of 0.1-1 trillion nanorobots each with 10,000 sorting rotors on its surface (extracting ~0.0001 molecules/rotor-sec ) can reduce bloodstream IL-1 or TNF concentrations by ~99% in ~20 seconds. Selective absorption of prostaglandins, present in blood plasma at ~400 pg/cm3 , might also serve to “manually” reduce the hypothalamic thermal set point. One other possible approach, adopted by certain vaccinia virus strains , is to suppress the fever response by releasing soluble IL-1 receptors that bind to IL-1, thus inhibiting this normal pathway.
It is possible that perfectly biocompatible-surfaced nanorobots cannot be designed, or that necessary additional anti-pyrogenic functions cannot be added to nanorobotic devices already hard-pressed for onboard space. Although not ideal, in such cases a collection of different nanodevices could be deployed to implement a given treatment. Some devices would attend to the primary therapeutic goal with others attending to the management of the unwanted biological responses, crudely analogous to drug combinations in current medical practice such as demerol plus vistaril or combinations of chemotherapeutics and anti-emetics.
The author thanks Stephen S. Flitman, M.D., and C. Christopher Hook, M.D., for helpful comments on an earlier version of this paper.
Copyright 2000 Robert A. Freitas Jr.
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