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 Nanoid Shock

Could the presence of medical nanorobots inside the human body produce shock? Shock is a life-threatening medical emergency in which blood pressure is too low to sustain life, due to inadequate pumping action of the heart or excessive vasodilation [361]. Shock may be caused by a wide variety of conditions including dehydration, drug reaction, hemorrhage, infection, myocardial infarction, poisoning, or trauma. There appear to be only three general classes of shock response that could be directly triggered by medical nanorobots. These three responses may collectively be termed “nanoid shock”:

(1) Anaphylactic Shock. (See Section Anaphylactic shock from complement activation (Section is another possibility.

(2) Septic Shock. Septic shock [2074-2076] is usually (though not always [2524]) caused by Gram-negative bacterial endotoxin (e.g., lipopolysaccharide or LPS) components of the cell wall that are released into the bloodstream when a microbe is destroyed or lysed. Endotoxins can activate Hageman factor, which can in turn activate the complement system, the bradykinin system (bradykinin release produces vasodilation, increased vascular permeability and blood volume depletion), the coagulation cascade, and the fibrinolytic system [2077]. Nanorobots with external surface-bound moieties or which emit chemical substances that have molecular homology with endotoxins (either of which can probably be avoided in a good nanomedical design) might elicit an analogous septic shock. The adverse effects of bacterial endotoxin are mediated by various active substances such as tumor necrosis factor (TNF) or cachectin, a cytokine produced by macrophages and other mononuclear cells (Section 15.2.7). If necessary, the nanorobot fleet could selectively absorb [2078] and neutralize those mediating substances, or release, say, TNF-specific antibodies [2079], antagonists [2080], inhibitors [2081], decoys [2084], or synthesis inhibitors [2082] to eliminate the risk of septic shock.

For example, with minor additions, phagocytic nanorobots called microbivores [2762] (Chapter 23) could be used to combat toxemia, the distribution throughout the body of poisonous products of bacteria growing in a focal or local site, and other biochemical sequelae of sepsis. For instance, E. coli-induced septicemic shock in vervet monkeys occurred at 425 x 106 CFU/ml and LPS endotoxin rose from normal at 0.076 ng/ml to a maximum of 1.130 ng/ml blood concentration [5499]. In another study, endotoxin levels during a Gram-negative bacterial infection rose from 0.2 to 2 ng/ml in pig blood [5500]. Eliminating a bloodstream concentration of ~2 ng/ml of ~8 kD LPS endotoxin [5501] would require the extraction and enzymatic digestion of ~8 x 1014 LPS molecules from the ~5400 cm3 human blood compartment, a mere ~800 LPS molecules per nanorobot assuming a single terabot dose (1012 devices) of modified microbivores.

The high mortality associated with Gram-negative sepsis is due in large measure to the patient’s reaction to LPS, which induces the production of cytokines such as IL-1beta and IL-6 which leads to an uncontrolled inflammatory reaction resulting in tissue damage and organ failure [5502]. Small quantities (~ng/ml) of LPS are released by living and growing bacteria (see previous paragraph), but the killing of bacteria using traditional antibiotic regimens often liberates large quantities of additional LPS, potentially up to ~105 ng/ml [5502]. Such massive releases as occur with the use of antibiotics will not accompany the use of microbivores [2762], because all bacterial components (including all cell-wall LPS) are internalized and fully digested into harmless nonantigenic molecules prior to discharge from the device. And of course nanorobots will themselves contain no LPS. Microbivores thus represent a complete antimicrobial therapy without increasing the risk of sepsis or septic shock. (Note that while Gram-positive organisms can also induce cytokine production, 100- to 1000-fold more Gram-positive bacteria are needed to induce the same concentration of cytokines as are induced by Gram-negative bacteria [5502].)

If the patient presents with a septic condition before the microbivores are introduced, a substantial pre-existing concentration of inflammatory cytokines will likely be present and must be extracted from the blood in concert with the principal antibacterial microbivore treatment. Unwanted cytokine molecules may be rapidly and systemically extracted from the blood using a modest dose of respirocyte-class nanodevices [3573], a combination-treatment approach previously suggested elsewhere [2762, 5503]. Specifically, a 1-terabot intravenous dose of micron-size pharmacytes (Section, Chapter 19) each having ~105 cytokine-specific molecular sorting rotors and ~0.5 micron3 of onboard storage capacity could reduce the blood concentration of ~20 kD IL-1beta and IL-6 cytokines from LPS-elevated levels of ~100 ng/ml [5502] (~3 x 10-9 molecules/nm3) down to normal serum levels of ~10 pg/ml [2163] (~3 x 10-13 molecules/nm3) after only ~200 sec of diffusion-limited pumping, using just ~0.1% of the available onboard storage volume. (Extracting an additional ~105 ng/ml of LPS from the bloodstream would take a similar amount of time and would use ~100% of the available onboard storage volume.) Cytokines that have exited the circulation must be removed by other means.

(3) Mechanical Shock. Traumatic shock may occur in cases of acute intestinal obstruction, crush injuries, perforation or rupture of viscera or blood vessels, pneumothorax, nerve injury due to contusion of highly sensitive parts (e.g., testicle, solar plexus, eye, urethra), gastrointestinal strangulation (e.g., hernias, intestinal intussusception or volvulus), or visceral torsion (e.g., of ovary, testicle) [2004]. Traumatic shock toxin (a thrombogenic aminophospholipid) occurs only on the cytosolic layer of cell membranes and is liberated by cell destruction, causing disseminated intravascular coagulation [2083]. Such mechanical traumas should be rare in the context of individual nanorobot locomotion and manipulation activities in vivo, but mechanical shock could result from poorly-planned large-scale coordinated transtissue nanorobot fleet movements (Chapter 14), from vascular blockage due to nanorobotic-induced emboli caused by “traffic-jam” control-failure effects (Chapter 12), or from incautious nanosurgical techniques (Chapter 12). These causes should be avoided in medical nanorobot mission design.


Last updated on 30 April 2004