A Personal Nanomedical Appliance to Replace Human
of Evolution and Technology
Vol. 11 - April
Robert A. Freitas Jr.
Christopher J. Phoenix
Copyright 1996-2002. All Rights Reserved
The vasculoid is a single, complex, multisegmented nanotechnological
medical robotic system capable of duplicating all essential thermal
and biochemical transport functions of the blood, including
circulation of respiratory gases, glucose, hormones, cytokines,
waste products, and cellular components. This nanorobotic system, a
very aggressive and physiologically intrusive macroscale nanomedical
device comprised of ~500 trillion stored or active individual
nanorobots, weighs ~2 kg and consumes from 30-200 watts of power in
the basic human model, depending on activity level. The vasculoid
system conforms to the shape of existing blood vessels and serves as
a complete replacement for natural blood. This paper presents a
preliminary theoretical scaling analysis including transport
capacity, thermal conduction, control and biocompatibility
considerations, along with a hypothetical installation scenario and
a description of some useful optional equipment. A discussion of
repair procedures and various applications of the personal vasculoid
appliance is deferred to subsequent papers.
OUTLINE OF THE PAPER
1.1 The Vasculoid Concept
1.2 Some Benefits of Vasculoid Installation
Physiological Materials Transport
2.1 Molecular Transport
2.1.1 Respiratory Gases
2.1.4 Nonprotein Nitrogenous Molecules
2.1.5 Plasma Proteins
2.1.7 Other Molecules
2.1.8 Summary of Molecular Transport
2.2 Cellular Transport
2.2.1 Leukocytes and Stem Cells
2.2.4 Summary of Cellular Transport
2.3 Ciliary Distribution Subsystem
2.3.1 Description of the Cilium
2.3.2 Ciliary Subsystem Requirements
2.4 Docking Bays and Cellulocks
2.4.1 Docking Bays for Tankers
2.4.2 Cellulocks for Boxcars
2.4.3 Container Routing and Identification
2.4.4 Potential Transport Bottlenecks
126.96.36.199 Water Absorption and Elimination
188.8.131.52 Glucose Absorption and Elimination
184.108.40.206 Boxcar Clearance in Narrow Capillaries
220.127.116.11 Tanker Monolayer Transport
2.5 Mobile Vasculocytes
2.6 Appliance Power Requirement
Preliminary Thermal Conductivity Analysis
Biocompatibility of Vasculoid Systems
Interaction with Vascular Endothelium
4.1.1 Modulation of Endothelial Phenotype and
4.1.2 Vascular Response to Stenting
4.1.3 Nanorobotic Destructive Vasculopathies
18.104.22.168 Nanorobotic Ulcerative Vasculopathy
22.214.171.124 Nanorobotic Lacerative Vasculopathy
126.96.36.199 Nanorobotic Concussive Vasculopathy
4.1.4 Mechanical Interactions with Glycocalyx
Interruption of Plasmatic Water and Lymphatic Flows
of Angiogenesis and Vasculogenesis
Patency and Relaxation
Control Systems and Computational Requirements
Overall System Reliability
Hypothetical Vasculoid Installation Scenarios
7.1 Cellular Ischemispecific Limits
7.2 Patient Preparation
7.3 Vascular Washout
7.4 Vascular Plating
7.6 Initialization and Cold Start
7.7 Vasculoid Removal
7.8 Aggressive Installation Scenario
Vasculoid Optional Equipment
8.1 External Ports
8.2 Thermal Comfort Subsystem
8.3 Internal Caching
8.4 Breathing in Low-Oxygen Environments
8.5 Lymphovasculoid and Pathogen Disposal
8.7 Active Thermal Damage Suppression
Active Resistance To Mechanical Damage
This paper reports the very preliminary technical examination of an
idea originally referred to as “roboblood” that was first proposed
by one of the authors (C. Phoenix) in June 1996 . The concept
stimulated informal interest in a particularly aggressive
nanomedical design and elicited considerable online popular
discussion on sci.nanotech and elsewhere. The need for a detailed
technical analysis soon became apparent, which led to an
intermittent but constructive collaboration between R. Freitas 
and C. Phoenix during 1996-2002, culminating in the present work.
This paper is not intended to represent an actual engineering design
for a future nanomedical product. Rather, the purpose here is
merely to examine a set of appropriate design constraints, scaling
issues, and reference designs to investigate whether or not the
basic idea of a blood replacement appliance might be feasible, and
to determine key limitations of such designs. The reader also is
warned that, in order to maintain tight focus, this paper
necessarily ignores many possible future nanomedical practices and
augmentations to human cellular, tissue, and organ systems that
would clearly be accessible to a molecular manufacturing
nanotechnology capable of building the vasculoid appliance, and
which might significantly influence vasculoid architecture, utility
or the advisability of its use.
1.1 The Vasculoid Concept
The idea of the vasculoid
originated in the asking of a simple question: Once a mature
molecular nanotechnology becomes available, could we replace blood
with a single, complex robot? This robot would duplicate all
essential thermal and biochemical transport functions of the blood,
including circulation of respiratory gases, glucose, hormones,
cytokines, waste products, and all necessary cellular components.
The device would conform to the shape of existing blood vessels.
Ideally, it would replace natural blood so thoroughly that the rest
of the body would remain, at least physiochemically, essentially
unaffected, but sustained in a cardioplegic state. It is, in
effect, a mechanically engineered redesign of the human circulatory
system that attempts to integrate itself as an intimate personal
appliance with minimal adaptation on the part of the host human
A robotic device that replaces
and extends the human vascular system is properly called a “vasculoid,”
a vascular-like machine. But the vasculoid is more than just an
artificial vascular system. Rather, it is a member of a class of
space- or volume-filling nanomedical augmentation devices whose
function applies to the human vascular tree. The device is
extremely complex, having ~500 trillion independent cooperating
nanorobots. In simplest terms, the vasculoid is a watertight
coating of nanomachinery distributed across the luminal surface of
the entire human vascular tree. This nanomachinery uses a ciliary
array to transport important nutrients and biological cells to the
tissues, containerized either in “tankers” (for molecules) or
“boxcars” (for cells). The basic device weighs ~2 kg and releases
~30 watts of waste heat at a basal activity level and a maximum of
~200 watts of power at peak (e.g., Olympic sprint) activity level
(Section 2.6). The power dissipation of the human body ranges from
~100 watts (basal) to ~1600 watts (peak) (, Section 6.5.2), so
the device presents no adverse thermogenic consequences to the
user. The appliance is powered by glucose and oxygen, as may be
common in medical nanorobotic systems [2-11].
The most important basic
structural component of the exemplar vasculoid robot (Table 1) is a
~300 m2 two-dimensional vascular-surface-conforming array
of ~150 trillion “sapphiroid” (i.e., using sapphire-like building
materials) basic plates. (Thermal conductivity favors
sapphire over diamond; Section 3.) These square plates are
nanorobots that cover the entire luminal surface of all blood
vessels in the body, to one-plate thickness. Each basic plate is an
individual self-contained nanorobot ~1 micron thick and ~2 micron2
in surface area, a size small enough to allow adequate clearance
even in the narrowest human capillaries. Molecule-conveying “docking
bays” (Section 2.4.1) comprise ~24 trillion, or 16%, of all
vasculoid basic plates. Tankers containing molecules for
distribution can dock at these bays and load or unload their cargo.
Cell-conveying “cellulocks” (Section 2.4.2) are built on
“cellulock plates” which span the area of 30 basic plates, or 60
micron2 each. Boxcars containing biological cells
for distribution can dock at these cellulocks and load or unload
their cargo. With only 32.6 billion cellulock plates in the entire
vasculoid design, cellulocks occupy the area of 0.978 trillion basic
plates or only 0.65% of the entire vasculoid surface. The remaining
~125 trillion basic plates are reserved for special equipment
(Section 8) and other as-yet undefined applications. All
nanomachinery within each plate is of modular design, permitting
easy replacement and repair by mobile repair nanorobots called
vasculocytes (Section 2.5).
Table 1. Number, Mass and Volume of
Exemplar Vasculoid System Components
24 x 1012
0.0326 x 1012
125 x 1012
166.2 x 1012
166.2 x 1012
0.032 x 1012
0.032 x 1012
0.200 x 1012
2.000 x 1012
0.5 x 106
16.3 x 1012
500.0 x 1012
(items in parens are already included in storage
Adjacent plates abut through
flexible but watertight mechanical interfaces on metamorphic bumpers
along the entire perimeter of each plate (some details are in ,
Section 5.4). Each bumper has controllable variable volume,
permitting the vasculoid surface: (1) to slightly expand or
contract in area, or (2) to flex, either in response to macroscale
body movements (Sections 7.4, 7.6, and 8.2) or in response to
vascular surface corrugations or other irregularities to the same
degree or better than the natural endothelium. Thus, plated
surfaces readily accommodate the natural cyclical volume changes of
various organs such as lung, bladder, or spleen. Rigidity of the
plate array is also subject to engineering control and to localized
real-time control as well, via the bumpers; diamondoid or sapphire
plating may be made substantially stiffer than natural endothelium,
if desired. The rupture strength of individual plates is ~40,000
atm (, Eqn. 10.13, taking plate wall thickness twall ~
0.1 mm, effective radius R ~ 0.5 mm, and working stress sw
~ 1010 N/m2 (, Table 9.3)). Bumper
actuation power is of order ~0.1 pW (, Section 5.3.3), comparable
to the power draw of a single plate cilium (Section 2.3.1).
1.2 Some Benefits of Vasculoid Installation
advantages of installing a vasculoid are potentially numerous. Many
of these benefits theoretically could be provided on a temporary or
more limited basis using terabot-quantity doses of considerably less
aggressive bloodborne nanomedical devices. However, the vasculoid
appliance simultaneously provides all benefits on an essentially
permanent and whole-body basis. Additionally, some benefits appear
unique to the vasculoid and can be achieved in no other way.
Whether the entire package is sufficiently attractive to warrant
installation will probably be a matter of personal taste rather than
of medical necessity, since a molecular nanotechnology capable of
building and deploying a complex vasculoid is likely to offer
complete non-vasculoid cures for most circulatory and blood-related
disorders that plague humanity today, and biological enhancements
may also be available. The choice between an augmentation
technology that works alongside a natural system (e.g., respirocytes
) and an augmentation technology that entirely replaces a natural
system (e.g., vasculoid) may involve significant safety,
psychological, and even ethical considerations.
most important benefits of vasculoid installation may include:
Exclusion of parasites, bacteria, viruses, and metastasizing cancer
cells from the bloodflow, thus limiting the spread of bloodborne
disease. Such microorganisms and cells are easily eliminated from
the blood using ~cm3 doses of appropriately programmed
nanobiotics [2-4], but such individual nanorobotic devices might not
normally be deployed on a permanent basis. Intracellular pathogens
that can infect motile phagocytic cells (e.g., the tuberculosis
Mycobacterium or the bacterium Listeria, both of which
can reside inside macrophages ) cannot be directly excluded from
the tissues when infected cells are transported by the vasculoid.
However, cell surface markers will often reveal such infection, so
vasculoid systems can check for the presence of such markers and
thus deny these cells re-entry to human tissues. For example, the
membrane surface of macrophages infected by Mycobacterium microti
is antigenically different from that of uninfected macrophages ;
Listeria-derived peptides are found acting as integral membrane
proteins in the plasma membrane of infected macrophages , and
other Listeria-infected antigen-presenting cells display
hsp60 on their plasma membranes only when infected . Note that
the natural bacterial inhabitants of the human gastrointestinal
tract should be relatively unaffected by the installation of a
vasculoid appliance, since gut microbes normally do not enter the
bloodstream; similar considerations apply to the natural microbial
flora of the skin, mouth, nasal passages, and so forth. The
vasculoid could also significantly reduce the prospect of death by
cancer by refusing either to transport angiogenesis factors (in
certain cases; Section 4.6) or to transport nonvalidated native stem
cells* (thus preventing metastasis), or by refusing to install
itself in any capillaries arising in locations where angiogenesis is
disallowed in an adult body.
(2) Faster and more reliable trafficking of
lymphocytes throughout the secondary lymphoid organs , allowing
them to survey for targeted antigens in minutes or hours, rather
than days (because both white cells and antigenic sources can be
efficiently concentrated), thus greatly speeding the natural immune
system response to foreign antigen. This lymphocyte function might
also be augmented or replaced using individual histomobile medical
nanorobots  or biorobots. If biorobots are developed first, many
vasculoid installations might take place in patients possessing
largely artificial immune systems, thus obviating the need for much
of the cellular component trafficking described in Section 2.2.
Eradication of most serious circulatory-related pathological
conditions including all vascular disease (e.g., aortic dissection,
vessel blockages, spasms, aneurysms, phlebitis, varicose veins),
heart disease, syncope (including orthostatic hypotension) and
shock, strokes, and bleeding, due to the elimination of
unconstrained metabolite and fluid circulation. Certain other
conditions due to localized prevention of blood flow such as
bedsores** and subclinical paresthesias*** (e.g., “pins-and-needles”
sensation) can also be ameliorated, since stiffened blood vessels
will not be nearly so easy to close via external compression.
Again, many of these conditions may already have adequate
nanomedical treatments by the time the vasculoid can be built, but
other conditions might not yet be readily or as conveniently
treatable, such as the dangers of large-scale bleeding (both
internal and external). Mechanical biocompatibility issues are
discussed at length in Section 4.1.
(4) Reduced susceptibility to chemical, biochemical,
and parasitic poisons of all kinds, including allergenic substances
in food, air and water, although bloodborne nanotankers or
pharmacytes [3, 4] may be able to partially duplicate this function
as well. Note that toxins, novel metabolites or other unknown
foreign substances may arrive in the tissues via solvents
penetrating the dermis (e.g., DMSO) or by other nonvascular routes,
and would be removed from the natural blood in due course by the
kidney which extracts all small molecules by default, then actively
reabsorbs only useful molecules such as glucose, electrolytes,
vitamins, and water. By contrast, in the present design the
vasculoid transports only recognized substances. Novel undesired
substances must therefore be removed by employing a small number of
previously unallocated applications plates: (a) as miniature
analytical laboratories which can detect foreign analytes and alter
a programmable binding site (, Section 188.8.131.52) to bind them,
allowing transport to the kidney for disposal; (b) as miniature
chemical processing systems, possibly involving well-designed sets
of artificial digestive enzymes , which can break down the
foreign substance into well-recognized simpler substances; or (c)
as analytical laboratories or chemical processing systems previously
described which can receive appropriate new instructions directly
from the patient, the physician, or other external sources of
information. The lymphatic system is unmodified in the basic
appliance design and may also serve to remove nonvascular toxins.
Processing of such toxins may be deferred to the points where the
lymph is reabsorbed into the vasculoid system, using either
dedicated application plates or specialized processing stations
(5) Faster metabolite transport and distribution,
significantly improving physical endurance and stamina, including
the ability to breathe at low O2 partial pressures
(Sections 8.3 and 8.4) and the ability to flush out unwanted
specific biochemicals from the body (a feature which might be
duplicated using bloodborne respirocyte-class devices [3-6]). The
architecture would also permit convenient long-term storage of
protein (Section 2.1.5), or amino acid recovery and recycling
(Section 8.1), which could prove nutritionally useful. As another
example, an installed vasculoid could mitigate the effects of
weightlessness or acceleration on nutrient transport and somatic
fluid distribution by decoupling transport from gravity. The
appliance can differentially control the release of water and
electrolytes in various regions of the body. In addition, by making
the transport function independent of gravity, vasculoid avoids the
hydrostatic effects of extreme, varying, or absent gravity vectors.
This would eliminate the facial puffiness seen in astronauts and the
dependence of fighter pilots on external prostheses to force blood
out of the legs during high-G maneuvers.
Direct, rapid user control of many hormonal- and
neurochemical-mediated, and all blood-mediated, physiological
responses. It would be difficult (though not impossible) to provide
equivalent comprehensive whole-body physiological control using
individual micron-scale bloodborne nanorobots alone. Additionally,
the appliance can continuously monitor the basic physiochemical
status of vascularized tissues to near-micron resolution if
necessary, since each micron-size plate is initialized with its
physical position relative to the vascular tree (Section 7.6), and
medically relevant information is communicated back to a central
user (or physician) interface. This can permit extremely rapid and
specific detection of health problems  as will generally be the
case in nanomedicine (, Section 1.3.3(8)), although the vasculoid
may provide an easier and more thorough method for accomplishing
Voluntary control of capillary conductance and rigidity permitting
conscious regulation of thermal energy exchange with the environment
(Sections 8.2 and 8.7) and at least limited control of whole-body
morphological structure, rigidity (e.g., stiffness, bending modulus,
etc.), and volume with ~millisecond response times (Section 8.8).
At least partial protection from various accidents and other
physical harm (e.g., insect stings, animal bites, collisions, bullet
or shrapnel penetrations, falling from heights) which may be
described in a future paper (Sections 8.3-8.8). This is perhaps the
only specific benefit of the vasculoid appliance that could not be
achieved by any less radical means: extreme trauma resistance,
especially resistance to exsanguination and cushioning against
Medically oriented readers might properly wonder why
anyone would want to discuss replacing a perfectly functional
natural fluid transport system with an untested, complex,
artificial, dry system with which humans have no experience today.
There are several answers to this very good question. First of all,
medical skeptics should bear in mind that the vasculoid appliance is
clearly a highly sophisticated medical nanosystem. It cannot be
built without using a manufacturing system based on a mature
molecular nanotechnology. Its use would come only after many
decades of previous engineering experience in building, testing, and
operating such highly complex systems inside the human body. In the
future nanomedicine-rich milieu in which it would be deployed, the
vasculoid as a medical intervention may be closer to the typical
than to the extreme (as it might appear today). It is as if we were
looking forward from the limited vantage point of the 1950s – a
technological era in which vacuum tubes still reigned supreme – to
the year 2002, and estimating the future feasibility of a 1 GHz
Pentium III laptop computer (a feat of prognostication actually
achieved by Sir Arthur C. Clarke ).
In the nanomedical era, it will be a matter of
personal preference and choice for each patient, in consultation
with their physician, whether the aforementioned benefits of the
vasculoid appliance are worth the risks. This paper is only a
preliminary scaling study intended solely to investigate whether the
machinery involved will fit in the allotted space, perform all
required functions fast enough to be useful, operate within an
acceptable energy budget even at peak loads, promise a strong
likelihood of being safe, reliable, and biocompatible, and so
forth. We turn now to a more detailed
discussion of the vasculoid design which includes a consideration of
molecular and cellular transport (Section 2), thermal conductivity
(Section 3), biocompatibility issues (Section 4), control and
computational requirements (Section 5), system reliability (Section
6), a possible vasculoid installation procedure (Section 7), and a
few of the more obvious alternatives for optional equipment (Section
* R. Bradbury notes that the
genetic dysregulation which occurs as cancer cells develop makes it
highly unlikely that they could masquerade as legitimate stem cells
or the other cells that require vasculoid transport. As a stopgap,
the vasculoid could refuse to transport more than a specified number
of suspicious cells per unit time, thus at least limiting the rate
of growth of such misprogrammed cells.
Bedsores can also occur in response to increased extravascular
pressure, and these cases might still occur, though perhaps less
easily, even with vasculoid.
*** Most clinically significant paresthesias are due to neuropathy
or cerebral dysfunction, and thus would not be prevented by
2. Physiological Materials Transport
outlined below, at peak average male human metabolic rates, ~5400 cm3
of circulating blood transports up to ~125 cm3 of
essential molecules and up to ~90 cm3 of essential
cellular elements (excluding erythrocytes; see Section 2.2.3).
Consequently ~96% of blood volume (mostly water) may be rendered
superfluous if its solvation* and suspension functions can be
replaced with a more efficient and highly reliable nanomechanical
Many alternative transport mechanisms were reviewed and rejected by
the authors.** The resulting baseline vasculoid device conveys
physiologically useful molecules and cells throughout its interior,
and thence to the biological tissues, by containerizing all
materials and then using a ciliary transport system to distribute
the containers to appropriate destinations. This architecture thus
utilizes the fractal branching vascular network that is
characteristic of efficient fluid transport systems , although
many architectures are possible in this design space.*** Section
2.1 describes molecular transport requirements; Section 2.2
describes cellular transport requirements. Descriptions of specific
subsystems follow, including the ciliary distribution system
(Section 2.3), docking bays and cellulocks (Section 2.4), and mobile
vasculocytes (Section 2.5).
Some solvent water is still required for limited purposes, as, for
example, to facilitate the mobility of soluble substances such as
glucose (Section 2.1.3) and to avoid irreversible denaturation of
certain proteins and other substances if solvation shells are
stripped before transport.
For example, molecule transport via simple open conveyor belts (the
original “roboblood” proposal) was rejected for energetic and
volumetric inefficiency, unreasonable glucose replenishment times
after strenuous activities, circuit complexity, and susceptibility
to breakage, contamination, leakage, tangling, and difficulty of
repair following exposure to anticipated emergency physical
stresses. Palletized conveyors have many similar problems.
Containerized transport along fixed tracks is more energy efficient
per molecule transported but has comparable safety risks and failure
modes, and has greater difficulty accommodating the aortic
bottleneck. Pressurized transport via diamondoid or sapphire
micropipes (of radius R at pressure P) is energetically efficient.
However, volumetric flow rate scales as PR4, so reducing
flow rate by 90% (allowing for some solvent) only reduces R by 45%,
seemingly not much improvement over natural plumbing (increasing P
is similarly ineffective) and still possessing many of the
deficiencies of the natural system (e.g. interior flooding upon
micropipe rupture, difficulty of repair, carrier fluids or larger
bore pipes required for lipids and blood cell components) which it
was desired to avoid. (An in vivo P > 1000 atm gas/fluid transport
system would introduce many unacceptable risks.) Linked or tethered
containerized transport through micropipes, diffusion-based
mechanisms, vacuum-ballistic and electrostatic transport systems
also were considered and rejected.
*** M. Krummenacker suggests a “vasculoid-lite” approach in which
the device interior is filled with saline solution instead of gas or
vacuum, and the key function of the appliance is to control
pathogens and to route gas containers and repair nanorobots to
wherever needed using a network or grid of tough fibers placed along
the vascular walls (in the manner of a railroad) for such
navigation, and perhaps replacing bulky blood components such as
erythrocytes and leukocytes with more efficient nanorobotic versions
such as respirocytes  and microbivores .
2.1 Molecular Transport
natural human physiology, the circulating blood moves ~2 x 1026
molecules/sec. However, most of these molecules are solvent water
not strictly necessary in human metabolism. In the vasculoid, all
non-cell materials transport takes place via ciliary transport of
tanker vessels at a very conservative mean transport velocity of 1
cm/sec. (For comparison, blood velocity in the natural vasculature
ranges from 0.02-0.15 cm/sec in the capillaries up to 117.5 cm/sec
pulses in the femoral artery (, Table 8.1).) Tanker vessels are
(1-micron) 3 mostly-sapphire (possibly chamfered) cubes
with 0.75 micron3 useful interior storage volume and ~8 x
10-16 kg dry mass. Gases are stored in tankers at 1000
atm pressure [5, 6]; this is highly conservative, as a sapphire
pressure vessel should easily withstand ~105 atm without
bursting . Liquids and solids are packed at normal macroscopic
densities. All tanker mechanical subsystems (other than passive
hull) have at least tenfold redundancy, hence are extremely reliable
(Section 6). Tanker docking bays are described in Section 2.4.1.
following is an approximate inventory and assessment of the minimum
human physiological molecular transport requirement.
2.1.1 Respiratory Gases
The human body consumes 1-20 x
1020 molecules/sec of O2, depending on
activity level . Similar numbers of CO2 molecules are
generated as waste products. The human red blood cell mass (~2.4
liters of RBCs) has a total storage capacity of 3.2 x 1022
O2 molecules, but since hemoglobin operates between
70%-95% saturation in normal physiological conditions, the active
capacity of human blood is only 8.1 x 1021 O2
molecules. Blood CO2 capacity is roughly the same, and O2/CO2
are loaded/unloaded reciprocally at lungs and tissues. Packing
density of CO2 molecules (1.11 x 1028
molecules/m3) is slightly lower than for O2
molecules (1.26 x 1028 molecules/m3) at 1000
atm, so CO2 packing density controls respiratory tanker
Assuming a mean circulatory
circuit of ~1.4 meter and a 1 cm/sec transport speed, continuous
transport at the maximum 20 x 1020 CO2
molecules/sec rate requires a circulating fleet of 33.6 trillion
respiratory gas tankers. At normal basal metabolic rates, only 1.68
trillion active tankers are required; the remainder are held in
reserve to support periods of more intense physical activity. Each
tanker can hold 9.48 x 109 oxygen molecules or 8.36 x 109
molecules of carbon dioxide at 1000 atm pressure. Highly efficient
reciprocal regenerative energy recovery is assumed during gas
loading and unloading operations (Section 2.4.1), and unrecoverable
gas compression energy losses should be minimal. Isothermal
compression of ~1010 O2 or CO2
molecules requires - Pi Vi ln(Vf/Vi)
~ (105 N/m2) (0.75 x 10-18 m3/tanker)
ln(1/1000) = 0.5 pJ/tanker. Assuming a need for 2 x 1020
molecules/sec for O2 and CO2 at basal demand
implies ~2 x 1010 tanker fills/sec or ~0.01 watt for both
sets of gases, or up to ~0.2 watts at peak demand, for compression
Conservatively taking the CO2
concentration in the vasculoid-endothelium interface fluid as equal
to the normal CO2 venous plasma concentration of C =
0.45-1.14 x 1024 molecules/m3 (, Appendix
B), then the diffusion limit for loading CO2 from the
tissues to one side of a square plate area of L2 = 2
micron2, with the diffusion coefficient D = 1.9 x 10-9
m2/sec for CO2 at 310 K (, Table 3.3), is J
= (4/p1/2) LDC = 2.7-6.9 x 109 molecules/sec
(, Section 3.2.2); a 10-second fill time (Section 2.4.1) allows
system operation at about one order of magnitude below the diffusion
limit. Similarly, normal alveolar partial pressure of O2
is >100 mmHg , or C ~ 3.1 x 1024 molecules/m3;
taking D = 2.0 x 10-9 m2/sec for O2
at 310 K (, Table 3.3), the diffusion limit for loading oxygen at
the lungs is J ~ 2 x 1010 molecules/sec, which again
allows system operation at about one order of magnitude below the
diffusion limit assuming a 10-sec tanker fill time.
Tankers are used to transport
O2 and CO2, rather than the vasculoid interior
in part because the theoretical rupture pressure (, Eqn. 10.14)
of the natural cylindrical aorta is pmax ~ 1 atm (taking
aortic wall thickness twall = 1.5 mm (, Table 8.1),
aortic radius R = 12.5 mm (, Table 8.1), and working stress sw
~ 106 N/m2 (, Table 9.3)) and the rupture
pressure of the vasculoid plate coating is pmax ~ 8 atm
(taking vasculoid plate tube thickness twall = 1 micron,
tube radius R = 12.5 mm (, Table 8.1), and working stress sw
~ 1010 N/m2 (, Table 9.3)). At peak
exertion levels, respiratory gases stored in the tanker fleet at
1000 atm would fill the 4.2 liters of free vasculoid internal volume
to 3.2 atm of pressure, too high for reliable safe operation under
all foreseeable circumstances. By comparison, the rupture strength
of individual tankers exceeds ~40,000 atm (the rupture strength of
individual plates; Section 1.1).
human body excretes 6-12 x 1020 molecules/sec of urinary
water under normal circumstances [3, 4]. The kidney continuously
filters ~18 gallons/hour of blood (~7 x 1023 H2O
molecules/sec) so much higher rates of urine generation are possible
in theory, but it seems unnecessary to accommodate the vasculoid
design to such extreme cases because the removal of waste molecules
can be accomplished by direct molecular sorting rotor extraction
rather than by bulk filtration and solvent repumping – that is, the
principle blood-cleansing function of the kidneys is to pump
nonaqueous molecules, not bulk water solvent molecules [20, 21].
With the vasculoid in place, only specific waste molecules and
minimal quantities of carrier water need be discharged into the
glomeruli of the ~106 nephrons of the kidney, with the
result that gross water flows through the kidney and energy
consumption in this biological organ can be significantly reduced
 – but not reduced so far as to induce urinary stone disease
 (urinary lithiasis  or urolithiasis ) or renal
cytotoxicity from excessive pH , salinity (e.g., hyperosmotic
stress) [27, 28], or toxin concentrations . The precise volume
and concentration of urine generated by the biological organ is
regulated by hormones that control kidney function [21, 30-34], and
these hormones may in turn be regulated by the vasculoid appliance.
Additionally, 2-186 x 1020 molecules/sec of water are
perspired through the skin, depending upon air temperature,
humidity, activity level and mental state [3, 4]. Assuming the same
transport parameters as before, the maximum requirement of 2.0 x 1022
H2O molecules/sec (~0.6 cm3/sec) requires
110.5 trillion water tankers to be available, of which only 4.5
trillion will normally be active with the rest held in reserve for
periods of peak exertion. Each tanker can hold 2.51 x 1010
water molecules in the liquid state.
Typically 1.6 x 1022 molecules of glucose are present in
the human bloodstream . A human on a standard 2000 kcal/day diet
metabolizes 3.08 x 1019 glucose molecules/sec throughout
the body. However, during strenuous exercise this requirement can
briefly rise to as much as 33,000 kcal/day, a 4.93 x 1020
molecule/sec rate. Assuming the usual ciliary transport parameters,
we require 17.6 trillion glucose tankers, providing storage of 6.91
x 1022 glucose molecules in the system, four times the
number present in normal blood. (Slightly smaller capacity might be
realized if the glucose must be stored as a 70% aqueous solution
concentrate to facilitate molecular mobility for sorting rotors
(e.g., , Section 184.108.40.206(B)).) Only 1.1 trillion glucose tankers
are needed to service basal metabolic needs; the remainder are held
in reserve for periods of extreme physical activity.
average human cell is a ~30 picowatt (basal) device, so each glucose
tanker, with its full complement of 3.93 x 109 glucose
molecules, yields ~400 basal cell-seconds of energy (assuming 65%
efficiency for the natural cellular metabolic pathways using
glycolysis and tricarboxylic acid cycles ). Note that at higher
power levels, the delivery rate increases correspondingly (Section
2.4.1), so that even with random delivery at peak demand all cells
should receive a sufficient fuel supply. Additionally, the average
tissue cell normally contains an internal inventory of ~3 x 1010
glucose molecules (Section 7.1), an in cyto buffer supply equivalent
to ~8 full tanker loads.
2.1.4 Nonprotein Nitrogenous Molecules
Normal bloodstream concentrations  of urea, uric acid,
creatinine, creatine, ammonium salts, cerebroside, amino acids, etc.
imply 1.73-2.49 gm present in the circulation and a maximum of 2.3
trillion tankers for full encapsulation and transport.
2.1.5 Plasma Proteins
All plasma proteins including
most notably albumen, globulins (including antibodies), complement,
fibrinogen and prothrombin constitute ~7% of adult blood plasma, or
210 gm, which would require 215 trillion tankers to encapsulate.
Fortunately, on a transactional basis this figure is a gross
overestimate. The RDA (Recommended Daily Allowance) active
requirement for protein is ~70 gm/day for a 70-kg male human, an 8.1
x 10-7 kg/sec transport demand requiring only 0.12
trillion protein tankers for continuous ciliary transport, reducing
mandatory instantaneous system storage capacity to ~0.12 gm of
plasma proteins. However, almost the entire RDA protein intake is
hydrolyzed to amino acids and dipeptides, so the actual protein
transport needs should be far less. With no need to maintain
osmotic pressure, there would be almost no reason to transport
albumin within the system, although the dosage of protein-bound
medication and hormones might need to be corrected. Finally, there
is sufficient tanker capacity to increase protein transport capacity
at least 100-fold above the RDA requirement if necessary, so the
design is not particularly sensitive to this transport requirement.
Note also that the five
antibody classes can be efficiently transported using just five
types of sorting rotors having binding pockets complementary only to
the constant Fc regions without regard to the numerous variable
domains these antibodies may encode on their antigen-binding Fab
regions, thus vastly reducing the required vasculoid rotor
specificities needed to accomplish this task. Complement (immune
system) components may be transported with similar efficiency.
The limited free enzyme
activities that occur in natural blood can still take place in the
fluids at the vasculoid-endothelial interface, with due care taken
to avoid inducing localized hyperenzymemia  (which is often
benign, as in hypertransaminasemia [37, 38]), although higher
concentrations may be expected because of the lower total volume of
the vasculoid-endothelial interface compared to the natural blood
mass of lipids including fatty acids, cholesterol, triacylglycerides
(transported in the plasma lipoproteins as triacylglycerols), and
phospholipids present in the human bloodstream totals roughly 35-42
gm , which would require 55-66 trillion tankers to encapsulate.
However, the RDA for fat is 23% of caloric intake. (Many people
consume several times this amount, but others survive on fat-free
diets, so the figure represents a reasonable compromise estimate of
the typical human active requirement.) This implies a demand of 6.9
x 10-7 kg/sec for a 2000 kcal/day diet, requiring only
0.15 trillion lipid tankers for continuous ciliary transport and
reducing the required vascular storage capacity to ~0.1 gm. As with
plasma proteins, there is sufficient tanker capacity to increase
lipid transport capacity to at least 100 times the RDA requirement,
so once again the design is not particularly sensitive to this
2.1.7 Other Molecules
Human blood plasma contains ~40 gm of salts (e.g., electrolytes)
including sodium, potassium, calcium, magnesium, chloride,
phosphate, and sulfate; ~1.2 gm lactic acid and other
non-nitrogenous waste products; ~0.23 gm of RNA and DNA; ~0.21 gm
of enzymes (protein); ~0.15 gm testosterone in the male, ~0.03 gm
progesterone in the female, ~0.02 gm of corticosteroids, and a total
of ~0.002 gm of more than fifty other major biologically active
hormones; ~0.04 gm of vitamins including A, B2, niacin, pantothenic
acid, biotin, pteroylglutamic acid, choline, inositol, C, D, and E;
~0.03 gm of essential trace elements including iron, zinc, copper,
manganese, iodine, and cobalt; and smaller masses of various
cell-signaling (e.g., cytokines, autocrines, neuropeptides) and
numerous other specialty proteins . Other nonprotein regulatory
molecules affecting numerous signaling pathways must also be locally
regulated with precision by the vasculoid appliance. For example,
in the present context the simple molecule NO is of particular
importance as a neurotransmitter and vasoconstrictor [39, 40],
though it is normally present only in exceedingly small quantities.
Other molecules that mediate certain regulatory pathways may become
unnecessary to transport after the vasculoid is installed, as for
example the renin-angiotensin pathway (since there is no blood
pressure to regulate).
capacity demand totals ~42 gm, which would require ~43 trillion
tankers for full encapsulation. However, the RDA for all minerals,
electrolytes, vitamins and trace elements is just 6.8-16.1 gm/day
for healthy adults, a maximum of 1.87 x 10-7 kg/sec,
requiring only 0.03 trillion tankers assuming ciliary transport
parameters as described above. (Sodium and potassium ion transport
in individual neurons is ~106 ions/discharge; assuming
~1010 active neurons firing at near-maximum ~100 Hz,
whole-brain ion transport rate is ~1018 ions/sec or ~7 x
10-8 kg/sec, well within the aforementioned mass flow
budget for mineral and electrolyte transport. However, Na+
and K+ are very quickly recycled after each discharge, so
the true transport requirement is more accurately measured by the
small amounts of these electrolytes that are lost in the gut, sweat,
and lymph.) Transport of lactic acid, RNA/DNA, enzymes (e.g., those
present as a result of normal tissue breakdown such as CPK and
transaminases), hormones, cytokines and so forth (~1.8 gm) requires
1.9 trillion additional tankers. In some cases these “other”
molecules may be shipped mixed in a single container (Sections 2.4.1
2.1.8 Summary of Molecular Transport
total of 166.2 trillion tankers are required to transport
all-important physiological molecules at maximum human metabolic
rates. At basal metabolic rates, only 11.78 trillion tankers will
typically be active. If, contrary to our assumption, RDA levels are
found to be an inadequate substitute for natural blood storage of
plasma proteins, lipids, minerals and vitamins, or if production and
demand occur at different times and the blood volume performs a
significant storage function, then vasculoid design may need to
include up to ~300 cm3 of auxiliary bulk storage or
caching (Section 8.3) to extend the “just in time” inventorying of
these vital substances.
2.2 Cellular Transport
addition to conveying molecules, the vasculoid must also transport
physiologically important cellular species throughout the body.
Cells to be transported (comprised mainly of white cells, platelets,
and the few remaining red cells) generally range in size from 2-20
microns . These are shipped in cylindrical mostly-sapphire
“boxcars” 100 microns long and 6 microns in diameter. These
containers, of which 75% (2120 micron3) is usable storage
volume (~2.4 x 10-12 kg dry mass per boxcar), will just
fit through average-sized capillaries (~8 microns diameter, ~1000
microns in length) and all larger vessels, after accounting for
plate thickness, and thus the boxcars have access to the vast
majority of human tissues. The largest transportable cells
(20-micron monocytes) must be temporarily dehydrated 50% by volume
prior to loading*; such desiccated cells quickly rehydrate by
natural osmosis upon release into the aqueous intercellular
environment. Spherical cells 17.5 microns in diameter or smaller
need not be dehydrated during loading, as they can fit into the
available volume via change of shape. Typical transit time from
point of entry to point of debarkation is ~70 sec (i.e., ~half the
mean circuit length of 1.4 m, at 1 cm/sec; Section 2.3.2), well
within cellular ischemic survival times (Section 7.1) except
possibly for oxygen, which may need slight supplementation during
Onboard computers and sensors embedded in interior boxcar walls
allow the detection and interpretation of surface antigens on
passenger cells to ensure that all transported cells are
non-hostile, and if not, to refuse transport, convey them to a
disposal site (Section 8.5), or destroy them after entry. Boxcar
docking mechanisms (cellulocks) are described in Section 2.4.2, and
small-capillary avoidance is discussed in Section 220.127.116.11.
following is an assessment of the minimum human cell transport
requirement for the vasculoid appliance.
Most mammalian cells can survive the loss of 50% of their water
. Fibroblasts (e.g., mouse L-929 cells) have survived from 45%
 to 65%  decrease in total cell volume (the latter
representing 85% water loss by volume ) via dehydration, and
erythrocytes have survived 73% volume reduction by dehydration
. Alternatively, desiccation for transport may be avoided by
doubling boxcar length, but at the cost of decreased vehicle
mobility, larger turning radius, and so forth – design tradeoffs
that deserve further investigation.
2.2.1 Leukocytes and Stem Cells
Under normal physiological conditions, 27-54 billion leukocytes
circulate in the human blood volume , although in cases of
chronic myelogenous leukemia the total count may increase to
0.13-2.7 trillion white cells . These 54 billion leukocytes
consist approximately of 35-41 billion neutrophils (10-12 microns in
diameter), 11-14 billion lymphocytes (8 microns), 1.6-4.3 billion
monocytes (12-20 microns, average 15 microns), 1.1-2.7 billion
eosinophils (12 microns), and 0.3 billion basophils (10 microns).
Based on maximum container packing densities for each type of cell,
12-28 billion boxcars are required to encapsulate and transport all
normal populations of bloodstream leukocytes. This will frequently
include more than one cell per boxcar – multiple cells should be
sedated for transport (using reversibly rotored molecular agents) to
avoid unwanted interactions such as clonal expansion or induction of
apoptosis. Principal origination sites are the bone marrow, the
spleen, and the lymph nodes, but leukocytes may be distributed to
almost any location in the body. Giant macrophages (e.g. >30
microns) and fibroblasts already present in the tissues (that
normally do not enter the bloodstream) cannot be relocated by the
appliance, although fresh stem cell precursors of fibroblasts with
appropriate activating cytokines can be relocated from their natural
source site, as required.
comparatively small population of circulating stem cells must also
be transported by the vasculoid. For example, vasculogenesis is
assisted by hematopoietic stem cells (surface marker CD34+) that
originate in the bone marrow and enter the peripheral blood in
response to colony stimulating factors, with 1-3% expressing the
common leukocyte surface antigen CD45. Upon reaching the vascular
surface and in the presence of the cytokine IL-3, these cells may
differentiate either into leukocyte precursor (CD34+/CD45+) or into
endothelial precursor (CD34+/CD45-); with the cytokine VEGF
present, the latter cells further differentiate into new endothelial
cells [47, 48]. The vasculoid must provide transport for stem cells
of these and other types, along with the required cytokines, to
ensure vascular repair of damaged endothelium and for other
purposes. Fortunately there are only a limited number of such cell
types, and the total population of stem cells requiring transport is
many orders of magnitude smaller than the population of leukocytes.
As a result, stem cell transport should be a comparatively minor –
if physiologically essential – task for the previously-specified
Although substitution of vasculoid transport for liquid blood
eliminates much of the conventional health risk due to bleeding,
blood vessel breaches that penetrate the endothelium but do not
penetrate the vasculoid will still exude large amounts of
extracellular serous fluid and other critical substances if the
leakage is not promptly staunched.* Furthermore, platelets are
storehouses for a variety of molecules that affect vascular tone,
fibrinolysis (subsequent clot dissolution), and wound healing.
These substances are released during the clotting process.
Platelets also communicate via chemical messengers with other blood
cells (e.g. macrophages and fibroblasts) and with the endothelial
cells that coat the interior of all blood vessels. Hence, platelets
still have an important role in human physiology even after the
vasculoid has been installed.
Approximately 2 trillion platelets (~2 microns in diameter)
circulate in human blood . Each boxcar can hold about 500
platelets, giving a requirement of 4 billion additional containers
for platelet transport. As with white cells, multiple cells could
easily activate and aggregate, hence their function should be
heavily suppressed during transport (again, using reversibly rotored
A more effective response to such a breach might be the release of
activated clotting factors, which are likely more stable during
transport, rather than whole platelets.
the vasculoid, all respiratory gases are transported in bulk and at
high pressure. Boxcars could in principle be used to transport red
cells, but RBCs have an effective storage pressure <<1 atm which is
far less efficient than the 1000 atm storage pressure of the
respiratory gas tankers. Consequently, the ~30 trillion red cells
normally present in the human bloodstream  are superfluous and
may be permanently removed from circulation. Beyond their
respiratory function, red cells also are mechanically involved in
the clotting process. However, the vascular plug typically contains
mostly platelets, plasma fibronectin and factor XIII-crosslinked
fibrin, plus small amounts of tenascin, thrombospondin, and SPARK
(secreted protein acidic and rich in cysteine)  with a
relatively minor RBC contribution, so RBCs probably are not
essential to the clotting process or are necessary only in very
sufficient oxygen concentration maintained in kidney peritubular
cells should reduce erythropoiesis to at most 1% of the normal rate
of red cell production , requiring only ~34,700 red cells/sec to
be conveyed from the erythroid marrow directly to the liver or
spleen for disposal. Alternatively, erythropoiesis can be reduced
by directly regulating the amount of erythropoietin that is allowed
to reach the bone marrow. With few erythrocytes remaining to be
destroyed in the liver, hepatic heme catabolism drops significantly,
greatly reducing the production of bilirubin, a yellow bile waste
pigment that plays no role in fat digestion in the gut but imparts
the brown color to feces; as with hepatitis patients, the stool of
the envasculoided user may become chalky white. Ciliary transport
of boxcars containing the few remaining red cells over a ~1.4 meter
circuit at a conservative mean velocity of 0.1 cm/sec (allowing
plenty of time for docking and cell unloading) requires a
circulating subfleet of just 34.7 million boxcars (only ~0.1% of the
entire boxcar fleet).
2.2.4 Summary of Cellular Transport
maximum of 32 billion boxcars are required to convey all essential
bloodborne cells during normal physiological conditions, although at
times as few as 16 billion boxcars may be actively involved in
cellular transport. Since a principal benefit of vasculoid
installation is a significant decline in susceptibility to microbial
invasion, the above figures can probably be further reduced in
actual clinical practice.
2.3 Ciliary Distribution Subsystem
interior volume of the vasculoid is lined with a sapphire surface
(comprised of watertight adjacent installed plates) from which
protrude trillions of mechanical cilia (, Section 18.104.22.168)
arranged in patterns designed to maximize transport speed and
reliability. A secondary role is to assist the vasculocytes (small
mobile nanorobots; Section 2.5) in cleaning up after accidental
internal spills, component malfunctions, or other pathological
events. Even by 1997 , prototype MEMS ciliary arrays (,
Section 9.3.4) of up to 1024 cilia had already demonstrated
transport speeds up to 200 microns/sec with ~3 micron positional
2.3.1 Description of the Cilium
While a highly efficient specialized ciliary mechanism can
undoubtedly be designed, for the present study each vasculoid cilium
is conservatively assumed to be similar in size, shape, and
performance characteristics to the vacuum-sealed robotic manipulator
arm described by Drexler . In brief, each cilium is a
cylindrical assembly 100 nm long and 30 nm in diameter, having a
transverse travel of 100 nm and a lateral speed of 1 cm/sec,
consuming 0.1 picowatt during continuous operation at low load.
Note that even if the vasculoid interior contained gas at 1 atm,
viscous drag would contribute an additional power loss of only
~0.001 pW per cilium (, Eqn. 9.75, taking viscosity hair
= 1.83 x 10-5 kg/m-sec at 293 K).
Mean cilium/cargo contact time is ~10 microseconds. This implies an
acoustic frequency >100 KHz, well above the conventional human
threshold of hearing; however, ultrasonic hearing up to 108 KHz via
otolithic conduction has been reported in humans , so further
study is required to ensure restriction of transport motions to
sufficiently high frequencies to preclude any perceptible hum
directly due to ciliary operations, and possibly involving a variety
of noise cancellation , anti-resonance (e.g., out-of-phase
operation) and acoustic dampening techniques. Additionally,
physical discomfort , intra-articular pain , and a lowering
of electrical pain sensation threshold  due to ultrasound
exposure have also been reported in humans. The possibility of
indirect audible or infrasonic vibrations due to beat frequencies,
spatial acoustic interference patterns, or various resonances should
be investigated further, along with the possibility of undesired
vibrational energy losses into the tissues.
Each cilium can apply ~1 nanonewton at the tip. This is sufficient
force to accelerate a 1 micron3 block of water (weight
~0.01 piconewton) at 105 G, or a 100-micron long,
6-micron wide water-filled sapphire-shell cylindrical boxcar at ~30
G. The human body is normally subject to accelerations far less
than 30 G; with tenfold grasping redundancy (Section 2.3.2), the
probability that a container will be shaken loose from the cilia and
tumble uncontrolled into the vascular lumen, due to normal
macroscale accelerations of the patient's body, is extremely
remote. In the rare instance where such detachment occurs, the
container will eventually be caught and returned to the flow;
kinetic impact energy in such cases is relatively small. Whether
such cross-luminal impacts can trigger a detachment avalanche should
be investigated using computer simulations.
Changeable cilium tool tips may permit rapid, reversible, “blind”
container grappling using van der Waals adhesive forces, which
forces may be controlled by varying adhesive pad surface
corrugations at the nanometer scale, or by other means. The cilia
might also have a reversing function (e.g., for loosening container
jams). Molecular dynamics simulations of these processes would be
2.3.2 Ciliary Subsystem Requirements
principal task of the ciliary distribution subsystem is to reliably
transport a maximum of 166.2 trillion 1-micron cubical tankers and a
maximum of 32 billion cylindrical 6 mm x 100 mm boxcars through a
physical circuit ~1.4 meters in length. Because of their smaller
size and greater number, ciliary subsystem design is driven almost
entirely by tanker, not boxcar, requirements.
Although a single cilium can apply sufficient force to grapple and
manipulate containers of either size, tenfold grappling is employed
in the baseline design to achieve firm contact, to avoid physical
escape of containers from the cargo traffic stream, to ensure
massive redundancy hence high subsystem reliability, and to allow
extremely precise steering. If a tanker occasionally encounters a
patch of 9-contact cilia, or the even rarer 8-contact patch,
steering or grappling capability should not be significantly
reduced. Fail-safe grappling modes must be designed for cilium
Each tanker is normally in continuous contact with 10 cilia at all
times during transport, so maximum ciliary spacing is 0.32 micron.
A minimum of 3000 trillion cilia are needed to achieve 100% service
over the entire ~300 m2 vascular (mostly capillary)
surface. A set of 3000 trillion cilia physically occupies ~2.1 m2
(~7%) of the vascular surface. Assuming natural background
radiation damage causes 1.5 x 107 fatal hits/kg/sec 
for nonredundant structures, the mean time to failure of a ~10-19
kg cilium is ~1012 sec, which implies a mean failure rate
of only ~2000 cilia/sec (~20 nanograms/day) throughout the entire
vasculoid. Using redundant structures, mean failure rate may be
Under resting metabolic conditions, 11.78 trillion tankers are
transported by 117.8 trillion cilia generating waste heat of ~11.8
watts, an increment of only ~12% over the basal human metabolic
rate. During periods of maximum exertion and thermoregulatory
stress, 166.2 trillion tankers are transported by 1662 trillion
cilia generating excess heat of ~166 watts, well below the maximum
human metabolic rate of 1600 watts and just slightly exceeding the
~100 watt effective load error  that could trigger a response
from the human thermoregulatory control system (, Section 6.5.2).
2.4 Docking Bays and Cellulocks
Once molecules or cells have
been transported to the appropriate site, the container in which
they reside must dock with the vasculoid surface on the interior
side, and pass the delivered materials through this surface to the
interstitial side of the vasculoid wall, whereupon the cargo can
diffuse or migrate into the tissues as required. Tankers offload
their molecular cargo in docking bays (Section 2.4.1) whereas
boxcars unload their cellular passengers at cellulocks (Section
Possible undesired long-term
chemical interactions of transported nutrients discharged into the
fluids of the vasculoid-endothelial interface at above-physiological
concentrations must be carefully analyzed. For example, high
concentrations of glucose akin to chronic hyperglycemia  could
enhance protein glycosylation of long-lived proteins (e.g., vascular
and myocardial collagen) which undergo continual cross-linking
during aging because of the formation of advanced glycosylation
end-products (AGEs) , most significantly (for this paper) in
endothelial cells , which may be partly responsible for arterial
stiffening and higher blood pressure with age (and which drugs like
ALT-711 [58, 59], benfotiamine , nitric oxide  and other
substances may reverse). AGEs can also induce apoptosis and
vascular endothelial growth factor overproduction in capillary
2.4.1 Docking Bays for Tankers
Physiologically relevant molecules are delivered to specific
locations by docking at 2 micron2 (~1.4-micron square)
tanker docking bays embedded at appropriate spatial intervals across
the vasculoid surface. After securely connecting to the docking bay
structure, and after the tanker's cargo manifest is scanned by the
docking bay computer and said cargo is approved for receipt (Section
5), the tanker can be pumped dry by molecular sorting rotors in ~10
seconds, then sealed, remanifested, undocked, and released empty
back into the traffic. Empty tankers may be reloaded with molecular
cargo by a similar process in a similar time. Note that tankers
carrying liquid or gas may discharge their contents into the narrow
end of a funnel-shaped manifold leading to the active rotor banks at
the wider end, to minimize the required tanker connection aperture.
In different operating modes, tankers might be only partially
emptied at each stop, or might be partially emptied more rapidly via
bulk-flow exhausting rather than molecular rotoring. Docking bays
include buffer tanks so that offloaded materials can be metered out
to the underlying tissues over time periods longer than 10 seconds.
the average endothelial cell (of which blood vessel walls are
comprised) has a flat luminal area of 300-1200 micron2
, then the ~300 m2 vascular surface may be comprised
of up to ~1 trillion endothelial cells.* This vascular surface
could theoretically accommodate a maximum of 300 trillion tankers
positioned side by side. At basal metabolic rates, only 11.78
trillion tankers are actively on the move (Section 2.1.8). Even
during peak exertion, a maximum of 166.2 trillion tankers are being
transported, requiring just 55% of the available vasculoid luminal
surface for their passage assuming all tankers are traveling in
monolayer (Section 22.214.171.124). Other functionally equivalent modes
might include operating all tankers at reduced capacity or reduced
duty cycle during periods of basal demand, or reducing the transport
velocity. A detailed computer simulation study of optimal traffic
patterns near peak capacity would be valuable to perform.
maximum of 166.2 trillion tankers circulating through an average
~1.4 meter circuit at ~1 cm/sec implies a docking bay cargo
unloading requirement of ~1.2 trillion tankers/sec. Docks operate
on a 50% duty cycle to allow plenty of time for maintenance and
repair, although in a less conservative design the duty cycle could
possibly be boosted as high as 99% (Section 2.5). Tankers are
emptied in 10 sec, so ~24 trillion docking bays are needed for
reliable operation at peak loads. Docking bays occupy ~16% of the
vasculoid surface and have a mean center-to-center separation of
~3.5 microns. Each endothelial cell is serviced by up to ~24
Normally only a small fraction of the body's tissue cells are
directly bathed in blood. Hence, delivery of molecules to each
endothelial cell surface must be sufficient to supply the needs of
the up to ~30 tissue cells that lie, on average, within ~3 cell
widths of the nearest capillary. The maximum whole-body transport
requirement of 2.25 x 1022 molecules/sec, consisting
principally of respiratory gases, water, and glucose, gives an
endothelial surface mass transport rate of 2.25 x 1010
molecules/sec/endothelial cell. This transport rate may be
satisfied using a minimum of 45,000 molecular sorting rotors (for
description, see [4-7]) per endothelial cell operating on a 50% duty
With 24 docking bays per endothelial cell, the requirement is ~0.94
billion molecules/sec per docking bay. Allowing tenfold
multiplicity of sorting rotors to ensure high reliability (Section
6) requires 18,750 sorting rotors per docking bay, of which only 67
will be active at the basal rate and up to 9375 will be active
during maximum physical exertion; 18,750 sorting rotors measuring
98 nm2 on the ventral surface (facing the endothelium)
 cover 1.84 micron2, essentially coating the entire
undercarriage of the 2 micron2 docking bay facility.
This provides a ~7.5 x 108 molecule/sec supply per tissue
peak metabolic load, maximum molecule offloading rates as
constrained by possible effervescence and crystallescence effects
(, Section 9.2.6) appear acceptable in this application for all
low-volume molecules and for glucose and CO2, but
unfortunately exceed the effervescence limit for O2 by a
factor of ten, due to the relatively poor aqueous solubility of
oxygen. Hence at peak load this gas must be offloaded either ~10
times more slowly than indicated above for a single release site, or
at the indicated flow rate from ten discrete release sites all
spatially separated by more than the largest possible O2
effervescence bubble radius.
simplify rotor system design, there are four classes of docking bays
approximately matching the anticipated four principal tanker
populations. Of the ~24 docking bays overlying each endothelial
cell, ~5 stations are designated to handle tankers carrying
respiratory gases, and possess rotors (on the tissue side) designed
to reversibly bind only oxygen or carbon dioxide molecules. Another
~14 docking bays receive only water-bearing tankers, and employ
rotors specializing in water molecule transport. Another ~3
stations accept only glucose cargoes, and use only glucose sorting
rotors. The remaining ~2 docking bays are general-purpose stations
equipped with rotors of up to tens of thousands of different types
capable of reversibly binding all remaining biologically useful
molecules (or classes of molecules) that must be transported through
the vasculoid surface.**
addition to gas, water, glucose, and specialty tankers, there is a
fifth class called power tankers that support the docking bay
oxyglucose metabolism. Power tankers transport stoichiometric
parcels of oxygen and glucose, and also remove carbon dioxide
byproduct for disposal at the lungs. (Vasculoid power may be
generated by glucose engines, glucose fuel cells, or other energy
conversion devices that consume oxygen and native glucose (,
Section 6.3.4); water produced by glucose engines may be vented
into the biological tissues.) All docking bays can accept power
tankers, which supply the docking bay's own internal energy needs.
Tankers reload their own oxyglucose engines and fuel tanks as they
make their rounds of the various docking bays. Tanker duties are
not energy intensive, so tankers refuel at most once a day, at the
Rotors conveying molecules from tankers (at high concentration)
through the vasculoid integument to the endothelial surface (at low
concentration) generate positive mechanical energy, which may be
used to largely offset the work of concentration that must be
expended to transfer molecules in the reverse direction when loading
tankers from the tissue space. Concentration work losses can be
reduced almost to zero in an efficient system, with systemwide
entropic losses in the compression-expansion cycle as low as
0.01-0.2 watts (Section 2.1.1). Hence the primary energy loss is
the drag power per rotor, ~10-16 watts or ~0.1
zJ/molecule assuming a transfer rate of ~106
molecules/rotor-sec (, Section 13.2.1.e). Taking the whole-body
transport requirement range as 10-225 x 1020
molecules/sec, the net molecular transport power dissipated per
docking bay is thus 0.004-0.09 picowatt depending on physical
exertion level, or 0.1-2.25 watts for the entire vasculoid docking
bay subsystem. (Rotor systems that do not include efficient energy
recovery and must dissipate the work of concentration, perhaps up to
~20 zJ/molecule (, Section 3.4.2), may require a different
hold docking bay subsystem total power requirement for computational
tasks to a 10-watt budget, nanocomputers using an appropriate mix of
local and distributed computing costing ~6 x 10-17
watts/(ops/sec) [4, 7] can provide ~200 billion MIPS systemwide or
~10,000 ops/sec per docking bay (Section 5), costing ~0.6 pW per
docking bay. These rates have been enhanced by employing reversible
logic [4, 7, 64]. Hence the total power per docking bay for both
mechanical and computational tasks ranges from ~0.604 pW (basal) to
~0.69 pW (peak), or 14.5-16.6 watts for the entire system of 24
trillion docking bays. If power is supplied by a glucose engine
achieving mechanochemical power conversion at ~109
watts/m3 [4-7], a 16.6 watt peak energy budget for all
docking bays requires one glucose engine only ~0.0007 micron3
in volume (~0.03% of bay volume), per dock, and a similar volume of
* Cardiac endothelium or
endocardium [65-67] has a somewhat different cell shape and
cytoskeletal organization than vascular endothelium, and differences
in permeability compared to the coronary vascular endothelium.
** This is almost certainly a
significant overestimate of the needed capabilities. For instance,
to reduce the required number of specific recognition devices (and
thus decrease system complexity), R. Smigrodzki suggests using
devices packaging all molecules of a particular size class, plus a
few specific transporters for small ligands. R. Bradbury notes that
heavily multipurpose rotor banks may be needed only at the
capillaries of the intestine and liver. It will soon be known
exactly which hormones are supposed to be delivered at what levels
to specific organs (e.g., insulin going mostly to the muscles and
liver, erythropoietin to the bone marrow, etc.), requiring the
transport of much lower quantities of most of these molecules
because they can be targeted more precisely to the tissues that use
them as signals.
2.4.2 Cellulocks for Boxcars
Biological cells are delivered to specific locations by docking at
cellulock stations embedded at appropriate intervals across the
vasculoid surface, often preferentially located near specialized
post-capillary blood vessels less than 30 microns in diameter found
in lymphoid tissues, commonly known as high endothelial venules
(HEVs) [68-73]. Cellulock density requirements also vary on a
tissue-by-tissue basis – for instance, intestines, lungs, throat and
nasal cavity probably have much higher requirements than heart or
brain. After securely docking with their loading face pressed
firmly against the vasculoid surface, boxcar doors dilate open to
make a 30 micron2 (~6.2-micron diameter circle)
aperture. Cellulock doors (constructed of self-cleaning sliding
spiral graphene segments in snug facial contact) then dilate to the
same diameter, exposing passenger cells to the interstitial fluid.
Passenger cells are gently pistoned out through the opening, taking
care to minimize extracellular fluid entry. The cycle ends as all
doors reseal and the boxcar undocks, resuming its travels.
Biochemical signals of cellular distress (e.g. cytokines such as
interleukin-1 or tumor necrosis factor) are received by sensors on
the interstitial side of the vasculoid. Upon receipt of this
chemical signal, the cilia at that site are programmed to call for
leukocyte activity there. Cellulock and boxcar interiors may employ
a small set of presentation semaphores  which expose to the
interstitial fluid minute quantities of various chemoattractants
[74, 75] and chemorepellents [75-78] keyed to each major type of
cell to be transported. These chemicals are permanently bound to
the rotors and are not released from the vasculoid; like
semaphores, each rotor position may present differing concentrations
of one chemical species, or a selection of different chemical
species. White cells of the type desired to be transported can be
encouraged to enter or exit, as required, by positioning
presentation rotor settings so as to create “chemotactic funnels” –
programmable patterns of varying concentration gradient to steer
motile cells toward, or away from, the cellulock aperture (e.g.,
haptotaxis [79-81]). Contact sensors around the aperture detect the
presence of a motile cell “requesting entry” to the transport
system. Motile cells presenting themselves for entry at the
interstitial side of the cellulock are, at minimum, subjected to a
rudimentary cell protein coat identification test before they are
allowed admittance. Affirmatively recognized harmful foreign
pathogens such as bacteria or viruses and infected native motile
cells may be transported to a specific disposal site or destroyed
(Section 8.5), rather than being admitted freely for transport
elsewhere in the tissues.
cellulock mechanism covers 60 micron2 (~7.7-micron
square) of vasculoid surface. If spiral door segments slide past
each other at 0.004 m/sec over an average of one-half rotation or
~15.4 microns, dilation (or resealing) of the cellulock door takes
3.85 milliseconds. Sliding friction for 16 nm2 contact
surfaces traveling 20 nm at 0.004 m/sec dissipates ~10-24
joules, or ~3.13 joules/m2-meter . Thus ~30 micron2
cellulock sliding door surfaces moving ~15.4 microns to open, then
again to close, require ~3 x 10-15 joules to complete one
dilation cycle. Assuming a maximum rate of 32 billion boxcars per
(normal blood circulation time of) ~60 sec to emulate typical
physiological delivery rates, the population of vasculoid cellulocks
must process a total of 533 million boxcars/sec. If there are
therefore also 533 million cellulock dilation cycles/sec, frictional
waste heat generated by moving door segments in the entire vasculoid
cellulock subsystem is a negligible ~1.5 microwatts. Taking
cellulock power as equal to the basal rate for 30 docking bays gives
a requirement of ~18 pW/cellulock, or ~0.59 watts for the entire
cellulock subsystem. Serum glucose and oxygen to provide cellulock
power (a minor volumetric requirement) may be rotored in directly
from the interstitial fluid on the external side of the vasculoid
Since the active tanker/boxcar ratio varies from 736 (basal) to 5194
(max) depending on metabolic load, there should be no less than one
cellulock per 736 tanker docking bays, or a total of 32.6 billion
cellulocks in the vasculoid surface, again allowing a 50% duty cycle
for maintenance and repair. Thus there is approximately one
cellulock for every boxcar in circulation. Cellulocks occupy ~0.65%
of the vasculoid surface and have a mean center-to-center separation
of ~96 microns. Each cellulock services an average of ~31
endothelial cells, though the actual spatial distribution of
cellulocks is expected to be highly nonuniform (e.g., clustering
near HEVs). The average capillary is ~1 mm long and is made up of
~60 endothelial cells, and there are ~19 billion capillaries in the
human body (, Table 8.1), so on average ~1 cellulock resides at
either end of every capillary vessel in the body.
maximum white cell transit rate through injured or diseased tissue
is ~1 cell/sec/mm3 . With 32.6 billion cellulocks
there are ~163 cellulocks/mm3 of tissue. Each cellulock
has ~163 sec to pass each white cell, even at maximum traffic
flows. This should be sufficient, given that cellulock doors open
and close in milliseconds, and natural white cell transendothelial
diapedesis may occur in as little as ~3 minutes . The creation of unnecessary interior voids where unwanted
opportunistic pathogens might flourish should be avoided. It is
probably unnecessary to maintain voids between vasculoid and
endothelium near cellulocks because: (1) the time allocated to
cycle the cellulocks appears adequate to permit WBC diapedesis, and
(2) diapedesis can probably be expedited using chemical factors
emitted by the vasculoid.
2.4.3 Container Routing and Identification
ideal method for container routing will be completely automatic,
consuming no incremental power or compute cycles. To this end, the
outer surfaces of each of the five types of tankers (Gas, Water,
Glucose, Power, and Other) and the four types of boxcars (Red Cell,
White Cell, Platelet, and Other) bear a specific repeating interlock
pattern (, Section 126.96.36.199), crudely analogous to Braille. These
patterns remain in place on the container surface unless the
container is affirmatively “reset” to carry a different cargo, in
response to varying physiological needs and local container
Cilia surrounding each docking bay or cellulock are outfitted with
gripper pads (Section 2.3.1) that adhere adequately to all container
surfaces, but strongly only to the surface pattern of the container
type sought by the docking bay or cellulock with which the cilia are
associated. These pad “recognition” types normally remain constant
over time, but, like the container surfaces, may be modified as
required in special circumstances. Efficient methods for handling
Other-type tankers that can avoid the need for time-consuming
docking and downloading of manifests should be investigated further.
Cilia that have “recognized” a desired container transmit a trigger
signal to nearby cilia, activating a collective stereotypical
docking sequence. Thus, although containers follow statistically
random paths across the vasculoid surface, each docking bay and
cellulock automatically receives the cargo it requires from the
passing container stream. Docking acquisition is demand-regulated
* R. Smigrodzki suggests that
a more sophisticated system might employ rewritable tags for (a) the
trafficking of waste, (b) the transport of nutrients in the hepatic
portal system, and (c) the transport of hormones in the
hypothalamic-pituitary portal system. Gas carriers could also be
routed between lungs and peripheral tissues, while the bulk of the
other carriers would never visit lungs, instead circulating between
the gut, kidney, and the peripheral tissue.
2.4.4 Potential Transport Bottlenecks
The exemplar vasculoid has
been scaled to transport essential molecules and cells at maximum
physiological transfer rates. However, all engineering systems
involve design tradeoffs and limitations, and the present design
invokes a number of potential transport bottlenecks including
intestinal water absorption and renal water elimination (Section
188.8.131.52), glucose absorption and elimination at peak loading
(Section 184.108.40.206), boxcar geometrical clearance in narrow
capillaries (Section 220.127.116.11), and geometrical limitations of tanker
monolayer transport (Section 18.104.22.168).
22.214.171.124 Water Absorption and Elimination
The ~6 meter-long intestinal
tract has a simple cylindrical surface area of ~0.65 m2,
but the ~5 x 106 villi of the small intestines (which is
most of the length) increase the effective absorbing surface to ~10
m2 . The ileum, the lower portion of the small
intestine, absorbs water into the bloodstream at the maximum rate of
~0.07 cm3/sec. The cylindrical villi, typically
measuring ~200 microns wide and ~1000 microns long, are heavily
capillarized; assuming ~1000 capillaries/mm3, each
villus has ~30 capillaries presenting a total ~8 x 105
micron2 of absorbing surface – for the entire ileum,
that's ~4 x 1012 micron2, a water transport
rate of ~6 x 108 molecules/sec-micron2. If
maintenance activities are temporarily suspended during peak demand,
water tankers loaded with 2.51 x 1010 water molecules at
2 micron2 docking bays can provide the same transport
rate of 6 x 108 molecules/sec-micron2 if 49%
of the vasculoid surface in the ileum is given over to water
transport – potentially crowding out some “applications plates” at
this surface. (The requirement for alimentary water can also be
greatly lessened by reducing the need for water solvent in urine
(Section 2.1.2), by reducing the need for water cooling in sweat
(Section 8.2), and possibly by reducing water losses in the alveoli
(which could be covered with an improved waterproofing surfactant.)
Excretion of ~0.023 cm3/sec
aqueous waste at the kidneys occurs primarily through the renal
glomeruli which have a total surface area of ~1.4 m2,
giving a maximum water export rate of ~5 x 108
molecules/sec-micron2. If maintenance activities are
temporarily suspended during peak demand, water tankers loaded with
2.51 x 1010 water molecules at 2 micron2
docking bays can provide the required transport rate if 40% of the
vasculoid surface in the glomeruli is given over to water
transport. The ~0.001 gm/sec (~4 x 106
molecules/sec-micron2) solute waste stream is conveyed on
mixed-cargo tankers carrying ~109 solute molecules per
tanker, which may be unloaded at mixed-cargo docking bays covering
only 8% of the vasculoid surface in the glomeruli. Other aspects of
water transport in relation to kidney requirements are discussed in
126.96.36.199 Glucose Absorption and Elimination
Glucose is absorbed in the small intestine, mostly in the duodenum
and the jejunum, at a maximum rate of ~1020 glucose
molecules/sec , somewhat less than our maximum glucose
requirement of 5 x 1020 molecule/sec (Section 2.1.3).
Given a capillary absorptive area of ~3 x 1012 micron2
in the upper small intestine, the natural glucose transport rate is
~3 x 107 molecules/sec-micron2. As before, if
maintenance activities are temporarily suspended during peak demand,
glucose tankers loaded with 3.93 x 109 glucose molecules
at 2 micron2 docking bays can provide the same transport
rate if 17% of the vasculoid surface in the duodenum and jejunum is
given over to glucose transport.
related issue is the vasculoid's response to severe gastrointestinal
overloading, as for example the rapid ingestion of a large quantity
of pure sugar by the user. Sugar has a tremendous irritating effect
on the stomach, with 15-30 gm (60-120 kcal) producing great
outpourings of stomach mucous; as little as 0.25 liter of 20% sugar
solution (78 gm, 300 kcal) is sufficient to cause vomiting in some
patients with chronic gastritis, according to century-old laboratory
experiments . A rapid 2000 kcal (1.75 x 1024 glucose
molecules) ingestion would represent a bulging stomach-full (<1.5
liters ) of >22% sugar solution (~526 gm of sugar) which would be
severely irritating to tissues and toxic to cells, almost certainly
exceeds the natural absorption abilities of the small intestine, and
would likely prove emetic. Urination at the physiological maximum
~1020 glucose molecule/sec elimination rate unloads a
2000 kcal sugar binge in ~5 hours, a renal export rate of 7.14 x 107
molecules/sec-micron2 that can be handled at glucose
docking bays covering 36% of the vasculoid surface in the renal
glomeruli. Alternatively, some excess sugar can be routed to the
liver or other organs for conversion to glycogen or starch.
188.8.131.52 Boxcar Clearance in Narrow Capillaries
Cell-carrying boxcars 6 microns in diameter cannot squeeze through
the narrowest of capillaries, most notably those found in the human
retina which may be as small as 4 microns wide (, Section
184.108.40.206). This has two operational implications.
First, boxcars carrying cellular cargo destined for tissues having
capillaries <8 microns must onload and offload at cellulocks located
outside such tissues, relying on natural transtissue mobility to
achieve the desired placement of the transported cells. In this the
vasculoid mimics the natural transport process.
Second, boxcars must be capable of being rerouted around narrow
capillary bottlenecks to their flow, else the carriers may lodge in
the narrow passage and become an obstacle to the free flow of
materials as sometimes occurs with leukocyte plugging in certain
pathological conditions such as diabetes [84, 85]. Cilia with
boxcar-coded gripper pads located at the entrances of difficult
passages may be programmed to refuse boxcars, and may also utilize
reverse ciliary flows to assist this process. Alternatively,
boxcars may be designed with flexible metamorphic surfaces  (and
thus a limited ability to change shape) to allow tight passage when
traveling empty. With metamorphic boxcars, cilia can allow boxcars
to pass that will empty their contents before reaching a capillary.
Another alternative is that the vasculoid could be used directly to
induce changes in capillary size.
220.127.116.11 Tanker Monolayer Transport
If container traffic is
strictly limited to a single monolayer at the artery or vein wall,
then ciliary transport produces a tanker bottleneck in medium- and
large-diameter vessels of the arteriovenous (noncapillary)
vasculature. This is most clearly illustrated in the aorta. The
circulation time of ~140 sec (1.4 m circuit at vtanker =
1 cm/sec transport speed) implies a system flux of 8.4 x 1010
tankers/sec at basal load and 1.2 x 1012 tankers/sec at
peak load. However, the luminal surface of an aorta of diameter 2Raorta
= 2.5 cm has room to accommodate only a flux of 2p Raorta
vtanker / Stanker = 7.9 x 108
tankers/sec per monolayer of coverage, assuming Stanker =
1 mm2 tankers traveling at vtanker = 1 cm/sec.
The operational implication is
that most tankers must be allowed to transit the aorta as a
multilayer averaging 0.11 mm deep (~110 tanker layers) or <1% of
available luminal diameter at basal load, and up to 1.5 mm deep
(~1,500 tanker layers) or ~12% of available luminal diameter at peak
load. This bottleneck extends to a lesser degree throughout the
arteriovenous vasculature, with the number of required tanker
transport layers decreasing rapidly with decreasing vessel
diameter. Purely monolayer tanker transport becomes tenable in
blood vessels with diameters <200 microns (e.g., arterioles and
large venules) at basal load or <20 microns (e.g., metarterioles) at
peak load. Tankers can employ one or more simple grapples or
temporary coupling mechanisms to join up into progressively
lengthening chains (of linked tankers) as they pass blood vessel
bifurcations moving upstream, and then to gradually detach and
shorten the chains as they move downstream. Even a single cilium
can exert sufficient force to pull a fully-loaded 1000-tanker chain
at ~100 G (Section 2.3.1), although the tanker at the base of each
chain will normally be grasped by up to 10 independent cilia
(Section 2.3.2). Nevertheless, chain linkage reliability and the
effects of such extended chains on flow viscosity should be studied
more thoroughly. Other approaches, including facultative lateral
links between chains to improve transport stability, tanker bloc
motions, independently ciliated tankers (allowing high flow rates in
large vessels with low inter-laminar slip rates ), mechanically
valved free flow, extensive water and respiratory gas caching to
reduce tanker count, and increasing transport speeds up to 1 m/sec
in large blood vessels, are potentially useful strategies but will
not be explored further here.
2.5 Mobile Vasculocytes
additional small population of mobile legged nanorobots, or
“vasculocytes,” continuously patrols the vasculoid interior.
Vasculocytes are independent nanodevices several microns in size,
replete with ambulatory appendages, manipulator arms, repair and
assembly tools/materials, onboard computers with mass memories,
communications and sensory equipment, and independent power supplies
and fuel tankage. A description of a similar system is in ; a
fuller discussion of these capabilities is in [3, 4] and is beyond
the scope of this paper. Like other vasculoid subsystems, to ensure
high reliability vasculocytes are designed with the usual tenfold
redundancy in most major components.
Vasculocytes in the vasculoid appliance have many important
functions, including: (1) general maintenance and repair
activities; (2) plugging internal leaks and breaches, cleaning
spills, leak scavenging, and maintaining an orderly particle-free
internal environment; (3) repairing or replacing malfunctioning
ciliary leg mechanisms (designed for modular changeout); (4)
clearing of jammed docking bays or cellulocks; (5) reconstruction
of the vasculoid sapphire surface plate array after a breach or
other catastrophic failure; (6) physical reconfiguration and
remodeling of the vasculoid microstructure, as for example to extend
additional segments into new capillaries following angiogenesis, to
remove vasculoid tendrils from dead capillaries, or to expand or
contract existing segments (details deferred to another paper); and
(7) installation and removal of vasculoid systems from the human
body (Section 7). Specialization of vasculocyte subspecies which
would each most efficiently serve just one or more of the above
functions should be investigated but is beyond the scope of this
With a vasculocyte mass of ~10 picograms, volume ~3 micron3,
and peak power consumption ~50 picowatts  to allow bursts of more
intensive computation (at up to nearly ~1 megaflop/sec ) or other
activity, a 10-watt vasculocyte subsystem energy budget permits the
deployment of 200 billion continuously active devices, a total 2-gm
mass of nanorobots. Deployment of this number of devices would
allow, for example, at least one vasculocyte to visit all 24
trillion docking bays once a day, spending 720 sec per visit, enough
time to perform ~109 manipulatory operations using a 106
Hz robotic arm . Alternatively, this would allow 7200 visits/day
per docking bay, each visit lasting ~100 msec (~105
operations; travel time between adjacent bays at 1 cm/sec is only
0.35 msec) which is long enough to run a simple diagnostic set and
to detect plate malfunction within just ~12 seconds (on average) of
its initial occurrence. It would also allow one visit per day to
each of 3000 trillion cilia, spending ~6 sec/visit (~107
operations). This seems sufficient.*
Assuming ~0.1 pW per vasculocyte leg (similar to cilium; Section
2.3.1) and 4 legs in motion, simple walking consumes only ~0.4 pW of
mechanical power; a 10,000 ops/sec computation budget to control
simple walking, costing ~6 x 10-17 watts/(ops/sec)
(Section 2.4.1), adds another ~0.6 pW, giving a total power
requirement of just ~1 pW for continuous simple walking. An onboard
1 micron3 fuel tank with energy storage density of ~2 x
1010 J/m3 for externally-supplied O2
(, Table 6.1), gives each 1-50 pW vasculocyte a range of
400-20,000 sec between refueling stops, or ~100-5,000 sec if the O2
is stored internally. The power draw of the entire 200 billion
vasculocyte fleet is 0.2-10 watts.
During vasculoid installation, the patient is injected with a
population of vasculocytes adequate to construct the initial
configuration in a reasonable period of time (Section 7). After
installation, a sufficient number of spare vasculocytes are stored
internally in dormant condition in the vesicles (Section 7.6) until
needed for repair, maintenance, or injury response functions.
Active vasculocytes have highly redundant subsystems, hence fail
infrequently. Upon such infrequent failure, they are replaced with
reactivated dormant devices. (Self-repairing vasculocytes are
possible in principle – e.g., modular repair-by-replacement – but
would add significantly to overall system complexity, hence are not
included in this scaling study.) Nanorobot detritus and internal
waste is containerized and ciliated to an appropriate internal
holding area located in the vesicles. New vasculocytes, replacement
modules, and other necessary spare parts and repair materials may be
exchanged into the user as consumables, when required.
Vasculocytes performing general repair and maintenance on tanker
docking bays have been allocated up to 10 sec per docking cycle for
this task (Section 2.4.1), a very conservative 50% duty cycle for
docking bays. Vasculocyte system subtasks which must be subsumed
within this time budget may include: (1) Detection and analysis of
system fault; (2) determination of appropriate response; (3)
dispatch of appropriate repair mechanism to problem site, including
travel time and docking; (4) on-site verification that the problem
is as reported, and that the repair plan is correct; (5) deployment
of tools and materials; (6) performance of repair work possibly
including plate changeout, rotor replacements, sensor recalibration,
etc.; (7) verification of correct completion of repairs and that
the faulty subsystem is now performing properly; (8)
retracting/repacking all tools with final verification of job
completion; and (9) undocking and return to transport stream for
storage or to receive instructions for the next assignment. The
vasculoid configuration, including numbers of components, their
locations, their accessibility for repair and their ease of
disconnection/reconnection will influence the rapidity of these
course, most of the time there will be no fault at a particular
docking bay, and running a diagnostic is much quicker than
correcting a fault. Since there are only enough vasculocytes to
allow up to 720 seconds/day of repair and maintenance activity at
each docking bay (see above), and since a 50% duty cycle implies
that each docking bay is allocated ~43,200 sec/day for this
activity, then it might be possible to significantly increase the
docking bay duty cycle up to (86,400 - 720)/(86,400) ~ 99% in a less
If diagnostics on “Other” docking bays prove too complex, these bays
might be replaced with simpler organ-specific docking bays that
handle far fewer molecule types.
2.6 Appliance Power Requirement
Power is supplied to the vasculoid appliance via the chemical
combination of oxygen and glucose (, Section 6.3.4), both of
which are plentiful in the human body. Total body power dissipation
is ~100 watts at the basal rate and ~1600 watts at peak (,
Section 6.5.2, Table 6.8). As a further point of comparison, the
basal human heart power output is pheart ~ Psystolic
Vblood / tcirc = 1.4 watts (taking pumping
pressure Psystolic = 120 mmHg (1.59 x 104 N/m2),
pumped blood volume Vblood = 5.4 liters, and circulation
time tcirc = 60 sec ), rising to ~8.0 watts when
cardiac output reaches ~30 liters/minute at peak exertion, assuming
no rise in pressure. Experiments confirm that the basal power
output of a 350 gm resting heart is ~3.5 milliwatts/gm or ~1.2 watts
, and patients with chronic congestive heart failure can achieve
measured peak cardiac outputs no higher than ~2 watts ;
efficient total artificial hearts (TAH) may draw ~5 watts of power
four most significant subsystems requiring a regular energy supply
include ciliary transport (11.8-166.2 watts; Section 2.3.2),
docking bays (14.5-16.6 watts; Section 2.4.1), vasculocytes (0.2-10
watts; Section 2.5), and cellulocks (~0.6 watts; Section 2.4.2),
giving a requirements range of 27.1 watts (basal) to 193.4 watts
(peak). There are also 125 trillion applications plates which are
unused in the basic vasculoid model described in this paper. If
each applications plate is allotted a 0.6 pW energy budget
comparable to the docking bays, and if all possible applications
plates are simultaneously activated,, then the applications
subsystem could require an additional 75 watts, boosting the total
power draw of the vasculoid appliance to 102.1-268.4 watts, which is
still only at the borderline of thermogenic significance (,
3. Preliminary Thermal Conductivity Analysis
Besides providing systemic materials transport throughout the human
body, the water component of blood also serves an important
thermoregulatory function. Removing most of the circulating water
from the vasculature eliminates one of the means by which the body
regulates its gross thermal conductivity. In addition, the
extremely high thermal conductivity of diamond imposes the
requirement for a vasculoid design using mostly sapphire, rather
than diamond, construction materials, even though diamondoid
materials have been more extensively discussed in connection with
molecular nanotechnology  and medical nanorobots [3-6] and may
still be employed in lesser quantities (e.g., as thin coatings)
throughout the vasculoid structure.
Aside from blackbody radiation, sweating, and behavioral
thermoregulation (including respiratory cooling), the body regulates
its temperature and offloads excess heat principally via two
First, there is passive conduction. Heat travels by pure conduction
through fat and muscle from the body core out to the periphery. The
thermal conductivity of human tissue is Kt ~ 0.5
watts/m-K, so for a typical L = 10 cm path length (~half-torso
thickness), heat flow Hf ~ Kt / L = 5 watts/m2-K,
or ~10 watts/K for a 2 m2 human body. In a cold room,
the mean temperature differential between core and periphery DT ~ 11
K , so Hf ~ 100 watts, which is approximately the
basal metabolic rate. Experiments confirm that 5-9 watts/m2-K
is the minimum heat flow in very cold conditions (the actual value
depending largely upon the thickness of subcutaneous fat layers)
. In this case, the peripheral capillary blood flow has slowed
to a trickle, producing the minimum thermal conductivity of the
human body in cold conditions. On the other hand, in a warm room or
during heavy exercise, DT ~ 1 K, so Hf ~ 10 watts. Thus,
paradoxically, at warmer temperatures when the human body is
generating considerable surplus heat, the body's passive heat flow
is actually very low because of the smaller temperature differential
between core and periphery.
Second, heat is transported via the active blood flow. In warm
rooms, not only are the peripheral capillary sphincters fully
dilated, allowing more blood to flow through the peripheral
capillaries relative to the core capillaries, but also the total
volume of blood flow may increase. (During heavy exercise, total
blood flow volume may rise by a factor of 4 or 5.) Diathermy
experiments suggest that the active blood flow mechanism alone may
carry off 100-200 watts of heat before core temperature starts to
rise . In cold rooms and in the absence of heavy exercise,
peripheral capillary sphincters are maximally contracted, thus
minimizing blood flow (and hence heat transport) to the periphery.
summarize: The passive conduction mechanism can throw off ~100
watts of waste heat when the human body is in a cold room but only
~10 watts when the body is in a warm room, while the active
conduction mechanism can throw off negligible heat in a cold room
but up to 100-200 watts in a warm room. Thus as the external
environment warms up, the human body shifts from passive conduction
to active conduction (via increased blood flow and capillary
sphincter widening); if the environment becomes hotter still, or
the person begins exercising, then sweating eventually comes to
dominate both processes.
we now remove the active blood flow regulatory mechanism, inhibit
capillary sphincter expansion, and emplace artificial tubes inside
all the blood vessels and capillaries of the body (i.e., install the
vasculoid), the sweating process and surface thermal radiation
remain unaltered. Thus the principal changes to the human
thermoregulatory system are in the passive and active conduction
First, consider the active conduction system. In a working
vasculoid operating at the maximum tanker flow rate, we have ~0.133
kg (dry mass) of tankers moving around the body in ~100 sec per
circuit. We assume all tankers are filled with water, for a total
water mass of 0.125 kg. Diamond has a heat capacity of 519
joules/kg-K; sapphire is 728 joule/kg-K and water is 4218
joule/kg-K at 310 K. Hence the circulating tanker fleet can
transport at most ~6 watts/K of heat from the core to the
periphery. Given that DT might be as small as 1 K, the “active
conduction system” is essentially disabled by installation of a
vasculoid that is constructed either of diamond or sapphire.
Second, consider the passive conduction system. For a natural
biological-tissue body, heat flow is Hf = Kt /
L = 5 watts/m2-K. For a human body shape comprised
entirely of pure diamond (Kt ~ 2000 watts/m-K at 310 K
) and again taking L = 10 cm, then Hf = 20,000
watts/m2-K. For a diamond-envasculoided human body,
taking a mass of ~1.7 kg of diamond thoroughly interwoven with 68.3
kg of mostly aqueous biological tissue mass (for a standard 70 kg
male body), as a crude estimate the effective heat flow becomes Hf
~ 500 watts/m2-K, or ~100 times more thermally conductive
than before. For comparison, a pure metal human form would have Hf
~ 170 watts/m2-K for stainless steel, ~350 watts/m2-K
for lead, ~780 watts/m2-K for iron, or ~3800 watts/m2-K
for copper. Hence a diamond-envasculoided human body would have
passive conduction properties similar to those of solid metal.
This has implications for the maximum DT that can be maintained
between core and periphery. Consider a human-shaped tissue-mass
with half-thickness L ~ 10 cm and surface area A ~ 2 m2,
sufficiently heated from the inside to cause P ~ 100 watts (human
basal rate) to flow via passive conduction from core to periphery,
establishing a temperature differential DT ~ P L / A Kt ~
10 K for natural human tissue with Kt = 0.5 watts/m-K.
Upon switching to diamondoid envasculoided tissue, mean tissue
thermal conductivity would rise to Kt ~ 50 watts/m-K and
so DT would fall to ~0.1 K. In effect, the entire human body would
become isothermal to within 100 millikelvins; even at the peak
power output of 1600 watts for the human body, DT rises to just ~1.6
K. Thus a diamond-envasculoided human body would tend to become
isothermal with its surroundings very quickly (although partially
offset by subcutaneous fat), a clear hazard to normal human health
especially in very hot or very cold environments. The thermal
equilibration time is approximately tEQ ~ L / vthermal
~ 0.1 millisec, where vthermal ~ Kt / hplate
CV = 1000 m/sec for neighboring vasculoid plates in good
thermal contact with each other and having thickness hplate
~ 1 micron, with Kt = 2000 watts/m-K and CV =
1.8 x 106 joules/m3-K for diamond at 310 K,
and taking L = 10 cm as before. This is far shorter than the
typical 1-10 sec thermal response time of the purely-biological
Substitution of sapphire for diamond significantly improves thermal
performance. The thermal conductivity of synthetic sapphire may be
as low as Kt ~ 2.3 watts/m-K for sapphire at 310 K ,
roughly a thousandfold lower than for diamond, when measured in the
direction normal to the symmetry or optic axis (c-axis); heat
capacity (CV = 2.9 x 106 J/m3-K)
and density (3970 kg/m3) of sapphire are slightly higher
than for diamond. Thus for a sapphire-envasculoided human body,
taking a mass of ~1.9 kg of sapphire (at 25 watts/m2-K
for L = 10 cm) thoroughly interwoven with 68.1 kg of mostly aqueous
biological tissue mass (at 5 watts/m2-K), the total heat
flow is just 5.5 watts/m2-K, which differs
insignificantly from natural biological tissue . At P = 100
watts, DT falls to 2 K compared to 10 K for natural tissue and 0.1 K
for diamond-envasculoided tissue; tEQ ~ 1 sec for
sapphire vs. 10-4 sec for diamond.
complications regarding sapphire require additional research.
First, the thermal conductivity of sapphire may vary significantly
with both composition and crystallographic orientation, a fact which
might impose additional and unknown constraints on the present
design. For instance, one source reports heat flow values
interpolated to 310 K of 21 watts/m-K normal to the c-axis and 23
watts/m-K parallel to the c-axis ; minor extrapolations of
other sources to 310 K (i.e. slightly outside the exact temperature
ranges measured experimentally) imply values of 2.0  and 2.3
 watts/m-K for heat flows normal to the c-axis. However, all
reported values for sapphire are at least two orders of magnitude
more insulating than diamond.
Second, much like diamond, the thermal conductivity of sapphire
varies with temperature. For example, at ~200 K (near dry ice
temperature) sapphire's thermal conductivity rises to 5 watts/m-K.
At liquid nitrogen temperature (77 K), Kt soars to ~1000
watts/m-K; the peak is ~6000 watts/m-K at 35 K [91-93]. (Diamond's
conductivity also rises as it cools [91-93].) At the other
temperature extreme, sapphire's thermal conductivity rises to 3.9
watts/m-K by 523 K. Diamond thermal conductivity also varies
significantly with isotopic composition (e.g., 12C vs.
13C [95, 96]); it is unknown whether similar
opportunities may exist for the engineering of desired levels or
patterns of thermal conductivity in isotopically-controlled
Finally, we note that much burn damage occurs due to a failure to
dissipate heat. Selectively increasing the thermal conductivity of
certain parts of the body at certain chosen times is a useful
feature that could mitigate the effects of transient local heating
(Section 8.2). Note that blood is an excellent electrical
conductor, and its replacement by an inorganic construct may reduce
the susceptibility of the body to electrical burns under ordinary
conditions. Pure single-crystal alumina (sapphire), roughly
analogous to the core material of the vasculoid plates, is one of
the best electrical insulators known . Pure bulk diamond is
also an excellent insulator, but hydrogen-terminated diamond surface
shows a high p-type surface conductivity , and slight impurities
(e.g., p-type (boron) or n-type (phosphorus) ) or dislocations
may also permit conduction, so a diamond-coated sapphire vasculoid
plate should be somewhat more electrically conductive than bulk
sapphire. The vasculoid is envisioned as a primarily mechanical
system and so its electrical characteristics have not yet been
investigated. The susceptibility of the appliance to electrostatic
charge transfer, electromagnetic interference or electromagnetic
pulses (EMP) is unknown.
4. Biocompatibility of Vasculoid Systems
A detailed study of biocompatibility issues will also
be necessary to firmly establish the feasibility of the present
proposal. Such issues, which may include the trimming of cellular
glycocalyx by spinning molecular sorting rotors, surface electrical
thrombogenicity, inflammation and phagocyte activation by diamondoid
or sapphire materials, and the impact of a cessation of mechanical
pulsing on tissue health and lymph flow, have been briefly examined
in  but need further study . A comprehensive treatment is
beyond the scope of this paper, but a few of the relevant issues may
be at least cursorily addressed here. Most of the discussion in
this Section is drawn from Chapter 15 of Nanomedicine, Volume II
, where the biocompatibility of diamond and sapphire materials is
more extensively reviewed in the context of medical nanorobotics.
4.1 Mechanical Interaction with Vascular Endothelium
Perhaps the single most important biocompatibility
factor involving the vasculoid has been termed “vascular
mechanocompatibility” by Freitas . Vasculoid nanorobots
in all their forms must be as mechanically biocompatible with the
vascular walls (Section 4.1.1) as are stents (Section 4.1.2) and
must not produce destructive mechanical vasculopathies (Section
4.1.3) or disrupt the endothelial glycocalyx (Section 4.1.4).
4.1.1 Modulation of Endothelial Phenotype and Function
luminal surfaces of all blood and lymph vessels consist of a thin
monolayer (the intima) comprised of flat, polygonal squamous
endothelial cells (EC) covering a much thicker layer (the media)
comprised of vascular smooth muscle cells (SMC). Under normal
physiological conditions, both layers are subject (and respond) to
tangential fluid shear stresses across the endothelial cell surface
due to the bulk flow of blood [103-108], normal hydrostatic pressure
stress acting radially on the vessel wall due to the propagation of
the pressure wave, and cyclic stretch or strain due to blood vessel
circumferential expansion in vivo [108-110], and thus might also be
sensitive to similar mechanical stresses that may be applied by
stationary or cytoambulatory intravascular nanorobots such as the
vasculoid basic plates.
Endothelial cells (EC) are randomly oriented in areas of low shear
stress but elongated and aligned in the direction of fluid flow in
regions of high shear stress [111-113]. In vitro endothelial cells
previously acclimatized to physiological fluid shear stresses
respond to artificial changes in local fluid shear stress only very
slowly, and in three stages . In the first stage, EC initially
respond to the imposition of stress within 3 hours by enhancing
their attachments to the substrate and to neighboring cells; the
cells elongate and have more stress fibers, thicker intercellular
junctions, and more apical microfilaments. In the second stage,
after 6 hours the EC show constrained motility as they realign,
losing their dense peripheral bands and relocating more of their
microtubule organizing centers and nuclei to the upstream region of
the cell. In the third stage, after 12 hours the EC become
elongated cells oriented in the new apparent direction of fluid
flow; stress fibers are thicker and longer, the height and
thickness of intercellular junctions are higher, and the number and
height of apical microfilaments are increased. This produces a new
cytoskeletal organization that alters how the forces produced by
fluid flow act on the cell and how the forces are transmitted to the
cell interior and substrate .
Physiological fluid mechanical stimuli (e.g., fluid shear stresses*)
are important modulators of regional endothelial phenotype and
function [114-118]. For example, endothelium exposed to fluid shear
stress undergoes cell shape change, alignment, and microfilament
network remodeling in the direction of flow (though this may be
blocked via microtubule disruption using nocodazole) .
Interestingly, the application of a steady laminar shear stress (a
physiological stimulus) upregulates the human prostaglandin
transporter (hPGT) gene at the level of transcriptional activation,
whereas a comparable level of turbulent shear stress (a
nonphysiological stimulus) or low stress (such as would be produced
by a vascular surface coated with sessile nanorobots) does not
. A few of the many quantitative experimental observations
(1) shear stresses from 0.02-1.70 N/m2 produce
flow-induced membrane K+ currents ;
(2) physiological shear stresses of 0.35-11.7 N/m2
stimulates mitogen-activated protein kinase in a 5-min peak response
(3) 0.04-6 N/m2 shear stress increases inositol
trisphosphate levels in human endothelial cells, with a 10-30 sec
peak response time [121, 122];
(4) shear stresses from 0.5-1.8 N/m2 regulate (in
frequency and amplitude) oscillating K+ currents known as
spontaneous transient outward currents or STOC which are observed
both in isolated bovine aortic endothelial cells and in intact
endothelium; activation of STOC depends on the existence of a Ca++
influx and is blocked by 50 microM of Gd+++ or is
significantly reduced by 20 microM of ryanodine ;
(5) shear stress of 1.2 N/m2 induces transcription
factor activation over response times ranging from 0.3-2 hours
(6) arterial shear stresses of 1.5-2.5 N/m2 (but
not a venous shear stress of 0.4 N/m2) induce endothelial
fibrinolytic protein secretion ;
(7) shear stress of 2 N/m2 induces TGF-b1
transcription and production in a ~60 sec initial response time,
with a sustaining increase in expression after 2 hours ;
(8) a shear stress of 2 N/m2 suppresses ET-1 mRNA
on confluent bovine aortic endothelial cell monolayers ; these
effects of shear may be completely blocked (thus allowing ET-1 to be
expressed) using 875 nM of herbimycin to inhibit tyrosine kinases or
10 microM of quin 2-AM to chelate intracellular Ca++,
partially inhibited using 3mM of tetraethylammonium (TEA), or
attenuated by elevated extracellular K+ at 70 mM or
completely inhibited by K+ at 135 mM ;
(9) shear stress of 3 N/m2
membrane currents in a 30 sec peak response time ;
(10) shear stress of 6 N/m2
applied for 12 hours causes endothelial cells to align with their
longitudinal axes parallel to flow ;
(11) membrane hyperpolarization occurs as a function of local
shear stress up to 12.0 N/m2, with an exponential
approach to steady state in ~1 minute; the process is fully
reversed once the artificial fluid flow stress is removed ;
(12) critical shear stress of 42 N/m2 is the
disruptive threshold for endothelial cells, inducing cell mobility
(13) shearing stresses of 5-100 N/m2 occur at the
contact interface when a leukocyte is adhering to or rolling on the
endothelium of a venule .
Endothelial cells thus respond to sustained physiological fluid
shear stresses from 0.02-100 N/m2, spanning the range of
normal arterial wall fluid shear stresses of 1.0-2.6 N/m2
from the aorta through the capillaries [19, 129] and 0.14-0.63 N/m2
for the venous circulation [19, 130]. By contrast, legged
vasculomobile medical nanorobots may apply shear stresses during
luminal anchorage or cytoambulation at velocities up to 1 cm/sec of
at least 40-200 N/m2 or higher (, Section 18.104.22.168).
(Self-expanding aortic stents forcibly pulled from the vessel
require an extraction force of ~400 N/m2 assuming a 10-cm
length, rising to ~1200-3600 N/m2 for stents anchored
with hooks and barbs ; varying the radial force applied by
stents against the vascular wall has little impact on the required
extraction force.) Such shear forces, if imposed unidirectionally
by large numbers of closely-packed co-ambulating nanorobots for time
periods of >103 sec, may induce significant changes in
shape, orientation, and physiological function in the underlying
endothelial cell population. If instead these forces are applied in
randomized directions varying over short time periods (<1 hour;
Section 7.4) by vasculoid nanorobots, then mechanically-induced
modulation of endothelial phenotype and function should not occur.
shear forces must not be eliminated, however. A nanorobot aggregate
that shields vascular cells from fluid shear for an extended time
may induce those cells to revert to their flow-unstressed phenotype
or to undergo apoptosis. Endothelial cells cultured in the absence
of shear stress tend to become dedifferentiated . In one study
, after blood shear was artificially reduced near a wound
lesion for 24 hours the local endothelial cells became less
elongated, contained fewer central microfilament bundles, and
exhibited a slower repair process. In another study , vein
grafts removed from the higher-shear arterial circulation and
reimplanted in the lower-shear venous circulation of the same animal
showed regression of intimal hyperplasia and medial rethickening in
14 days, apparently due to induction of smooth muscle cell apoptosis
by a reduction in pressure or flow forces.
Endothelial cells can also respond to persistent static
overstretching in many ways, up to and including apoptosis. For
instance, hypertension caused by hydrostatic edema can induce
apoptosis in capillary EC .
Additionally, vascular wall cells respond to lateral stretch forces
due to cyclical blood vessel expansion in vivo. For example, in one
experiment  bovine aortic endothelial cells were seeded to
confluence on a flexible membrane to which cyclic strain was then
applied at 1 Hz (0.5 sec strain, 0.5 sec relaxation) for 0-60 min.
After 15 minutes of this cyclic stretching, there was an increase in
adenylyl cyclase (AC), cAMP, and protein kinase A (PKA) activity of
1.5-2.2 times at 10% average strain as compared to unstretched
cells, but there was no activity increase at 6% strain – evidently,
cyclic strain activates the AC signal transduction pathway in
endothelial cells by exceeding a strain threshold, thus stimulating
the expression of genes containing cAMP-responsive promoter
elements. Stretch-activated cation channels in bovine aortic EC are
inhibited by GdCl3 at 10 microM . Human umbilical
EC subjected to a 3-sec stretch pulse show an intracellular
rapid-increase Ca++ spike, followed by a
(ryanodine-inhibitable) slow-decline, due to Ca++ entry
into the cell through stretch-activated channels; Mn++
also permeates mechanosensitive channels (but not Ca++
channels) and enters the intracellular space immediately after an
application of mechanical stretch . Cyclic strains of 10% at 1
Hz induce intracellular increases in Ca++ ,
diacylglycerol [137, 138], inositol trisphosphate [136-138] and
protein kinase C (PKC)  in peak response times of 10-35 sec,
often sustained for up to ~500 sec, and induce transcription factor
activation over response times ranging from 0.25-24 hours
[100-105]. Several endothelial cytokines are induced by cyclic
mechanical stretch , and cyclic mechanical strain modulates
tissue factor activity differently in endothelial cells originating
from different tissues .
Similarly, bovine aortic smooth muscle cells (SMCs) seeded on a
silastic membrane and subjected to cyclic strains up to 24% enhanced
SMC proliferation at any strain level , although SMC under high
strain (7-24%) showed more proliferation than SMC at low strain
(0-7%) in this experiment. High-strained SMC aligned themselves
perpendicular to the strain gradient, whereas low-strained SMC
remained aligned randomly; PKA activity and CRE (cAMP response
element) binding protein levels increased for highly strained cells,
compared to low-strained cells . Other experiments have found
that small mechanical strains of 1-4% at 1 Hz applied to human
vascular smooth muscle cells can inhibit intracellular PDGF- or
TNFa-induced synthesis of matrix metalloproteinase (MMP)-1 ;
that saphenous vein SMC distention by 0.5 atm pressure subsequently
elevates cell apoptosis ; that cyclic mechanical strain at
normal physiological levels decreases the DNA synthesis of vascular
smooth muscle cells, holding SMC proliferation to a low level
; that 1 Hz, 10% cyclic strain on SMC activate tyrosine
phosphorylation and PKC, PKA, and cAMP pathways over response times
from 10 sec to 30 min [141, 144]; and that vascular SMC exhibited
stretch-induced apoptosis when subjected to cyclic 20% elongation
stretching at 0.5 Hz for 6 hours . Consequently, medical
nanorobot aggregates which shield the vasculature from normal
cyclical strains might elicit excess growth of vascular smooth
muscle cells, which growth is normally held in check by the rhythmic
stretching from the arterial pulse . Intravascular nanorobot
aggregates that apply cyclic mechanical strains exceeding a few
percent might encourage increased SMC proliferation and activate
mechanosensitive and stretch-activated channels in EC, along with
cellular realignment and subsequent SMC apoptosis at the highest
2002 it was unknown whether high frequency (>KHz) cyclic mechanical
strains likely to be employed by vasculomobile medical nanorobots
( and , Section 22.214.171.124) would have biological effects similar
to or different from those described above for low-frequency cyclic
strains, excepting certain specialized mechanoreceptor cells such as
the cochlear stereocilia [145, 146], other hair cells [147-149], and
somatosensory neurons [150-152], since most mechanical cell
stimulation experiments have been conducted at low frequencies.**
Unrecognized effects that might be triggered by high-frequency
cyclic strains cannot be ruled out. However, given the relative
safety of procedures involving intravascular ultrasound [153-162]
with its low complication rate (e.g., only 1.1%, including spasms,
vessel dissection and guidewire entrapment ) using frequencies
as high as 10-20 MHz [153-155], it seems improbable that KHz or MHz
acoustic waves of the intensities that might be employed by medical
nanorobots for communication (, Section 7.2.2) or power supply
(, Section 6.4.1) will damage the luminal vascular walls.
Continuous low-power ultrasound exposures exceeding ~104
sec are considered safe (, Figure 6.8), but there are few studies
on the safety of long-duration chronic exposures. (Interestingly,
relatively high-intensity intravascular ultrasound has been used to
dissolve occlusive platelet-rich thrombi safely and effectively in
myocardial infarctions  and in restenosed stents .)
necessary, large wave motions and pressure patterns that are
characteristic of normal blood flow can in principle be simulated by
the vasculoid plate array by a combination of motile ciliary
activity and periodic manipulations of interplate bumpers.
It is likely that the
vasculoid appliance will need to control smooth muscle cell
proliferation [163-170], in the simplest case releasing specific
cytokines into the vasculoid-endothelial space.*** Such factors may
include known SMC proliferation promoters [171, 172] such as
thrombin (esp. alpha-thrombin), PDGFs (esp. PDGF-AA), FGF (esp.
basic FGF), HBEGF (heparin binding epidermal growth factor), TGFb
(transforming growth factor-beta) at low concentrations, angiotensin
II, thrombospondin-1 (stretch/tension), and known SMC
proliferation inhibitors [220, 173-178] such as heparin/heparan
sulfate, TGFb (transforming growth factor-beta) at high
concentrations, nitric oxide, prostaglandins, calcium antagonists,
agonists that activate guanylate and adenylate cyclases, inhibitors
of angiotensin-converting enzyme, interferon gamma,
18-beta-estradiol, sodium salicylate, and the topoisomerase I
inhibitor topotecan. Adult arterial walls contain both
differentiated and immature SMCs . R. Bradbury notes that
further research is needed regarding how SMCs handle conflict
resolution between “divide” and “don't divide” signals that it may
be receiving from both internal and external sensors. Given the
large number of signals that SMCs currently respond to, it seems
highly likely that the vasculoid can “manage” them, along with other
secretion products of SMCs that play important roles in the
prevention of vascular disease, such as extracellular superoxide
* For laminar fluid flow in
cylindrical tubes of radius R and length L through a pressure
differential of DP, the fluid shear stress  is RDP/2L.
Specifically, between 0.05-5 Hz (, Section 126.96.36.199.1) and more
recently at: 0.01 Hz , 0.05 Hz [182, 198], 0.1 Hz [181, 186],
0.2 Hz , 0.3 Hz [184-187], 0.4 Hz , 0.5 Hz [195-198], 1 Hz
[187-193], 3 Hz , 4 Hz , 5 Hz , 6 Hz ,
4/10/20/50 Hz , and DC-100 Hz .
*** Other approaches, though less desirable, might also work. R.
Bradbury notes that overproliferating SMC could be induced to
undergo apoptosis, perhaps at the cost of telomere shortening in any
SMC stem cells that might be present as they proliferate to replace
those being eliminated by the vasculoid. ECs play a role in
attracting and regulating SMCs , so controlling the ECs could
indirectly control the SMCs; indeed, all SMCs could be lost with
minimal effects beyond changes in nutrient diffusion times, and
could possibly reduce the body’s O2 and glucose demand.
Once there is no heartbeat, SMCs are no longer strictly required for
day-to-day vasculoid operations but would still be necessary to
preserve reversibility of vasculoid installation if the patient’s
physician desires to avoid having to reseed the SMC from stem cells.
4.1.2 Vascular Response to Stenting
Mechanical biocompatibility must also be demonstrated by
intravascular nanorobots that are intended to remain in long-term
near-contact with blood vessel walls. A related medical analog is
the vascular stent – a flexible metal coil or open-mesh tube that is
surgically inserted into a narrowed artery, expanded, and pressed
into the vascular wall at up to 10-20 atm pressure, in order to
ensure long-term local vascular patency by providing a scaffold to
hold the artery open. Within 4 days, SMC begin to appear in the
intima . After a few months the stent is completely overgrown
with new endothelium, forming a neointima, although the media is
usually compressed with smooth muscle cell atrophy in all stented
regions; stenosis is prevented in vessels 10 mm or greater in
diameter but is not precluded in vessels smaller than 6 mm .
Histologically, in-stent restenosis appears to derive almost
exclusively from neointimal hyperplasia [205, 206], which appears
more abundant following stent implantation than balloon angioplasty
and in stents of greater stent length and smaller vessel caliber (or
inadequate stent expansion) . Restenosis occurs in 22-46% of
all stents emplaced within 6-12 months [208-213]), in some cases
requiring the insertion of a second stent into the first , and
varies according to the material used. In one experiment , the
thickness of the neointimal layer formed over wire-mesh stents
placed in canine aortas was 83.9 microns thick for gold, 103.6
microns for stainless steel, 115 microns for Teflon, 209.6 microns
for silicone, and 228.6 microns for silver; a copper stent produced
severe erosion of the vessel wall, marked thrombus formation, and
aortic rupture. Stent surface coating and texture also affects
leukocyte-platelet aggregation and platelet activation .
Improved prospects are reported
for diamondoid stents (, Section 188.8.131.52). For instance,
diamond-coated stents produced by
 are inserted at 16 atm pressure (vs. 2-3 atm normally for
stents) and yet do not dislodge surface (thrombogenic) antigens and
selectins: “The results show that in none of the control systems
(systems without stents) [could] a change in glycoprotein expression
(i.e. all antigens) ... be detected. With the exception of one
measurement also the structural epitopes (CD 41a, CD 42b) show no
significant changes during the test period. The reason is most
probably that the shearing strength of the system was too weak or
the expression of the antigens was too strong. Whereas for the
thrombocyte activation, remarkable difference in the expression of
CD 62p and CD 63 could be detected. The thrombocyte activity marker
CD 62p is reduced in diamond-like coated stents and diamond-like
coated stents with heparin compared with uncoated stents.”
However, stent devices are far from ideally mechanocompatible with
blood vessel walls. For example, stents placed endovascularly in
dog aorta for 4-45 weeks and then examined histologically show
medial atrophy, intimal hyperplasia (tissue ingrowth), and
proliferation of the vasa vasorum (the microvasculature of the
aorta) more prominently for covered stents than for bare stents,
probably due to hypoxia in the aortic wall . Cellular
proliferation is highest when the artery wall is most hypoxic
; but vasculoid nanorobot aggregates (e.g., basic plates) that
entirely cover the vascular endothelium can precisely regulate
oxygenation of the underlying tissue (using data from oxygen sensors
in the plate wall contacting the endothelium), thus largely
eliminating the possibility of hypoxia. Stentlike vascular-coating
structures also may be able to inhibit stenosis due to vascular
smooth muscle proliferation, migration, and neointima formation,
without inducing apoptosis, by releasing the topoisomerase I
SMC-proliferation inhibitor topotecan in a localized 20-min exposure
, or by using other similar drugs.
4.1.3 Nanorobotic Destructive Vasculopathies
physical configurations or activities of medical nanorobotic
aggregates could in some circumstances be destructive of vascular
tissue . Owens and Clowes  point out that the severity of
arterial injury is important in determining the ultimate
pathophysiologic response and describe a classification system 
based on the immediate histologic effect of the injury:
Type I injuries involve no significant
loss of the vessel’s basic cellular architecture, although there may
be a slight change in endothelial architecture and associated
cellular adhesion. Examples include the fatty streak (an early
atherosclerotic lesion), hemodynamic factors and flow disturbances
which produce, at most, only a modification of the established
Type II injuries involve loss of the
endothelial layer, perhaps inducing platelets to adhere and begin
forming a thrombus at the area of loss, but the internal elastic
lamina remains intact and there is little or no damage to the
media. Examples include injuries incurred during simple arterial
catheterization, endovascular procedures, vein graft preparation, or
gentle filament-induced endothelial denudation of the carotid artery
in a rat model .
Type III injuries involve transmural
damage in which the endothelium is removed, the internal elastic
lamina is often disrupted, and a significant portion of the medial
cells are killed [224, 225]; platelets deposit and a thrombus forms
at the site of endothelial loss, and an inflammatory response
(vasculitis) including intimal hyperplasia  is initiated within
the vessel wall. Examples include spontaneous vascular dissection
and various forms of surgical repair or reconstruction such as
balloon angioplasty, endarterectomy and atherectomy.
Medical nanorobot device and mission designs should always seek to
avoid Type II and Type III injuries, although in some special
circumstances the potential even for Type III injuries may be
inescapable. Destructive mechanical vasculopathies that might be
caused by vasculoid nanorobots may be classified as ulcerative
(184.108.40.206), lacerative (220.127.116.11), or concussive (18.104.22.168).
22.214.171.124 Nanorobotic Ulcerative Vasculopathy
Pressure ulcers are normally caused by a prolonged mechanical
pressure against epidermal tissues (e.g., the skin of a person who
is lying down; decubitus ulcer, or bedsores), typically at sites
over bony or cartilaginous prominences including sacrum, hips,
elbows, heels and ankles. The combination of pressure, shearing
forces, friction and moisture [226, 227] leads to tissue death due
to a lack of adequate blood supply; if untreated, the ulcer
progresses from a simple erosion to complete involvement of the
dermal deep layers, eventually spreading to the underlying muscle
and bone tissue . In rare cases , mechanical frictional
stimulation of the skin can precipitate systemic cutaneous necrosis
and calciphylaxis, a state of induced tissue sensitivity
characterized by calcification of tissues. Stercoral ulcers
[230-232] are caused by the necrosis of intestinal epithelium due to
the pressure of impacted feces. Fluid mattresses can greatly reduce
pressure ulcers in long-duration surgeries  and
pressure-relieving surfaces have been investigated for surgical
patients [234, 235], wheelchair users [236-239], and for other
circumstances [240-242].) It is generally recommended that the
interior surface should employ materials having roughly the same
mechanical properties as the enclosed tissue [243-246], and the
applied interfacial pressures should be reduced to below 1 psi 
or ~ 50 mmHg.
Similarly, a macroscale nanorobot aggregate such as a vasculoid
appliance may cause luminal vascular ulceration by prolonged
mechanical pressure against intimal tissues, similar to epithelial
pressure ulcers, necrotizing vasculitis, or pressure necrosis. For
example, mechanical stretch induces apoptosis in mammalian
cardiomyocytes  and hypertension caused by hydrostatic edema
can induce apoptosis in capillary endothelial cells . Another
example is IUD-induced metrorrhagia (nonmenstrual uterine bleeding),
wherein the IUD (intra-uterine device) elicits a vascular reaction
most pronounced in the endometrium adjacent to the device and
includes increased vascularity, degeneration with defect formation,
congestion, and poor hemostatic responsiveness to increased vascular
permeability and damage, leading to interstitial hemorrhage due to
vascular damage from mechanical stress transmitted by the IUD
through the endometrium to its vascular network .
Indwelling catheters can rest very snugly against the vascular walls
without complication for brief periods . A biological-like
interface may reduce ulceration in longer-term missions. In one
study, a stented aortic graft was placed endovascularly in the
native aorta of male sheep, and a histological examination 6 months
later found good incorporation of the graft with no pressure
necrosis, although there was a foreign body reaction around the
graft and an organized blood clot was noted between the graft and
the aortic wall  (the inner, but not the outer, aortal surfaces
would be expected to have clotting-suppressive properties).
However, long-duration nanoaggregates (such as vasculoid plates)
that must maintain close contact with endothelium should employ a
mechanically compliant coating having properties similar to
extracellular matrix. All such linkages should be not just
immunocompatible (Section 4.3) but also mechanocompatible,
possessing equivalent elasticity or mechanical compliance  as
the underlying tissue to which attachment must be secured. With
conventional implants, compliance design may include assessments of
circumferential compliance (measurement of changes in vessel
diameter over a complete cardiac cycle, including pressure-radius
curves , dynamic compliance , and mechanical hysteresis
effects) , longitudinal compliance (elasticity of selected
lengths of the vascular system, including any localized stiffening)
, tubular compliance (imparity of elasticity between a
prosthetic conduit and the native artery, elastic energy
reservoiring, and pulsatile energy losses due to interfacial
impedance mismatches) , and anastomotic compliance (suture line
anastomotic compliance mismatch and the para-anastomotic
hypercompliance zone [256, 257], localized regions of excessive
mechanical stress [258-260], and cyclic stretch effects on
replication of vascular SMC and extracellular matrix [259, 262]). A
mismatch in mechanical properties between relatively compliant
arteries and less-compliant metallic stents  and tissue grafts
has been thought to influence patency  and pseudointimal
hyperplasia [259-261]. Larger more central arteries are more
compliant than the distal small caliber arteries , wall shear
stress from blood flow differs on either side of a curving vessel
and the stress is out of phase with the pulsing circumferential
stretch strain , and compliance mismatch between host artery
and prosthetic graft may promote subintimal hyperplasia .
Analogous compliance issues may be assessed once the static and
dynamic stress patterns in the vasculoid transport system are more
Post-installation vascular conditioning can be
maintained on a permanent basis because the vasculoid appliance
exercises precise control over the transport of most metabolic and
cellular traffic – e.g., of cholesterol, leukocytes and platelets,
the principal participants in the arteriosclerogenic process, or of
various circulating pluripotent stem cells and their activating
126.96.36.199 Nanorobotic Lacerative Vasculopathy
Individual vasculomobile nanorobots or nanorobotic aggregates may
occasionally scratch, scrape, or gouge the vascular luminal surface,
causing partial or complete loss of local endothelium (Type II
damage), a form of mechanical vasculitis or capillaritis,
particularly during installation of the vasculoid appliance (Section
7). Since the typical dimensions of nanorobotic vasculoid
components approximate the endothelial thickness, transmural Type
III damage to the media is unlikely. Turnover studies of rat
endothelium show that (a) injured endothelium can recover an area
one cell wide (~1000 micron2) in ~3 hours , (b) the
natural loss rate is ~0.1% of endothelial cell area per day (~1
micron2/day) , and (c) the steady-state vascular
denudation area is ~0.125 micron2/cell .
Smooth nanorobot hulls, boundary layer effects and low fluid flow
velocity throughout most of the vasculature during installation
(Section 7) should ensure that major “sandblasting” type erosion
[269, 270] is unlikely to occur inside human blood vessels even at
the highest nanocrits consistent with continuous flow.
Free-floating nanorobots that collide with blood vessel walls (given
the no-slip condition at the wall) produce minimal shear forces, on
the order of <~0.1 N/m2 (, Section 188.8.131.52) – this is
less than the 1.0-2.6 N/m2 shear forces normally
encountered in arteries and capillaries due to normal blood flow and
the 0.14-0.63 N/m2 shear forces in veins, but may be
sufficient to cause a small biological response from the vascular
endothelium (Section 4.1.1). Applying the maximum possible
bloodstream velocity of 1 m/sec to the impact-scratch relation (,
Section 184.108.40.206, Eqn. 9.96), it is clear that particle-wall
collisions should produce only harmless submicron nicks even in the
most turbulent arteries.
Nevertheless, some caution is warranted because natural endothelial
cell wounding of ~1-18% of all cells, possibly erosionally-derived,
has been observed in rat aorta . Erosion of cultured
fibroblast monolayers (simulating the vascular endothelium) using
MHz ultrasound at acoustic pressures of ~106 N/m2
is enhanced by the presence of a microbubble (particulate) contrast
agent . Injection of crystalloid cardioplegic solutions into
canine hearts at pressures >110 mmHg and at peak flow rates >25
ml/sec also causes a higher incidence of mechanical-physical trauma
to the vascular endothelium and the endocardium . In another
unusual case, intravenous self-injection by a drug abuser of
dissolved tablets containing microcrystalline cellulose as filler
material produced numerous microcrystalline cellulose pulmonary
emboli, intravascular foreign body granulomas, focal necrosis and
edema of the pulmonary parenchyma, and fatal vascular destruction
Endothelial abrasion alone may
not stimulate neointimal thickening  but inevitably must
involve some endothelial cell loss  and other biological
responses. For example, mechanically scraping cultured endothelial
cells causes growth factor to be released within 5 minutes, not
abating for at least 24 hours thereafter, due to plasma membrane
disruption . In the case of vascular dissection, a piece of
the endothelium peels up, making an intimal flap that defines
regions of true and false lumina, and sometimes may induce an
intramural hematoma in the aortic wall . Endothelial cells
mechanically damaged with a razor blade activate
extracellular-signal-regulated kinases within ~300 sec, releasing
fibroblast growth factor (FGF-2) which in turn induces intimal
hyperplasia . Nanorobots which detect FGF-2 are alerted that
mechanical endothelial injury has taken place; by absorbing the
cytokine using molecular sorting rotors, the hyperplasia signal may
be suppressed by a nanorobot, if desired (, Section 220.127.116.11).
However, shear-induced endothelial denudation of healthy canine
arterial endothelium appears not to occur at shear stresses up to at
least 200 N/m2 . The role of erythrocyte collisions
with vascular walls on the detachment rate of endothelial cells is
just starting to be seriously investigated .
K. Clements suggests that some
provision might be also be made for emergency plate disconnects in
certain unusual accident situations, e.g., where the user has
irreversibly caught his hand in a machine applying superior force,
and now risks not just amputation of the original biological limb,
but also faces either (1) forcible extraction of the diamondoid
appliance from the remaining biological tissues, or (2) progressive
amputation of additional biological tissues because the vasculoid
network has become caught in the machine.
18.104.22.168 Nanorobotic Concussive Vasculopathy
a patient experiences significant external crushing or concussive
forces, resident medical nanorobots that are present in small
numbers can simply move out of the way, as described previously by
Freitas [4, 6, 281] in connection with the risks of dental grinding
(e.g., , Section 9.5.1). In the case of macroscale intravascular
nanoaggregates, there are several additional risks that should be
avoided in specific appliance designs.
First, there is the possibility that a sudden mechanical external
tissue compression could push macroscale nanorobotic aggregates
through the soft tissues, causing deep tissue penetrations,
perforations, or other serious mechanical trauma. Similarly,
because the vasculoid materials may have higher density than the
surrounding biological tissues, very high accelerations (Section
8.8) could produce effects on those tissues that would be not unlike
pushing gelatin through a metal wire strainer. Simple activities
such as hand clapping or fistfights are unlikely to produce the high
accelerations required for serious damage, but this risk should be
quantified in future studies. Possibly relevant analogies in the
medical literature include:
(1) ulnar artery erosion, thromboemboli, digital ischemia and
skin necrosis from a glass foreign body in a patient’s hand ;
(2) tantalum coil stent damage that was induced or aggravated
by intravascular ultrasound inside a coronary artery .
(3) a chronic indwelling catheter that led to erosion and
rupture of the anterior wall of the right ventricle, producing a
near-exsanguinating hemorrhage ;
(4) cardiac perforation by a subclavian catheter ;
(5) pulmonary artery catheter-induced right ventricular
perforation during coronary artery bypass surgery ;
(6) an ICD patch that migrated and perforated the right
ventricular cavity ;
(7) a stent that migrated to an oblique position across the
aorta, producing a 7-cm pseudoaneurysm after 3 years ;
(8) catheter-induced pulmonary artery rupture (a
well-recognized complication of invasive monitoring) that often
leads to fatal hemorrhage [288-290];
(9) femoral artery catheterization trauma producing hematoma,
pseudoaneurysms and arteriovenous fistulas of the femoral vessels
(10) iatrogenic subclavian artery injury due to central venous
(11) repeated and prolonged vein catheterization that led to
subsequent stenosis (presumably due to luminal vascular mechanical
(12) high-pressure injection injury that induced inflammation
and foreign body granulomatous reaction, progressing to necrosis
(13) mechanical tearing of arteries due to overstretching
(14) spontaneous coronary artery dissection (mechanical
arterial wall failure) .
(Most of these cases pertain to injury from objects much stiffer and
larger than vasculoid components, or are due instead to intrinsic
vessel dysfunction (as in spontaneous arterial dissection.)
Second, a sudden external tissue compression could force nanorobotic
aggregates into physical contact with neighboring nanoaggregates,
possibly causing major structural damage or fragmentation of the
devices. This risk increases as the nanodevices become more densely
packed, especially along the crushing axis. Nanoorgans (as well as
looser aggregates) can be crushed if sufficient force or mechanical
shock is applied. Again, a few possibly relevant analogies from the
medical literature include:
(1) external compression of emplaced stents that produced
premature stenosis ;
(2) a transabdominal teflon stent that broke intraperitoneally
during tuboplasty procedure ;
(3) a strongly-beating heart that sheared off a pericardial
drainage catheter ;
(4) a Hickman catheter that suffered rupture and embolization
during normal use ;
(5) an indwelling catheter that fractured and a distal remnant
embolized to the right ventricular outflow tract and main pulmonary
artery, precipitating cardiopulmonary near-collapse ;
(6) a catheter embolism that was produced when a catheterized
patient engaged in power training exercises, externally crushing the
catheter, although no symptoms or complications accompanied this
(7) spontaneous fracture of indwelling venous catheter,
leading to vascular leakage ; and
(8) other instances of
catheter fracture and embolism [304-307], including one case that
led to cardiac arrest .
(Here, too, many of these
cases might differ substantially from the vasculoid, since the
catheters were made from a bulk material that depended on its
integrity for function while the vasculoid would consist of a large
number of semi-independent components capable of restoring
functional connections on their own.)
Third, there is a small risk
that poor device design, poor mission design, or a loss of control
might cause nanoaggregates to operate in a dangerous manner, causing
macroscale concussive injury to biological tissues. For example,
iatrogenic vascular trauma caused by intra-aortic balloon pumps is
well-known . In one case, balloon expansion during angiography
ruptured the pulmonary artery . In a canine model , an
aortic valve balloon dilation to 5-12 atm pressure produced valve
leaflet connective-tissue injury and hemorrhage. In an experiment
with canine intestine, excessive lymph pressures (>850-1630 N/m2)
produced artificially in the central lacteals caused fluid to leak
out of the villi and caused intestinal epithelial cells to be shed
into the intestinal lumen . These risks can be largely avoided
or at least minimized by good design and experience with related
systems, initially in animal models.
4.1.4 Mechanical Interactions with Glycocalyx
cells are surrounded by a well-developed extracellular glycocalyx
. If this outer margin is traumatized, receptor sites and
fibronectin may be exposed [314, 315] which could then become
available for bacterial adhesion [316, 317].
Nanorobots that rely upon absorption of local oxygen
and glucose for their power supply (, Section 6.3.4) or whose
missions include extensive small-molecule exchanges with the
environment  may have ~104-105 molecular
sorting rotors (, Section 3.4.2) embedded in their exterior
surfaces [2, 6]. These spinning sorting rotors are unlikely to
cause direct physical damage to cell surfaces for several reasons.
First, rotors are atomically smooth and recessed into the housing,
reducing physical contact with colliding surfaces and eliminating
potential nucleation sites that may trigger thrombogenesis, gas
embolus formation, or foaming. Second, only a small fraction of all
available sorting rotors may be actively spinning at one time,
further reducing the likelihood of physical trauma. And such
limited contact, when it occurs, should be relatively benign:
Maximum rotor rim velocity of 2.6 mm/sec is less than 1% of mean
aortic blood velocity and lies only slightly above maximum capillary
flow speed (, Table 8.2).
Many disease processes are known that involve damage to the
glycocalyx [318-329], including some bacteria that phagocytose 
or otherwise destroy [331-334] the cellular glycocalyx during an
infection. Damage to the glycocalyx creates conditions that favor
the binding of immune complexes, complement activation, and
intravascular coagulation, with loss of gradients between blood and
parenchyma ; desialylated glycocalyx of endothelium also allows
an increased rate of endothelial cell detachment from arterial walls
. Could the glycocalyx strands present at all tissue and
nontissue cells surfaces get trimmed, even by a recessed sorting
rotor? Nanorobot sorting rotor binding sites for small molecules
(<20 atoms) involve pockets measuring <2.7 nm in diameter (,
Section 13.2.1.a), too small to physically accommodate the 10-20 nm
thick plasma membrane or the main body of the glycocalyx projections
typically measuring 5-8 nm thick and 100-200 nm long ,
consisting of glycoproteins comprised of 10,000 atoms or more.
While an occasional sugar residue may get clipped, binding sites can
be designed for maximum steric incompatibility with glycocalyx
glycoproteins and proteoglycans, further minimizing the
opportunities for trimming. Note that clipping a covalent C-C, C-O,
or C-N bond probably requires a clipping energy >500 zJ/molecule
(, Table 3.8), but sorting rotors designed to pump against
pressures of ~30,000 atm can only apply ~100 zJ/molecule (i.e., per
binding site) so an accidentally-bound glycocalyx moiety seems more
likely to jam the rotor than to be clipped off by the rotor. If
this happens, the result may be a glycocalyx-tethered nanorobot, in
which case a rotor-dejamming protocol* will be required to free the
Natural rates of glycocalyx damage are just starting to be
quantified [338, 339], and many tissue cells replace their
glycocalyx or are retired in times ranging from 103-106
sec. For example: Schistosome parasites can shed some
tegument-bound complexes in only ~1200 sec  to 3600 sec ;
plasma membrane turnover rate is ~1800 sec for macrophage  and
~5400 sec for fibroblast ; cholesterol turnover rate in RBC
membrane is ~7200 sec ; membrane phospholipid half-life
averages ~10,000 sec ; neutrophil lifespan in blood is ~11,000
sec ; enterocyte glycocalyx is renewed in 14,000-22,000 sec,
as vesicles with adhered bacteria are expelled into the lumen of
small and large intestine ; some schistosome membrane antigen
turnover may require from 68,000  to 160,000-430,000 sec
; typical protein turnover half-life is ~200,000 sec [345,
350]; cell turnover time is ~86,000 sec in gastric body, ~200,000
sec for duodenal epithelium, ~240,000 sec for ileal epithelium, and
~400,000 sec for gastric fundus ; neutrophil lifespan in
tissue is ~260,000 sec ; glycocalyx turnover in rat uterine
epithelial cells is ~430,000 sec ; and platelet lifespan is
~860,000 sec .)
the cell coat is a secretion product incorporated into the plasma
membrane that undergoes continuous renewal, any trimmed glycocalyx
glycoproteins from tissue cells would be rapidly replaced via
biosynthesis in the ribosomes of the endoplasmic reticulum, followed
by final assembly with the oligosaccharide moiety in the Golgi
complex and subsequent export to the plasma membrane .
Glycoprotein strands or stray sugar residues released into the
extracellular medium as a consequence of such trimming are
nonimmunogenic and would be quickly metabolized, although it is
possible that nearby parasites could absorb this released material
onto their surface, affording themselves some camouflage protection
against natural host immune defenses  but little protection
against vasculoid defenses since parasite antigens should still be
visible at cell surfaces.
One obvious backflushing procedure would use follower rods to
affirmatively push unwanted ligands out of the binding pocket.
Additionally, some molecular sorting rotor designs (, Section
13.2.1.d) assume a compliant mechanical coupling that permits the
rotor to spin backward a short distance as if in free rotational
diffusion, thus allowing improperly bound ligands to be freed.
4.2 Interruption of Plasmatic Water and Lymphatic
nanorobotic aggregate covering a macroscale area of the capillary
luminal surface may reduce the normal flow of plasma water  and
other substances that leaves the circulation via ultrafiltration,
unless the necessary water is replaced by the nanosystem. The
plasma water flow helps to remove waste products from the
extracellular spaces around tissue cells, a function that could be
compromised by the shielding presence of the nanoaggregate unless
the aggregate replaces this flow with water transported through or
around the device, by various means. Consequently, both
lymph volume and the gross water flows between tissues may be
affected by vasculoidization, given that the vasculoid substitutes
encapsulated fluid transport in place of bulk-flow and diffusive
fluid transport in the principal global materials distribution
system of the human body. More specifically, ~20 liters/day (0.23
cm3/sec) of plasma water exit the natural circulation via
ultrafiltration through leaky capillaries, of which 18 liters/day
are reabsorbed after passing through the lymphatic capillaries and
back into the venous loops , leaving a net flow of ~2 liters/day
to pass onward through the lymphatic system.
The maximum vasculoid water transport rate has been
scaled to 0.60 cm3/sec or ~52 liters/day, which is the
most that the water tanker subsystem can handle (Section 2.1.2).
Under normal conditions only ~4% of the water tanker fleet is in
use, which still allows the transit of at least 0.024 cm3/sec
or ~2.1 liters/day of water which if not re-imported by the
vasculoid on the venous side of the capillary bed is forced to enter
the lymphatic system, maintaining normal flow and volume. This flow
should be sufficient because the direct removal from the
intercellular fluids of pure waterborne electrolytes, solutes, and
other physiological substances by the vasculoid (through the plates)
can create pericellular concentration gradients sufficient to ensure
injection and removal of such substances from the vicinity of the
bathed cells. This should greatly reduce the gross intercellular
fluid flow rate required to maintain proper physiological
additional concern might arise because lymph is moved primarily by
peristaltic one-way valving. Envasculoided tissues adjacent to
lymphatic capillaries may have slightly higher mechanical stiffness,
hence may transmit somewhat less peristaltic action resulting in
reduced lymphatic flow rates. But lymph fluids transport solutes at
far below maximum concentration – for example, lymph normally
contains ~0.003 gm/cm3 NaCl, two orders of magnitude less
than the ~0.36 gm/cm3 maximum solubility at 310 K  –
and bacterial entry will be largely precluded by the appliance, so
small reductions in lymph flow rates are probably tolerable.
Lymphatic venules do exhibit small-amplitude pulsations
on their own, and it may be desirable for
other reasons (e.g., Section 4.1.1, Section 7) to simulate the
stiffness and motion (including motion resulting from blood flow) of
pre-vasculoid tissue. Lymph movement also may be replaced by an
optional “lymphovasculoid” appliance (Section 8.5).
Similar considerations and conclusions apply to other
fluid spaces within the body that communicate, directly or
indirectly, with the blood, including
the choroid plexus and cerebrospinal fluid, as well as the
pericardial, pleural, peritoneal, synovial, and intraocular fluid
If it proves necessary to maintain
gross intercellular fluid flow rates at original physiological
levels, in principle the entire 20
liter requirement may be supplied by local counterflows of tankers
moving from the venous loops back through the capillaries.
Transporting the needed ~0.2 cm3/sec of water across a
distance of ~1 mm (typical capillary length; , Table 8.1),
taking account of the ~10 sec tanker discharge time at docking bays
(Section 2.4.1), requires only an additional ~2.7 trillion water
tankers (adding ~60% to the basal active water tanker fleet;
Section 2.1.2) – about 140 new water tankers per capillary, or only
~0.6% of capillary wall surface area committed to this special
4.3 Immune System Interactions
(chemical vapor deposition) diamond coatings are said to have “low
immunoreactivity”  and there were no reports of diamond
immunogenicity in the medical literature as of 2001. Indeed,
diamond is often used as an experimental control because it is so
chemically inert and biologically inactive . Pure sapphire
also appears fairly nonimmunogenic, although similar hydrophilic
surfaces do adsorb immunoglobulin IgG ; single-crystal
sapphire has excellent biological inertness and chemical stability
[360, 404]. However , both diamond nanoparticles  and various
soluble aluminum salts (e.g., alum, aluminum hydroxide, aluminum
phosphate ) have been shown to serve as adjuvants which enhance
vaccines or immune system responses to foreign antigens.
Exposed to water, the polished
single-crystal a-alumina (0001) surface elicits a hydration
reaction, with a water vapor pressure of ~1 torr sufficient to fully
hydroxylate the surface . Alumina is corrosion-resistant
because it exists in the highest oxidation state that aluminum metal
can possess, and has the potential for microstructural control of
the interface (with tissue) without formation of toxic corrosion
products . Yet it is also known that a-alumina is very
slightly soluble in highly acidic or alkaline aqueous environments
(, Section 22.214.171.124.6). Since Al+++ ions can produce
“dialysis dementia” [365-367] and are generally considered toxic
[368-372], it is of interest to determine whether or not these ions
can leach into the body from alumina implants or sapphire
nanorobots. Early studies in the 1970s found no movement of known
contaminants into the surrounding tissue from sintered alumina
implants inserted into the iliac crests (hip bones) and mandibles of
rabbits . During the 1980s and 1990s, small increases in blood
aluminum concentrations were demonstrated in smelter workers ,
though the potential exposure level is several orders of magnitude
greater for body uptake of more soluble aluminum compounds used as
food additives , as antacid medication , or from food
packaging materials and cooking utensils . In 1990,
Lewandowska-Szumiel and Komender  investigated aluminum release
from an alumina bioceramic during standardized biocompatibility
testing in an animal experiment. Alumina implants introduced into
rat femurs and guinea-pig mandibles and then removed 6-8 months
later were found to be well tolerated, and no changes in the
surfaces of the removed implants were observed under SEM
examination. The researchers decided to compare the aluminum
content of the femurs of experimental and control rats using atomic
absorption spectroscopy, and discovered that the level of aluminum
was higher in the bones of the experimental animals. In 1991,
Arvidson et al  investigated the corrosion resistance of
single-crystal sapphire implants with respect to the release of
aluminum ions, and found no ions in the test solutions. The next
year, Christel  reported that alumina exhibited greater
bioinertness than all other implant materials currently available
for joint replacement, and that no lymphocyte or plasma-cell
infiltration into joint implants is observed “because of the absence
of soluble component release.” However, two studies in the early
1990s [379, 380] found some detectable aluminum ion release, so more
research is clearly required on this issue. In any case, a thin
veneer of diamond on sapphire  should suffice to prevent
aluminum ion release in vivo.
An allergic reaction or
“hypersensitivity” is an acquired and abnormal immune system
response to a substance, called an allergen, that normally does not
cause a reaction. An allergy requires an initial exposure to an
allergen which produces sensitization to it; subsequent contact
with the allergen then results in a broad range of inflammatory
responses. Sapphire or alumina ceramic [382-384] is considered
nonallergenic – ceramic coatings are used to eliminate metal
allergies on implant surfaces [385, 386], and hypersensitivity to
oral ceramic is reported only rarely [387-390]. There are no
reports of allergenicity for diamond, sapphire, fullerenes, or other
probable diamondoid nanorobot exterior materials and such
allergenicity appears unlikely, but experiments should be done to
positively confirm this expectation. The immune system could also
react to small subcomponents like cilia, especially if they form
aggregates with proteins, possibly requiring clonal deletion or
tolerization to deal with such issues (, Section 15.3.3).
Could the vasculoid surface in contact with the vascular endothelium
trigger general inflammation in the human body? One early
experiment  to determine the inflammatory effects of various
implant substances placed subdermally into rat paws found that an
injection of 2-10 mg/cm3 (10-20 micron particles at 105-106
particles/cm3) of natural diamond powder suspension
caused a slight increase in volume of the treated paw relative to
the control paw. However, the edematous effect subsided after 30-60
minutes at both concentrations of injected diamond powder employed.
Another experiment  at the same laboratory found that
intraarticulate injection of diamond powder was not phlogistic
(i.e., no erythematous or edematous changes) in rabbit bone joints
and produced no inflammation. Diamond particles are traditionally
regarded as biologically inert and noninflammatory for neutrophils
[393-396] and are typically used as experimental null controls
. CVD diamond  and DLC diamond  surfaces elicit
minimal or no inflammatory response, and atomically smooth diamond
may perform even better. Diamond particles are said to have little
or no surface charge [395, 399] but unmodified graphene (,
Section 2.3.2) surfaces readily acquire negative charges in aqueous
suspension [400, 401], so experiments are needed to determine if
negatively charged fullerenes or other diamondoid substances can
contact-activate Hageman factor or kallikrein and trigger an
Experiments with sapphire have
generally found no serious inflammation in soft tissues [402-405] or
bony tissues [406-408], or only mild reactions , though there
are a few modest exceptions [410, 411] including a brief acute
inflammatory response [412, 413].
Blood coagulation involves a complex series of reactions in which
various proteins are enzymatically activated in a sequential manner,
transforming liquid blood into a gel-like clot which is then
stabilized to form a thrombus (clot) consisting of platelets,
fibrin, and red cells. The series of reactions is classically
divided into two pathways – extrinsic and intrinsic – involving more
than a dozen factors that converge on a single common final pathway,
resulting in clot formation [346, 414-420]. Since these factors are
carried by the blood, the vasculoid can regulate their local
concentration and thus prevent thrombogenic pathways from proceeding
Additionally, platelets must undergo adhesion and activation for
coagulation to occur. The adhesion of platelets to exposed collagen
in injured blood vessels is mediated by a bridging molecule called
von Willebrand's factor  that is secreted by endothelial cells
into plasma, which prevents platelets from detaching under the high
shearing stresses developed near vessel walls. The activation of
normally quiescent platelets is a complex phenomenon that includes
changes in cell shape, increased movement, release of the contents
of their granules (containing nucleotidyl phosphates, serotonin
, various factors, enzymes and plasma proteins), and
aggregation. The most potent activator of platelets in vivo is
thrombin , which interacts with a receptor on the platelet
plasma membrane, followed by transmembrane signaling and subsequent
activation of the cell. Collagen  is the other most important
platelet activator; ADP can stimulate aggregation but not granule
release. In principle, the blood-contacting surfaces of a
nanoorgan, or of nanorobots in sufficient bloodstream numbers and
concentrations, could activate platelets (and thus either of the two
coagulation pathways), but careful choices of materials and of
allowable mechanical motions should reduce or eliminate inherent
nanodevice thrombogenicity. For example, DLC diamond-coated stents
[425, 426], heart valves [427, 428] and other blood-contacting LVAD
surfaces [429-432] or substrates [433, 434] generally show reduced
thrombogenicity and no platelet activation . Sapphire (alumina
ceramic) has low thrombogenicity [435-437] and both platelet
adhesion  and activation  are low. Hemolysis is near-zero
for diamond [434, 439] and alumina  powders. Additionally, in
the vasculoid plateletogenesis and release of platelets could be
actively regulated and reduced to minimal levels.
Future experiments must
determine if ordinary diamondoid surfaces will have to be
supplemented with additional antithrombogenic coatings in order to
achieve vasculoid performance objectives. If such coatings are
required, one simple possibility is surface-immobilized heparin, a
~15 kD straight-chain anionic (acidic) mucopolysaccharide
(glycosaminoglycan) that forms polymers of various lengths.
Heparin, first discovered in 1916 , is produced naturally by
human liver mast cells and basophil leukocytes, and inhibits
coagulation primarily by accelerating the interaction between
antithrombin and thrombin. Nanorobot exteriors can be “heparinized”
[441-450], and thereby rendered thromboresistant by immobilized
heparin on all blood-contacting surfaces at ~monolayer surface
concentration (e.g., 7-10 pmol/cm2 ). Cellulose
membranes coated with 3.6 pmol/cm2 of
endothelial-cell-surface heparan sulphate show complete inhibition
of platelet adhesion . If satisfactory passive nonthrombogenic
surfaces cannot be found, nanorobots might employ any of several
active strategies to prevent iatrogenic coagulation (, Section
4.6 Regulation of Angiogenesis and Vasculogenesis
During development and after
physical injury, new blood vessels may originate from pre-existing
blood vessels by angiogenesis or from endothelial cell precursors
(angioblasts) by a process called vasculogenesis; both processes
are mediated by paracrine growth factors [452-457]. In certain
circumstances, such as wound healing, post-ovulation capsule repair,
and exercise-related capillary formation to support development of
new skeletal muscle [458-460], angiogenesis is critical in the adult
human body and its lack has been associated with chronic renal
failure  and other pathological conditions.
Without the ability to incorporate vasculoid plates into new capillary
vessels, masses of new non-envasculoided tissue would accumulate
around the original (envasculoided) tissues over time, reducing the
effectiveness of the appliance. In principle, vasculoid can
support angiogenesis and vasculogenesis by extending itself into the
newly-formed space. Watertight multicomponent metamorphic surfaces
have been described by Freitas , Section 5.3), but special
techniques will be required to extend a new vascular branch while
maintaining continuous watertightness. An angiogenesis event can be
detected by monitoring concentrations of angiopoietin-2, VEGF, and
other relevant factors. Conversely, detection of tumor angiogenesis
factors could induce a vasculoid-mediated reduction in oxygen
supply, increased local delivery of antibodies, refusal to deliver
angiogenesis factors, and optional intervention such as delivery of
chemotherapeutic drugs or external signaling to call for targeted
It is envisioned that self-repair capabilities
(Section 2.5) via active replacement of damaged components (from
onboard inventories of spare parts including spare plates; Sections
7.6 and 8.3) will be an important feature of the complete vasculoid
system design. These capabilities may
be extended to support angiogenesis. When angiogenesis is not
desired (for example, near tumors), local concentrations of
angiogenic factors can be regulated by the vasculoid appliance to
minimize vessel formation, and the vasculoid can refuse to deliver
nutrients to the undesired tissues even if ersatz capillaries form.
Attention must also be paid to
the removal and disposal (or temporary onboard warehousing; Section
8.3) of damaged plates. In rare cases, traumatic events may
damage plates (rather than simply causing them to separate
temporarily), and radiation damage may cause rare failures. A
capillary damaged beyond repair (e.g., in a severe contusion) may be
abandoned and dismantled by the body; in such a case the vasculoid
should cease delivery to that region and remove the plates.
Damaged endothelial cells can be detected based on
sensory data indicating localizing chemical imbalances, and new stem
cells or endothelial precursor cells (Section 2.2.1) can be
transported to the vicinity of the damaged site to help restore the
natural vascular integrity. Such restoration in some cases may
require repositioning of a few plates using the motive cilia
(Section 7.4), but the description of detailed specific angiogenic
response, plate replacement or vascular repair activities are beyond
the scope of this paper.
4.7 Vascular Patency and Relaxation
One important function of fluid flow in blood vessels
is to ensure vascular patency. But replacing bulk fluid with a
vasculoid appliance is unlikely to cause the smaller vessels to
collapse because the buckling force is increased by up to several
orders of magnitude by the addition of the plates in the capillaries
and related small vessels, even in the absence of bulk fluid
(Section 8.8). The largest vessels such as the aorta will lose
significant luminal support (even if filled with gas), but – in
addition to the external muscular and elastic support from the
surrounding tunica media and tunica adventitia layers – such vessels
also possess an extensive capillary vasculature which, greatly
stiffened and at typical capillary densities, should provide
adequate replacement support. Intravascular (cross-luminal)
spring-loaded diamondoid scaffolding could also be added at need.
Arterioles in the natural vascular system perform
extensive regulatory functions. These and related functions
(including vasoconstriction and vasodilation) can be controlled, in
turn, by the vasculoid (e.g., by monitoring local NO
concentrations; Section 2.1.7). The underlying vascular
musculature will probably be maintained in the relaxed state if this
maximizes tissue stability and simplicity of control, although
further research of this question is warranted.
5. Control Systems and Computational Requirements
Numerous local, intermediate-scale, and global control systems and
protocols will be required to ensure the proper autonomic operation
of the vasculoid appliance. Special communications subsystems for
local plate configuration maintenance, cargo traffic control, and
fast systemic response to large-scale external stimuli must be
designed. An interplate packet-switching network for long-range
communications, and to support real-time autogenous user control,
should be considered. System control might be simplified using
local computing centers throughout tissues, directing immune,
angiogenetic, and trophic functions. Besides the interplate
network, trans-tissue sonic or optical communication in principle
could be employed between spatially close but topologically distant
portions of the vasculoid network. Precise knowledge of the
functions of various cytokines and other substances will enable the
vasculoid to respond appropriately to sensor data reporting local
extravascular concentrations of signaling molecules. Complexity of
stimulation patterns must mirror physiological conditions as much as
possible. Highly responsive and user-friendly graphic user
interfaces may be useful to allow the patient to communicate quickly
and easily with his or her appliance; several aspects of such
interfaces have been described elsewhere (, Section 7.4), but
considerably more work remains to be done . The computational
requirements of directed container switching/routing by the ciliary
system should be investigated further.
great number of software and computational architectural issues are
as yet unresolved, including a detailed molecular routing logic for
each substance to be transported, comprehensive details of nanorobot
control protocols, container traffic flow patterns (e.g. flow
lensing, lane definition, congestion waves and gridlock, flow
viscosity, etc. ), and software requirements including software
complexity for large-scale control issues, a discussion of which are
beyond the scope of this paper. (For example, it might be
interesting to apply existing vehicular traffic simulations to
transport in fractal structures.) Only since the mid-1990s have
multirobot control issues begun to be seriously addressed by the
broader research and technical community [462-469]. Computation for
vasculoid accident recovery and repair will be considerably more
intensive than computation for maintenance or installation, and must
also be deferred to another paper.
However, a few basic observations may be made here regarding
vasculoid materials transport computation requirements.
Concentrations of water and glucose are normally maintained by the
appliance near typical serum levels, using simple feedback loops
driven by concentration sensors located on the tissue side of the
vasculoid device. Oxygen and carbon dioxide are similarly
controlled using sensors capable of measuring partial pressures,
though the precise triggering thresholds may be modified in special
circumstances (e.g. high altitudes, deep sea diving, hyperbaric
chambers). A simple rate-control mechanism driven by sensor data
compiled once every second, employing ~1000 distinguishable
concentration levels requires ~10 bits/sec per molecular type, or
~40 bits/sec for all four molecules. Most of the time, entire rotor
banks are engaged using a single command. Ciliary motions, largely
stereotypical, likely require a similarly small computational
Establishing or maintaining appropriate concentrations of
mixed-cargo molecules is far more computationally complex. These
other molecules include minerals, vitamins, lipids and waste
products, but the most numerous and difficult to coordinate are the
blood proteins and sterols including control molecules such as
insulin, leptin, gastrin, resistin, estrogen, or testosterone;
synaptic transmitters and other neural biochemicals such as
acetylcholine, adrenalin, dopamine, nitric oxide, or serotonin;
cytokines and other signaling molecules such as follicle stimulating
hormone, epidermal growth factor, or tumor necrosis factor; and
many thousands of specific antibodies that reflect the body's unique
learned recognition of specific antigens. (Embedded analytical
units scattered throughout the vasculoid surface can test for rising
concentrations of hitherto unrecognized nonmetabolizable molecules,
and configure a set of programmable binding sites (, Section
126.96.36.199) to rotor these molecules out of the tissues as well, though
this should be a relatively rare occurrence.) Since the human
genome contains ~40,000 genes, most of which may encode several
proteins each, we assume there may be on the order of ~100,000
distinct biomolecules that must be recognized, monitored,
transported, and regulated at the docking bays. This is likely a
generous estimate, given that most of the proteins produced remain
intracellular, but our conclusions do not depend sensitively upon
the precise figure chosen.
Upon receipt of any tanker, each docking bay scans the tanker
manifest before offloading the contents. In the case of gas, water,
and glucose tankers, the manifest is extremely brief, since only one
or two molecules are involved. This content information can be
encoded in as little as 15 bits. A precise molecule count of up to
3 x 1010 molecules per tanker requires an additional 35
bits, but in most cases a precise molecule will not be necessary and
a range figure requiring fewer bits should suffice. At the maximum
rate of one tanker unloading every 20 seconds (Section 2.4.1), the
manifest-reading bit rate is at most ~2.5 bits/sec.
In the case of mixed-cargo
tankers, 17 bits uniquely specify the identity of each of 100,000
distinct molecules; each tanker can hold a total mixed-cargo
molecule count of ~109, requiring up to 30 bits per item
to ensure an exact count. Based on existing human physiology, we
posit a specification that each vascular cell must have access to at
least 5% of all ~100,000 molecular types during one blood
circulation time, ~60 sec. Since each cell is supplied by two
mixed-cargo docking bays, then restricting tankers to a maximum of
834 different molecules per load fulfills our specification,
requiring in the worst case a 39,198 bit manifest to be read in 20
seconds, a maximum bit rate of ~2,000 bits/sec. Again assuming ~10
bits/sec per molecular type for rate-control of rotor mechanisms,
rotor control will require a maximum ~8,340 bits/sec. (One design
alternative is to allow stochastic mixing and transport of the
low-concentration molecules which would mimic the natural process,
reduce the computational needs, and impose only a very small burden
on the transport capacity.)
In sum, docking bay process
control appears to require ~10,000 bits/sec of computation.
Cellulock control requires reading manifests of up to ~1000 cells of
at most ~1000 different types, which is ~20 bits/cell type or
~20,000 bits/manifest. Cellulocks unloading one boxcar every 60
seconds (Section 2.4.2) will require a bit rate of ~333 bits/sec.
Other control tasks will add only fractionally to the ~10,000
ops/sec budget previously estimated for individual docking bays
(Section 2.4.1), a capacity that can be used for other purposes
between docking events.
6. Overall System Reliability
detailed assessment of vasculoid system reliability also lies beyond
the scope of this paper, especially given the possibility for prompt
and severe damage if the robot is subjected to extreme accelerative
loads or unplanned segmentations. However, if we assume normal
gravitational loading and ignore catastrophic accidents, we find
that the vasculoid promises an annual survival probability well in
excess of “six nines” (failure probability < 10-6) at
least against radiation damage if all major subsystems incorporate
tenfold redundancy as specified in Section 2.
Adopting Drexler's  radiation damage model for the first part of
this analysis and applying it to a system comprised of N components,
with each component comprised of n redundant parts, the probability
P that the system remains operational after T years is approximated
by: P = exp [-N (1 - p)n], where p = the probability
that an individual part remains operational; p ~ exp(-1015
Dm), where m = mass of the part in kg and D = radiation dose in rads
~ 0.5 T for normal background radiation in the terrestrial
environment. As a further simplifying assumption for this analysis,
we shall presume that all vasculoid modular “parts” are similar in
mass to the ~4,000,000-atom robotic manipulator device described in
, after which the vasculoid cilium is patterned (Section 2.3.1).
From the above formulae, p ~ 0.999960 for each such cilium-like
part, per year, even with no internal redundancy within the part.
vasculoid ciliary subsystem (Section 2.3) includes a minimum
requirement of N = 300 trillion cilia incorporating a redundancy of
n = 10, giving a total of 3000 trillion cilia. From the above, the
annual probability of failure of the ciliary subsystem is < 10-29;
assuming a redundancy of only n = 5, failure probability is still <
Each vasculoid plate is ~2 micron3 in volume. Given that
there are ~150 trillion plates, with zero redundancy among them,
then to be assured of a complete plate subsystem annual failure rate
< 10-6, the annual probability of failure per plate must
be reduced to ~10-20. This is achieved for plates
comprised of a total of ~88,000 “parts” as described above, with a
redundancy of ~6 among such parts. However, in this study we have
specified a more generous (i.e., safer) redundancy of 10 among such
parts (Section 2.4.1).
Each vasculocyte repair robot is ~10-14 kg in mass.
Given that there are ~200 billion active vasculocytes, and assuming
zero redundancy among them, then to be assured of a vasculocyte
subsystem annual failure rate < 10-6, the annual
probability of failure per robot must be reduced to ~10-17.
This is achieved for robots comprised of a total of ~125,000 “parts”
as described above, with a redundancy of ~5 among such parts; we
have again assumed a more generous redundancy of 10 among such parts
Non-radiation failure mechanisms have not been examined in the above
analysis. Software failure modes have been ignored, and even plate
computers may be complex enough to host intentionally disruptive
programs such as computer viruses. Many other more subtle or
second-order difficulties also have been ignored in the present
paper, such as the potentially destabilizing effects of dynamic
oscillations and resonances among the various moving components
which would require a detailed design before undertaking a
comprehensive analysis. For instance, we should try to avoid Per
Bak’s notion of self-organized criticality [470-474] when complex
systems are pushed too close to their design limits, as in car
traffic simulations. Numerous specific failure modes have not yet
been exhaustively analyzed, including complete single-plate failures
and the seizing or locking of individual cilia while a transfer
operation is in progress, e.g., near a capillary entrance where such
failures could prove most troublesome. However, the vasculocyte
fleet has been scaled to accommodate a reasonable repair mission
requirement (Section 2.5). A discussion of possible autogenous and
autonomic repair behaviors in response to major device trauma has
also been deferred to subsequent papers.
Vasculoid tankers are
micron-size compressed-gas containers which may rupture explosively
– though this event is extremely improbable, since tankers with
rupture strength exceeding 40,000 atm are loaded to only 1000 atm
pressure (Section 2.1.1). If this unlikely rupture event occurs in
a large vessel such as the aorta, the possible failure modes may
resemble those involved in a detachment avalanche (Section 2.3.1),
but the low tanker mass should preclude any serious direct
infrastructural damage. However, if the explosive event occurs
within a smaller vessel such as a capillary, the risk of breach is
considerably greater. However, the maximum overpressure that can be
explosively applied to the appliance walls is limited to the ~1000
atm compression pressure of the tanker contents (Section 2.1.1),
which likely does not exceed the theoretical rupture strength (,
Eqn. 10.14) of the vasculoid walls in capillaries which may be
crudely estimated as pmax ~ 3300-33,000 atm, taking
vasculoid plate tube thickness twall = 1 micron,
capillary tube radius R ~ 3 microns (, Table 8.1), and working
stress sw ~ 1010 N/m2 (, Table
9.3) for solid tube walls or maximum interbumper working stress sw
~ 109 N/m2 (, Section 5.4.3) for more
realistic plated walls jointed with bumper interconnects. Whether
such explosive events will occur with sufficient frequency to
warrant explicit corrective protocols (beyond conventional vasculoid
self-repair activities; Section 2.5) deserves further study. A
shockwave cascade failure (such as recently occurred at the Super
Kamiokande neutrino detector facility, wherein the initial implosion
of a single photomultiplier tube (PMT) during refilling of the water
tank triggered a runaway cascade, destroying 6,665 of the 11,146
PMTs in a few seconds ) seems unlikely in the vasculoid but
also should be investigated theoretically.
In practice, one should expect
that a few contaminant molecules will make their way into the
vasculoid, perhaps from local strain that exceeds the adjustment
capabilities of the metamorphic bumpers, accidental spills, and so
forth. A molecule that is small enough to be mobile at room
temperature is small enough to be captured by a sorting rotor.
Larger molecules can be physically handled by vasculocytes. A
specialized class of vasculocyte, also measuring several microns in
size and moving at ~1 cm/sec, can employ a 0.25-mm-wide chemotactic
detector bank on each mobile nanorobot to search for, bind, and
remove large molecules – a complete sweep of the entire vasculoid
luminal surface once a minute requires the activity of only 1% of
the total active vasculocyte fleet. The motion of the tankers
creates a net motion of the nitrogen atmosphere that can sweep
molecules toward centrally placed filters. Thus a combination of
internal sorting rotors, filters, and vasculocyte activity can
quickly extract contaminants from the vasculoid volume. Once
contaminants are trapped, they may be dealt with in ways suggested
previously (e.g., Section 8.3; , Section 10.4.2; etc.). The
volumetric capacity of the appliance to deal with internal
contamination must be scaled according to anticipated applications
and event scenarios, which should be studied further but are beyond
the scope of this paper.
7. Hypothetical Vasculoid Installation Scenarios
Installation of the vasculoid
involves, at the least, complete exsanguination of a sedated patient
and an intricate vascular plating operation. Two hypothetical
installation scenarios are presented. The first scenario (Sections
7.1 to 7.7) is a detailed description of a procedure that would be
feasible using the technology available in 2002. This is to
demonstrate that vasculoid installation can in principle be carried
out without violating any well-established medical or physical
limits. However, the authors are aware that by the time a
vasculoid-class device can be built, medical technology will have
advanced significantly. We therefore also briefly sketch out a
highly speculative second scenario (Section 7.8) which, if
practicable in some future era, might be considerably more
convenient and up to 100 times faster. This second procedure would
be unduly aggressive by today's standards but might be feasible and
safe, given the supporting technology available in a
nanotechnology-rich medical environment.
principal installation scenario involves complete exsanguination of
a sedated and hypothermic patient, replacement of the natural
circulatory fluid with various installation fluids, followed by
mechanical vascular plating, defluidization, and finally activation
of the vasculoid and rewarming of the patient. Installation takes
~6.5 hours from start to finish and requires a peak ~200-watt power
draw midway through the procedure. (By comparison, present-day
kidney dialysis treatments require 4-12 hours and the equipment also
draws a few hundred watts.)
discussion first considers the lifespan of cells temporarily denied
access to external molecular transport mechanisms (Section 7.1). We
next describe the details of vasculoid installation including
patient preparation (~24 hours; Section 7.2), vascular washout (~4
hours; Section 7.3), vascular plating (~1 hour; Section 7.4),
defluidization (~0.3 hour; Section 7.5), and initialization and
cold start (~1.2 hours; Section 7.6). We conclude with a brief
discussion of vasculoid removal (Section 7.7).
hypothetical installation protocol described below has been selected
for maximum comfort, reversibility, and reliability. The correct
performance of the system is verified at every step, providing a
plateau of safe operation before moving on to the next step. Since
the entire procedure is intended to be fully reversible at each
step, any step which fails or does not proceed in a manner
acceptable to the installing physician may be quickly abandoned with
a retreat to the previous plateau of established safety, after which
a decision may be made to try again or to abort the installation.
Patients must be made aware that they are about to undergo a major
medical procedure which involves replacing ~8% of their body mass
with complex nanomachinery. They must be psychologically prepared
to deal with the personal implications of this.* From the
turn-of-the-century perspective, vasculoid installation appears
massively intrusive especially when compared to other superficially
related procedures with which we are commonly familiar such as
intubation, kidney dialysis, blood transfusion and blood replacement
therapies, installation of pacemakers or artificial organs, and
coronary angioplasty or fiberoptic endoscopy. However, in a future
era when nanomedical systems are widely employed and generally
accepted as standard treatment, vasculoid installation may be
regarded with considerably less trepidation than it would today.
* One recent recipient of an
artificial heart reports  that living with an artificial heart
entails adjusting to some strange new sensations: “The biggest
thing is getting used to not having a heartbeat, except a whirring
7.1 Cellular Ischemispecific Limits
classical medicine, “ischemia” refers to a local inadequate blood
supply which is usually caused by a mechanical arterial obstruction
(e.g. clot), a spasm wherein a blood vessel pinches shut, arterial
narrowing (e.g. arteriosclerosis), or cessation of cardiac
activity. The principal clinical outcome of local ischemia is a
shortage of oxygen. Because of the high continuous biological power
density of nerve cells, neurons and the brain succumb most rapidly
to oxygen starvation. The precise survival limit of human brain
tissue under hypoxic conditions (after which time some decline
begins to occur) depends on many factors. Traditionally this has
been reported as ~4 minutes (240 sec), although more recently it has
been shown that 10 minutes of warm ischemia (even followed by
another 10 minutes of trickle-flow CPR) is reversible without
neurological deficit if followed by mild hypothermia when normal
blood flow is restarted , and even modest advances in
technology will likely extend this still further. Much longer
periods of cold ischemia are tolerable – for example, survival with
complete functional and histologic cerebral recovery has been
achieved with brain temperature at 5-10 oC during 1 hour
of circulatory arrest , and stable spontaneous circulation has
restored after water ice submersion of up to 90 minutes .
nanomedicine, where it is possible to achieve precise control of
human physiology at the cellular and molecular levels, ischemia may
refer to an interruption in the extracellular mass transport of any
vital molecular species within the human body. Failure to
adequately import a particular nutrient, or to adequately export a
specific harmful waste product, or to properly regulate the
transport of a particular signaling molecule, may produce some of
the classical symptoms of cellular ischemia. Since the entire
bloodflow must be interrupted during the vasculoid installation
process (producing whole-body ischemia), it is useful to estimate
how long tissue cells can maintain normal metabolism and avoid
toxemia after cellular access to the bloodflow is denied. This time
period – the ischemispecific limit – varies with each important
cytometabolic molecule, as summarized below. (The limit also varies
by cell type; a more detailed study would likely reveal specific
tissues where ischemic sensitivity is higher than average for a
Oxygen. The average (20
micron)3 tissue cell consumes ~107
molecules/sec of O2 at the basal (resting) rate of ~30
picowatts. The cytosol of such a cell can dissolve up to ~6 x 108
O2 molecules at 310 K. If suddenly cut off from all
external supply, the average cell has only enough O2 in
inventory to survive ~60 sec at the basal metabolic rate.
Glucose. Assuming ~50%
energy conversion efficiency  and ~10-3 gm/cm3
glucose in the cytosol (, Appendix B), then ~3 x 1010
glucose molecules are available in the average tissue cell. For a
power demand of 30 picowatts, ~4800 zJ/glucose molecule, and ~50%
energy conversion efficiency, then the basal glucose consumption
rate is 1.25 x 107 glucose molecules/sec and the basal
cellular ischemispecific limit for glucose is ~2400 sec.
Carbon Dioxide. The
metabolic “combustion” of one molecule of glucose with six molecules
of O2 produces six molecules of CO2, hence the
average tissue cell produces ~107 molecules/sec of CO2
at the basal rate. The cytosol of an average cell should normally
dissolve up to ~1010 molecules of CO2 at 310 K
(assuming working tissue PCO2 = 54 mmHg (, Table 1)
and applying the Henry’s law constant for CO2 (, Table
9.2)), an estimate which compares favorably with the measured ~5
millimoles/kg intracellular CO2 concentration (2.4 x 1010
molecules/cell assuming an 8000 micron3 cell) in various
frog tissue cells at 302 K . Hence the cellular
ischemispecific limit for CO2 is ~1000 sec, consistent
with maximum physiological cellular and plasma pH levels. It may be
possible to dissolve more CO2 but this will lower pH,
leading to toxic acidosis of the cell. (Acidosis has two major
components, CO2 and lactic acid. The absence of oxygen
blocks electron transport and stalls the Krebs cycle, halting CO2
production, so glucose is shunted to lactic acid in anoxia.)
Additional amounts of CO2 may be stored in combination
with plasma proteins as carbamate.
anaerobic conditions, lactic acid is produced during the metabolism
of glucose (glycolysis) in most cells , glycogenolysis in
muscle  and glucolysis ; two molecules of lactic acid are
produced per molecule of glucose metabolized. Thus at the basal
rate the average anaerobic tissue cell can produce at most 2.5 x 107
lactate molecules/sec – though this is an overestimate by perhaps a
factor of 2  because in most cells the pyruvate (the immediate
precursor of lactic acid) formed at the end of glycolysis enters the
TCA cycle and is further oxidized by mitochondria [484, 485]. The
maximum normal blood concentration of lactate (, Appendix B)
equates to ~1.1 x 1010 molecules/cell, potassium channel
openings are induced by 2-20 nM lactate (0.96-9.6 x 1010
molecules/cell) applied to the cytosol of rabbit ventricular
myocytes , and the brain lactate threshold for cerebral
ischemic damage is 17 mmol/gm  or ~8.1 x 1010
molecules/cell, so the ischemispecific range for lactate is
Nitrogenous Waste Products.
Urea is the principal mammalian waste product due to protein,
purine, and pyrimidine nitrogen metabolism, constituting ~85% of
human nitrogen excretion. However, urea is formed in the human
liver through reactions of the Krebs ornithine cycle, a process not
available to tissue cells denied access to the circulation. Ammonia
 is the chief byproduct of protein and amino acid metabolism in
the cell, with one molecule of ammonia produced per molecule of
amino acid broken down. The daily RDA for protein represents an
upper limit on the breakdown rate of ~5 x 105 amino acid
molecules per cell-sec, assuming mean amino acid MW ~ 100 Da,
implying a maximum ammonia generation rate of ~5 x 105
molecules/cell-sec. Given the maximum observed concentration of
ammonia of ~6 x 108 NH3 molecules/cell in
whole blood cells (, Appendix B), the ischemispecific limit for
nitrogenous wastes is ~1200 sec.
Acetate. Acetic acid
(MW = 60 Da) is the simplest possible fatty acid having an even
number of carbon atoms. It is most notably produced during the
breakdown of acetaldehyde (the second step in the metabolism of
alcohol), bacterial fermentation in the gut, and in other
circumstances. The typical human intracellular production of acetic
acid has been roughly estimated from rat studies  as ~8 x 106
molecules/cell-sec. This chemical is highly metabolizable in vivo,
but assuming a maximum nontoxic limit of ~10-4 gm/cm3
(vs. ~4 x 10-3 gm/cm3 for all esterified fatty
acids in cells) or ~1010 molecules/cell, then the
ischemispecific limit for acetic acid is ~1300 sec.
circulatory removal and in cases of low glucose levels, the
metabolism of fats may produce abnormal amounts of toxic ketones
including primarily beta-hydroxybutyric and acetoacetic acids (and
their decarboxylation product acetone) which may be present up to ~6
x 108 molecules/cell assuming MW ~ 86 Da for ketones.
Given the RDA for lipids of ~7 x 10-7 kg/sec (Section
2.1.6), and since one palmitic acid (typical lipid) molecule (MW =
256 Da) would convert to ~3 molecules of acetoacetic acid (MW = 86
Da), the maximum natural ketone generation rate is ~5 x 105
molecules/cell-sec and the minimum ischemispecific limit for ketones
is >1200 sec.
Summary of Cellular
Ischemispecific Limits. If the average
human tissue cell is denied access to all extracellular molecular
transport systems, the major byproducts of normal cellular
metabolism may build to near-toxic levels from a near-zero initial
concentration in ~103 sec. Glucose reserves last >103
sec, but oxygen runs short in ~102 sec without external
resupply. These theoretical limits appear crudely consistent with
the concept of the “Golden Hour” in traditional trauma care
[490-495]. For instance, ischemia induced by aortic cross-clamping
in dogs has been survived for up to 20-60 minutes without inducing
paraplegia  (though decline of spinal cord electrical function
is detected in the ~20-30 minute range for dogs and rabbits
[497-499]). Cardiac ischemia induced by aortic cross-clamping in
dogs is survived for 30 minutes during normothermic (37 oC)
cardioplegia , 45 minutes during mild hypothermic (28-30 oC)
cardioplegia [501, 502], and 90 minutes using potassium verapamil
during profound hypothermic cardioplegia at 8-10 oC
. The duration of cold ischemic tolerance is enhanced by the
administration of excess insulin  and other pretreatments
[505-507], possibly involving gene products  that will be
well-known in a future nanomedical era in which vasculoid
installation is commonplace. (Interestingly, wood frogs can endure
freezing for >2 weeks with no breathing, no heart beat or blood
circulation, and with up to 65% of their total body water as ice
7.2 Patient Preparation (~24 hours)
Before the vasculoid may be installed, the patient must be prepared
(1) Vascular Conditioning. The day before the installation,
the patient receives an injection containing a treatment dosage (~1
cm3) of vascular repair nanorobots , or ~70 billion
individual devices. These 8-picogram, 7 micron3 mobile
legged artery-walking nanodevices clean out all fatty streaks,
plaque deposits, complex atherosclerotic lesions, infections,
vascular wall tumors, and parasites, and repair all other vascular
lesions as required in less than 24 hours, in a multistep process
described elsewhere in detail . As one additional task, these
nanorobots inject each of the ~1012 endothelial cells
lining the human vascular tree (a) with cytokine blockers to at
least partially inhibit the cells' natural surface pressure and
shear force responses [510-515], and (b) with adhesion-inducing
glycoproteins to forestall cell migration during the installation
procedure by encouraging firm anchoring. All vascular repair
devices are then exfused before vasculoid installation begins; the
results of their vascular reconnoiter protocol may be downloaded to
an external computer and used to prepare a detailed map of the
patient's vascular tree to improve efficiency during plating
(Section 7.4) and plate initialization (Section 7.6). The patient
may be started on a diuretic (e.g. furosemide) to reduce blood
volume a few hours before the installation procedure begins.
(2) Sedation. On the day of the operation, the patient
arrives at the installation facility and is administered a
preoperative sedative such as sodium pentobarbital an hour before
the procedure is to begin, to encourage drowsiness.
(3) Cannulation. A standard closed-chest cardiopulmonary
bypass  (aka. heart-lung machine support) or CPB is employed.
Usually this involves a combination of femoral and thoracic vessel
cannulation, but in this case a fem-fem bypass (cannulation of the
vena cava and aorta via the femoral vein and artery) might suffice.
This procedure, by definition, continuously supplies the equivalent
of resting cardiac output through the femoral vessels and the blood
pump/oxygenator circuit – typically a 50-70 cm3/sec flow
rate during hypothermic CPB , allowing the entire human blood
volume can be exchanged about once every few minutes. Fresh
oxygenated blood flows retrograde up the femoral artery into the
aorta, and oxygen-depleted blood flows retrograde down the vena cava
to return to the heart lung machine via the femoral vein. The leg
inferior to the cannulation point is supplied by collateral
vessels. At this point in the procedure, the patient’s own blood
continues to circulate through the body. (Note that the above
“manual cannulation” scenario is included for illustrative purposes
only. In an era when advanced medical nanotechnology is available,
self-directing nanocannulators  will make it easy to quickly and
safely establish flow-regulated channels into any desired artery or
vein, up to and including the aorta and vena cava, so much higher
flow rates than the conservative figures used in this Section are
theoretically available if required.)
(4) Heparinization. Heparin and streptokinase are injected
(a) to prevent clotting and promote lysis of hemostatic fibrin, (b)
to break up axial red cell rouleaux that form spontaneously at low
blood flow shear rates, and (c) to help ensure patency of the
catheters throughout the procedure. The conventional cocktail of
drugs given to patients placed on bypass leading up to a cold
circulatory arrest procedure is rather complicated and will not be
elaborated further here, but there are established procedures in
conventional medical practice for cooling patients and diluting
their blood for work at very cold temperatures .
(5) Cytoactivity Restraint. The installing physician next
administers: (a) an erythropoietin antagonist to maximally suppress
erythrocyte production; (b) agents to temporarily suppress all
leukocyte production, reversibly depress leukocyte intracellular
metabolism and cytokine sensitivity, and briefly reduce or block
antigen reactivity; (c) agents to temporarily suppress platelet
production, reversibly depress platelet intracellular metabolism and
cytokine sensitivity, and temporarily toughen the platelet
cytomembrane to reduce the likelihood of shear damage; (d) minute
traces of normal bloodstream hormones, cytokines, and other control
biochemicals designed to minimize production of natural secretions
such as insulin, adrenalin and testosterone, glucose and
cholesterol, sebum and semen, etc., as well as angiogenesis
inhibitors to halt the development of new capillaries; and (e)
broad-spectrum antibiotics or programmable nanobiotics such as
microbivores  designed to prevent microbial attack during the
brief period of immunological vulnerability. For example, one
element of this complex and as yet incompletely specified
biochemical cocktail might be dexamethasone, the most powerful
anti-inflammatory and immunosuppressive adrenocortical steroid;
another element might be anti-CD18, an antibody known to prevent
leukocytes from sticking to blood vessel walls in the brain. (Some
of these and related restraints may not be absolutely essential,
since the processes in question are quite slow compared to the time
course of installation.)
patient is now ready for vascular washout.
7.3 Vascular Washout (~4 hours)
Vascular washout (to prepare the patient for vasculoid plating) may
be performed as follows:
(1) General Anesthesia. A general anesthetic such as
propofol is administered by the installing physician at sufficient
dosage (~90 mg) to establish a condition of surgical anesthesia.
(2) Respirocyte Infusion. Over a period of 3 hours, the
patient's entire blood volume is replaced with a suspension of fully
charged respirocytes (1 micron3 spherical O2/CO2
1000-atm pressure vessels [5, 6]) in an isotonic aqueous 0.01 M
glucose solution (double the natural serum concentration) also
containing most of the cytoactivity restraint substances described
in Section 7.2 and additionally a mixture of appropriate
electrolytes and other components commonly found in hypothermal
blood substitutes [520-522]. A 5% (by volume) respirocyte
suspension, containing ~1011 respirocytes/cm3,
is sufficient to provide oxygen and carbon dioxide transport
equivalent to the entire human red cell mass for ~104 sec
(almost 3 hours) after the cessation of respiration. The
respirocyte fleet generates ~17 watts of waste heat while supplying
oxygen at the human basal rate, producing at most a negligible ~0.1
oF rise in core body temperature. Typically ~20 liters
of infusant is required to completely clear the vessels of all
natural blood components. Exfused blood cells are removed,
collected and saved for emergency reperfusion, if required.
is true that the reduction of cerebral blood flow by 50% can produce
marked disturbances in brain metabolism , and at 20% of normal
flow the neurons can depolarize with rapid loss of intracellular
potassium into extracellular spaces . But the infusant
composition can be adjusted to maintain physiological electrolyte
(esp. Na+, K+, and Ca++)
concentrations and osmotic balances, and to extract any excitotoxins
that might be released  – or else respirocyte-class pharmacyte
nanorobots [3, 4] can be employed to similar effect. Since blood
cells have been removed, leukocyte plugging and other forms of
neutrophil-related damage  cannot occur. The basal metabolism
remains sufficiently active throughout the procedure so that tissue
cells suffer minimal ischemic damage. The infusant constitutes an
adequate temporary replacement for the natural blood which is being
removed. This is based on an established medical technology: It is
well-known that the entire blood supply of a human being can be
replaced with cell-free blood substitute at a low temperature, with
the patient then reperfused with blood and recovered, as was first
demonstrated clinically 30 years ago as a treatment modality for
hepatic coma .
(3) Cooldown. Once the entire blood volume has been
completely exchanged with the respiro-infusant described in (2) in
the unconscious patient on CPB (as in conventional medical
settings), control of perfusate temperature will suffice to control
body temperature. Core temperature follows the perfusate
temperature fast and close, with any perfusate/core temperature
difference decaying with a ~10 minute half-life. The heat capacity
of the body is so large that the 200 watts of power dissipated by
vasculoid installation over an hour or so would heat the patient by
only a couple of degrees, which is tolerable. (By comparison,
external cooling of a body in circulatory arrest is so inefficient
that even placing the patient in an ice water bath would yield
surface-to-core temperature differences decaying with a half-life of
hours.) The patient's average core temperature is reduced from 310
K (37 oC) to 280-290 K (7-17 oC) in ~1 hour, a
cooldown rate of ~0.5 oC/minute. This cooldown schedule
is qualitatively similar to hypothermic schedules commonplace in
current resuscitation medicine  and hypothermic CPB procedures
. Mivacurium, rocuronium, or older agents such as vecuronium
or metubine (recently withdrawn) may be administered to inhibit
shivering and as a reversible nondepolarizing muscle relaxant; the
effect of vecuronium bromide may be reversed by acetylcholinesterase
inhibitors such as neostigmine or pyridostigmine.
Wowk notes that there are three broad categories of clinical
hypothermia used in medicine. First, there is mild hypothermia
(a few degrees below normal body temperature). This is very
commonly used during cardiopulmonary bypass for open heart surgery,
and often occurs as an incidental effect of general anesthesia
during other surgeries. Second, there is deep hypothermia
(15-20 oC). This is used when significant periods of
circulatory arrest (up to 1 hour) are required for complex bloodless
surgeries such as repair of cerebral aneurisms or congenital defects
of the aortic arch. Hemodilution (partial blood substitution) is
used during these surgeries, in part to avoid red blood cell
agglutination at low temperatures. Third, there is profound
(or ultraprofound) hypothermia (0-10 oC).
Profound hypothermia does not yet have routine clinical use but is
the subject of active investigation in relevant animal models
[518-520] with an eye toward human use , and preliminary human
clinical results recently have been reported [530-532]. Total blood
substitution, as proposed in the vasculoid installation protocol, is
the norm for profound hypothermia. Specialized perfusates such as
hypothermosol [520-522] are necessary to overcome physiological
problems with this temperature regime that ordinary plasma can’t
handle. Dogs have been held for three hours in profound hypothermia
during perfusion of a blood substitute , and the record for
profound hypothermic perfusion without neurological deficit is said
to be ~6 hours; the record for profound hypothermic circulatory
arrest (as distinct from continuous perfusion) in dogs at <5 oC
is ~3 hours [533, 534].
(4) Cardioplegia. After the cooldown process has begun, the
heart (already in bradycardia from the muscle relaxant) may be
stopped by direct infusion of cold potassium chloride solution
(reversible with atropine or digitalis) or other standard
cardioplegic solution. However, if the target is ultraprofound
hypothermia there is no need to stop the heart with drugs during
this process because the heart will stop itself when the temperature
falls below 15-20 oC.
~4 hours, washout, cooldown and cardioplegia are completed.
Cytometabolic processes continue, but, at 280 K, with reduced
metabolic requirements and hence reduced oxygen demand. This
potentially allows infused respirocytes to provide complete
respiratory gas maintenance for up to ~105 sec (~1 day)
before they would be exhausted after complete cessation of
circulatory flow via the catheters, giving a significant safety
margin for the next phase of the installation procedure. However,
B. Wowk notes other risks of profound hypothermic circulatory arrest
beyond mere hypoxia, including the failure of ion pumps (causing
growing intra- and extracellular imbalances of calcium ions), the
alteration of cell membrane permeability (allowing normally
extracellular solutes to slowly leak into cells), and the decoupling
of certain cellular metabolic processes (which does not occur during
mild hypothermia). The vasculoid installation process may fit
within the circulatory arrest times achievable with the standard
off-the-shelf deep hypothermic (not profound hypothermic) protocols
of conventional medicine. Further study is required to determine
the optimum temperature for hypothermic installation.
anesthetized patient is finally ready for intravenous deployment of
7.4 Vascular Plating (~1 hour)
original 5% respirocyte suspension is replaced by a new suspension
containing 1% fully-charged respirocytes and 10% cargo-bearing
vasculocytes (plus cytoactivity inhibitors and glucose), creating a
mixture whose viscosity and flow characteristics are roughly equal
to normal-hematocrit human blood. At an ~11% nanocrit, partial plug
flow might ensue in a few of the smallest capillaries, but complete
plug flow (requiring much higher pumping power and pressure than
laminar flow) can be avoided .
Each 3 micron3 vasculocyte grasps a single 2 micron3
plate, ready for installation, thus the new vasculo-infusant
contains ~20 x 109 vasculocytes/cm3.
Installing ~150 x 1012 basic plates thus demands a
minimum of 7500 cm3 of vasculo-infusant, requiring ~3800
sec or ~1 hour assuming a very gentle flow rate of only ~2 cm3/sec.
Each vasculocyte drifts quietly in the flow until it encounters a
vessel wall for the Nth time (N is an integer control variable),
which activates it, causing it to attempt to release its cargo in a
clear space. (Slowly increasing N during the installation process
produces a crudely progressive plating pattern.) If the immediate
area is already fully plated, the legged vasculocyte walks across
the surface until it reaches a clear area to deposit its cargo.
Corner registration of adjacent plates is verified prior to plate
release, to ensure a maximally dense tiling pattern. Because of
their small size, vasculocytes can enter even the narrowest
capillaries and install plates by tiling motions (Section 188.8.131.52).
This process may be loosely regarded as a robotically-guided variant
of fluidic self-assembly, a well-known existing commercial process
. Special procedures must also be devised to handle encounters
with nonendothelial materials (e.g., fibrin strands) or stray cells
(e.g., adherent leukocytes) that may be blocking the endothelial
surface, or denuded patches of vasculature lacking full endothelial
cell coverage, although most of these defects should have been
remedied during preoperative vascular conditioning (Section 7.2).
Once its cargo plate is in place, the vasculocyte releases back into
the flowing fluid, powers down, and is eventually exfused from the
body. Approximately 42 billion plates/sec are deposited during this
1-hour process. We generously assume that each 1-50 picowatt
vasculocyte requires ~100 sec of active operation up to peak power
to find a clear space to deposit its cargo before resuming its
fluidborne dormancy – though early arrivers will spend less time
searching for gaps in the structure than later arrivers. Thus there
are at most ~4 trillion vasculocytes active at any moment and the
total power released as waste heat by the vasculo-infusant is under
~200 watts, thermal energy which is easily carried off by the cold
infusant. Given that one plate is installed by one vasculocyte
carrier that performs ~106 mechanical motions/sec during
a ~10 sec install time, this implies ~107 motions/plate
and allows an allocation of ~1800 motions per nanometer of plate
perimeter during the installation of each plate, which seems
plates are not passive during the installation process. Besides the
20 cilia positioned atop each plate to provide tanker and boxcar
mobility as part of the ciliary subsystem (Section 2.3), plates also
possess “motive cilia” to assist in both installation and repair
operations. Each motive cilium is fully retractable when not in
use. Complete positional, rotational and translational control
during installation (and functional redundancy) requires at least
one motive cilium on each of the 4 sides and at least four on the
underside to establish a stable tripod while walking. The motive
cilia allow limited trans-endothelial cytoambulation by each plate
(using adherent tool tips) and fine control of plate/plate jostling
A working cilium consumes 0.1
picowatt during continuous operation at 1 cm/sec (Section 2.3.1),
roughly the speed of jostling motions involving motions of ~1% plate
width per microsecond. Even with all motive cilia operating at
once, plate power is under ~1 picowatt; even with all 150 trillion
jostling at once, maximum power would be under 150 watts – energy
easily obtained from glucose and oxygen provided by the
vasculo-infusant medium, and waste heat that is easily dissipated by
thermal conduction. However, the motive ciliary power draw of the
entire plate population normally should not exceed ~1 watt during
installation because once properly positioned in a regular grid
pattern (in <1 sec) all local plate jostling ceases and the motive
cilia are stowed.
The installation process may
be made more efficient if plates are programmed to dynamically shift
holes (in the plating pattern) upstream. This ensures that gaps are
unlikely to persist in the developing vasculoid structure (except in
cases of plate malfunction), and also ensures that shifted holes
will arrive in a known region of the upper vascular tree where they
are most convenient for vasculocytes to quickly find and fill.
Out-of-register plate domains that collide during this dynamic
repositioning process require a simple interaction protocol to allow
them to mutually align correctly (such a protocol has not yet been
devised). Once plates are in place, their surface cilia can be
adjusted to provide variable drag on the circulating fluid. This
can be used as a crude method of directing resources for more
Plates also assist the
vasculocytes in system validation. Upon installation, plates
briefly activate all subsystems to verify that everything is working
properly. With all 18,750 sorting rotors spinning, individual
plates momentarily draw up to ~2 picowatts (Section 2.4.1).
Malfunctioning plates jettison themselves back into the fluid flow
for ultimate removal, or if this is not possible, take other action
to bring their condition to the attention of the circulating
vasculocyte fleet so that they may be replaced at once.
Following supravascular positioning and subsystem validation, each
plate inflates fluidtight metamorphic bumpers [4, 8] along its
contact perimeter with its neighbors. This provides at least ~14%
linear effective elasticity (1.6 microns vs. 1.4 microns,
center-to-center, comparable to the usual stretch requirements of
the elastic arteries during normal cardiac pumping) and permits
plates to track lateral movements of the underlying tissue while
avoiding any relative movement of the opposing surfaces. Ventral
lipophilic anchors dropped into the lipid bilayer cytomembrane of
the adjacent endothelial cells of the vascular wall serve as sensors
to detect any such relative movement, providing continuous feedback
to control bumper inflation – although with cardioplegia such wall
movements will be quite small because infusant pressure may be held
nearly constant throughout the installation procedure. Neighboring
plates lock their bumpers firmly together with reversible fasteners
embedded in the bumpers.
Along vessels whose diameters change rapidly as a function of axial
position, orthogonal plate alignment along a circumference can be
maintained via bumper expansion. Once maximum bumper extension is
reached, a further increase in vessel circumference is accommodated
in the next row by deflating bumpers in the circumferential
direction and inserting one additional plate. Incommensurate
offsets are reconciled using multiple ports in the bumper
structure. If bumpers can expand by up to 20%-30% , then the
blood vessel being plated can change in width by 20%-30% before such
a pattern discontinuity is required, so such discontinuities should
be relatively uncommon in most of the plated vasculature. Computer
modeling of the dynamic adjustments required to achieve continuous
plating at blood vessel bifurcations and in tapered vessels would be
the natural vascular surface is covered by the growing vasculoid,
individual plates that have completed self-testing procedures and
are locked in place activate a sufficient number of rotors to begin
providing full molecular transport services to the underlying
tissues. Any plate malfunctions are corrected by the circulating
vasculocytes, via plate changeout. Metabolism in the underlying
cellular tissues continues normally, just as it did before these
tissues were plated with the vasculoid. Rotors on the ventral plate
face (away from the lumen) gain access to nutrients in the
vasculo-infusant fluid via gated channels leading to the dorsal
plate face (toward the lumen) which is directly exposed to the
fluid; cellular waste products escape to the fluid by a similar
route. Plate power requirements normally range from ~0.004 picowatt
(basal rate) to ~0.09 picowatt (peak rate) plus ~0.6 pW for
computation (Section 2.4.1). At 280 K the patient's cells would
require only a fraction of the basal rate; after plating is
complete and in the absence of significant computation, the entire
population of 150 trillion installed plates might generate only ~1
Specific procedures for
cellulock installation have not been examined in detail because
these vasculoid components are relatively few in number (Section
2.4.2) and require a net installation rate of only ~9 million/sec
(compared to 42 billion/sec for basic plates). To the extent
cellulock placement can be governed by easily detected geometric
factors such as vascular diameter (e.g., near capillary entrances),
cellulock placement may occur similarly to plate deposition, but
using vasculocytes programmed with specific geometric release
criteria. Some modest number of cellulocks destined for specific
vascular addresses may be installed after plate initialization
(Section 7.6) using a combination of vasculocytes and now-active
cargo cilia, by replacing temporary plates with cellulocks.
Nontubular vascular segments
including flaps, valves, sphincters, portals, sinuses, plexuses,
nodes, and discontinuous microvascular beds such as the red pulp of
the spleen constitute only a tiny fraction of the vascular surface
but may require special procedures by the vasculocytes whose
description is beyond the scope of this paper. Vasculoid
interaction with angiogenesis and related processes is briefly
discussed in Section 4.7. Endothelial pressure/shear responses
(Section 4.1.1) may be managed by continuous emission of appropriate
blockers, inhibitors or cytokines; the response may be reversibly
disabled or eliminated using a designed vector to insert a short
segment of revised DNA into the cells' nucleus. The vasculoid also
includes an explicit mechanism to inhibit the electrical output of
the sinoatrial node, thus maintaining a permanent (but in theory
reversible) state of cardioplegia.
After ~1 hour, the structure
of the vasculoid is almost complete. All major components have been
tested and are in good working order – indeed, the still-submerged
vasculoid is already maintaining full cell metabolism in the tissue
below. The patient is now ready for defluidization.
7.5 Defluidization (~0.3 hour)
At this stage, the 1-micron
thick monolayer of nanorobotic plates forms a chemically inert,
flexible sapphire liner on the luminal (interior) surface of the
entire vascular tree. This liner may be made fluidtight and
airtight to at least modest pressures. Vasculo-infusant fluid is
purged from the body by introducing ~6 liters of oxygenated* pure
anhydrous acetone** as a dehydrating rinse followed by pressurized
dry air at 2 atm through the input catheters and allowing all lavage
fluids to exit through the output catheters for ~15 minutes. If
necessary, surface cilia may assist in the distribution of fluid or
air flow to help ensure that no pockets of fluid remain trapped
anywhere in the system, and to ensure that no respirocytes,
inoperative or damaged vasculocytes, or other stray particles are
upper limit for laminar flow (Reynolds number ~ 2000) of aqueous
vasculo-infusant fluid passing through a smooth 9-mm diameter exit
catheter occurs at ~1 m/sec. Assuming a constant laminar outflow
velocity of 1 m/sec, flow volume through each of the two cannula is
~60 cm3/sec and the vasculoid lumen is emptied of all
installation and rinse fluids in ~100 sec. (This step is easily
reversed by re-introducing an aqueous oxygen-rich or
respirocyte-laden nutrient solution.) Acetone viscosity is ~40%
that of water , so pumping power may be reduced as the rinse
Oxygen needed to sustain human life is slightly restricted for only
~100 sec*** during the pure acetone rinse, and thereafter is
continuously available at the requisite concentration from the dry
purge gas. A temporary supply of dry air with 20% O2 at
2 atm puts 5 x 1022 O2 molecules into the
vasculoid lumen, which when burned with glucose at 50% efficiency in
tissue cells produces ~20,000 joules, equivalent to ~2000 sec of
power at the reduced metabolic rate of ~10 watts in a human body
cooled to 280 K. The plate population consumes only an additional
~1 watt. As long as fresh purge gas continues to circulate, the
oxygen requirements of both human and vasculoid can be satisfied
Cellular glucose reserves will last ~105 sec at the
reduced metabolic rate; subject to cautions noted earlier (Section
7.3), cellular waste products may not approach toxic levels for ~104
sec. Vasculoid plates can also continue functioning in the
temporary absence of glucose. Assuming a power requirement of ~0.6
pW/plate at the basal rate, then a ~1 hour supply of glucose may be
stored in a small fuel tank inside each plate, representing only ~9%
of the 2 micron3 plate volume.
* The oxygen should dissolve
readily at normal atmospheric pressure. For instance, N2
(a gas with solubilities similar to O2) is 11 times more
soluble in acetone than in water (177 ml gas per kg of acetone vs.
16 ml/kg of water at 298 K and ambient pressure ). Highly
pressurized oxygenation, which might produce an explosive mixture,
should not be required.
rinses commonly consist of acetone, chloroform, ethanol, ether,
water, or other solvents, but acetone is often considered superior
when it is necessary both to solvate organic contaminants and to
remove excess water . Ether and acetone are more volatile than
ethanol (hence are more quickly removed by aspiration) though more
flammable . Both ethanol (>1 mg/ml ) and acetone (>0.01-0.1
mg/ml [539-542]) have been found in human blood, often as common
metabolites, and in acetonemia . Toxicity effects are similar
to within an order of magnitude – for example, lethal blood
concentration is 0.55 mg/ml for acetone  vs. 4 mg/ml for
ethanol ; and 10-20 ml of acetone have been taken by mouth
without ill effect , though high vapor concentrations induce
anesthesia . Rinse solution alternatives for vasculoid
installation should be analyzed in more detail.
*** If all 24 trillion
docking bays have their buffer tanks fully charged with oxygen at
the outset, then the docking bay system collectively holds ~2.3 x 1023
molecules of O2 or ~28 times more than the active
capacity of the entire natural human red blood cell mass, providing
an additional margin of safety against the risk of ischemia during
7.6 Initialization and Cold Start (~1.2
final steps of vasculoid installation include:
(1) Plate Initialization. To aid in injury response and
medical diagnosis, each plate may be assigned a unique position and
identity code which can be echoed upon interrogation. With 200
billion operational vasculocytes and 150 trillion plates to
initialize, each active vasculocyte must contact and initialize ~750
plates. Traveling at a net velocity of 10 microns/sec across the
vasculoid, a vasculocyte can traverse (and initialize) 750 plates in
~100 sec. The address block is 100 bits in length; 50 bits are
sufficient to specify 250 = 1000 trillion unique objects
in the system, but additional bits are required to specify each
plate's branch level in the fractal vascular tree and 10 bits are
reserved for self-correcting parity checks.
(2) Install Storage Vesicles. The vesicles are small
storage garages containing reserves of mobile and cargo-carrying
nanodevices, other auxiliary nanodevices, spare parts, replacement
modules and repair materials, critical biochemical consumables, and
compressed refuse. Vesicles may also incorporate nanoscale
bioprocess plants to manufacture small quantities of artificial
biochemicals not normally produced in the body. Each vesicle is ~1
mm3 in volume, providing enough space to store ~1 billion
tankers, ~300 million vasculocytes, or 350,000 boxcars. Vesicles
may be attached directly to the vasculoid surface using sapphire
struts affixed to reinforced base plates, or may be attached to each
other to build convenient three-dimensional configurations (e.g.
“bunch of grapes” formations).
an order-of-magnitude estimate of the total number of vesicles that
might be required, the volume required to store a complete
replacement for the entire mobile container population would include
166.2 trillion tankers (1 micron3/tanker) or 166.2 cm3,
32 billion boxcars (2827 micron3/boxcar) or 91.7 cm3,
and 2 trillion backup vasculocytes for tenfold redundancy (3 micron3/vasculocytes)
or 6 cm3, totaling ~264 cm3 of storage.
Including additional space for bioprocess plants, spare parts,
consumables and refuse storage may boost total vesicle volume to
~500 cm3, requiring ~0.5 million vesicles which would
fill roughly the combined internal volume of the four cardiac
chambers  which are no longer needed for pumping blood. However,
conservative design principles would suggest that vesicles should be
widely distributed throughout the body to maximize system
survivability in the event of massive trauma.
Infusion of 500 cm3 through the two catheters at a modest
infusion velocity of 1 cm/sec requires ~200 sec for infusion of all
vesicle components and their contents. Each 3 mg (fully loaded)
vesicle is installed by a team of ~3000 vasculocytes which can
collectively apply ~30,000 nanonewtons of force (using only 10
active legs among the ~100 available on the ventral side of each
vasculocyte) resulting in a vesicle acceleration of ~1 g (enough to
overcome gravity in a supine patient, and easily increased if
needed). Simultaneously installing all 500,000 vesicles requires
the cooperative activity of ~1.5 billion 1-50 picowatt vasculocytes
(Section 2.5) which consumes a total power of 1.5-75 milliwatts
during the installation.
(3) Install sealed carotid, jugular, or navel access port
(Section 8.1), as required (~40 sec).
(4) Activate ciliary distribution system (~10 sec). This
should probably include a brief stereotypical self-cleaning protocol
to further ensure that all particles and stray nonessential
nanorobots have been removed from the appliance interior.
(5) Introduce into the vasculoid interior the entire 257.9
cm3 operational tanker and boxcar population, requiring
~100 sec at a modest ~1 cm/sec dry infusion velocity.
(6) Warm the patient (~1 hour) using heat generation from
excess ciliary activation, energy from onboard thermogenerative
systems or external heat sources imported via enhanced plate
conductivity (Section 8.2), or simple electrical or rf heating.
Restart normal respiration as soon as possible. (The heart remains
permanently inhibited, although the endocardium is coated with
(7) Reverse cytoactivity inhibition that was initiated
during patient preparation (Section 7.2), as appropriate.
(8) Remove catheters and seal all vascular and dermal
The vasculoid is now fully
operational and self-contained. The patient is warm and breathing.
All essential metabolic and immunological systems have returned to
normal function. Healthy vascular conditioning is maintained on a
permanent basis (post-installation) because the vasculoid exercises
precise control over the transport of cholesterol, leukocytes and
platelets, the principal participants in the arteriosclerogenic
process. Skin and tissue suppleness may be controlled by adjusting
the spring constants of linked bumpers between adjacent plates
A number of cosmetic issues
must be addressed. For example, unpigmented tissues (e.g. the
tongue and gums, fingernail dermae, the uvea and lacrimal apparatus
of the eye, and brain tissue) will appear a pale, waxy translucent
white owing to the complete absence of red cells; pigmented tissues
(e.g. dark skin) should be largely unchanged. For more
traditionalist users or for other aesthetic reasons, semi-natural
coloration might be restored by retaining blue sapphire in venous
channels but substituting red ruby (chemically similar to sapphire)
in arterial plate materials. However, transmission and reflection
properties of these substances may differ markedly, and such colors
would likely require at least small numbers of potentially
troublesome impurity atoms (10-3-10-4 of Fe,
Ti, or Cr atoms; , Section 5.3.7) to be present. Alternatively,
a thin diamondoid-veneered sublayer of organic chromophores of
appropriate colors might be employed.
After a brief period of rest,
postoperative checkout, and familiarization with user interfaces,
the patient is released from the installation facility.
7.7 Vasculoid Removal
procedures outlined above for vasculoid installation are designed to
be fully reversible at every step. Thus, vasculoid removal may be
accomplished by reversing the installation procedure, except that
patient preparation should be performed first. If the patient has
worn his or her vascular appliance for a considerable time, heart
muscles [547-549], venous valves, splenic filtration systems and the
erythroid marrow may have significantly atrophied, requiring
remedial cellular repair . (The conditions and procedures
necessary for maintaining such tissues in a healthy state,
post-installation, have not been thoroughly examined and require
further study.) Homologous formed blood elements such as RBCs must
also be premanufactured for postoperative infusion prior to
vasculoid removal, and any genetically modified endothelial cells
must be reprogrammed back to their original state.
7.8 Aggressive Installation Scenario
For our highly speculative
second scenario, we briefly (and only superficially) describe an
aggressive installation procedure that attempts to install the
vasculoid into a fully metabolizing normothermic human body about
100 times faster than the hypothermic procedure detailed in the
principal scenario. As discussed in Section 7.2, vascular
conditioning and mapping should occur before installation, in part
to allow the manufacture of a folded, pre-assembled custom appliance
tailored to the patient’s unique vasculature which is then presented
to the physician for installation. Our aggressive procedure
involves three steps: (1) pre-charging the body with respirocyte
infusant and removal of bloodborne cells; (2) physical installation
of vasculoid plates as continuous rolling sheets, coincident with
removal of infusant fluid; and (3) configuration and permanent
connection of the appliance, followed by removal of support
structures and system activation. It is intended that all steps
will be carried out within the ~103 sec (~15 min)
ischemic time limit (Section 7.1) imposed by non-respiratory
The aggressive procedure
begins by accessing one or more large veins to permit rapid infusion
and exfusion. The blood is quickly replaced, as it circulates, with
an infusant solution containing electrolytes, glucose, and other
essential substances, plus a sufficient nanocrit of
respirocyte-class devices to provide respiratory support. The
transfusion is speeded by using moderate numbers of “dragnet” style
nanorobots as described in other contexts by Freitas [9, 550] – each
such nanorobot manipulates an adjustable 1-100 micron diameter net
in order to physically gather bloodborne cells that may be trapped
in eddies near venous valves, vascular sinuses, and similar spaces.
Within a few circulation times, perhaps ~200 sec, the vascular
compartment is cleared of all free cells and most macromolecules.
Exfused blood is retained until the procedure is complete, to
facilitate reversal in the event of a medical emergency. The heart
is now stopped. Respirocytes continue to provide oxygen and absorb
carbon dioxide; even a modest 1% respirocrit can provide ~25
minutes of resting metabolism without recharging, perhaps slightly
less in the most energy-intensive tissues such as the brain. But
because fresh infusant can be introduced continuously, the patient
can be parked in this state indefinitely if need be.
Next, the vasculoid is
introduced into the arteriovenous vasculature directly through the
heart via cardiopuncture or cardiocentesis [551-563].
Cardiocentesis involves the surgical puncture of the heart, most
often used today in utero on developing fetuses [558-563]
either to extract [559-561] or to insert [562, 563] fluids into the
vasculature (e.g., blood transfusion ), or more rarely on adult
organisms for related purposes [551-557]. Cardiocentric
installation of the vasculoid is required because the human
circulation consists of two independent arterial circuits (pulmonary
and systemic) each containing their own capillary beds.
The appliance is installed as
a continuously-everting concentric tube, a process called
progressive fractal eversion that may be visualized as turning a
glove inside out. Basic plates, docking bays and cellulocks are
prefastened in the proper configuration to fit the various diameters
and branchings of the blood vessels that they will coat. The
necessary flexibility of this sheet of plates is provided by
sophisticated watertight jointed interplate bumpers that have yet to
be designed. Eversion may be powered by compressed gas, ciliary
action between opposed plates, or by other appropriate means; the
presence of pressurized gas (e.g., pure dry N2) would
also help to minimize the occurrence of leaks during installation.
Each docking bay has an appropriate tanker already docked. As soon
as the plate makes contact with the endothelial surface, the docking
bay begins to work. Since the vasculoid contains a sufficient
number of docking bays to accommodate peak metabolic loads, the
preattached tankers can supply oxygen, glucose, and other nutrients,
and accumulate wastes. Most critically, 5 trillion oxygen tankers
are attached to all available respiratory-tanker docking bays,
providing ~474 sec (~8 min) of oxygen at the basal rate. This
sustainable duration is easily extended to ~1318 sec (~22 min) of
basal oxygen supply by redesigning 13.9 trillion of the 24 trillion
docking bays that are not needed for nonrespiratory transport
(Section 2.1) to include the capacity for gas transfer during
installation, since at the basal rate docking bays require only 67
active sorting rotors (Section 2.4.1).
Installation is initiated
cardiocentrically as two primary segments imported via two
cardiopuncture entry points through the relatively thin walls of the
right atrium and the left atrium, respectively. Installation works
outward from each chamber opening, usually in the natural direction
of valve motion, moving towards the distal capillary beds. From the
right atrial entry point, the unfolding right atrial appliance
segment has four “fingers” and simultaneously plates: (1) the
superior vena cava; (2) the inferior vena cava; (3) the coronary
sinus (which receives cardiac veins from heart tissue); and moves
through (and plates) the right atrial and ventricular chambers,
thence to plate (4) the pulmonary artery. The right atrial segment
also must plate all of the numerous Thebesian veins; these venules
return blood from the myocardium without entering the venous
current, and open directly into the right atrium. From the left
atrial entry point, the unfolding left atrial appliance segment has
five “fingers” and simultaneously plates: (1&2) the two left
pulmonary veins (which frequently terminate by a common opening);
(3&4) the two right pulmonary veins; and moves through (and plates)
the left atrial and ventricular chambers, thence to plate (5) the
Additionally, a third
vasculoid segment called the portal segment must be inserted through
a third abdominal entry point in order most efficiently to plate the
portal vein, which lies midway between the hepatic capillary beds
and the intestinal capillary beds.
Advancing at 1 cm/sec (2
cm/sec internal speed between the installed surface and the inverted
tube), the vasculoid requires only 70 sec to plate the maximum
~70-cm main arterial or venous course (, Table 8.1). Fluid and
respirocytes are withdrawn through the center of the inverted tube.
As the vasculoid reaches the capillaries, the progression of the
eversion may slow to ~10 micron/sec of travel, requiring another
~100 sec to complete all capillary plating. Human capillaries
contain ~14% of blood volume but comprise ~95% of the surface area
of the vascular system (, Table 8.1), so most of the appliance’s
plates are installed during this final ~100 seconds. If all 150
trillion plates are active throughout this process, the power draw
is a physiologically-tolerable 150 watts (Section 7.4). Upon first
contacting the endothelium, each 2 mm2 plate has ~0.1414
seconds – time enough for 14,140 localized 100-nm movements at 1
cm/sec (100 KHz; Section 2.3.1) – to adjust its position and bumper
configurations, and to clear away any detritus trapped beneath it
(e.g., respirocytes, stray cells, etc.), before the next plate is
placed. This seems sufficient.
Once the vasculoid has filled
the capillaries, the arterial and venous branches are joined,
detaching the internal fluid transfer channels running through the
vasculoid lumen which are quickly retracted from the interior. The
ciliary system can then be activated and tankers will begin to be
delivered to and from the capillaries, starting ~200 sec after the
first transcardial introduction of the vasculoid mechanism.
Interior rinse is unnecessary because the luminal surface of the
appliance was installed dry. Vesicle installation is performed
post-installation via component injection, and assembled using
vasculocytes, at leisure.
Since this advanced model of
the vasculoid comes preassembled, it can continually report its
status and monitor physiological indications of the patient during
installation, via an interplate communication network (, Section
5.4.2). In the event of an unforeseen medical catastrophe during
installation, the vasculoid may be evacuated using an emergency
extraction protocol if the appliance itself has not suffered a major
loss of integrity and the transfer channels are still attached. In
the emergency extraction protocol, the vasculoid undergoes partial
flattening with circumferential fission in the capillaries. Then
the arterial and venous sides of the vasculoid are withdrawn as they
were inserted, using a reverse-eversion process with progressively
increasing velocities possibly reaching ~10 cm/sec in the largest
arteries. During such an extraction, only a ~1.4-micron-wide
annular ring will be moving at this high speed adjacent to tissue –
the installed vasculoid does not move, and the moving vasculoid is
surrounded by immobile vasculoid. As a result, installed appliance
plate-sheets may be pulled out by applying an extraction force to
the fluid transfer channel structures that are still attached to the
terminus of each capillary tube. Continuous pressurized return of
respirocyte-charged infusant to the natural vasculature through
these channels prevents pulling a vacuum behind the retreating
tendrils of the appliance, which would cause the collapse of blood
vessels as the appliance was removed. Thus in less than a minute,
the patient has returned to the relative safety of the
respirocyte-infused parked state from which the installation
procedure was begun. In the context of a medical technology capable
of manufacturing a vasculoid, the temporary bloodless state would
not appear to be a cause for concern.
8. Vasculoid Optional Equipment
following is a selection of a few additional devices, options, or
subsystems that may be added to the basic vasculoid installation to
achieve enhanced functionality.
8.1 External Ports
facilitate physical communication with the external environment, the
vasculoid may be equipped with mechanical external ports which
permit the ready attachment of cables or peripheral equipment as an
alternative to purely wireless (e.g., radio, optical) communication
links. Vasculoid ports include an appropriate macroscopic connector
receptacle in hard contact with the sapphire structure. Ports may
include connections to the internal plate-to-plate acoustic
communications network (, Section 7.3) or to docking bays and
cellulocks to permit access to the internal material flow and thus
allow inserting or extracting: (1) molecules and cells; (2) fresh
vasculocytes and spare parts; (3) bioprovisions including
respiratory gases, water and energy supplies; and (4)
nanomechanical or other waste material. Extracorporeal user control
interfaces could also be connected via an external port, if needed.
Convenient and aesthetic locations for external ports include the
navel or the nape of the neck.
Respiratory gas and glucose transport requirements could be reduced
by importing externally-supplied electrical energy – e.g., wall
sockets (110 VAC at 0.9 amps equals the 100 watt human basal rate),
backpack generators, solar collectors, nuclear batteries (,
Section 184.108.40.206), etc. – to be distributed throughout the appliance
via wiring in the plates. These sources could be used to power:
(1) local recycling of CO2 and H2O waste back
into O2 and high-energy carbohydrate fuel (mimicking
photosynthesis energized by light), (2) the reconstitution of amino
acids and proteins from urea and other nitrogenous wastes (as found
in ruminants  and in hibernating bears [565-567]), and (3)
other “reversible nutrition” processes, converting the body of the
envasculoided user into a more closed-cycle system with reduced
dependence on certain material and energy inputs. However, this
approach would correspondingly increase user dependence on the
chosen external power source and would require new in-plate or
in-vesicle chemical processing plants without completely eliminating
the need for any existing subsystem, hence may not be worth the
8.2 Thermal Comfort Subsystem
Vasculoid installation leaves
the user's gross thermal mass largely unchanged, as only ~4.4 kg of
bloodborne water (~9% of the ~50 kg normally present in the human
body) is removed and replaced with ~2 kg of sapphire vasculoid with
a heat capacity equivalent to ~0.2 kg of water. Total passive
aqueous heat capacity drops from 50.4 kcal/K down to 46.3 kcal/K.
Nevertheless, 20th century
patients with extensive metallic implants (e.g. pins, plates, bolts
and joints) occasionally report brief chilly sensations during
periods of cold weather [568, 569] and in other circumstances ,
due to the high thermal conductivity of metal compared with natural
biomaterials (Section 3) or with plastics . Some organs such
as the cornea are quite sensitive to sudden temperature changes – as
little as a 0.3 K drop over a 0.785 mm2 area for a
duration of 0.9 sec (~700 nanojoules) is detectable by patients
. A thermally conductive sapphire or diamondoid-coated
sapphire vascular implant could extend these unpleasant sensations
throughout the entire body, even for activities as simple as
manually grasping a cold object . A targeted thermogenerative
subsystem could help to eliminate this effect.
will continue as before. However, as explained in Section 3 the
active heat transfer mechanism of blood will be completely
disabled. Normal capillary vasoconstriction/vasodilation mechanisms
may be at least partially suppressed to avoid unnecessary tensions
at the vasculoid-vessel interface. Detection of these responses, or
direct temperature measurement, may be used to adjust passive
thermal conductivity over a wide range, as follows. Each plate
abuts neighboring plates through metamorphic bumpers [4, 8], with
optimal thermal contact along stripe-like diamondoid buttons.
Within each bumper, we may place an opposed pair of diamondoid
pistons, separated by vacuum when they are pulled apart. When
pulled apart, heat can be conducted only through the sapphire
infrastructure, or vacuum in the plate, or through a surrounding
aqueous medium, and is thus very slow, almost the same as normal
tissue. But when the two pistons are pressed tightly together
against diamondoid bumper buttons that are in good thermal contact,
heat conduction largely bypasses the poorly-conducting sapphire
regions and flows almost exclusively through the diamondoid contact
region. Thus with pistons apart, the envasculoided human body has
near-normal thermal conductivity; with pistons in contact, the
body's thermal conductivity becomes near-metallic, perhaps as
conductive as stainless steel (Section 3). This transition is
subject to user or program control, is switchable in microseconds,
and may be directed only to specific volumes or pathways within the
body if so desired*. A more complex system might employ thermal
rectifiers , or, as J.S. Hall suggests, “heat pumps could be
placed in the joints to make the whole phenomenon usefully
controllable, augmented if necessary with tankers of ice and/or
* For example, the brain has
some special vascular supply, with venous blood in the nose and from
the face providing additional cooling. During even the most
strenuous exercise in hot environments, with temperatures in the leg
muscles reaching 44-45 oC, the brain remains at a balmy
38-39 oC, preventing heat stroke. This functionality may
be replicated by the vasculoid appliance.
8.3 Internal Caching
Installation of a full vasculoid appliance permanently displaces
~4.2 liters of natural blood volume, freeing up ~1 gallon of
internal storage volume. At least some of this volume may be used
for containerized temporary caching of consumables including surplus
glucose, fats, water, oxygen (e.g. a high-pressure nanolung ),
minerals or other useful biomaterials, or various bio- and
nano-wastes. For example, a 1-liter 1000-atm O2
solid-walled cache holds ~34 hours of oxygen at the human basal
metabolic rate or ~2 hours at the maximum rate .
free ~4.2-liter volume could also be used to store a wide variety of
useful equipment or tools including computers, computer memories,
external communications or navigational devices, solar energy
accumulators, weapons, spare vasculocytes and other special purpose
nanorobots, spare parts, or useful tools. An entire spare vasculoid
(~558 cm3) could even be stored in this volume.*
New technologies are not always employed for sober purpose. The
authors hesitate to note that 4.2 liters is exactly the volume of
ethanol present in 14 metric (750 ml) bottles of 80-proof vodka,
bringing new meaning to the idiom “hollow leg”.
8.4 Breathing in Low-Oxygen Environments
The vasculoid, like the
micron-sized respirocytes proposed elsewhere [5, 6], will offer the
ability to breathe at low O2 partial pressures. The
vasculoid gas tanker fleet can hold ~20 minutes of oxygen at the
basal metabolic usage rate, or up to ~100 minutes if most of the
tanker fleet is diverted to respiratory gas carriage in lieu of
Vasculoid installed in
underwater divers who are breathing pressurized air to modest depths
should allow only enough nitrogen into the body to forestall
mechanical tissue damage, then rotor it back out again as the diver
surfaces to avoid decompression sickness. At 100% saturation the
body absorbs ~1021 excess N2 molecules per
meter of depth. Each tanker could hold ~7.98 x 109
nitrogen molecules (at 1000 atm), requiring the storage capacity of
0.125 trillion tankers per each 1 meter of decompression. Given a
reconfigurable fleet of ~166 trillion tankers, expedited
decompressions from ~100 meters are probably achievable using the
present design. To establish a greater vasculoid operating depth,
in theory an auxiliary 1000-atm storage tank “nanolung” 
installed in the vasculoid wall could provide ~9.43 cm3 N2
storage capacity per each 100 meters of decompressible diving
depth. However, nitrogen should not be used to hyperpressurize the
tissues due to nitrogen narcosis . It should also be noted
that obesity is a risk factor in decompression sickness 
because nitrogen is 5 times more soluble in fat than in water and
because of reduced blood access to adipose tissue, and also
compression and decompression are asymmetrical: a nitrogen load
acquired in a few minutes may take hours to fully deplete purely by
diffusion (and the extraction rate varies markedly by tissue type),
so extravasculoid (Section 8.6) respirocyte-class nanorobots may be
required for optimal results. Clearly the vasculoid can achieve a
decompression rate comparable to breathing pure oxygen, but without
the oxygen toxicity . Helium may be useful for mixed-gas
diving, but is prone to leakage (, Section 10.3.4); some will be
lost from the body during use and cannot effectively be replaced
from the environment.
8.5 Lymphovasculoid and
The lymphatic system extends
into all the same tissues as capillaries and is structurally similar
to the venule network. However, since lymph vessels constitute a
“cul-de-sac” system, not a “circulatory” system, it is unnecessary
to install vasculoid systems in the lymphatics in order to achieve
most of the positive benefits expected from an arteriovenous
vasculoid. With the circulatory vasculoid in place, the workload of
the natural lymphatic system may be greatly reduced – protein
leakage from capillaries, entry of particulates into the tissues,
and the presence of pathogens requiring immune system response all
should be greatly reduced (Section 4.1).
More properly, lymphovasculoid
should be regarded as optional equipment which may permit more
precise control of the immune system in general and of lymphocyte
traffic in particular. Total adult lymph flow is typically ~2
liters/day, so transport requirements within the lymphovasculoid
should not be particularly severe (Section 4.2). If implemented,
the lymphovasculoid would be emplaced as two distinct installations
– a right lymphatic and a thoracic subsystem – following the natural
division in the human body. Special lymph-recycling facilities may
be required at the locations where the thoracic duct and the right
lymphatic duct join the venous tree.
Pathogen disposal sites using an enzyme-based digest and discharge
protocol  may be located near lymphoid tissues and organs (to
permit immune system processing) and near excretory organs such as
kidney, liver, gallbladder, and gut (to facilitate removal from the
body). Specialization of this function at specific locations
appears more efficient than on-site pathogen processing systems
which would need to be numerous, widely distributed, and usually
8.6 Extravasculoid Devices
may be useful to deploy sensor probes which can leave the vasculoid
and enter the surrounding tissues to detect and monitor remote
events (such as angiogenesis, tumors, or pathogens) that otherwise
might not be conveniently detected from within the vasculoid.
Additionally, large blocks of tissue are only lightly vascularized
or have no capillaries whatsoever, as for instance the synovial
chambers in skeletal joints and the epidermis. Medical nanorobots
capable of migrating through noncellular tissue might be useful both
for repair purposes and for maintaining a disease-free condition in
these tissues . Extravasculoid devices may also constitute
general-purpose mobile cell repair machines with even broader injury
response and prevention capabilities.
8.7 Active Thermal Damage Suppression
Although the vasculoid itself is essentially fireproof (sapphire and
ruby will not burn in oxygen), the overlying human tissue is not.
Thus another optional upgrade to the basic vasculoid package is an
active damage control subsystem that offers some protection from
severe thermal burns. This optional subsystem would include
installation of biocompatible sensor-tipped diamondoid or sapphire
pores that pass from the epidermis through the dermis to the nearest
envasculoided capillaries. The comparative human skin response to
sapphire vs. fluid cooling has been studied experimentally .
Upon detection of a potentially harmful thermal event, sacrificial
water is pumped from internal reservoirs into channels in the
plates, and from there into the pores, eventually emerging as
billions of aqueous microstreams. Touching a red hot object
stimulates a nearly instantaneous emission of ablative water,
producing a protective layer of heated water and steam between the
hot object and the skin. Protection of the human hand (~150 cm2)
up to ~1300 K (~decomposition temperature of diamond) for a ~1
second exposure requires a 162 kilowatt/m2 heat
dissipation rate and a ~1 cm3 sacrificial water
reservoir. Of course, this system could easily be overwhelmed if
the user is exposed to intense IR radiation, such as inside burning
buildings or near large explosions, and in any case the hair is not
protected as well as the skin.
8.8 Active Resistance to Mechanical Damage
The overall static structure
of the basic vasculoid appliance is an array of rigid plates,
strongly fastened together, entirely covering a curved
two-dimensional surface embedded in a three-dimensional space. The
plates conform to ordinary movement, but may adequately resist
certain kinds of destructive movement such as separation due to
cutting, rapid accelerations or decelerations, and crushing
injuries. Although local endothelial cells may be damaged during
such sharp movements, an envasculoided tissue should be somewhat
more resistant to gross damage.
For example, the critical
buckling pressure of a hollow tube of circular cross-section
deformed into an elliptical cylinder by external pressure is given
by Freitas (, Eqn. 10.20) as pcrit = (E htube3)
/ (4 rtube3 (1 - cPoisson2))
where E is Young’s modulus (~106 N/m2 for
vascular tissue and ~1011 N/m2 for sapphire
(, Table 9.3)), htube is tube wall thickness (~1 mm
for aorta, ~ 1 mm for capillary and for vasculoid plate-tube; ,
Table 8.1), rtube is tube inner radius (~25.0 mm for
aorta, ~8 mm for capillary, ~7 mm for vasculoid plate-tube; ,
Table 8.1), and cPoisson is the Poisson ratio for the
material (~0.3 for vascular tissue, ~0.1 for diamondoid). Using
this formula and the stated values, pcrit for aorta is
~59 N/m2 and the vasculoid coating adds only negligible
additional resistance to crushing, pcrit ~ 0.002 N/m2.
However, for the ubiquitous capillaries pcrit ~ 540 N/m2
but adding the vasculoid coating can dramatically increase crushing
resistance up to ~7 x 107 N/m2, or ~700 atm of
overpressure. Since the mechanical coupling between plate bumpers
is subject to both design and conscious user control (, Section
7.4.2), the crushing resistance of capillary beds can be
autogenously varied over five orders of magnitude. Of course, high
overpressures may seriously damage the underlying natural
endothelium (Section 220.127.116.11) but this might nevertheless be
acceptable over small areas during emergency situations. For
instance, resistance to deep incision-slash wounds would be markedly
improved. Crushing strength may be increased using thicker plates
or stronger bumpers.
Similarly, the bending
stiffness of a hollow tube is given by Freitas (, Section
18.104.22.168) as kshaft = 3p E (Rtube4 -
rtube4) / (4 Ltube3),
where the outside tube radius is Rtube = rtube
+ htube and the tube length is Ltube (~400 mm
for aorta, ~1 mm for capillary; , Table 8.1). Using this
formula and the stated values, the resistance to bending (stiffness)
of the aorta increases 60-fold (to ~230 N/m) when coated with a
single layer of vasculoid plates, but the stiffness of capillaries
increases nearly 70,000-fold (to ~0.4 N/m) when coated with
diamondoid plates. The buckling strength (, Eqn. 9.44) of coated
vessels compared to natural vessels may exhibit similar
orders-of-magnitude improvement, though in practical systems some of
this potential will be lost because interbumper connection rupture
strength may be only 107-109 N/m2
(, Section 5.4.3), 1-3 orders of magnitude less than for solid
diamondoid materials. The natural musculature may be too weak to
move soft tissues that are thoroughly penetrated with ultrastiff
capillaries, but selective autogenous control of plate bumper
expansion and contraction should make possible any necessary
macroscale voluntary movements, or on-demand mechanical
rigidification of specific limbs or organs. Bumpers may be driven
at ~KHz frequencies (, Section 5.4.3), permitting positional
adjustments on millisecond timescales. Such motions will require
additional energy expenditure.
complete examination of the acceleration tolerance of the
envasculoided whole human body would have to take into account a
wide variety of factors including differential density of body parts
(e.g., lung, soft tissue, skeleton), magnitude and direction of the
stress vector (e.g., positive or negative, axial or transverse,
etc.), duration and timing of the stress vector (e.g., acute or
chronic, linear or periodic), rate of onset and pulse shape of the
acceleration, and the mechanical characteristics both of linked
vasculoid components and of the vasculoid-endothelial interface – a
major analysis that is quite beyond the scope of this paper.
However, a simple order-of-magnitude estimate may be cautiously
ventured, as follows.
vasculoid appliance of differential density Drvasc
relative to soft tissue and mean thickness hvasc in
contact with biological tissues that are subjected to a linear
acceleration of a = (aG g), where g = 9.81 m/sec2,
pushes the vasculoid into the tissues with a pressure force of Pvasc
~ hvasc Drvasc
g aG. Because the vasculoid tube has 2 opposed walls,
each 1 mm thick, and because the tanker fleet covers 4%-55% of the
surface of each of these opposed walls (Section 2.4.1) with tankers
that are 1 mm thick, then the effective capillary thickness of
pushed vasculoid under acceleration ranges from hvasc ~
2.1-3.1 microns. Tissue density is rtiss
~ 1050 kg/m3 (, Table 8.12); sapphire tanker density
is rtank ~
993-1738 kg/m3 if filled with vacuum or water at 310 K,
and plate density is rplate
~ 2000 kg/m3 (Table 1), giving an effective vasculoid
density of rvasc
~ 1643-1988 kg/m3 under various usage conditions. Hence
Drvasc = rvasc
- rtiss ~
593-938 kg/m3 and so the maximum tolerable G-force for
envasculoided tissue is aG ~ Pvasc / (hvasc
Drvasc g) =
24.4 Pvasc ~ 4880 G, taking Pvasc ~ 200 N/m2
as the tentative limit for acute vascular damage because this has
been found experimentally not to cause gross injury or denudation of
canine arterial endothelium by shear force .
However, endothelial transcription factor responses (protein
expression) can be triggered by shear forces as low as 0.02-2 N/m2
(aG ~ 0.5-48.8 G) (Section 4.1.1) and normal
physiological blood shear forces are 0.14-2.6 N/m2 (aG
~ 3.4-63.4 G), so the maximum chronic external acceleration
indefinitely tolerable by an envasculoided human body probably may
not exceed 50-100 G without producing altered, possibly
pathological, cytochemical states. (The operational limit of the
current vasculoid design is also ~30-100 G; Sections 2.3.1 and
22.214.171.124.) This still would represent a substantial improvement over
the natural acceleration tolerance of the unaided human body – the
mean relaxed tolerance is ~3.23 G  and loss of brain blood flow
occurs at +Gz > 4.5 G . Consciousness has been
retained for a maximum of 45 seconds at 9 G using G-protective
equipment and straining maneuvers developed for the U.S. Air Force
, and for 4 minutes at 12 G or 4 seconds at ~16 G using water
immersion . Severe impact injury to humans occurs from +Gz
accelerations of 30 G exceeding 100 millisec or 100 G exceeding 2
millisec  – the recordholding primate is evidently one of
Colonel Stapp’s chimpanzee test subjects that survived ~1 millisec
of 247 G in the -Gx direction on a rocket sled, suffering
only “moderate” injuries . Thus the basic vasculoid may
improve maximum human acceleration tolerance by a factor of 10-20,
or more, and higher-G-tolerant architectures can probably be
With sufficient capability,
the vasculoid structure could allow the non-local distribution of
stress – for example, by spreading the force of an impact in a
manner similar to a bulletproof vest, also helping to quickly close
any vascular breaches that might occur. A common and significant
personal injury mechanism is brain-skull impact, and a tough
interwoven vascular support scaffolding could help to fix the brain
within the skull, potentially reducing the danger of concussion for
at least moderate decelerative loads. (Active suppression of
rotational impact trajectories may enhance cerebral durability, as
demonstrated using high-speed cinematograph films of woodpeckers
which regularly survive 6-7 m/sec cranial impact velocities with
~1000 G decelerations [582, 583].) Positional information and
selective sectioning could allow unavoidable partitions of tissue to
occur along straight planes, producing a minimum of damage when
compared with ordinary tearing injuries. Whether the vasculoid
appliance would be a liability in explosive overpressure situations,
where a fluid-filled vasculature might not (e.g., lethal effects in
humans noted for 40 psi  to 50 psi  overpressure
shockwave; 300 psi (~20 atm) record for successful deep water
submarine escape ), deserves further study.
More speculative capabilities,
such as temporary life support of sectioned tissue and repair of
severe wounds, are beyond the scope of this paper.
This paper has presented a preliminary scaling study for a
conceptual design of a single, complex, multisegmented
nanotechnological robot that appears capable – with numerous
caveats, as noted – of duplicating all essential thermal and
biochemical transport functions of the blood, including circulation
of respiratory gases, glucose, specialty biochemicals, waste
products, and all bloodborne cellular elements. The vasculoid, a
2-kg ~200-watt intimate personal appliance, conforms to the shape of
the existing vasculature and may serve as a complete replacement for
natural blood while greatly improving the durability and
functionality of the human body.
authors are well aware that the device described in this paper would
represent a most extreme intervention using a very advanced medical
molecular nanotechnology. It also should be noted that our current
knowledge of the biological functions of the circulatory system is
incomplete, so the design presented here must be considered
provisional at best. But the principal challenge of the present
work was to advance a plausible argument that a nanomechanical
whole-body thermal and biomaterials transport system would violate
no known physical, engineering, or medical principles, could
presumptively be made adequately safe for the user, and might confer
some significant advantages over simpler whole-body systems
exclusively employing unlinked populations of individual bloodborne
and tissueborne nanorobots.
Ultimately, and from the standpoint of human-guided evolution, the
body exists primarily to ensure the survival of the mind – not the
replication of the genes, which was the ancient paradigm [586,
587]. It would seem that a somewhat more advanced and compact
version of the proposed device could function independently of
nearly all noncortical tissue. Thus the vasculoid is most
fascinating because it may represent one last outpost of humanity at
the final frontier of biological evolution.
The authors thank Robert J.
Bradbury, Ken Clements, J. Storrs Hall, Hugh Hixon, Tad Hogg, Markus
Krummenacker, Jerry B. Lemler, M.D., James Logajan, Ralph C. Merkle,
Rafal Smigrodzki, M.D., Carol Tilley, Tihamer Toth-Fejel, Brian
Wowk, and two unnamed referees for their comments, contributions,
and review of an earlier version of this paper.
Christopher J. Phoenix, “Early Nanotech Project: Replace Blood?”
sci.nanotech posting on 14 June 1996;
2. Robert A. Freitas Jr.,
“Microbivores: Artificial Mechanical Phagocytes using Digest and
Discharge Protocol,” Zyvex preprint, March 2001;
See also: Robert A. Freitas Jr., “Microbivores: Artificial
Mechanical Phagocytes,” Foresight Update No. 44, 31 March 2001, pp.
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