||Microbivores: Artificial Mechanical Phagocytes
Nanorobotic "microbivores" traveling in the bloodstream could be 1000 times faster-acting than white blood cells and eradicate 1000 times more bacteria, offering a complete antimicrobial therapy without increasing the risk of sepsis or septic shock (as in traditional antibiotic regimens) and without release of biologically active effluents. They could also quickly rid the blood of nonbacterial pathogens such as viruses, fungus cells, or parasites.
Originally published April 2001 in IMM
Report Number 25: Nanomedicine, in conjunction with Foresight
Update 44. Published on KurzweilAI.net April 11, 2002.
Nanomedicine  offers the prospect of powerful new tools for
the treatment of human diseases and the augmentation of human biological
systems. Diamondoid-based medical nanorobotics may offer substantial
improvements in capabilities over natural biological systems, exceeding
even the improvements possible via tissue engineering and biotechnology.
For example, the respirocytes  - artificial red blood cells comprised
of microscopic diamondoid pressure tanks that are operated at up
to 1000 atm of pressure - could carry >200 times more respiratory
gases than an equal volume of natural red blood cells. The clottocytes
 are artificial platelets that could stop human bleeding within
~1 second of physical injury, but using only 0.01% the bloodstream
concentration of natural platelets - in other words, nanorobotic
clottocytes would be ~10,000 times more effective as clotting agents
than an equal volume of natural platelets.
In this article I'd like to examine the future nanorobotic equivalent
of the third major class of natural blood cells - the white cells.
This paper summarizes the results of a recently completed scaling
study of artificial mechanical phagocytes of microscopic size, called
"microbivores." Microbivores constitute a potentially
large class of medical nanorobots intended to be deployed in human
patients for a wide variety of antimicrobial therapeutic purposes,
for example, as a first-line response to septicemia. The analysis
focuses on a relatively simple device: an intravenous (I.V.) microbivore
whose primary function is to destroy microbiological pathogens found
in the human bloodstream, using the "digest and discharge"
protocol first described by the author elsewhere . The full technical
paper describing the microbivore scaling design study is already
available online .
Septicemia, also known as blood poisoning, is the presence of pathogenic
microorganisms in the blood. If allowed to progress, these microorganisms
can multiply and cause an overwhelming infection. Bacteremia is
the presence of bacteria in the human bloodstream. Although bacterial
nutrients are plentiful in blood, the healthy human bloodstream
is generally considered a sterile environment. Major antimicrobial
defenses include the circulating neutrophils and monocytes (white
cells) capable of phagocytosis (engulfing and digesting other cells)
and the supporting components of humoral immunity including complement
Still, it is not unusual to find a few bacteria in blood. Normal
activities like chewing, brushing or flossing teeth causes movement
of teeth in their sockets, infusing a burst of commensal oral microbes
into the bloodstream . Bacteria can enter the blood via an injury
to the skin, the lining of the mouth or gums, or from gingivitis
and other minor infections in the skin and elsewhere . Bacteria
can also enter the blood during surgical, dental, or other medical
procedures such as the insertion of I.V. lines (providing fluids,
nutrition or medications), cystoscopy (a viewing tube inserted to
examine the bladder), colonoscopy (a viewing tube inserted to view
the colon), or heart valve replacement with a prosthetic . Such
bacteria are normally removed by circulating leukocytes (along with
fixed reticuloendothelial phagocytes in the spleen, liver, and lungs),
but a few species of bacteria are unusually virulent and can overwhelm
the natural defenses. The Center for Disease Control estimates that
~25,000 U.S. patients die each year from bacterial sepsis. Current
therapies often involve multiple antibiotics administered simultaneously
in multi-gram quantities per day. These treatments can sometimes
take weeks or even months to bring under control certain hardy infectious
microorganisms like Pseudomonas aeruginosa or enterobacteria
such as Escherichia coli and Salmonella.
A nanorobotic device that could safely provide quick and complete
eradication of bloodborne pathogens using relatively low doses of
devices would be a welcome addition to the physician's therapeutic
armamentarium. Such a machine is the microbivore, an artificial
The microbivore is an oblate spheroidal nanomedical device consisting
of 610 billion precisely arranged structural atoms plus another
~150 billion mostly gas or water molecules when fully loaded. The
nanorobot measures 3.4 microns in diameter along its major axis
and 2.0 microns in diameter along its minor axis, thus ensuring
ready passage through even the narrowest of human capillaries which
are ~4 microns in diameter . Its gross geometric volume of 12.1056
micron3 includes two normally empty internal materials processing
chambers totalling 4 micron3 in displaced volume. The nanodevice
consumes 100-200 pW of continuous power while in operation and can
completely digest trapped microbes at a maximum throughput of 2
micron3 per 30-second cycle, large enough to internalize a single
microbe from virtually any major bacteremic species in a single
gulp. As in previous designs , to help ensure high reliability
the microbivore has tenfold redundancy in all major components,
excluding only the largest passive structural elements. The microbivore
has a dry mass of 12.2 picograms.
Here's how the nanorobot works. During each cycle of operation,
the target bacterium is bound to the surface of the microbivore
like a fly on flypaper, via species-specific reversible binding
sites . Telescoping robotic grapples emerge from silos in the
device surface, establish secure anchorage to the microbe's plasma
membrane, then transport the pathogen to the ingestion port at the
front of the device where the pathogen cell is internalized into
a 2 micron3 morcellation chamber. After sufficient mechanical mincing,
the morcellated remains of the cell are pistoned into a 2 micron3
digestion chamber where a preprogrammed sequence of 40 engineered
enzymes are successively injected and extracted six times, progressively
reducing the morcellate ultimately to monoresidue amino acids, mononucleotides,
glycerol, free fatty acids and simple sugars. These simple molecules
are then harmlessly discharged back into the bloodstream through
an exhaust port at the rear of the device, completing the 30-second
digestion cycle. This "digest and discharge" protocol
 is conceptually similar to the internalization and digestion
process practiced by natural phagocytes, except that the artificial
process should be much faster and cleaner. For example, it is well
known that macrophages release biologically active compounds during
bacteriophagy , whereas well-designed microbivores need only
release biologically inactive effluent.
Natural phagocytic cells are 100-1000 times larger in volume than
microbivores but may consume almost as much power during comparable
activities. For instance, heat production rises from 9 pW in unstimulated
human neutrophils up to 28 pW during phagocytosis, with the rise
proportional to the number of particles ingested . The basal
rate for a resting ~400 micron3 T-cell lymphocyte is ~20 pW, rising
to ~65 pW during antigen response .
Microbe ingestion times for natural professional phagocytes can
be quite rapid, often a matter of minutes, but full digestion and
excretion of the target pathogen may require hours. While macrophages
can ingest up to ~25% of their volume per hour , microbivores
can process ~2000% of their volume per hour, thus are ~80 times
more efficient as phagocytic agents. In other words, a given volume
of microbivores can digest bacterial pathogens 80 times faster than
an equal volume of white cells or macrophages could digest them.
Many natural professional phagocytic cells such as neutrophils
also have a maximum capacity for phagocytosis during their short
lifetime, typically a few hours in blood or a few days in tissue.
In one experiment , 1-100 S. aureus or S. faecalis
bacteria were presented to each neutrophil, which digested more
of them at the higher concentrations. At the highest concentration
(100:1), neutrophils from normal patients could only kill a mean
of 9 S. aureus bacteria per phagocyte, while neutrophils
from carriers of chronic granulomatous disease could kill a mean
of 14 S. faecalis bacteria per phagocyte. By comparison,
a single microbivore could completely digest up to ~3000 microbes/day
of P. aeruginosa bacteria with no well-defined maximum lifetime
capacity for phagocytosis.
In the accompanying technical paper  a simple mathematical model
for microbivore pharmacokinetics quantifies the activity of a specific
dose of nanorobots injected into the human bloodstream, with the
conclusion that a 1-terabot (1012-device) dose of microbivores
employed in the treatment of a mild bacteremia (0.1 x 106 colony-forming
units (CFU) per ml) can reduce the initial whole-bloodstream bacterial
load of 5.4 x 108 CFU down to <1 CFU in 460-5400 sec (8-90 min),
if 1-10 bacterium-microbivore collisions are required for the bacterium
Similarly, a severe bacteremia (100 x 106 CFU/ml) is eliminated
in 620-7300 sec (10-120 min). Note that a single 1-terabot intravenous
dose (a ~12 cm3 injection) of microbivores produces a nanocrit
of Nct ~ 0.2% in the blood of a normal adult human male patient
and could liberate up to 100-200 watts of systemic waste heat which
is very near the maximum thermogenic limit for in vivo medical nanorobot
While microbivores can fully eliminate septicemic infections in
minutes to hours, natural phagocytic defenses - even when aided
by antibiotics - can often require weeks or months to achieve complete
clearance of target bacteria from the bloodstream. Thus microbivores
appear to be up to ~1000 times faster-acting than either unaided
natural or antibiotic-assisted biological phagocytic defenses.
Another useful comparative perspective is that the administration
of antibacterial agents (e.g., against E. coli) typically
may increase the LD50 of that pathogen by ~500-fold using antibiotics
 or ~850-fold using monoclonal antibodies . For example,
the mammalian LD50 for E. coli is ~0.1-1 x 106 CFU/ml, rising
to ~108 CFU/ml with the administration of antibiotics. By employing
a suitable dose of microbivores, a bloodstream bacterial concentration
up to the theoretical maximum of ~1011 CFU/ml (~20% of blood volume
assuming ~2 micron3 organisms) could be controlled, bringing another
~1000-fold improvement using nanomedicine and at last extending
the therapeutic competence of the physician to the entire range
of potential bacterial threats, including locally dense infections.
With minor additions to the basic design, microbivores 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 bacterial lipopolysaccharide (LPS) endotoxin rose from normal
at 0.076 ng/ml to a maximum of 1.130 ng/ml blood concentration .
In another study, endotoxin levels during a gram-negative bacterial
infection rose from 0.2 to 2 ng/ml in pig blood . Eliminating
a bloodstream concentration of ~2 ng/ml of ~8 kDa LPS endotoxin
 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 1-terabot dose
of modified microbivores.
The high mortality (up to 30%-50%) associated with gram-negative
sepsis is due in large measure to the patient's reaction to LPS,
an endotoxin 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 . We've already noted that
small quantities (~ng/ml) of LPS are released by living and growing
bacteria, but the killing of bacteria using traditional antibiotic
regimens often liberates large quantities of additional LPS, potentially
up to ~105 ng/ml . Such massive releases as occur with the
use of antibiotics will not accompany the use of microbivores, because
all bacterial components (including all cell-wall LPS) are internalized
and fully digested into harmless nonantigenic molecules prior to
discharge from the device. Microbivores thus represent a complete
antimicrobial therapy without increasing the risk of sepsis or septic
If the patient presents with a septic condition before the microbivores
are introduced, a substantial preexisting concentration of inflammatory
cytokines will likely be present and must be extracted from the
blood in concert with the primary antibacterial microbivore treatment.
All unwanted cytokine molecules may be rapidly and systemically
extracted from the blood using a modest dose of respirocyte-class
nanodevices  such as pharmacytes , a combination-treatment
approach previously suggested elsewhere [1, 18]. Specifically, a
1-terabot intravenous dose of micron-size pharmacytes  each having
~105 cytokine-specific molecular sorting rotors and ~0.5 micron3
of onboard storage capacity could reduce the blood concentration
of ~20 kDa IL-1beta and IL-6 cytokines from LPS-elevated levels
of ~100 ng/ml  (~3 x 10-9 molecules/nm3) down to normal serum
levels of ~10 pg/ml  (~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
use ~100% of the available onboard storage volume.)
Microbivores could also be useful for treating infections of the
meninges or the cerebrospinal fluid (CSF) and respiratory diseases
involving the presence of bacteria in the lungs or sputum, and could
also digest bacterial biofilms. These handy nanorobots could quickly
rid the blood of nonbacterial pathogens such as viruses (viremia),
fungus cells (fungemia), or parasites (parasitemia). Outside the
body, microbivore derivatives could help clean up biohazards, toxic
biochemicals or other environmental organic materials spills, as
The author thanks C. Christopher Hook, M.D., Stephen S. Flitman,
M.D., Ronald G. Landes, M.D., and also Forrest Bishop, Robert J.
Bradbury, and Ralph C. Merkle, for helpful comments on the technical
paper from which this summary article has been abstracted.
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Copyright 2001 Robert A. Freitas Jr. All Rights Reserved. Used
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