Nanomedicine, Volume IIA: Biocompatibility
© 2003 Robert A. Freitas Jr. All Rights Reserved.
Robert A. Freitas Jr., Nanomedicine, Volume IIA: Biocompatibility, Landes Bioscience, Georgetown, TX, 2003
Human core temperature (Section 184.108.40.206) is tightly regulated through the preoptic nucleus of the anterior hypothalamus  to a mean “set point” of 37 oC with circadian variations around this mean rarely exceeding 0.6 oC , although set point is lowered 0.5-1.0 oC in mammals on calorie restriction diets [5930-5932]. An array of thermoregulatory mechanisms  ensures that the hypothalamic thermal set point temperature is maintained to within a natural “load error” of 0.2-0.5 oC . 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 (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 (Section 6.5.2), dehydration, immersion in hot fluids (Section 220.127.116.11), or from waste heat thrown off by energy-consuming nanorobots in vivo (Sections 6.5.2 and 6.5.3). 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, hot flashes [5357-5361], hypothalamic insult (caused by drugs, infection or tumor), malignant hyperthermia, or thyroid storm, can cause extreme pyrexia with temperature rising to 41.1 oC or higher . Protein denaturation begins at ~42 oC, and heating blood above 47 oC 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 ~6.5-10 oC in tooth pulp temperature for >30-45 seconds can permanently damage the pulp . If nanorobots are the cause of hyperthermia, it is because local or systemic thermogenic limits (Section 6.5.2) are being exceeded. Obeying these operational limits avoids the problem.
In fever, the second cause of pyrexia, the hypothalamic thermal set point is shifted higher by the action of circulating pyrogenic cytokines, causing intact peripheral mechanisms to conserve and generate heat until the body temperature increases to the elevated set point . 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. Rather, it represents an elevated set point . Fever is triggered by the release of endogenous pyrogenic cytokines (fever-producing substances) from cells of the immune system into the bloodstream. Mononuclear phagocytes are the main source of endogenous pyrogens, and a variety of these substances , 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. There they bind with high affinity to 80 kD 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, 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-1alpha, MIP-1beta), and possibly  platelet-derived growth factor (PDGF).
IL-1 (17.4 kD) 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 . IL-1 induces additional IL-1 production  and additional IL-1 receptor expression on certain target cells . IL-1 stimulates immune cells thus enhancing host defense mechanisms. The cytokine stimulates lactoferrin release by neutrophils (e.g., neutrophils have ~1700 IL-1 receptors per cell ), which reduces serum iron levels during many bacterial infections, thus retarding bacterial growth. (IL-1 also acts on the central nervous system to induce sleep  and has numerous other helpful and deleterious biologic properties.)
TNF is another pyrogenic cytokine that acts directly on the hypothalamus to elevate the thermal set point. It also causes fever by inducing IL-1 production. LPS-activated macrophages are the main source of TNF, along with monocytes and NK cells as well as antigen-stimulated T-cells and activated mast 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 different receptors 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  (Section 18.104.22.168). TNF is a mediator of both natural and acquired immunity as well as specific responses and acute inflammation .
Can nanorobots act as pyrogens, inducing systemic fever (nanopyrexia )? Any external nanorobot organic coatings (Section 15.2.2) should be verified as nonpyrogenic. For example, phagocytosed latex particles do not stimulate pyrogen production in macrophages . But 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 (irritable bowel disease), pulmonary emboli  and atelectasis [2406, 2407] (but compare Engoren ), and sometimes certain drugs [2112, 2113, 2409-2411] such as Dilantin . Fever can also be produced by mechanical tissue disturbance such as a thoracic esophageal perforation , knee and hip arthroplasty [2401-2403], excision of Teflon particulate masses , or shock wave lithotripsy [2087-2089], confirming the need for cautious nanosurgery (Chapter 12).
S. Flitman also notes the significance of Shapiro Syndrome, a spontaneous recurrent hypothermia and hyperhidrosis usually associated with agenesis of the corpus callosum [5910-5912] but also with hypothalamic lesions  and lipomas . Dopaminergic denervation of the hypothalamic thermoregulatory center has also produced hyperthermia or “reverse Shapiro Syndrome” , and Flitman has observed this effect in a patient with hypothalamic damage due to encephalitis, producing a fever long after the normalization of CSF pleocytosis (and hence the eradication of acute infection). The relevance to nanomedicine is that nanorobots passing through, or taking up residence in, the corpus callosum or hypothalamus must tread lightly to avoid inducing hypo- or hyperthermia, as this seems to occur with even a mild infiltration of the preoptic nucleus, according to Flitman.
As of 2002, there were 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  and from inhaled or ingested hydrocarbons . With rare exception , bulk Teflon appears nonpyrogenic in vivo [2116-2118] – although perfluorocarbon emulsion can cause cutaneous flushing and fever at low doses  (see also Section 22.214.171.124 and Chapter 22), and “polymer fume fever” [1683, 2120, 2121] or “Teflon fever”  is the result 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 . And while ceramics appear generally to be 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 [2124-2126] and excess trace elements such as copper and zinc can induce fever . Phagocytosed silica crystals elicit pyrogen production [2128, 2129] and silicotic materials can produce fever [2131-2133]. Various low-solubility substances that crystallize in the human body can trigger fever once the crystals have formed. For example, monosodium urate monohydrate crystals [2128-2130], which are deposited in synovial fluid during gout, cause fever [2134, 2135] and stimulate IL-1 , TNFalpha , and IL-6  production in monocytes or synoviocytes. The smaller 10- to 40-micron crystals are less pyrogenic than the larger aggregates . Calcium pyrophosphate dihydrate (CPPD) deposited in the fibrocartilage during chondrocalcinosis (aka. CPPD crystal deposition disease) is pyrogenic [2137-2143], 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) [2146, 2147], 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 [2151-2153], 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 (whether singly or in combination) 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 . NSAID prostaglandin inhibitors like aspirin or ibuprofen are also effective antipyretic agents that block prostaglandin synthase (cyclooxygenase) enzyme activity and thus block the production of prostaglandins. Antagonists of the IL-1 receptor have been identified [2156-2160]. Glucocorticoids inhibit the production of IL-1, TNF and IL-6 . Other inhibitors of TNF are known (Section 15.2.7) such as the anti-TNF monoclonal antibody Etanercept [2412, 2413], currently used in rheumatoid arthritis patients with excellent results. Nonsteroidal anti-inflammatory antipyretic drugs are employed for treatment of gout and other crystal-induced arthropathies . Additionally, many endogenous antipyretics that limit the rise in body temperature have been identified , including arginine vasopressin, glucocorticoids, melanocortins (e.g., alpha-MSH), TNF (under certain circumstances), IL-10, and most recently, cytochrome P-450 [5045, 5046]. Nanorobots may release these or similar inhibitors, antagonists, or down-regulators in a targeted fashion to interrupt the pyrogenic pathway. Alternatively, they may use molecular sorting rotors to selectively absorb the endogenous pyrogens, chemically modify them, and then release them back into the body in a harmless inactivated form.
For example, typical bloodstream concentrations are ~10 pg/cm3 for IL-1beta  and ~100 pg/cm3 for TNF , or ~0.0003-0.003 molecules/micron3 assuming a molecular weight of ~17.4 kD 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 ~0.001 molecules/rotor-sec) can reduce bloodstream IL-1 or TNF concentrations by ~90-99% in ~2-20 seconds. Selective absorption of prostaglandins, present in blood plasma at ~400 pg/cm3 (Appendix B), 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 while others would attend to the management of the unwanted biological responses, crudely analogous to drug combinations in current medical practice such as demerol plus vistaril [2414-2416] or combinations of chemotherapeutics and anti-emetics [2417-2420]. Mechanisms of tachyphylaxis  could also be investigated for possible relevance.
The impact of nanorobots and nanorobotic organs on the thermophysical properties and thermoregulatory mechanisms of the human body is briefly discussed in Section 15.3.8.
Last updated on 30 April 2004