CHAPTER 15

Potential Strategies for Advanced Nanomedical Device Ingress and Egress, Natation, Mobility, and Navigation
F. Boehm

15.1

Introduction
Nanomedicine is rapidly emerging as one of the most important facets of applied nanotechnology. Envisaged nanomedical devices hold immense potential for initially enhancing, and eventually superseding many conventional medical technologies and procedures. Paradigm shifts are poised to occur in virtually every sector of the medical field, encompassing preventative medicine, diagnostics, therapeutics, tissue engineering, genetics, regenerative medicine, and patient health monitoring/surveillance. (Note: For the sake for brevity in this chapter, nanodevice will be synonymous with nanomedical device.) A significant departure from the status quo will also be apparent toward addressing the cumulative degenerative processes that are involved in the seemingly unavoidable disease state that we presently call aging. Within the next several decades we may well witness the advent of a virtually limitless array of beneficial nanomedical applications related to practically every major human disease state, and injurious condition. When conceptualizing future nanomedical devices and systems, nanoengineers and designers will be required to consider and address an extensive range of challenges. Of these, innovative strategies will have to be devised for approaching an array of problems related to how nanodevices might safely and efficiently enter the human body (ingress); how they will propel themselves and be precisely guided in vivo once internal access has been achieved; and finally, how they will exit the patient (egress) once their assigned medical tasks have been completed. A critical component for any advanced nanomedical procedure that may involve from several hundred to perhaps millions of nanodevices working together in parallel would be a sophisticated and powerful outbody navigational control and tracking capability. Contingent upon the particular species of nanodevice that a physician may select to perform a specific medical task, dynamic modes of propulsion would be required to traverse the complex and relatively harsh conditions (from the perspective of a nanodevice) present within the human vasculature, various internal organ structures, as well as among and within the myriad types of tissues and cells.

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Potential Strategies for Advanced Nanomedical Device Ingress and Egress

If a particular nanomed assignment should entail the targeting and destruction of cancer cells or the incremental treatment of a tumor that is resident within a patient, for instance, a prescribed unit of nanodevices might be administered in the most appropriate manner so as to expedite the procedure. Once internalized, the nanodevices might initially make several circuits of the vasculature, for power up, preliminary orientation, and self-organization. This may also allow time for the initialization, calibration, and lock-in of the navigation system. Ideally, an operating room scale GPS system might be invaluable for facilitating precision in vivo nanodevice navigation. Based on specific coordinates and trajectories provided by previously obtained 3-D diagnostic maps, nanodevices would be guided precisely to targeted treatment sites. Once the treatment is verified as complete, patient egress commands would be issued to guide these entities to the most appropriate exit site. Once gathered at this egress site, all nanodevices in the unit would be accounted for (e.g., via scanning of individual onboard identification tags) and extracted. There may be instances whereby nanodevices might congregate, embed themselves, and power down to become dormant within fingernail or toenail beds, or within the roots of follicles for eventual egress via these routes.

15.2

Potential Nanodevice Ingress Strategies

One of the many technical challenges to confront nanomedical conceptualists, engineers and designers will involve the formulation of strategies for how future medical nanodevices might be administered and introduced into the human body. Innovative logistics will be required when considering various approaches for the ingress of functionalized microscopic and nanoscopic entities into the patient. Each potential method of entry will be associated with its own attendant set of physiological hurdles. Primary modes for transferring nanomedical devices into the human in vivo environment may include hypodermic injection, aerosol inhalation, ingestion via a pill, or conveyance using a transdermal patch or topical gel. Injection may be the most straightforward, albeit, the most invasive of these ingress methods. Various concentrations of nanodevices, dependant on the specific treatment prescribed for administration, could be infused within an appropriate fluid as a colloidal suspension.
15.2.1 Hypodermic Injection and Dermal Burrowing

There are currently a variety of injection options that might be employed (e.g., intravenous, intramuscular, intradermal, subcutaneous, intraperitoneal, and intraosseous), and these modes may still be utilized for the deployment of early generations of Nanomedical devices. Future versions of existing MED-JET [1] or ultrasonic SonoPrep [2] injection systems might be used in similar fashion, but may be damaging to cells and tissues that lay in the direct path of the ballistic pressures and sonic vibrations that are imparted by these devices, in addition to any attendant pain. However, in 10 to 20 years, with the arrival of advanced nanodevices that are endowed with the capacity for automatically burrowing through the skin into

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capillaries, (Figure 15.1) and finally into the bloodstream, hypodermic injection might have long been relegated to the annals of medical history. Nanometric telescoping manipulator arms that are envisaged to enable micron-sized ice-burrowing nanorobots to progress at ~1 m/s might be adapted to traverse the extracellular matrix within the various layers of skin tissue. As to possible negative effects imparted by such motility, some level of discomfort might be caused by nanodevices that may have rough edges or sharp tips that happen to mechanically disturb free nerve endings. They also pose the risk of engaging of the immune system, which may result in itching or a rash. Hence, smooth surfaces are likely to be preferred for the prevention of these types of irritation [3]. Exceptions may be those instances where there are requirements that correspond to particular applications (e.g., vascular plaque removal or the selective lancing of undesired cells or pathogens). However, even under these circumstances, any sharp-edged nanoscale instrumentation would likely be designed to be retractable and thus would remain internalized within nanodevices until deployed for a specific function. Spiral-type magnetically driven micromachines were developed by Ishiyama et al. at Tohoku University in 2002, with the envisaged application of burrowing into tumors and killing them via hyperthermia. In experiments, these devices were induced to propel themselves through viscous media, such as gels, by the spinning motion imparted by a rotating magnetic field [4].

Hair shaft Sweat pore Dermal papila Sensory nerve ending for touch Stratum corneum Pigment layer Stratum germinativum
Stratum spinosum Stratum basale

Epidermis

Dermis

Arrector pili muscle Sebaceous (oil) gland Hair folicle

Papilla of hair Nerve fiber Blood and lymph vessels

Subcutaneous fatty tissue (hypodermis)

Vein Artery

Sweat gland Pacinian corpuscle

Figure 15.1

Cross-section of skin layers.

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Potential Strategies for Advanced Nanomedical Device Ingress and Egress

The lateral extension of nanometric crampons with each incremental forward stroke of a dermal burrowing nanodevice, which is designed to be unobtrusive and harmless to the patient by virtue of their infinitesimal size, may facilitate their movement through the skin layers, until onboard sensors indicate that they have arrived at a capillary. Dermatologist Adnan Nasir, at Duke University and UNC Chapel Hill, speculates as to whether nanoparticles might penetrate skin and organs through the use of chemical, electrical, or magnetic gradients, and if motility might be enhanced by employing nanoparticles that are fashioned like lances or barbs, allowing for exclusive one-way transit. He cautions, however, that potential tissue layer damage may be caused by this mode of nanodevice migration, as well as the possibility for the initiation of cysts, and injury to the epithelial lining via squamous metaplasia dysplasia, and neoplasia [5, 6]. Because of their diminutive physical dimensions (e.g., ~1 micron in diameter), the envisaged beneficial activities of nanomedical devices should be designed to proceed painlessly and to be completely undetectable by the patient. Verification of the safety of future nanomedical technologies will, of course, will be a critical issue to address concurrently with the progress made in their efficacy. It is likely, in view of the current rapidly escalating surge in nanomedical research, coupled with the growing number of clinical trials involving functional nanoparticles that the positive health effects imparted by even first generation nanodevices may be significant and extensive.
15.2.2 Aerosol Inhalation and Traversing the Blood/Brain Barrier (BBB)

Nanomedical devices might be inhaled as an aerosol via the use of a nebulizer and may enter the bloodstream via the pulmonary capillaries. They would be required (in this scenario) to migrate through the three layers of the respiratory membrane to access the bloodstream. Detailed permeability studies of the respiratory membrane (0.51.0 m thick), comprised of alveolar epithelial membrane, capillary endothelial membrane, and fused basement membrane that separate the two, would elucidate whether ~1 m in diameter nanodevices might be small enough to diffuse across this membrane, or if an alternate method of vascular ingress from the lungs may be required [7]. Additional investigations would aim to specifically elucidate what effects that lung resident cilia may have on nanodevices (in that the cilia will attempt to sweep them out of the lungs, handling them as they would foreign particulates). Nanodevices might also become trapped within the sacs of the alveoli en-route to a vascular ingress site. In regard to neurological maladies, it has been estimated that approximately 99% of drugs that may be of potential benefit are not capable of traversing the blood/brain barrier (BBB) [8]. Nanodevice administration via a nasal spray might be advantageous if, for example, applying nanomedical therapeutics for the purpose of dissolving amyloid plaque material in Alzheimers patients, due to the close proximity for the rapid transit of nanodevices through the BBB via the nasal mucosa. Intranasal delivery can apparently circumvent the BBB using pathways through the olfactory epithelium, olfactory and trigeminal nerves [9].

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The BBB can be accessed by osmosis or via biochemical or pharmacological methods through the administration of hyperosmotic mannitol and arabinose compounds. They have the effect of reversibly widening the tight junctions of the BBB, thereby increasing the permeability of endothelial cells via temporary dehydrative shrinkage. This transitory state has the disadvantage, however, of increasing the likelihood that undesirable neurotoxic elements may be allowed to pass into the brain [10]. It has been discovered by Krueter et al. [8, 11] and Schroeder, et al. [1215] that poly(butylcyanoacrylate) nanoparticles (200300 nm) coated with hydrophilic surfactants (e.g., polysorbate 80) have the capacity for adsorbing a variety of drugs, in unaltered form, to effectively circumvent the BBB to target the brain. It has been determined that the most likely mechanism for the transit of these nontoxic coated nanoparticles into the brain is not by opening the BBB, and thereby making it vulnerable, but rather by receptor-mediated endocytosis [10].
15.2.3 Transdermal Patch, Diffusive Gel, or Eye/Ear Drops

An adhesive patch or the application of a viscous diffusive gel suspension (e.g., similar to the consistency of aloe vera) that contains a predetermined population of nanodevices may provide a preferable method for administration, as the devices would unnoticeably diffuse through the various epidermal cell layers assisted by paracellular fluid movement (e.g., passage of water between cells), or through the pores, and into the bloodstream [16]. A self-contained smart transdermal patch may impart a low voltage into the skin surface that could potentially facilitate nanodevice ingress into the patient [17]. Alternately, a physician may select eye or ear drops for the localized administration of nanomedical devices if specifically treating these areas. Advances to increase the permeability of the skin using patches that are currently under development include iontophoresis, ultrasound, gels, microneedles (Figure 15.2) sonophoresis, lasers, and electroporatic techniques. Iontophoresis

(a)

(b)

Figure 15.2 (a) AdminPatch Microneedles (From nanoBioSciences, LLC, http://www.nanobiosciences.com/), and (b) artistic depiction of ultrasharp nanoscale needles.

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makes use of repulsive electromotive forces that employ a small applied voltage to positively and negatively charged chambers that contain solvents and active ingredients that have an opposite charge. Thus, the chambers act to strongly repel their contents, and as a result, force their expulsion into to skin [18]. Antares Pharma has developed a product called CombiGel that includes a hydro alcoholic gel mixed with enhancers. This transparent gel is formulated for quick transfer through the skin. The company has adapted this technology to produce the first transdermal testosterone gel for men. Though a number of hurdles still exist toward the maturation of this technology, it seems inevitable that many other drugs may soon be administered by employing this technique. Conceptual tissue migrating nanodevices might have a much less cumbersome route to negotiate through epidermal layers before finally accessing the capillaries if they enter via the sweat glands. This might be an appropriate venue for the ingress of nanodevices that are applied as a topical gel suspension or ejected from a transdermal patch. The soporiferous or sweat glands are located in almost every area of the skin, positioned in small pits slightly beneath the corium (a deep sensitive layer under the epidermis), or more commonly, in the subcutaneous areola (small spaces in between fibrous tissue), surrounded by a mass of fatty tissue. Each sweat gland is comprised of a single tube with a deeper section that is shaped like an oval or spherical ball, which is the body of the gland. The shallow part, or duct, opens at the exterior of the skin as a funnel-shaped orifice [19]. On the palm of the hand there are ~370 pores per/cm2, back of the hand ~200 per/cm2, forehead ~175 per/cm2, breast, abdomen, and forearm ~155 per/cm2, and on the leg and back from ~6080 per/cm2. A typical skin pore diameter is ~50 microns, and the estimate of the total pore population for the epidermis of entire human body is ~2 million [19]. Entry through the pores of the palm of the hand might prove to be a good strategy for nanodevice ingress due to the optimal number of potential entry points, and hence the possibility for expediting device diffusion.

15.3

Molecular Motors
Various categories of molecular motors, whether they are manifest as completely synthetic, bio-based, or hybrid constructs, will likely form the hearts of nanomedical device propulsion systems. Their critical task will be to efficiently convert chemical or thermal energy, which is harvested from the in vivo environment of a patient, into molecular level mechanical torque, providing lateral, radial, or linear thrust. Alternatively, motor components might be activated and manipulated by outbody systems that broadcast photonic, acoustic, magnetic, or radio frequency stimuli to induce the generation of useable voltage within nanodevices. As relates to the activation and kinetics of molecular motors, some type of reversible switch may be incorporated into the system. Switches are not capable of utilizing chemical energy to sustainably drive a system away from equilibrium, whereas motors can have this ability. The majority of molecular machines to date (2008) may be classified as switches that toggle between on and off states, rather than motors, which impart force to travel along a certain trajectory. The

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chemistries of these systems must, at a fundamental level, be capable of constraining the motion of its components whose changes of position in three-dimensional space are stimulated by an external energy contribution [20].
15.3.1 Powering Molecular Motors

There are a range of stimuli, as mentioned above, which might be employed for the activation and control of molecular motors within nanodevices. These may consist of pulsed signals that emanate from dedicated beacons that are situated externally to the patient. Alternatively, or working in conjunction with these signals, the provision of energy for powering molecular motors may be derived from the in vivo environment, via controlled chemical reactions or the extraction of energy from thermal fluctuations. The second law of thermodynamics will forbid the conversion of heat into useful work if there is no temperature differential that exists between the ambient in vivo environment and the components residing within nanodevices. It should also be noted here that temperature gradients cannot be sustained over nanoscale distances. There will be a requirement for the continuous movement of systems away from equilibrium via the continuous input of external energy. The preservation of a thermally initiated stepping down process will bias Brownian motion toward equilibrium [21]. By managing to adapt to and compensate for Brownian motion, an important step will have been taken toward the powering and controlled manipulation of nanomedical devices. A subsequent and critical issue, however, will concern how harvested or generated power might be conveyed to perform mechanical tasks at the nanoscale.
15.3.2 Piezoelectric Elements

Piezoelectricity is a unique mode of voltage generation that might exhibit utility for the powering of nanomedical devices. Piezoelectric elements (e.g., quartz, zinc oxide nanowires, lead-zirconate-titante, or PZT), are comprised of crystalline structures that will create a voltage when mechanically stressed or deformed. Conversely, these materials will physically deform if a voltage is applied to them (e.g., enabling nanoscale actuators or artificial muscles). Perhaps supplemental energy might be harvested from the action of Brownian motion on the external surfaces of nanodevices if they were to be studded, for instance, with arrays of ultra thin, yet stiff piezoelectric zinc oxide nanowires or ribbons (Figure 15.3). Hence, they may prove to have significant utility when designed into such diminutive mechanisms.
15.3.3 Molecular Propellers

Molecular scale propellers might be devised (Figures 15.4 and 15.5) where tight steric (atomic level packing conditions) prevail. This may initiate the formation of molecular scale blades derived from helically configured structures [2224]. The rotation of molecular elements can be made to occur around C-C single bonds by interfacing triptycene (an aromatic hydrocarbon) with other molecules that have

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Potential Strategies for Advanced Nanomedical Device Ingress and Egress

Conductive plate Piezoelectric nanoribbons (static)

Piezoelectric nanoribbons (mechanically stressed) Conductive substrate Cumulative voltage generation

Figure 15.3

Conceptual piezo power generation.

Streptavidin

Actin filament Peripheral stalk ATP ADP + P1 Central stalk

Proton half-channel

Phospholipid bilayer membrane Proton half-channel C-ring rotation (only orange components rotate) C-ring

Figure 15.4 (Color plate 25) ATP synthase-based nanopropeller. (Adapted from W. Junge, et al., TIBS, 22 (1997) and Duncan et al. Proc. Natl. Acad. Sci., 92 (1995).)

complementary affinities [25]. Induced conformational changes or the altered orientation of molecular elements (e.g., ions) can be employed as braking mechanisms.

15.4

Constraints on Molecular Motors

There are several constraints, as described below, which will be imposed on the functionality of molecular scale motors. They will act to impede their operation

15.4 Constraints on Molecular Motors

401

N Me2N N02

Si

S S S
Figure 15. 5 Dipolar rotor. (From [9].)

unless the molecular motors can be cleverly conceived and designed to harness these forces to perform useful work.
15.4.1 Brownian Motion

The inception and foundation of the possibility of synthetic molecular machines can be ascribed to Robert Brown, the Scottish botanist, who observed the relentless random motion of particulates within pollen grains that were suspended in water [26]. This ceaseless molecular activity, commonly known as Brownian motion, will have a major influence over, and impacts on, any mechanical apparatus that is intended to operate at the nanoscale. This is a critical issue that will have to be reckoned with, for no matter how exquisitely fabricated or efficiently operating nanodevices are envisaged to be, they will have to somehow accommodate, or ideally exploit, these fluctuations. Despite the effects of these thermal vibrations, we are compelled to recognize that useful and prolific work may indeed be accomplished at nanometric scales. This is definitively evidenced by the elegant and precise functionality of natural biological molecular machines such as the multisubunit ribosome. This amazing molecular assemblage rapidly churns out nanometric linear polypeptide chains that automatically, and for the most part, flawlessly fold into the proteins that are vital for the functionality of living organisms. Biological motor proteins devour ATP (adenosine triphosphate) molecules at a rate of 100 to 1,000 per second. This correlates to an energy output of 1016 to 1017 W per molecule. When we consider that the constant and random collisions mole-

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Potential Strategies for Advanced Nanomedical Device Ingress and Egress

cules are subject to in aqueous media are equivalent to 10-8 W, it is indeed extraordinary that such precise and organized operations can be accomplished at all [20, 27, 28].
15.4.2 Brownian Shuttles

Catenanes and rotaxanes are interlocking mechanical systems whose degrees of freedom are highly inhibited by mechanical bonds. However, the remaining allowable direction of movement can be exploited to serve as linear shuttles (Figure 15.6). Rotaxane-based shuttles can linearly relocate in response to external stimuli (e.g., fluctuations in temperature) [29] that will disrupt the systems equilibrium (e.g., destabilization of a favored binding site or increasing the binding strength of a less attractive site). The resolution of positional control can occur for distances in the 15 range over 100-s timelines [20]. The first authentic switchable Brownian motion-driven molecular shuttle that utilized a dual station design was reported in 1994. This shuttle could change position by the addition or removal of electrons [30].
15.4.3 Viscous Forces

There is another critical issue to address that will compound the pervasive presence of Brownian motion at the nanoscale, and which will place further constraints on the motility and general functionality of nanomedical devices. Macroscopic level motion is directed by inertial forces. When we shrink to the mesoscopic and nanometric domains, however, inertia no longer has effect and viscous forces come

Figure 15.6

Molecular shuttle. (From [9].)

15.5 Traversing the Circulatory System

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into play. Bacteria, at the size range of about 0.2 to 5 m and viruses, with dimensions of from 0.005 to 0.1 m are already under its influence. Viscosity at the molecular level is quantified by the Reynolds number (e.g., ratio of inertia to viscous forces). At very low Reynolds numbers nanoscale entities will be devoid of momentum and hence cannot be set in motion once pushed, as is experienced in the macroworld. Together with Brownian motion, the ambient viscosity of blood plasma, and within the cytoplasmic interiors of cells, will influence the motion and operation of nanomedical mechanisms. Therefore, any nanodevice design should include strategies for the compensation or exploitation of these molecular forces. The high ratio of surface area to volume will make nanodevices inherently sticky (e.g., via surface charges) and will therefore have a significant impact on how they interact with each other and when engaged with the cells and tissues they are designed to diagnose and treat. We cannot presume that there will be any linear correlation insofar as the form and function of macroscale mechanisms and those that will operate at the nanoscale. Motors and machines do, however, operate quite efficiently at the nanoscale as is validated by biology [27]. It is quite likely that once a deeper elucidation of critical natural processes has been achieved, the resulting insights will serve as a guide to assist with the envisaging of useful synthetic nanomedical constructs. A variety of apparatus within biological systems have evolved over millennia that utilize membrane encapsulated partitions that reside and function within cells and organelles. Disparate gradients are thus established and maintained between discrete cellular compartments and those which exist within organelles, which are mediated by membrane bound channels and gates. The transit of charged ions and other carrier groups facilitate movement between segregated compartments [31]. These systems typically exhibit optimal performance when they are kept far from equilibrium and operate through a transitory relaxation from a higher to a lower gradient, which moves the system toward thermodynamic equilibrium, but never achieves it. This sophisticated strategy allows natural systems at the nanoscale to perform useful work despite the significant constraints imposed by both Brownian motion and aqueous viscosity. Biomembrane embedded ion channels operate via the coupling of structural alterations with charge mediated binding affinities at particular transmembrane sites. These transformations direct the availability and access to these sites from either side of the membrane, and hence control ion direction and flow [32].

15.5

Traversing the Circulatory System

15.5.1 Whole Blood Composition and Viscosity

At a fundamental level, whole human blood might be considered as a colloidal suspension. This non-Newtonian fluid is comprised primarily of water, and is combined with red cells, white cells, proteins, platelets, nutrients, electrolytes, individual hormones, gases, and metabolic waste products suspended in an aqueous plasma media. The viscosity of the blood plasma (1.2 centiPoise (cP) at 37C), which is itself a Newtonian fluid, is slightly higher than that for water (~1 centiPoise (cP) at 20C) [33].

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Formidable technical obstacles will confront nanomedical engineers toward the development of advanced autonomous nanomedical devices when evolving strategies for potentially traversing the nearly 19,000 km of human vasculature under outbody computer control. Some questions for consideration may include: 1. What might the optimal mode/s of propulsion be for nanodevices deployed within the aqueous whole blood environment with its varying levels of viscosity, blood velocity, and shear flow? Investigative simulations of symmetrical propulsive power strokes, imparted by nanoscale fins or blades in viscous aqueous fluids with low Reynolds numbers, have revealed that an initial power stroke will allow an incremental movement forward. However, on the second power stroke, the device will return to its original position. It is these types of insights that may facilitate the development of asymmetrical propulsive elements that may successfully propel nanodevices through the viscous media of the human vasculature [34]. 2. How will nanomedical devices manage to successfully navigate through the myriad of arterioles and arteries (~0.124.0 mm in diameter), venules and veins (~0.1530.0 mm in diameter), and capillaries (~4.08.0 m in diameter) [35]? An additional challenge when navigating the circulatory system will involve the development of intuitive algorithms to assist with correctly directing autonomous nanomedical devices as they approach innumerable bifurcations (divisions of the vasculature into smaller branches). On this topic, innate logic would dictate that for all intents and purposes nanomedical devices that are destined to traverse the human vasculature should always go with the flow. Although there may be contingencies whereby nanoscale devices would be required to venture upstream against prevailing vascular currents (e.g., for the almost instantaneous repair of serious injuries or the stabilization of sudden physical trauma), it seems likely that the majority of diagnostic and therapeutic operations might be effectively conducted within reasonable timelines when nanodevices travel with the blood flow. To rectify those instances where nanodevices should happen to miss their mark, or be somehow blocked from arriving at their intended exit sites, they might reposition themselves and take corrective measures during subsequent rounds through the circulatory system (typically ~60 seconds in duration) [35]. If nanodevices are deployed to work in massively parallel fashion, they would likely be communicating with each other as well as with external sources. It is thus conceivable that at least one nanodevice will arrive at an assigned in vivo diagnostic or treatment site. 3. How might nanomedical devices avoid, or deal with, inevitable collision events with red blood cells (RBCs) and other blood resident constituents? When one considers that there are approximately 5 billion RBCs per milliliter of blood, exclusive of all other suspended blood borne elements, this fact will definitely give new meaning to the term collision avoidance for nanomedical devices [33]. As relates to nanodevices that are designed to

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traverse the vascular system, it is inevitable that multiple collision events will occur during a diagnostic scan, or a particular course of therapeutic treatment. To maintain precision in the case of the acquisition of in vivo spatial data, appropriate compensatory measures (e.g., dedicated algorithms) might be implemented. It may turn out to be far less problematic to integrate ruggedized features into the designs of nanodevices to counteract or tolerate the constant pummeling that they will undoubtedly encounter from a diverse array of biomaterials suspended in blood or lymph, than to risk overloading primary systems. Corrective measures, outside the scope of normal operating procedures using propulsive and navigation systems, might be implemented only in extreme instances, where nanodevices have been knocked far off course, or have somehow become trapped. For earlier generations of nanomedical devices, if enough identical entities are deployed, the perceived complexity of a given task might be reduced to a statistical probability issue. In one hypothetical scenario, for example, if only 700,000 out of a million injected nanodevices manage to successfully accomplish a task at hand with enough efficacy, and within an appropriate timeline (e.g., targeted delivery of potent drug molecules, photothermal therapy at a tumor site, or molecular materials transport to osteoporosis ravaged bones), this percentage may be deemed as sufficient to qualify the treatment as a success. With each additional circuit through the vasculature this percentage might also be likely to increase. Therefore, optimal treatment exposure times might be established and standardized for particular classes of nanomedical devices intended to address specific conditions. A high degree of inherent redundancy for all critical components and systems should be included as a matter of course when considering any advanced nanodevice design. Ideally the goal would be to have all nanodevices complete their assigned tasks with negligible error levels. There have been investigations into collisions of rigid and pliable spheres, hydrodynamics of individual swimming cells, interactions between two parallel swimming cells, and solid wall effects [3543]. When flagellar entities approach a boundary there is a reduction in velocity of ~5% at a distance of 10 object radii from the boundary [44]. In addition, when two cells are traveling side by side they will be attracted to each other as opposed to a repulsive action that will occur when they are swimming one in front of the other [45]. An observation made by Purcell states Turn anythingif it isnt perfectly symmetrical, youll swim. Within the viscosity-dominated in vivo domain, locomotion designs based solely on reciprocal deformation or thrusting will not make forward progress. This is based on the so-called scallop theorem. The device will move forward as the result of an initial power stroke; however, it will then revert back to its original position [34, 46]. Nanomedical devices might utilize mechanisms that are analogous to ciliary propulsion, as exhibited in Paramecium caudatum. This ciliate uses the ~2,500 cilia on its outer surface to propel itself, and can adjust its beating wave patterns to traverse a range of viscous environments [4749]. An appropriate velocity for an in vivo nanomedical device might be set at ~48 cm/sec, having a shear force of ~26N/m2 . This is within the normal range of human blood and most likely nonthrombogenic to platelets. However, Freitas pro-

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poses a conservatively safe nanodevice speed limit of 1cm/sec based on potential red cell impact pressures. A higher velocities, device/cell impacts may cause changes in red cell surface area and possible damage. RBCs are subject to deformation at ~>2m/s and may rupture at ~>20m/s [3]. Swimming speeds of certain species of sperm cells approach ~100 to 200 m/s [50]. Some other examples of in vivo locomotion might include devices using screw and corkscrew drives [51]. Bacterial flagellum is activated by a ~0.0001 pW motor that can rotate up to 300 Hz at 310K (~15 Hz under load). It can reverse direction in ~1 millisec, and burns up 0.1% of its metabolic energy (under growth conditions) to rotate the flagellum [4549]. The E-colibacterium can swim at a velocity of 30 m/sec having a thrust force of 0.5 pN at less than 1% efficiency [52].

15.6

Traversing the Lymphatic System

The lymphatic system is comprised of a network of organs, tissues, nodes, vessels, and capillaries that serve a number of important functions:

Collects and drains protein containing interstitial fluid from the intracellular spaces of tissues, which has leaked from blood capillaries; Assists with the transfer of fats from the gastrointestinal tract back into the bloodstream; Serves as a sentinel infrastructure for the immune system to provide protection of the human body from non-self cells, microbes, and cancer cells through the use of lymphocytes working in cooperation with macrophages.

Lymphatic capillaries have microscopic openings that exist between the endothelial cells that make up its walls. Fluid flow can proceed into these capillaries but it is blocked from exiting. The entire lymphatic system is equipped with a series of one-way valves to ensure delivery of the lymph to the thoracic duct and into the bloodstream through the right heart [33]. Future nanomedical devices may be directed to traverse the lymphatic system subsequent to any given diagnostic or therapeutic procedure. This strategy may be advantageous in that it might be much easier to locate egress sites utilizing this slower, low pressure aqueous environment, which will be relatively clear of circulating elements in comparison whole blood. Hence, there would be a far lower energy expenditure required for the engagement of collision avoidance maneuvers within the lymph. One issue to be mindful of when traversing the lymphatic system might be the requirement to compensate for changes in viscosity that will likely be encountered as nanodevices make their way through the body.

15.7

Phagocyte Avoidance Strategies

Ideally, for many diagnostic and therapeutic applications, administered nanomedical devices would arrive at their targets, complete their assigned tasks, and proceed to exit the patient before eliciting detection and response by the immune

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system. From a practical standpoint, virtually all classes of motile nanodevices that are prescribed to remain in vivo for longer periods should be enabled with a suite of capacities for the avoidance of ingestion by circulating phagocytes. The most direct and successful strategy for circumventing an immune response might be to sheath the exteriors of nanodevices with inert biocompatible nanomaterials (e.g., diamondoid, sapphire) or compounds (e.g., polyethylene glycol PEG). With the advent of advanced nanodevices, integrated immune response circumventing strategies might include the initiation of evasive maneuvers in order to avoid physical contact with white cells via some form of dedicated identification and proximity detection. If nanodevices do happen to collide with phagocytes, which may indeed occur quite frequently while they inhabit the vasculature, protocols for the prevention of binding to their surfaces might be instituted. It has been suggested that the surfactant sodium dodecylsulfate might be released by nanodevices in these cases to prevent antigen-antibody binding [35]. As estimated by Freitas, the velocity of blood within a 1 mm in diameter artery is about 100 mm/s [35] If there are a total of 1012 nanodevices in the bloodstream, the probability of collision with a white cell for each nanodevice of 2 m size might be once every ~3 seconds, along the inner surface of the lumen, and about once every ~300 seconds along the central luminal axis. The process of macrophage ingestion may take from 10 or 20 seconds, up to a half-hour to conclude, depending on the size of the particulate that is being internalized. Therefore, nanodevices should have ample time to identify approaching macrophages, to escape from those that are in their pursuit, and to take appropriate actions for avoiding them [35].

15.8 Nanometric Biomimetic Analogs for Potential Nanomedical Device Motility and Ambulatory Movement
As alluded to above, nature will undoubtedly provide invaluable inspiration for the conceptualization and design of a wide range of nanometric propulsive mechanisms for use within the in vivo aqueous environments of the human body. It is probable that important lessons will be gleaned from the natural world, which will assist with the endowment of therapeutic nanodevices with the capacity for penetrating cell and organelle membranes, and to enable their ambulatory traversal of internal and external biosubstrates. Some useful elucidations as to the primary characteristics of molecular biological systems that might be taken into account when considering the design of potential nanomedical biomimetic analogs have been listed by Kay et al. [20]:

Biomechanisms are labile. Nanometric biosystems operate at close to ambient temperatures, and so any generated heat will be dissipated almost immediately. Temperature differentials are not available to them for exploitation. Biomotors utilize chemical energy (e.g., breaking of covalent bonds, formation of high energy compounds such as ATP, NADH, NADPH, and the use of concentration gradients).

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Biomachines typically function in solution, or at highly viscous surfaces. Brownian motion is exploited rather than opposed. (a) Biomolecular entities need not employ chemical energy exclusively in order to attain mobility. Because of these thermal perturbations their components are never at rest. Hence, this activity can be harnessed via ratcheting. (b) Continuous thermal motion within minute reaction vessels such as organelles and cells guarantee an exceptionally quick and thorough mixing of bio molecules, regardless of the highly viscous environment. Low friction, smooth surfaces are not required by bioentities that are continually subject to thermal activity in the aqueous, high viscosity environment that exists within the human body. Molecular scale, biological mechanisms such as kinesin and other entities utilize infrastructures (e.g., tracks) to constrain their degrees of freedom to accurately perform critical operations. Ion pumps maintain functional integrity through the use of compartmentalization, which negate the chances of ions interacting where they shouldnt. Biomachines exploit aqueous media, and are controlled in this environment via the utilization of non-covalent interfaces. Most bioentities are comprised of a surprisingly small set of constituents (e.g., amino acids, nucleic acids, lipids, and saccharides). Biological life forms function far from equilibrium. This condition is initiated and sustained by the separation of processes via the use of discrete compartments (e.g., vesicles, organelles, and cells).
Cilia and Flagella

15.8.1

Microorganisms manage to convey motility through the use of functional components such as bacterial flagellar motors. Cilia exist in the groups of protozoa, sponges, coelenterates (hydras, jellyfish, sea anemone, corals), ctenophores (comb jellies), turbellarians (flatworms), rotifers (small ~1,000-celled animal), annelids (worms and leeches), echinoderms (sea stars), ectoprocts (moss animals, filter feeders), tunicates (sea squirts), and vertebrates. The common function of cilia and flagella organelles relates to the transfer of fluids relative to their attached orientation. If the entity bearing the cilia or flagella is diminutive enough, these organelles will move the body, conversely fluid will be moved over the surface of a static body. The difference between cilia and flagella is essentially a functional one. Cilium fluid movement is at right angles to its long axis, whereas for flagella, fluid movement is along the length of the central axis. Cilium moves fluid only during part of its beat cycle, but flagella moves fluid constantly. Therefore, the flagella are more efficient as they work cumulatively to propel a body forward. In bacterial flagella, protons are transited through the motor and their energy is extracted as they pass through the electrically charged cell wall [52, 53]. In flame cells (found in some invertebrates), the flagella run along the interior lumen of tubular channels such that their activation propels fluid toward an external opening, from base to tip. This might be accomplished with cilia; however, their

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bodies would have to be oriented at right angles to the intended direction of motion. Flagella is not in all cases longer than cilia, as cilia may be compounded to form structures much longer than a flagellum. Flagella incorporate several bending waves within their length. Length may be limited by factors such as efficient metabolite transfer to furnish energy for contraction [54]. When many cilia move in concentrated groups they exhibit the ciliary beating pattern, which may be more efficient than the flagellar pattern, and more adaptable (e.g., in instances where a reversal of direction is required). A consistently even flow of fluid is ensured via rhythmic beating (which is synchronized metachronically) of the cilia. At any given time there will be cilia in various phases of their stroke, some will be in active phase and others will be in recovery and preparing to initiate another. Cilia moves a shallow layer of fluid over the cell surface, but can produce further reaching currents when longer and sweep through a more substantial liquid volume. The comb-plates of ctenophores, comprised of compound cilia, are perhaps the extreme depiction of these propulsive entities. Their dimensions are such that a succession of plates beat and move through water analogous to a paddle wheel [52, 54, 55]. Coordination of flagella beating patterns may be accomplished by mechanical interactions imparted and transferred through water [52]. Flagella attached to small bodies displace water from base to tip initiating a forward thrust, but in the process cause gyration and rotation. Cilia, flagella, and sperm tails share a common structural design (Figure 15.7). Cilia are made up of a number of longitudinal fibrils, geometrically arranged as a ring of nine duplets surrounding a central two. A membrane that is continuous with
Inner dynien arm Outer dynien arm Central pair of singlet microtubules Radial spoke Spokehead Plasma membrane

Nexin

Inner sheath

A tubule
Figure 15.7

B tubule

Flagellar doublet. (From B. Huang, et al., Cell, 29 (1982).)

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the cell membrane sheaths the entire bundle (axoneme). The diameter of cilia is ~0.15-0.3 m and ~5 to 20 m long. They can be combined to attain lengths of ~2,000 m. (flagella length is ~5150 m, with sperm tails at ~200 m). The outer membrane of the main shaft is a three-layered lamination, two dense layers ~20- to 30 thick, sandwiching a less dense layer that is 30 thick, giving a total thickness of ~70 to 90 [54]. The two central tubular fibrils run parallel for the entire length of the shaft, conferring a bilateral symmetry. These are positioned at ~300 to 350 from center to center, with a total diameter of ~150 to 250 and a ~40 to 50 wall thickness. A sheath can link or surround the two central fibrils. Around the central duplet are nine longitudinal peripheral fibrils that form a cylindrical diameter of ~1,600. Each of these is a double set of tubules ~200 to 250 in diameter with ~60 thick walls. One tubule (A) is larger than the other and is comprised of 13 protofilaments, and the other (B) has 10, and the connection between them is strengthened by a 2 nm in diameter by ~48 nm long protein called tektin (-helical structure). This protein runs longitudinally along the joining wall between A and B [54, 56]. Attached to the A tubule of each duplet are inner and outer dynein arms that reach out to adjacent B tubules. These may assist in the sliding of the tubules past one another during the beating motion. Three sets of cross-linked proteins bind the axoneme together. The central pair is tethered by periodic bridges, and the outer doublet tubules are joined by the nexin protein, spaced at 86-nm intervals and are most likely elastic to accommodate the sliding duplets as well. A third linkage is comprised of radial spokes. These emanate from the central pair and connect to each A tubule of peripheral duplets, are arranged in pairs that have a 96-nm periodic distance. The diameter of the cilia gradually decreases to the tip and individual tubule lengths end at varying intervals as they elongate toward the tip. Where the cilia attaches to the cell, the axoneme links with the basal body containing nine triplets of microtubules [54, 56].
15.8.2 Myosin and Actin

In muscle tissues myosins are thick filaments (~1218 nm), whereas actins are thin filaments (~58 nm). Myosins interpenetrate actins and utilize ATP to temporarily attach the cross-bridges present on its surfaces to the actin filament. Thus, myosins traverse along actin filaments via sequences of binding events to initiate muscle contraction [30, 57].
15.8.3 Kinesin and Dynein

Biomimetic versions of kinesin and dynein walking may be employed to facilitate the design of surface-roving nanodevices for nanomedical applications. The transportation of molecular scale materials within cells is facilitated by entities such as kinesin and dynein. Kinesins are two-legged molecular motors that transfer vital molecular-scale payloads within cells by traversing hollow cylindrical microtubules. They employ a head over head walking motion that is powered by the cleaving of ATP molecules at its heads. They are responsible for the separation of chromosomes during cell division, and the transport of nerve cell neurotransmitters.

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15.9

Nanodevice Aqueous Motility

A diverse range of strategies might be employed for efficiently propelling nanomedical devices through various types of aqueous media within the human body. Described below are a number of potentially feasible techniques toward the eventual realization of this capability.
15.9.1 Biomimetic Flagellar Propulsion Using Nanotubes

A microrobot has been conceptualized and designed to swim inside the human ureter for the purpose of destroying kidney stones noninvasively. The device uses multiwall carbon nanotubes that serve as biomimetic synthetic flagella, driven into rotating helical profiles by micro motors (Figure 15.8). Estimated swimming speeds of 1 mm/sec were deemed possible using 1 nW of power. Two orthogonal comb drives per motor (e.g., the aim is high efficiency) are used to convert electric potential into mechanical work and imparts rotating motion to the nanotubes. A thin wire or radio receiver allows for external communications exchange [59]. The microrobot is 1 mm3, nanotube radius is ~30 nm, and the rotation translating substrate is about ~100 m long. A swimming speed of 0.5 mm/sec was projected at a displacement of 10 m at 100 Hz with an efficiency of 2%. Assuming that the rotary comb drive could achieve a torque of 130 Nnm in operation with an efficiency of 0.1%, the total power draw would be 1 nW [59].

Multiwall carbon nanotubes

Rotating base

Figure 15.8

Nanotube flagella. (From [59].)

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15.9.2

Nanoscale Earthworm Analog

One team has devised a propulsive method that consists of three spheres connected by two rodlike structures. One actuation cycle involves first shortening the left arm, and then shortening the right arm. Next, the left arm is lengthened and then the right. The resulting movement is akin to an earthworm pushing through soil (Figure 15.9) [60]. A swimming robot only a few centimeters long has also been developed that uses polymer actuators, sensors, and a power source [5463].
15.9.3 External Magnetic Propulsion

A magnetic means for propelling a microrobot having an embedded ferromagnetic core uses a strong and variable magnetic field emanating from an MRI machine. The MRI magnetic field is capable of exerting forces in three dimensions and its inherent imaging attributes can assist in tracking device displacements and the acquisition of positional feedback. The proviso is that external magnetic forces must dominate over the drag force of the blood flow impacting on the microrobot [64].
15.9.4 Ultrasonic Peristaltic Propulsion

The smallest ultrasonic rotary motors fabricated to date are ~1.4 mm in diameter by 5 mm long [65]. In the linear category, German company Physik Instrumente has developed the worlds smallest ultrasonic piezomotor linear drive. This device has dimensions of 9 5.7 2.2 mm, has velocities of up to 80 mm/sec, and operates on 3V [66]. Progress has been made in the fabrication of ultrasonically activated pumps having no moving parts (Figure 15.10). A unique volume displacing mechanism using flexural traveling waves operates peristaltically to displace fluid. This innovation

Figure 15.9

Biomimetic earthworm. (From [60].)

15.10 Ambulatory Nanomedical Devices

Piezoelectric polarization Piezoelectric actuator

413

Flexural traveling waves Induced chamber Drive elements

Figure 15.10

Peristaltic propulsion. (From [68].)

allows the induction of the pumping effect while eliminating of any valves or moving parts. The pumping action is accomplished by utilizing multiple chambers formed between the peaks and valleys of a traveling wave [67, 69]. Propulsion through the human vasculature using ultrasonic propulsion may be possible contingent on investigations into, and the quantification of, safe operating parameters for such devices in vivo. An in-depth study may be warranted to elucidate the specific effects of sustained ultrasonic emanation from nanodevices on human whole blood components and tissues.
15.9.5 Nanofluidic Channels: Behavior and Potential for Propulsion

Nanofluidic propulsion systems would most likely be dealing with quite different environments than their microfluidic counterparts. There are totally different fluidic behaviors apparent within this domain in that the physical device dimensions are on par with relative length scales of elements within the fluids themselves. The distances involved are so small that diffusion processes prevail in mass and heat transfer at very small timescales [71]. Studies have been conducted involving fluid flow through micro/nano channels with diameters ranging between 20 nm and 20 m with applied voltages of 0.4 +0.4V. Under conditions of partial double layer overlap, asymmetrical I-V behavior was observed. The primary transport mechanism driving fluid through the orifice was via electro-osmosis. This shows potential for the design of nanochannels having rectified eletro-osmotic flow properties [7173].

15.10

Ambulatory Nanomedical Devices

Ambulatory classes of nanomedical devices might be deployed in vivo to traverse cellular interfaces within various tissues in order to access diseased sites, or to

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deliver bone rebuilding materials specifically to bone resident void sites for repair in osteoporosis patients. These same nanodevices might also be prescribed over the course of multiple treatments to add bone mass or to top dress particularly fragile areas on certain bones. This capability might be envisaged, as well, for facilitating the maintenance of bone mass for astronauts during long space missions, as an enhancement in addition to their regularly scheduled exercise regimes. Nanomedical devices might also be programmed to either penetrate or traverse the entire external surfaces of various organs; certain sections of the vasculature; traverse the blood/brain barrier to locate and dissolve beta amyloid plaque material; make their way to specific tissue areas anywhere within the human body via the extracellular matrix to deliver drugs; scan for signs of disease; or to perform molecular level biopsies on site. In addition, they might be deployed for more long-term body security tasks. For instance, they could serve as mobile sentinels to potentially enhance weakened immune systems, or to make healthy immune systems even more robust, enabling very rapid responses for the eradication of any threatening contagion, toxin, or other biochemical threat. Within air-exposed cavities (nasal, oral, ear canal) and external human tissues, ambulatory nanomedical devices might patrol dermal surfaces and subdermal layers for signs of disease, perform on-site treatments for melanomas, or to effect cosmetic repairs. In the field of nanodentistry, dedicated or ideally, multifunctional nanodevices might be administered by a mouthwash to survey all tooth enamel surfaces, and the interfaces between the teeth and gums to eradicate accumulated plaque material and bacteria, and to perform repairs on cavities. Cell-sized entities under external computer control might be deployed to provide painless, yet highly effective anesthesia. Multitudes of nanodevices would migrate, via ambulation, to the pulp chambers of all teeth within several minutes. They would then stand by, poised to disrupt local nerve impulses, and hence would instantly numb any tooth on command, as issued by the dentist. This operation would be completely reversible, and on orders from the dentists computer, normal nerve impulse flow would be restored [74].
15.10.1 DNA Robot

Ned Seemans group at New York University were the first to succeed in creating a nanoscale biped. This DNA robot uses 10-nm long segments of DNA as its legs, which can walk along a track that is also comprised of DNA, by performing sequential attachment and detachment operations. Each leg is 36 base pairs in length and is comprised of two oligonucleotides that combine to form a duplex, which is connected at the top. At the lower foot portion of the assembly, an extra length of single-stranded sticky DNA protrudes from each of the duplex legs. These entities are immersed in a nondenaturing buffer solution, to prevent DNA degradation. The DNA track has segments of unpaired bases studding its surface to serve as footholds, and that are designed to bind separately with either the left or right foot. Single strands called anchors bind to a foot on one end and a foothold on the other. To walk, a free section of DNA called an unset strand is added that preferentially binds to the anchor strand and thus strips it away, which liberates the foot [75].

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15.10.2

Nanowalker

A research group lead by Ludwig Bartel at the University of California, Riverside, attached walking linkers serving as feet for a 9, 10-Dithioanthracene, (DTA) molecule. The resulting nanowalker molecule exhibits bipedal motion to traverse a flat copper substrate. It is supplied with heat energy, which it utilizes to alternately lift only one linker at a time to traverse a flat plane, in a straight line, without the use of guidance rails or grooves. It was demonstrated that this walking molecule could make 10,000 steps flawlessly [76]. In a further development, the group managed to induce a 9, 10-dioxanthracene (anthraquinone) molecule to transport a payload of two CO2 molecules [77].

15.11 Hypothetical Concept for Clinically Localized GPS Navigation Applied to an Advanced Autonomous Nanomedical Devices
Investigations into the potential for precise nanomedical device positional determination and effective guidance via triangulation in a clinical setting may be a worthy endeavor. Navigational control of singular and multiple in vivo nanodevices from external outbody sources may perhaps be accomplished by using beacons as analogues of multiple satellite configurations that are typically employed as components of commercial and military GPS systems. Might it be possible to use near-infrared light (e.g., full body coverage, programmable lasers) to accurately guide and track multitudes of ~1 micron nanomedical devices inside the human body? Could directed ultrasound be used in conjunction with specific types of lasers as a nanomedical navigational tool? Radio frequencies in the 0.1-MHz range can traverse human tissues to a depth of 20 cm without being dissipated, and may consequently prove useful for accessing and even powering in vivo nanodevices [3]. The near infrared light spectrum resides in wavelengths that range from 800 to 25,00 nm, and in one study tissue penetration depths were obtained for the neonatal head that ranged from between 6.3 and 8.5 mm [78]. In a light therapy investigation by NASA, the combination of three optimal wavelengths for LEDs in the near-infrared reached depths of 23 cm through surface tissue and muscles [79]. Standard global positioning system (GPS) frequencies and associated wavelengths would most likely be inappropriate for in vivo nanomedical applications. To achieve the required resolution, a scaled down analogous system might utilize frequencies that are transmitted and received at much higher ranges, with wavelengths in the nanometer domain. One scenario for such a system might employ three or four beacons referenced to each other in a dedicated spatial metrics room (Figure 15.11). The self-referencing of the beacons might be accomplished when they transmit a particular signal that intersects at a specific point in space relative to the patient. This process might spatially demarcate with high precision a reference set point that is defined by the confluence of the beams from three or four beacons, which would be registered in the outbody computer system. The system would then lock on to and be calibrated to this single sustained reference point.

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Scanning volume

Confluence fiducial Navigation beacon

Figure 15.11

Conceptual spatial metrics room.

All subsequent movements made by internalized nanomedical devices might be directed, tracked, and visualized in relation to this confluence fiducial. Each nanodevice would be tagged and tracked via embedded metallic nanoshells or other nanometric entity, each with its own unique identifying frequency signature. The outbody navigational computers would calculate the time lapse of signals sent from the external beacons to each nanodevice (based on the speed of light) to determine its real-time orientation in 3-D space (cross-referenced to the intersect node mentioned above) and velocity (perhaps using a fourth beacon). The system might be equipped with atomic clocks to ensure highly localized time/distance calculations. Positions of all nanodevices in 3-D space would be triangulated by the three beacons set against the established intersect node. Steering each individual nanodevice through the vasculature may well present very significant and complex challenges, as they would be required to be endowed with the capacity for traveling in multiple directions (perhaps following the axes of all vascular entities) at prescribed velocities.

15.12

Nanodevice Egress Strategies

Strategies having an equal importance to nanomedical device ingress would be the formulation of techniques for efficient egress out of the patient, post-treatment. One hypothetical (albeit quite protracted) method would be to instruct the nanodevices to migrate to the germinal matrix (behind the nail beds of the fingers and toes), where they would embed themselves in the matrix that forms the nail material (com-

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417

prised of proteins, keratin, and sulphur) and would then permanently shut down. They would remain encapsulated there to eventually and grow out of the body naturally with the nails, at a rate ~.05 to 1.2 mm/week. Another, more rapid method of egress might be to direct the devices to embed themselves within the matrix of forming hair follicles (comprised of keratin, trichohyalin granules, melanin) to subsequently exit with the hair at a growth rate of ~1 cm per month. The diameter of hair follicles range from ~17 to 181 m, thereby providing a substantial mass of material in which a 1-m nanomedical device may embed itself [80, 81]. Even more rapid egress scenarios (within ~24 hours) may include exiting the body naturally via migration to, and self-embedding within the biomass of the intestinal tract, or by natural diffusion or flushing from the system with bodily fluids (e.g., urine, sweat) after primary systems shut down. Yet another scenario might induce all nanodevices, subsequent to the completion of a procedure, to respond to and gravitate toward a homing signal that would emanate from a dedicated retrieval patch adhered to the skin. Upon arriving at the source site, the devices would diffuse, or burrow up through the epidermal layers and adsorb to a specifically designed patch undersurface to be subsequently removed. Dependant on the level of individual nanodevice and infrastructure sophistication, this approach might take place within tens of minutes. Primary considerations for any of these egress options would be that all devices, first of all, are accounted for via all-clear protocols, and secondly, that the selected mode of egress should proceed in a completely discreet and innocuous manner. This process should be as unnoticeable as the low-level perspiration that is continuously emanating through the pores of the skin.

15.13

Conclusion
It is hoped that this brief, and by no means comprehensive, survey of several potential propulsive, ambulatory, and navigational strategies that might be employed by future nanomedical devices may provide some modicum of what may be possible toward their development. The author has the humble and hopeful aim of serving to possibly inspire the design and development of a myriad of innovative and highly effective nanomedical tools. The careful, deliberate, and thoughtful creation of safe yet robust nanoscale instruments of health may have strong potential in leading to many positive health impacts for all of humankind.

Problems
15.1 Describe five potential techniques whereby nanomedical devices may perform ingress into the human body. 15.2 How might more sophisticated nanodevices gain access to the bloodstream? 15.3 What is one way by which nanodevices might circumvent the blood/brain barrier to diagnose or treat the brain?

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15.4 What is iontophoresis? 15.5 What are two significant physiological obstacles that nanodevices will have to overcome in order to effectively propel themselves within the aqueous in vivo environment of the human body? 15.6 Name several types of molecular mechanisms that might be integrated into future nanomedical devices. 15.7 What type of power stroke might enable nanodevices to traverse the viscous whole blood/plasma media of the human vasculature, and which type of power stroke will be ineffectual at the nanoscale? 15.8 Which class of nanomaterials might serve as biomimetic analogs of flagella or cilia for the potential propulsion of nanodevices through the human circulatory system?

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