sch-ch15 second proof

8/14/2019 Sch-ch15 Second Proof

1/29

C H A P T E R 1 5

Potential Strategies for Advanced

Nanomedical Device Ingress and Egress,Natation, Mobility, and NavigationF. Boehm

1 5.1 Int ro duct io n

Nanomedicine is rapidly emerging as one of the most important facets of appliednanotechnology. Envisaged nanomedical devices hold immense potential for ini-

tially enhancing, a nd eventua lly superseding ma ny conventional medical t echnolo-gies and procedures. Pa rad igm shifts are poised to occur in virtually every sector o fthe medical field, encompassing preventative medicine, diagnostics, therapeutics,tissue engineering, genetics, regenerative medicine, and patient healthmonitoring/surveilla nce.

(N ote: For the sake for b revity in t his chapter, nanodevice w ill be synonymouswith nanom edical device. )

A significant departure from the status quo will also be apparent towardad dressing the cumulative degenera tive processes that a re involved in the seeminglyunavoidable disease state that we presently call aging. Within the next severaldecades we may well witness the advent of a virtually limitless array of beneficialnanomedical applications related t o 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 chal-lenges. Of these, innovative strategies will have to be devised for approaching anarra y of problems related to how nano devices might safely and efficiently enter thehuman body (ingress); how they w ill propel themselves and be precisely guided invivo once internal access has been achieved; and finally, how they will exit thepatient (egress) once their assigned medical tasks have been completed.

A critical component for any advanced nanomedical procedure that mayinvolve from several hundred to perhaps millions of nano devices working t ogetherin parallel w ould be a sophisticated a nd pow erful outbody navigational controland tra cking capa bility. Co ntingent upon the part icular species of nanodevice tha t aphysician may select to perform a specific medical t ask, dynamic modes of propul-sion would be required to traverse the complex and relatively harsh conditions(from the perspective of a nano device) present w ithin the human vasculature, va ri-ous internal organ structures, as well as among and within the myriad types oftissues and cells.

393


2/29

If a particular nanomed assignment should entail the targeting and destruc-tion of cancer cells or the incremental treatment of a tumor tha t is resident w ithin apat ient, f or instance, a prescribed unit of na nodevices might be administered inthe most a ppropriate manner so as to expedite the procedure. Once internalized, the

nanodevices might initially make several circuits of the vasculature, for power up,preliminary o rienta tion, a nd self-organizat ion. This may a lso allow time for the ini-tialization, calibration, and lock-in of the navigation system.

Ideally, an operating room scale G PS system might be invaluab le for fa cilita tingprecision in vivo na nodevice naviga tion. B ased on specific coordinat es and tra jecto-ries provided by previously obtained 3-D diagnostic maps, nanodevices would beguided precisely to targeted treatment sites. O nce the treatment is verified as com-plete, pa tient egress commands w ould b e issued t o guide these entities to the mostappropriate exit site. Once gathered at this egress site, all nanodevices in the unitw ould 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 pow er dow n to become dorma nt w ithin fingernail or toenailbeds, or w ithin the root s of f ollicles for eventua l egress via these routes.

15.2 Potential Nanodevice Ingress Strategies

O ne of the many technical cha llenges to conf ront na nomedical conceptualists, engi-neers and designers w ill involve the formula tion of stra tegies for how future medicalnano devices might be administered and introd uced into the human body . Innovativelogistics will be required when considering various approaches for the ingress offunctiona lized microscopic and na noscopic entities into the patient. Each potentialmethod of entry will be associated with its own attendant set of physiologicalhurdles.

Primary modes for transferring nanomedical devices into the human in vivoenvironment may include hypodermic injection, aerosol inhala tion, ingestion via apill, or conveyance using a transdermal patch or topical gel. Injection may be themost straightforw ard, albeit, the most invasive of these ingress methods. Va riousconcentrations of nanodevices, dependant on the specific treatment prescribedfor administration, could be infused within an appropriate fluid as a colloidalsuspension.

15.2.1 Hypode rmic Injection and Dermal Burrowing

There are currently a va riety of injection options that might be employed (e.g., intra-venous, intramuscular, intradermal, subcutaneous, intraperitoneal, andintraosseous), and these modes may still be utilized for the deployment of early gen-erations of Na nomedical devices. Future versions of existing MED -JET [1] or ultra-sonic SonoPrep [2] injection systems might b e used in similar fashion, but may beda maging t o cells and tissues tha t lay in the direct path of the ballistic pressures andsonic vibrations that are imparted by these devices, in addition to any attendantpain.

H ow ever, in 10 to 20 years, w ith the arrival of adva nced na nodevices that a reendowed with the capacity for automatically burrowing through the skin into

394 Potential Strategies for Advanced Nanomedical Device Ingress and Egress


3/29

capillaries, (Figure 15.1) and finally into the bloodstream, hypodermic injectionmight have long been relegated to the anna ls of medical history.

Nanometric telescoping manipulator arms that are envisaged to enablemicron-sized ice-burrow ing nanoro bots to progress at ~ 1 m/s might be ada pted to

traverse the extracellular matrix within the various layers of skin tissue. As to possi-ble negative effects imparted by such motility, some level of discomfort might becaused by nanodevices that may have rough edges or sharp tips that happen tomechanically disturb free nerve endings. They also pose the risk of engaging of theimmune system, w hich may result in itching or a rash. H ence, smooth surfaces arelikely to b e preferred for the prevention of these types of irritation [3]. Ex ceptionsmay be those instances w here there are requirements tha t correspond to pa rticularapplications (e.g., vascular plaq ue remova l or t he selective lancing of undesiredcells or pathogens). However, even under these circumstances, any sharp-edgednanoscale instrumentation would likely be designed to be retractable and thusw ould remain internalized w ithin nanodevices until deployed for a specificfunction.

Spiral-type magnetically d riven microma chines w ere developed by Ishiyama etal. a t Tohoku University in 2002, w ith the envisaged application of burrow ing intotumors a nd killing them via hyperthermia. In experiments, these devices w ereinduced to propel themselves through viscous media, such as gels, by the spinningmotion imparted by a rotating magnetic field [4].

15.2 Potential Nanodevice Ingress Strategies 395

Pacinian corpuscle

Sweat gland

Blood and lymphvessels

Nerve fiber

Papillaof hair

Stratumgerminativum

Stratum corneum

Hair folicle

Sebaceous (oil) gland

Arrector pili muscle

Pigment layer

Hair shaft

Sweat pore

Dermal papila

Sensory nerve ending for touch

ArteryVein

Subcutaneousfatty tissue(hypodermis)

Dermis

Epidermis

StratumbasaleStratum spinosum

Figure 1 5.1 Cross-section of skin layers.


4/29

The lateral extension of nanometric crampons with each incremental forwardstroke of a dermal burrow ing nanodevice, w hich is designed to b e unobtrusive andharmless to the pat ient by virtue of their infinitesimal size, may fa cilita te their move-ment through the skin layers, until onb oa rd sensors indicate tha t they ha ve arrived

at a capillary. Dermatologist Adnan Nasir, at Duke University and UNC ChapelH ill, speculates as to w hether nanoparticles might penetrate skin and organsthrough the use of chemical, electrical, or magnetic grad ients, and if mot ility mightbe enhanced by employing na noparticles tha t are fa shioned like lances or barbs,allowing for exclusive one-way transit. He cautions, however, that potential tissuelayer dama ge may b e caused by t his mode of nanodevice migration, as w ell as thepossibility for t he initiat ion of cysts, and injury to the epithelial lining via squa mousmetaplasia 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 pro-ceed painlessly and to b e completely undetectab le by the patient. Verification o f thesafety of future nanomedical technologies will, of course, will be a critical issue toad dress concurrently w ith the progress mad e in their efficacy. It is likely, in view ofthe current rapidly escalating surge in nano medical research, coupled with the grow -ing number of clinical trials involving functional nanoparticles that the positivehealth effects imparted b y even first generat ion na nodevices may be significant andextensive.

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 andmay enter the bloodstream via the pulmonary capillaries. They would be required(in this scenario) to migrate thro ugh the three layers of t he respiratory membrane toaccess the bloodstream. D etailed permeab ility studies of t he respiratory membrane(0.51.0 m thick), comprised o f a lveolar epithelial membrane, capillary endothe-lial membrane, and fused basement membrane that separate the two, would eluci-date whether ~1 m in diameter nanodevices might be small enough to diffuseacross this membrane, or if an alternate method of vascular ingress from the lungsmay be required [7].

Additional investigations would aim to specifically elucidate what effects thatlung resident cilia ma y have on nano devices (in that t he cilia w ill attempt to sweepthem out of the lungs, handling them as they would foreign particulates).Na nodevices might also become trapped w ithin the sacs of the alveoli en-route to avascular ingress site.

In regard to neurological ma ladies, it has been estimated t hat approximately

99% of drugs that may be of potential benefit are not capable of traversing theblood /bra in barrier (BBB) [8]. Na nodevice ad ministra tion via a na sal spray might bead vantageous if, for example, applying nanomedical therapeutics for the purpose ofdissolving amyloid plaq ue material in Alzheimers pat ients, due to the close proxim-ity for the rapid transit of nanodevices through the BBB via the nasal mucosa.Intranasal delivery can apparently circumvent the BBB using pathways through theolfa ctory epithelium, olfa ctory and trigeminal nerves [9].



5/29

The BBB can be a ccessed by osmosis or via biochemical or pharmacologicalmethods through the ad ministra tion of hyperosmotic mannitol and a rab inose com-pounds. They have the effect of reversibly w idening the tight junctions of t he BBB,thereby increasing the permeability of endothelial cells via temporary dehydrative

shrinkage. This transitory state ha s the d isadva ntage, how ever, of increasing thelikelihood that undesirable neurotoxic elements ma y be allow ed to pass into t hebrain [10].

It has been discovered by Krueter et a l. [8, 11] and Schroeder, et al. [1215] tha tpoly(butylcyanoa crylate) nanopa rticles (200300 nm) coat ed w ith hydro philic sur-factant s (e.g., polysorba te 80) have the capa city for adsorbing a va riety of d rugs, inunaltered form, to effectively circumvent the BBB to target the brain. It has beendetermined that the most likely mechanism for the tra nsit of these nontoxic coa tednanoparticles into the brain is not by opening the BBB, and thereby making it vul-nerable, but rather by receptor-mediated endocytosis [10].

15.2.3 Transdermal Patch, Diffusive Gel, or Eye/ Ear DropsAn adhesive patch or the application o f a viscous diffusive gel suspension (e.g., simi-lar to the consistency of aloe vera) that contains a predetermined population ofnanodevices ma y provide a preferable method for administration, as the deviceswould unnoticeably diffuse through the various epidermal cell layers assisted byparacellular fluid movement (e.g., passage of water between cells), or through thepores, a nd into the bloodstream [16]. A self-conta ined smar t transdermal patchmay impart a low voltage into the skin surface that could potentially facilitatenanodevice ingress into the patient [17]. Alternately, a physician may select eye orear drops for the localized administration of nanomedical devices if specificallytreating these areas.

Advances to increase the permeability of the skin using patches that are cur-rently under development include iontophoresis, ultrasound, gels, microneedles(Figure 15.2) sonophoresis, lasers, and electroporatic techniques. Iontophoresis

15.2 Potential Nanodevice Ingress Strategies 397

(a) (b)

Figure 1 5.2 (a) AdminPatch M icroneedles (From nanoBioSciences, LLC,http:/ /www.nanobiosciences.com/), and (b) artistic depiction of ultrasharp nanoscale needles.


6/29

makes use of repulsive electromot ive forces tha t employ a small a pplied vo ltage topositively and negatively charged chamb ers tha t conta in solvents and active ingredi-ents that have an opposite charge. Thus, the chambers act to strongly repel theircontents, and as a result, fo rce their expulsion into to skin [18].

Antares Pha rma ha s developed a product called Comb iG el tha t includes a hyd roalcoholic gel mixed with enhancers. This transparent gel is formulated for quicktra nsfer through the skin. The company ha s ada pted this technology to produce thefirst transdermal testosterone gel for men. Though a number of hurdles still existtow ard t he maturation of this technology, it seems inevitab le tha t many o ther drugsmay soon be administered by employing this technique.

Conceptual tissue migrating nanodevices might have a much less cumbersomeroute to negotiate through epidermal la yers before finally a ccessing the capillaries ifthey enter via the sweat glands. This might be an appropria te venue for the ingress ofnanodevices tha t are a pplied as a topical gel suspension or ejected from a trans-dermal pat ch. The soporiferous or sweat glands a re located in almost every a rea ofthe skin, positioned in small pits slightly beneath the corium (a deep sensitive layerunder the epidermis), or more commonly, in the subcutaneous areola (small spacesin between fibrous tissue), surrounded by a mass of fa tty t issue. Each sweat gla nd iscomprised of a single tube w ith a deeper section that is shaped like an ova l or spheri-cal ba ll, which is the body o f the gland. The shallow part, or duct, opens at the exte-rior of the skin as a funnel-shaped orifice [19].

On the pa lm of the hand there are ~ 370 pores per/cm 2, back of the hand ~ 200per/cm 2, f orehead ~ 175 per/cm 2, breast, ab domen, a nd fo rearm ~ 155 per/cm2, andon the leg a nd back from ~ 6080 per/cm 2. A typical skin pore diameter is ~50microns, and the estimate of the total pore population for the epidermis of entirehuman body is ~2 million [19]. Entry through the pores of the palm of the handmight prove to be a good strategy for nanodevice ingress due to the optimalnumber of potential entry points, and hence the possibility for expediting devicediffusion.

15 .3 Molecula r Moto rs

Various categories of molecular motors, whether they are manifest as completelysynthetic, bio-ba sed, or hyb rid constructs, will likely form the hearts of nanomedicaldevice propulsion systems. Their critical ta sk will be to efficiently convert chemicalor thermal energy, w hich is harvested from the in vivo environment of a patient, intomolecular level mechanical torque, providing lateral, radial, or linear thrust. Alter-natively, moto r components might b e activated and manipulated by outbody sys-

tems that broadcast photonic, acoustic, magnetic, or radio frequency stimuli toinduce the generation o f useable voltage w ithin 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 ca pab le ofutilizing chemical energy to sustainably drive a system away from equilibrium,w hereas mo tors can have this ability. The majority of molecular machines to date(2008) may be classified as switches tha t toggle betw een on and off states,rather than motors, which impart force to travel along a certain trajectory. The



7/29

chemistries of these systems must, at a funda mental level, be capa ble of constrainingthe motion of its components w hose changes of position in three-dimensiona l spaceare stimulated by an external energy cont ribution [20].

15.3 .1 Powering Molecular Motors

There are a range of stimuli, a s mentioned above, w hich might be employed for t heactiva tion a nd contro l of molecular moto rs w ithin nanodevices. These may consistof pulsed signals that emanate from dedicated beacons that are situated externallyto the patient. Alternatively, or w orking in conjunction with these signals, the provi-sion of energy for powering molecular motors may be derived from the in vivo envi-ronment, via controlled chemical reactions or the extraction of energy from thermalfluctuations.

The second la w of thermodynamics will forb id the conversion of heat into use-ful work if there is no temperature differential that exists between the ambient invivo environment and the components residing within nanodevices. It should alsobe noted here that temperature gradients cannot be sustained over nanoscale dis-tances. There w ill be a requirement fo r the continuous movement of systems aw ayfrom eq uilibrium via the continuous input of external energy.

The preservation of a thermally initiated stepping down process will biasBrow nian motion tow ard equilibrium [21]. By ma naging to ad apt to and compen-sate for Brow nian motion, an important step w ill have been taken tow ard the pow -ering and controlled manipulation of nanomedical devices. A subsequent andcritical issue, however, will concern how harvested or generated power might beconveyed to perform mechanical tasks at the nanoscale.

15.3 .2 Piezoelec tric Elements

Piezoelectricity is a unique mode of vo ltage generat ion tha t might exhibit utility fo rthe powering of nanomedical devices. Piezoelectric elements (e.g., quartz, zincoxide nano w ires, lead -zirconate-tita nte, or PZ T), are comprised of crystalline struc-tures that will create a voltage when mechanically stressed or deformed. Con-versely, these materials w ill physically deform if a voltage is applied to them (e.g.,enabling nano scale actuato rs or a rtificial muscles).

Perhaps supplemental energy might be harvested from the action of Brownianmotion on the external surfaces of nanodevices if they were to be studded, forinstance, w ith a rrays o f ultra t hin, yet stiff piezoelectric zinc oxide nanow ires orribbons (Figure 15.3). Hence, they may prove to have significant utility whendesigned into such diminutive mechanisms.

15.3 .3 Molecular Propellers

Molecular scale propellers might be devised (Figures 15.4 and 15.5) where tightsteric (at omic level packing conditions) prevail. This may initiate the forma tion o fmolecular scale blades derived from helically configured structures [2224]. Therotation of molecular elements can be made to occur around C-C single bonds byinterfacing triptycene (an a romatic hydrocarbon) w ith other molecules tha t have

15.3 Molecular Motors 399


8/29

complementary a ffinities [25]. Induced conformationa l changes or the altered orien-ta tion o f mo lecular elements (e.g., ions) can be employed as b raking mechanisms.

15.4 Constraints on Molecular Motors

There are several constraints, a s described below , w hich w ill be imposed on thefunctionality of molecular scale moto rs. They w ill act to impede their operation


Piezoelectric nanoribbons(mechanically stressed)

Piezoelectricnanoribbons(static)

Conductivesubstrate

Cumulativevoltage generation

Conductiveplate

Figure 1 5.3 Conceptual piezo power generation.

Protonhalf-channel

Protonhalf-channel

Peripheralstalk

C-ring

C-ring rotation(only orange componentsrotate)

Phospholipidbilayer membrane

Central stalk

Streptavi in

Actin filament

ATP

ADP +P1

Figure 15 .4 (Color plate 25) ATP synthase-based nanopropeller. (Adapted from W. Junge, et al.,TIBS, 22 (1997) and Duncan et al. Proc. N at l. Acad. Sci ., 92 (1995).)


9/29

unless the molecular motors can be cleverly conceived and designed to harness theseforces to perform useful w ork.

15 .4 .1 Brownian Mot ion

The inception and f ounda tion of the possibility of synthetic molecular machines canbe ascribed to Robert Brow n, the Scottish botanist, who observed the relentless ran-dom mo tion of particulates w ithin pollen grains tha t w ere suspended in w ater [26].This ceaseless molecular a ctivity, commonly know n as Brow nian mot ion, w ill havea major influence over, and impacts on, any mechanical apparatus that is intendedto operate at t he nanoscale. This is a critical issue that w ill have to be reckoned w ith,for no matter how exq uisitely fa bricated or efficiently operating nanodevices areenvisaged to be, they will have to somehow accommoda te, or ideally exploit, thesefluctuations.

Despite the effects of these thermal vibrations, we are compelled to recognizethat useful a nd prolific w ork ma y indeed be accomplished at nanometric scales.

This is definitively evidenced by the elegant and precise functionality of natural bio-logical molecular machines such as the multisubunit ribosome. This a mazingmolecular a ssemblage rapidly churns out na nometric linear polypeptide chains tha tautoma tically, and for the most part, fla w lessly fold into t he proteins that a re vitalfor the functionality of living organisms.

Biological motor proteins devour ATP (adenosine triphosphate) molecules at ara te of 100 to 1,000 per second . This correlates to an energy output of 1016 to 1017

W per molecule. When we consider tha t the constant and rand om collisions mole-

15.4 Constraints on Molecular Motors 401

Me2N

Si

S

S

S

N

N02

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


10/29

cules are subject to in aqueous media are equivalent to 10-8 W, it is indeed extraordi-nary that such precise and organized operations can be a ccomplished at all[20, 27, 28].

15.4.2 Brownian Shut t les

Catenanes and rotax anes are interlocking mechanica l systems w hose degrees of free-dom a re highly inhibited b y mechanical bo nds. H ow ever, the remaining a llowa bledirection 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.,destabilizat ion of a favored binding site or increasing the binding strength of a lessattractive site). The resolution of positional control can occur for distances inthe 15 range over 100- s timelines [20]. The first authentic sw itchab le Brow nianmotion-driven molecular shuttle that utilized a dual station design w as reportedin 1994. This shuttle could change position by the a ddition or removal ofelectrons [30].

15 .4 .3 Viscous Forces

There is another critical issue to address that will compound the pervasive presenceof Brow nian motion a t the nanoscale, a nd w hich w ill place further constraints onthe motility and general functionality of nanomedical devices. M acroscopic levelmotion is directed by inertial forces. When we shrink to the mesoscopic andnano metric domains, how ever, inertia no longer has effect a nd viscous forces come


Figure 1 5.6 Molecular shuttle. ( From [9].)


11/29


12/29

Formidab le technical obsta cles will confront na nomedical engineers tow ard t hedevelopment of advanced autonomous nanomedical devices when evolving strate-gies for potentially traversing the nearly 19,000 km of human vasculature underoutbody computer control. Some questions for consideration may include:

1. What might t he optimal mod e/s of propulsion be for na nodevices deployedwithin the aqueous whole blood environment with its varying levels ofviscosity, blood velocity, and shear flow ?

Investigative simulations of symmetrical propulsive pow er strokes,imparted by nanoscale fins or blades in viscous aqueous fluids with low Reynolds numbers, have revealed that an initial power stroke will allow anincremental movement forward. However, on the second power stroke, thedevice w ill return to its original position. It is these types of insights that mayfacilitate the d evelopment of asymmetrical propulsive elements that maysuccessfully propel nanodevices through the viscous media of the humanvasculature [34].

2. H ow w ill nanomedical devices manage to successfully navigate through themyriad of arterioles and arteries (~0.124.0 mm in diameter), venules andveins (~ 0.1530.0 mm in diameter), and capillaries (~ 4.08.0 m indiameter) [35]?

An additional challenge when navigating the circulatory system willinvolve the development of intuitive algorithms to assist with correctlydirecting a utonomous na nomedical devices as they approach innumerablebifurcations (divisions of the vasculature into smaller branches). On thistopic, innate logic would dictate that for all intents a nd purposesnanomedical devices that are destined to traverse the human vasculatureshould alw ays go w ith the flow .

Although there may be contingencies whereby na noscale devices wo uldbe required to venture upstream against prevailing vascular currents (e.g.,for t he almost instanta neous repair o f serious injuries or the stabilizat ion ofsudden physical trauma), it seems likely that the majority of diagnostic andtherapeutic operations might be effectively conducted within reasonabletimelines when nanodevices travel with the blood flow. To rectify thoseinstances w here nanodevices should happen to miss their mark, or besomehow blocked from arriving at their intended exit sites, they mightreposition themselves and take corrective measures during subsequentrounds through the circulatory system (typically ~60 seconds in duration)[35]. If nanodevices are deployed to w ork in ma ssively parallel fashion, theywould likely be communicating with each other as well as with external

sources. It is thus conceivable that a t least one nanodevice w ill arrive at a nassigned in vivo d iagnostic or treatment site.3. H ow might na nomedical devices avoid, or deal w ith, inevitable collision

events w ith red blood cells (RBCs) and other blood resident constituents?When one considers that there are approximately 5 billion RBC s per

milliliter of blood, exclusive of all other suspended blood borne elements,this fact w ill definitely give new meaning to t he term collision a voidancefor nanomedical devices [33]. As relates to nanodevices that are designed to



13/29

traverse the vascular system, it is inevitab le tha t multiple collision events w illoccur during a diagnostic scan, or a particular course of therapeutictreatment. To ma intain precision in the case of the acq uisition of in vivospatial data, appropriate compensatory measures (e.g., dedicated

algorithms) might be implemented.

It ma y turn o ut to be far less problematic to integrate ruggedized features intothe designs of nanodevices to counteract or tolerate the constant pummeling thatthey w ill undoubtedly encounter from a diverse array of b iomaterials suspended inblood or lymph, than to risk overloading primary systems. Corrective measures,outside the scope of no rmal operating procedures using propulsive and naviga tionsystems, might be implemented only in extreme instances, where nanodevices havebeen knocked far off course, or have somehow become trapped.

For earlier generat ions of na nomedical devices, if enough identical entities aredeployed, t he perceived complexity o f a given ta sk might be reduced to a stat istical

proba bility issue. In one hypothetical scenario, for exa mple, if only 700,000 out of amillion injected nanod evices mana ge to successfully accomplish a ta sk at ha nd w ithenough efficacy, and within an appropriate timeline (e.g., targeted delivery ofpotent drug molecules, photothermal therapy a t a tumor site, or molecular ma teri-als tra nsport to osteoporosis ravaged bo nes), this percentage may be deemed as suf-ficient to q ualify the treatment as a success. With each add itiona l circuit through thevasculature this percentage might also be likely to increase. Therefore, optimaltreatment exposure times might be established and standardized for particularclasses of nanomedical devices intended to address specific conditions. A highdegree of inherent redundancy for all critical components and systems should beincluded as a mat ter of course when considering any advanced na nodevice design.Ideally the goa l w ould be to ha ve all nanodevices complete their a ssigned ta sks with

negligible error levels.There have been investigations into collisions of rigid and pliable spheres,

hydrodynamics of individual swimming cells, interactions between two parallelswimming cells, a nd solid w all effects [3543]. When fla gellar entities approa ch aboundary there is a reduction in velocity of ~5% at a distance of 10 object radiifrom the boundary [44]. In ad dition, w hen two cells are traveling side by side theyw ill be attra cted to each other as opposed to a repulsive action that w ill occur whenthey are sw imming one in front o f the other [45].

An observation made by Purcell states Turn anythingif it isnt perfectly sym-metrical, you ll swim. Within the viscosity-domina ted in vivo doma in, locomot iondesigns based solely on reciprocal deformation or thrusting will not make forwardprogress. This is ba sed on the so-called scallop theorem. The device w ill moveforw ard a s the result of an initial pow er stroke; however, it w ill then revert back toits original position [34, 46]. Nanomedical devices might utilize mechanisms thatare ana logous to ciliary propulsion, as exhibited in Param ecium caudatum . This cil-iate uses the ~2,500 cilia on its outer surface to propel itself, a nd ca n adjust its beat -ing w ave pa tterns to t raverse a ra nge of viscous environments [4749].

An appropriate velocity fo r an in vivo na nomedical device might be set a t ~ 48cm/sec, having a shear force o f ~ 26N/m 2 . This is within the normal range ofhuman blood and most likely nonthrombogenic to platelets. However, Freitas pro-

15.8 Nanometric Biomimetic Analogs for Potential Nanomedical Device Motility 405


14/29

poses a conservat ively safe nanodevice speed limit o f 1cm/sec ba sed on po tentia l redcell impact pressures. A higher velocities, device/cell impacts ma y ca use changes inred cell surface area and possible damage. RBCs are subject to deformation at~ >2m/s and ma y 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]. Ba cterial f lagellum is activated by a ~ 0.0001 pW moto rtha t can rota te up to 300 H z at 310K (~ 15 Hz under loa d). It can reverse direction in~ 1 millisec, and b urns up 0.1% of its meta bolic energy (under grow th conditions) torotate the flagellum [4549]. The E-colibacterium can swim at a velocity of 30 m/sec having a thrust f orce of 0.5 pN a t less tha n 1% efficiency [52].

15.6 Traversing the Lymphatic System

The lymphatic system is comprised of a netwo rk of orga ns, tissues, nodes, vessels,and capillaries that serve a number of important functions:

Collects and drains protein containing interstitial fluid from the intracellularspaces of t issues, w hich has leaked from b lood capillaries;

Assists with the transfer of fats from the gastrointestinal tra ct ba ck into thebloodstream;

Serves as a sentinel infrastructure for the immune system to provide protectionof the human bod y fro m non-self cells, microbes, and cancer cells throughthe use of lymphocytes working in cooperation with macrophages.

Lymphatic capillaries have microscopic openings that exist between the endo-thelial cells that ma ke up its w alls. Fluid flow can proceed into these capillaries but itis blocked from exiting. The entire lymphatic system is equipped with a series ofone-way valves to ensure delivery of the lymph to the thoracic duct and into theblood stream through the right heart [33].

Future nanomedical devices may be directed to traverse the lymphatic systemsubsequent to any given dia gnostic or therapeutic procedure. This strategy ma y beadvantageous in that it might be much easier to locate egress sites utilizing thisslower, low pressure aq ueous environment, which w ill be relat ively clear of circulat-ing elements in comparison w hole blood. H ence, there would be a fa r low er energyexpenditure required for the engagement of collision avoidance maneuvers withinthe lymph. O ne issue to b e mindful of w hen traversing the lymphat ic system mightbe the requirement to compensate for changes in viscosity that will likely be encoun-

tered as nanodevices make their way through the body.

15.7 Phagocyte Avoidance Strategies

Ideally, for many diagnostic and therapeutic applications, administered nano-medical devices w ould a rrive a t their ta rgets, complete their a ssigned tasks, a ndproceed to exit the patient before eliciting detection and response by the immune



15/29

system. From a practical sta ndpoint, virtua lly all classes of motile nanod evices thatare prescribed to remain in vivo for longer periods should be enabled with a suite ofcapacities for the avoida nce of ingestion by circulating phagocytes. The most directand successful stra tegy fo r circumventing a n immune response might be to sheath

the exteriors of nanodevices w ith inert biocompatible nanomaterials (e.g.,diamo ndoid, sapphire) or compounds (e.g., polyethylene glycol PEG ).

With the advent of advanced nanodevices, integrated immune response circum-venting strategies might include the initiation of evasive maneuvers in order toavoid physical contact w ith w hite cells via some form of dedicated identificationand proximity detection. If nanodevices do happen to collide with phagocytes,w hich may indeed occur quite frequently while they inhab it the vasculature, proto -cols for the prevention o f bind ing to their surfaces might be instituted. It has beensuggested that the surfactant sodium dodecylsulfate might be released bynanodevices in these cases to prevent antigen-antibody binding [35].

As estimat ed by Freitas, the velocity of blood w ithin a 1 mm in diameter arteryis abo ut 100 mm/s [35] If there are a total o f 10 12 nano devices in the bloo dstream,the probab ility of collision w ith a w hite cell for each nanod evice of 2 m size mightbe once every ~3 seconds, along the inner surface of the lumen, and about onceevery ~ 300 seconds a long the centra l luminal axis.

The process of macrophage ingestion ma y take from 10 or 20 seconds, up to ahalf-hour to conclude, depending on the size of the particulate tha t is being internal-ized. Therefore, nanodevices should have ample time to identify approachingmacrophages, to escape from those that a re in their pursuit, and to take appropriateactions fo r a voiding them [35].

15.8 Nanometric Biom ime tic Analogs for Potential Nanomed icalDevice M otility and Ambulato ry Mo veme nt

As alluded to a bove, nature w ill undoubt edly provide invaluab le inspiration for theconceptualiza tion and design of a w ide range of nanometric propulsive mechanismsfor use within the in vivo aqueous environments of the human body. It is probablethat important lessons w ill be gleaned from the natural w orld, w hich w ill assist withthe endow ment of therapeutic nanod evices w ith the ca pacity for penetrating celland organelle membranes, and to enable their ambulatory traversal of internal andexternal biosubstra tes.

Some useful elucidations a s to the primary cha racteristics of molecular biologi-cal systems that might b e taken into a ccount w hen considering the design of pot en-tial nanomedical biomimetic analogs have been listed by Kay et al. [20]:

Biomechanisms are labile. Na nometric biosystems operat e at close to a mbient temperatures, and so any

generated heat w ill be dissipated a lmost immediately. Temperature differen-tials are not a vailable to them for exploitation.

Biomotors utilize chemical energy (e.g., breaking of covalent bonds, forma-tion of high energy compounds such as ATP, N ADH , NAD PH , and the use ofconcentra tion gra dients).



16/29

Bioma chines 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 thermalmotion w ithin minute reaction vessels such a s orga nelles and cells guaranteean exceptionally quick and thorough mixing of bio molecules, regardless ofthe highly viscous environment.

Low friction, smooth surfa ces are not required by bioentities that a re continu-ally subject to thermal a ctivity in the aq ueous, high viscosity environment tha texists within the human body.

Molecular scale, b iological mechanisms such a s kinesin and other entities uti-lize infrastructures (e.g., tracks) to constrain their degrees of freedom to accu-rately perform critical operations. Ion pumps ma intain functional integritythrough the use of compartmentalization, w hich negate the chances of ions

interacting where they shouldnt. Biomachines exploit aqueous media, and are controlled in this environmentvia the utilizat ion of non-cova lent 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 fa r from equilibrium. This condition is initiatedand susta ined b y the separat ion of processes via the use of discrete compart -ments (e.g., vesicles, organelles, and cells).

15.8.1 Cilia and Flagella

M icroorganisms manage to convey motility through the use of functional compo-nents such as bacterial flagellar motors. Cilia exist in the groups of protozoa,sponges, coelenterat es (hydra s, jellyfish, sea anemone, cora ls), ctenophores (combjellies), turbellarians (flatworms), rotifers (small ~1,000-celled animal), annelids(w orms and leeches), echinoderms (sea stars), ectoprocts (moss a nimals, filterfeeders), tunicates (sea sq uirts), a nd vertebrates. The common function o f cilia andflagella organelles relates to the tra nsfer of fluids relative to their attachedorientation.

If the entity bearing the cilia or flagella is diminutive enough, these organellesw ill move the body, conversely fluid w ill be moved over the surface of a sta tic body .The difference between cilia and flagella is essentially a functional one. Cilium fluidmovement is at right angles to its long ax is, whereas fo r flagella, fluid movement is

along the length of the central axis. Cilium moves fluid only during part of its beatcycle, b ut fla gella moves fluid constant ly. Therefore, the flagella a re more efficientas they w ork cumulatively to propel a body forw ard. In bacterial fla gella, protonsare transited through the motor and their energy is extracted as they pass throughthe electrically charged cell wall [52, 53].

In fla me cells (found in some invertebrates), t he flagella run along the interiorlumen of tubular channels such that their activation propels fluid tow ard a n externalopening, from base to tip. This might be accomplished with cilia; however, their



17/29

bod ies w ould have to be oriented at right angles to the intended direction of motion.Flagella is not in a ll cases longer tha n cilia, as cilia may be compounded to fo rmstructures much longer than a flagellum. Flagella incorporate several bending waveswithin their length. Length may be limited by factors such as efficient metabolite

transfer to furnish energy for cont raction [54].When many cilia move in concentrated groups they exhibit the ciliary beating

patt ern, w hich may b e more efficient than the flagellar patt ern, and mo re adaptab le(e.g., in instances w here a reversal o f direction is required). A consistently even flow of f luid is ensured via rhythmic beat ing (which is synchronized metachronically) ofthe cilia. At any given time there will be cilia in various phases of their stroke, somewill be in active phase and others will be in recovery and preparing to initiateanother.

Cilia moves a shallow layer of fluid over the cell surface, but can produce fur-ther reaching currents w hen longer and sweep through a more substantial liquidvolume. The comb-plat es of ctenophores, comprised of compound cilia, a re perhapsthe extreme depiction of these propulsive entities. Their dimensions are such that asuccession of plates beat a nd move through w ater analogous to a paddle wheel [52,54, 55]. Coord ination o f flagella beat ing patterns may be accomplished by mechan-ical interactions imparted and transferred through water [52]. Flagella attached tosmall bodies displace w ater from ba se to tip initiating a fo rw ard thrust, but in theprocess cause gyration and rotation.

Cilia, f lagella, a nd sperm tails share a common structural d esign (Figure 15.7).Cilia are made up of a number of longitudinal fibrils, geometrically arranged as aring of nine duplets surrounding a central tw o. A membra ne that is continuous with


Central pairof singletmicrotubules

Outerdynienarm

Innerdynien

arm

Plasmamembrane

Nexin

Radialspoke

Spokehead

Innersheath

A tubule B tubuleFigure 1 5.7 Flagellar doublet. (From B. Huang, et al., Cell , 29 (1982).)


18/29

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, w ith sperm tails at ~ 200 m). The outermembrane of the main shaft is a three-layered lamination, tw o dense layers ~20- to

30 thick, sandw iching a less dense layer that is 30 thick, giving a tota l thicknessof ~ 70 to 90 [54].

The two central tubula r fibrils run para llel for the entire length of the shaft , con-ferring a b ilateral symmetry. These are positioned a t ~ 300 to 350 from center tocenter, w ith a t ota l diameter of ~ 150 to 250 and a ~ 40 to 50 wa ll thickness. Asheath can link or surround the two central fibrils. Around the central duplet arenine longitudinal peripheral fibrils that form a cylindrical diameter of ~1,600.Each o f these is a do uble set of tubules ~200 to 250 in diameter w ith ~ 60 thickw alls. O ne tubule (A) is larger tha n the other and is comprised of 13 protof ilaments,and t he other (B) has 10, and the connection betw een them is strengthened by a 2 nmin diameter by ~ 48 nm long protein called tektin ( -helical structure). This proteinruns 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 thatreach out to ad jacent B tubules. These may assist in the sliding of the tubules pastone another during the beating motion. Three sets of cross-linked proteins bind theaxoneme together. The central pair is tethered by periodic bridges, and the outerdoublet tubules are joined by the nexin prot ein, spaced a t 86-nm intervals a nd a remost likely elastic to a ccommoda te the sliding duplets as w ell.

A third linkage is comprised o f ra dia l spokes. These emana te from the centra lpair and connect to each A tubule of peripheral duplets, are arranged in pairs thathave a 96-nm periodic distance. The diameter of the cilia gradually decreases to thetip and individual tubule lengths end at va rying intervals as they elongat e tow ard thetip. Where the cilia a tta ches to the cell, the ax oneme links with the basal b ody con-taining nine triplets of microtubules [54, 56].

15.8.2 Myosin and Actin

In muscle tissues myosins a re thick filaments (~1218 nm), w hereas actins a re thinfilaments (~58 nm). M yosins interpenetra te actins a nd ut ilize ATP to t emporarilyat tach the cross-bridges present o n its surfa ces to the act in filament. Thus, myosinstraverse along actin filaments via sequences of binding events to initiate muscle con-tra ction [30, 57].

15.8.3 Kinesin and Dynein

Biomimetic versions of kinesin and dynein walking may be employed to facilitatethe design of surface-roving na nodevices for nano medical applications. The trans-portation of molecular scale materials within cells is facilitated by entities such askinesin and dynein. Kinesins are two-legged molecular motors that transfer vitalmolecular-scale payloa ds w ithin cells by tra versing hollow cylindrical microtubules.They employ a head o ver head wa lking motion tha t is pow ered by the cleaving ofATP mo lecules a t its heads. They a re responsible for the separa tion of chromo-somes during cell division, a nd t he transport of nerve cell neurotransmitters.



19/29

15.9 Nanodevice Aqueous Motility

A diverse range of strategies might be employed for efficiently propellingnanomedical devices through various types of aqueous media within the human

body. Described below are a number of potentially feasible techniques toward theeventual realization of this capability.

15.9.1 Biomimetic Flagellar Propulsion Using Nanotubes

A microrobot has been conceptualized and designed to swim inside the humanureter fo r the purpose of destroy ing kidney stones noninvasively. The device usesmultiwall carb on na notubes that serve as biomimetic synthetic flagella, driven intorotating helical profiles by micro motors (Figure 15.8). Estimated swimming speedsof 1 mm/sec w ere deemed possible using 1 nW of po w er. Tw o orthogona l combdrives per motor (e.g., the aim is high efficiency) are used to convert electric poten-tial into mechanical work and imparts rotating motion to the nanotubes. A thinw ire or rad io receiver a llow s for external communica tions exchange [59].

The microrob ot is 1 mm 3, na notube radius is ~30 nm, a nd the rotation tra nslat-ing substrate is about ~ 100 m long. A swimming speed of 0.5 mm/sec w as pro-jected at a displacement of 10 m at 100 Hz with an efficiency of 2%. Assumingthat the rotary comb drive could achieve a torque of 130 Nnm in operation w ithan efficiency of 0.1%, the total power draw would be 1 nW [59].

15.11 Hypothetical Concept for Clinically Localized GPS Navigation 411

Multiwallcarbonnanotubes

Rotatingbase

Figure 1 5.8 Nanotube flagella. ( From [59].)


20/29


21/29

allows the induction of the pumping effect while eliminating of any valves ormoving parts.

The pumping action is accomplished by utilizing multiple chambers formedbetw een the peaks and va lleys of a tra veling w ave [67, 69]. Propulsion through thehuman vasculature using ultrasonic propulsion may be possible contingent oninvestigations into, and the qua ntification of, safe operating pa rameters for suchdevices in vivo. An in-depth study may be warranted to elucidate the specific effectsof sustained ultrasonic emanation from nanodevices on human w hole bloodcomponents and tissues.

15.9 .5 Nanofluidic Channels: Behavior and Potential for Prop ulsionNanofluidic propulsion systems would most likely be dealing with quite differentenvironments than their microfluidic counterparts. There a re t ota lly differentfluidic behaviors apparent w ithin this doma in in that the physical device dimensionsare on pa r w ith relative length scales of elements w ithin the fluids themselves. Thedistances involved are so small that diffusion processes prevail in mass and heattransfer at very small timescales [71].

Studies have been conducted involving fluid flow thro ugh micro/nano channelswith diameters ranging between 20 nm and 20 m with applied voltages of0.4 + 0.4V. Under conditions of partial double layer overlap, asymmetrical I-Vbehavior w as observed. The primary tra nsport mechanism driving fluid through the

orifice wa s via electro-osmosis. This show s potential for the design of na nochannelshaving rectified eletro-osmotic flow properties [7173].

15.10 Amb ulatory Nanomedical Devices

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

15.10 Ambulatory Nanomedical Devices 413

Flexuraltravelingwaves

Inducedchamber

Driveelements

Piezoelectricpolarization

Piezoelectricactuator

Figure 15 .10 Peristaltic propulsion. ( From [68].)


22/29

deliver bone rebuilding ma terials specifically to bone resident void sites for repairin osteoporosis patients. These same nanodevices might also be prescribed over thecourse of multiple treatments to add bone mass or to top dress particularly fra gileareas on certain bones. This capability might be envisaged, as well, for facilitating

the maintenance of bone mass for astronauts during long space missions, as anenhancement in addition to their regularly scheduled exercise regimes.

Na nomedical devices might also be programmed to either penetrate or tra versethe entire external surfaces of various orga ns; certa in sections of the vasculature; tra -verse the blood/bra in barrier to locate and d issolve beta amy loid plaq ue material;make their way to specific tissue areas anywhere within the human body via theextracellular matrix to deliver drugs; scan for signs of disease; or to perform molecu-lar level biopsies on site.

In addition, they might be deployed for more long-term body security tasks.For instance, t hey could serve as mob ile sentinels to potentially enhance weakenedimmune systems, or to make healthy immune systems even more robust, enablingvery rapid responses for the eradication of any threatening contagion, toxin, orother biochemical threat.

Within a ir-exposed ca vities (nasal, o ral, ear cana l) and external human tissues,ambulatory nanomedical devices might patrol dermal surfaces and subdermallayers for signs of disease, perform on-site treatments for melanomas, or to effectcosmetic repairs.

In the field of nanodentistry, dedicated or ideally, multifunctional nanodevicesmight be administered by a mouthw ash to survey all too th enamel surfaces, and theinterfaces betw een the teeth and gums to eradicate accumulated plaq ue material andba cteria, and to perform repairs on cavities. Cell-sized entities under external com-puter control might be deployed to provide painless, yet highly effective anesthesia.M ultitudes of na nodevices wo uld migrate, via ambulat ion, to the pulp chambers ofall teeth within several minutes. They would then stand by, poised to disrupt localnerve impulses, a nd hence w ould instantly numb a ny tooth on command, a s issuedby the dentist. This operation w ould be completely reversible, a nd on ord ers fromthe dentists computer, norma l nerve impulse flow w ould be restored [74].

1 5.1 0.1 DNA Ro b ot

Ned Seemans group a t N ew York University w ere the first to succeed in creat ing ananoscale biped. This DNA robot uses 10-nm long segments of DNA as its legs,w hich can w alk along a tra ck that is also comprised of D NA, by performing sequen-tial a tta chment and detachment operations. Ea ch leg is 36 ba se pairs in length and iscomprised of tw o o ligonucleotides that combine to form a duplex, w hich is con-

nected a t t he top. At the lower foot portion of the a ssembly, a n extra length ofsingle-stranded sticky DNA protrudes from each of the duplex legs. These entitiesare immersed in a nondenaturing buffer solution, to prevent DNA degradation.

The DN A track ha s segments of unpa ired b ases studding its surface to serve asfoo tholds, and tha t a re designed to b ind separa tely 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 preferentiallybinds to the anchor strand and thus strips it away, which liberates the foot [75].



23/29

1 5.1 0 .2 Nano wa lke r

A research group lead by Ludwig Bartel at the University of California, Riverside,at tached w alking linkers serving as feet for a 9, 10-Dithioanthracene, (DTA) mole-cule. The resulting nano w alker molecule exhibits bipedal motion to traverse a f latcopper substrate. It is supplied w ith heat energy, w hich it utilizes to a lternately liftonly one linker at a t ime to traverse a f lat pla ne, in a straight line, w ithout the use ofguidance rails or grooves. It was demonstrated that this walking molecule couldmake 10,000 steps flawlessly [76]. In a further development, the group managed toinduce a 9, 10-dioxanthracene (anthraquinone) molecule to tra nsport a payloa d oftwo CO2 molecules [77].

15 .11 Hypo thetical Concept for Clinically Localized GPS Naviga tionApplied to an Advanced Autonomous Nanomedical Devices

Investigations into the potential for precise nanomedical device positional determi-nat ion and effective guidance via t riangulat ion in a clinical setting may be a worthyendeavor. Navigational control of singular and multiple in vivo nanodevices fromexternal outbody sources may perhaps be accomplished by using beacons as ana-logues of multiple satellite configurations that are typically employed as compo-nents of commercial and military GPS systems.

Might it be possible to use near-infrared light (e.g., full body coverage, pro-grammable lasers) to accurately guide a nd track multitudes of ~1 micronnanomedical devices inside the human b ody? Could d irected ultrasound b e used inconjunction w ith specific types of lasers as a nano medical navigat ional to ol? Radiofrequencies in the 0.1-MHz range can traverse human tissues to a depth of 20 cmw ithout being dissipated, a nd ma y consequently prove useful for a ccessing and even

powering in vivo nanodevices [3]. The near infrared light spectrum resides inw avelengths tha t ra nge from 800 to 25,00 nm, and in one study t issue penetra tiondepths were obtained for the neonata l head that ranged from between 6.3 and 8.5mm [78]. In a light therapy investigation by NASA, the combination of threeoptimal w avelengths for LED s in the near-infrar ed reached depths of 23 cm throughsurface tissue and muscles [79].

Standard global positioning system (GPS) frequencies and associated wave-lengths would most likely be inappropriate for in vivo nanomedical applications.To achieve the required resolution, a scaled down analogous system might utilizefrequencies tha t are tra nsmitted a nd received at much higher ranges, w ith w ave-lengths 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-referenc-ing of the beacons might be a ccomplished w hen they tra nsmit a particular signalthat intersects at a specific point in space relative to the patient. This process mightspatially demarcate with high precision a reference set point that is defined by theconfluence of the beams from three or fo ur beacons, w hich w ould be registered inthe outbody computer system. The system wo uld then lock on to a nd be calibra tedto this single sustained reference point.

15.11 Hypothetical Concept for Clinically Localized GPS Navigation 415


24/29

All subsequent movements made by internalized nanomedical devices mightbe directed, tracked, and visualized in relation to this confluence fiducial. Eachnanodevice would be tagged and tracked via embedded metallic nanoshells orother nanometric entity, each with its own unique identifying frequency signature.The outbody naviga tiona l computers w ould calculate the time lapse of signals sentfrom the external beacons to each nanodevice (based on the speed of light) to deter-mine its real-time orienta tion in 3-D space (cross-referenced to the intersect nodementioned abo ve) a nd velocity (perhaps using a fourth beacon). The systemmight be equipped w ith ato mic clocks to ensure highly localized time/distancecalculations.

Positions of all nanodevices in 3-D space w ould be triangula ted by the three bea-cons set a gainst t he estab lished intersect no de. Steering each individua l na nodevicethrough the vasculature may w ell present very significant a nd complex cha llenges,as they would be required to be endowed with the capacity for traveling inmultiple directions (perhaps following the axes of all vascular entities) at prescribedvelocities.

15.12 Nanodevice Egress Strategies

Strategies having an equal importance to nanomedical device ingress would be theformula tion of t echniques for efficient egress out of t he pat ient, post-treatment. Onehypothetical (albeit quite protra cted) method w ould be to instruct the nano devicesto migrate to the germinal matrix (behind the nail beds of the fingers and toes),w here they would embed themselves in the mat rix that fo rms the nail material (com-


Scanningvolume Confluence

fiducial

Navigationbeacon

Figure 15 .11 Conceptual spatial metrics room.


25/29

prised of proteins, keratin, and sulphur) and would then permanently shut down.They would remain encapsulated there to eventually and grow out of the bodynaturally w ith the nails, at a rate ~.05 to 1.2 mm/w eek.

Another, more rapid method o f egress might be to d irect the devices to embed

themselves w ithin the ma trix of forming ha ir f ollicles (comprised of keratin,trichohyalin granules, melanin) to subsequently exit with the hair at a growth rateof ~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 nanomedicaldevice may embed itself [80, 81].

Even more rapid egress scenarios (within ~24 hours) may include exiting thebody naturally via migration to, and self-embedding within the biomass of theintestinal tract, or by natural diffusion or flushing from the system with bodilyfluids (e.g., urine, sweat) after primary systems shut down. Yet another scenariomight induce all nanodevices, subsequent to the completion of a procedure, torespond to a nd gravitate tow ard a homing signal that w ould emana te from a dedi-cated retrieval patch adhered to the skin. Upon arriving at the source site, thedevices would diffuse, or burrow up through the epidermal layers and adsorb to aspecifically designed patch undersurface to be subsequently removed. Dependanton the level of individual nanodevice and infrastructure sophistication, thisapproach might take place within tens of minutes.

Primary considerat ions for any of these egress options wo uld be tha t all devices,first of a ll, are accounted fo r via a ll-clear protocols, a nd secondly, t hat the selectedmode of egress should proceed in a completely discreet and innocuous manner. Thisprocess should be a s unnoticeable as the low -level perspirat ion that is continuouslyemanat ing through the pores of the skin.

1 5.1 3 Co nclusio n

It is hoped that this brief, and by no means comprehensive, survey of several poten-tial propulsive, ambulatory, and navigational strategies that might be employed byfuture nanomedical devices may provide some modicum of what may be possibletow ard their development. The author has the humble and hopeful aim of serving topossibly inspire the design and development of a myriad of innovative and highlyeffective nanomedical too ls. The careful, deliberate, and tho ughtful creat ion of safeyet robust nano scale instruments of health ma y ha ve strong pot ential in lead ing tomany positive health impacts for all of humankind.

Problems15.1 Describe five potential t echniques w hereby nanomedical devices ma y

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 /bra in barrier to d iagnose or treat the brain?

15.13 Conclusion 417


26/29

15.4 What is iontophoresis?15.5 What a re two significant physiological obsta cles that na nodevices will

have to overcome in order to effectively propel themselves within theaqueous in vivo environment of the human body?

15.6 Na me several ty pes of molecular mechanisms that might b e integratedinto future nano medical devices.

15.7 What type of pow er stroke might enable nanodevices to tra verse theviscous whole blood/plasma media of the human vasculature, and w hichtype of power stroke will be ineffectual at the nanoscale?

15.8 Which class of nanomaterials might serve as biomimetic a nalogs offlagella or cilia for the potential propulsion of nanodevices through thehuman circulatory system?

References

[1] M ED-JET, Medical International Technology, http://w ww .mitcanada .ca/products/med.html.

[2] SonoPrep Facilitated Transdermal Vaccination, Sontra M edical C orporation, 2004,http: //sontra .icorpsdev.com/products/drugd elivery/, and http: //sontra .icorpsdev.com/product s/vaccinedelivery/.

[3] Robert A. Freitas Jr., Nanomedicine, Volume I, Basic Capa bilities, L andes Bi oscience ,1999.

[4] K. Ishiyama, K.I. Arai, M . Sendoh, A. Yama zaki, Spiral-type micro-machine for medicalapplications, Journal of M icromechatr onics , Volume 2, (1), 77-86, (10), 2002.

[5] A. Na sir, Na notechnology and Dermatolo gy, Presentati on at the A merican Academy of D ermatology , San Antonio, Texas, Feb. 2008.

[6] P.R. Lockman, J.M . Koziara, R.J. M umper, D .D. Allen, Nanoparticle surface chargesalter blood -brain ba rrier integrity and permeability, J. Dr ug Target , 12, 635-641, 2004.

[7] H.M . Mansour, A.J. Hickey, Raman Characterization and Chemical Imaging ofBiocolloidal Self-Assemblies, Drug Delivery Systems, and Pulmonary Inhalation Aerosols:A Review , A A PS PharmSciT ech , 8.4, E99: 1-16:140-155, 2007.

[8] J. Kreuter, R. N. Alyautin, D. A. Kharkevich, a nd A. A. Ivanov, Passage of peptidesthrough the bloo d-brain barrier w ith colloidda l polymer particles (nanopa rticles) , Brain Res. , 674, l7l, 1995.

[9] S. Talegaonkar, P. R. M ishra, Intrana sal delivery: An approach to bypass the blood bra inbarrier, I ndian Journ al of Pharmacology , 36, 3, 140-147, 2004.

[10] K. Ringe,C . M . Walz,B . A. Sabel, Nanopa rticle D rug Delivery to the Brain, Encyclope- dia of N anoscience and N anotechnolo gy , Ed. H ari Singh Nalw a, American Scientific Pub-lishers, 2004.

[11] J. Kreuter, V E. Petrov, D. A. Kharkevich, and R . N. Alyautdin, Influence of the type ofsurfactant on the a nalgesic effects induced by the peptide dalargin a fter its delivery acrossthe bloodbra in barrier using surfacta nt-coated na noparticles, J. Cont rol led Release , 49,81-87, 1997.

[12] U. Schroedear, B. A. Sabel, Na noparticles, a drug carrier system to pa ss the blood-brainbarrier, permit centra l analgesic effects of i.v. da larg in injections, Br ain Res. , 7l0, l2l124,1996.

[13] U. Schroeder, P. Sommerfeld, B. A. Sabel, Efficacy of Ora l Dala rgin-load ed Nanopa rticleD elivery across the BloodBrain Ba rrier, Pept id es , 19, 777-780, 1998.



27/29

[14] U. Schroeder, P. Sommerfeld, S. Ulrich, B. A. Sabel Nanopa rticle technology for deliveryof d rugs across the blood-brain ba rrier, J. Pharm. Sci. , 87, 1305-1307, 1998.

[15] U. Schroeder, B. A. Sabel, H . Schroeder, Body distribution o f 3HH -labelled dalarginbound to poly(butyl cyanoacryla te) nanoparticles after I.V. injections to mice, L if e Sci. ,66,495-502, 2000.

[16] J.P. Ry man-Rasmussen, J. E. Riviere, N. A. Monteiro-Riviere, Penetration of Inta ct Skinby Quantum Do ts w ith D iverse Physicochemical Properties, T ox icol ogical Sciences ,91(1), 159-165, 2006.

[17] D. V. McAllister, P. M. Wang, S. P. Davis, J-H . Park, P. J. Cana tella, M . G. Allen, M. R.Prausunitz, Microfabricated needles for transdermal delivery of macromolecules andnanoparticles: fabrication methods and transport studies, Proc. N atl . Acad. Sci. USA ,100, 13755-13760, 2003.

[18] T. Mo rrow , Transdermal Patches are More Than Skin Deep, M anaged Care M agazine ,Vol. 13, No . 4, April 2004, pp. 5051, http://w w w .manag edcarema g.com/archives/0404/0404.biotech.html.

[19] H . G ra y, A nat om y of t he H u man Body , 1918, f rom bart leby. com,htt p://w w w .ba rtleby.com/107/pages/page1070. html

[20] E. R. Kay, D. A. Leigh, F. Z erbetto, Synthetic Molecular Motors and MechanicalMachines, Angew. Chem. Int. Ed , 46, 72-191, 2007.

[21] P. A. Skordos, W. H. Zurek, A m. J. Phys ., Ma xw ells demon, rectifiers, and the secondlaw : Co mputer simulation of Smoluchowskis trapdoor, 60, 876882, 1992.

[22] Z. Ra ppoport, S. E. Biali, Threshold Rota tional Mechanisms and Enantiomerization Bar-riers of Polyarylvinyl Propellers, A cc. Chem. Res. 30 , 307314, 1997.

[23] M. Oki, Ungew hnlich hohe Rota tionsbarrieren a m tetraedrischen Kohlenstoffatom,Angew. Chem. , 88, 6774, 1976.

[24] Y. Tabe, H . Yokoya ma, Co herent collective precession of molecular rotors w ith chiralpropellers, N at. M ater. 2 , 806809, 2003.

[25] J. P. Sestelo, T. R. Kelly, A prototype of a rationally designed chemically pow eredBrownian motor, Ap pl. Phys. A , 75, 337343, 2002.

[26] R. Brown, Th e M iscellaneous Bot anical W ork s of Rob ert Br ow n , Vol. 1 (Ed.: J. J.Bennett), Ra y Society, Lond on, pp. 463486, 1866.

[27] M. Schliwa ,M olecular Motors , Wiley-VCH , Weinheim, 2003.[28] R. D. Astumian, P. H. Xnggi, Brownian Mo tors, Phys. T oday , 55 (11), 33-39, 2002.[29] G . Bottari, F. Dehez, D. A. Leigh, P. J. Nash, E.M. Perez, J. K.Y. Wong, F. Z erbetto,

Entropy-Driven Translationa l Isomerism: A Tristable Mo lecular Shuttle, Angew.Chem. , 2003, 115, 60666069; A ngew. Chem. Int . Ed. , 42, 5886-5889, 2003.

[30] R. A. Bissell, E. Cordo va, A. E. Kaifer, J . F. Stodda rt, A chemically and electrochemicallyswitchable molecular shuttle, N ature , 369, 133-137, 1994.

[31] R. B. Gennis, Biom emb ranesM olecular Str uctur e and Functi on , Springer, New York,1989.

[32] P. Lauger, El ectrogenic Io n Pumps , Sinauer Associates, Sunderland, MA, 1991.[33] C.R . Ethier, C. A. Simmons, In tro ductory Biom echanics, From Cells to O rganisms , Cam-

bridge University Press, 2007.

[34] E.M. Purcell, Life at low R eynolds number, A m. J. Physics 45 , 3-11, 1977.[35] Robert A. Freitas Jr., H ow N anoro bots Can Avoid Phagocytosis by White Cells Part I,

Foresight U pdate , 45, 10-12, 2001, http ://w w w .imm.org/Repo rts/Rep027.php.[36] H .L. G oldsmith, S.G. M ason, The flow of suspensions through tubes. III. Collisions of

small uniform spheres, Proc. R. Soc. A 282 , 569-591, 1964.[37] J. Lighthill, Flagellar hydrodyna mics, SI A M Review 18, 161-230, 1976.[38] J.J.L. Higdon, The hydrod ynamics of flagellar propulsion: Helical wa ves, J. Flui d M ech.

94 , 331-351, 1979.

References 419


28/29

[39] M . Ra mia, D .L. Tullock, N. Pha n-Thien, The role of hydrod ynamic interaction in thelocomotion of microorganisms, Bi oph ys. J. 65 , 755-778, 1993.

[40] H . Winet, Wall dra g on free-moving ciliated micro-orga nisms,J. Exp. Biol. 59 , 753-766,1973:

[41] M.D . Levin, C .J. M orton-Firth, W.N. Abouhamad, R.B. Bourret, D. Bray, Origins ofindividual swimming behavior in bacteria, Bi ophy s. J. 74 , 175-181, 1998.

[42] M . Ra mia, D .L. Tullock, N. Pha n-Thien, The role of hydrod ynamic interaction in thelocomotion of microorganisms, Bi oph ys. J. 65 , 755-778, 1993.

[43] K.C . Chen, R.M . Ford, P.T. Cummings, Ma thematical models for motile bacterial trans-port in cylindrical tubes, J. Theoret. Biol. 195 , 481-504, 1998.

[44] S.H. Lee, L.G . Leal, Mo tion of a sphere in the presence of a plane interface. Part 2: Anexact solution in bipolar coordina tes, J. Flui d M ech. 98 , 193-24, 1980.

[45] Rob ert Dillon, Lisa Fauci, Do nald G aver III, A M icroscale Model of Bacterial Sw imming,Chemota xis and Substrate Transport, J. Theoret. Biol ogy , 177, 325- 340, 1995.

[46] S. Childress, M echanicsof Swi mmi ng and Flyin g, C ambridge University Press, C ambridge,UK, 1981.

[47] James A. Wilson, Prin ciples of A nimal Physiology , Macmillan Publishing Company, New

York, 1972.[48] H . M achemer, Ciliary activity and the origin of metachrony in Pa ramecium: Effects ofincreased viscosity, J. Exp . Biol . , 57, 239-259, 1972.

[49] S. Gueron, K. Levit-G urevich, Co mputation of t he internal forces in cilia: a pplication tociliary motion, the effects of viscosity, a nd cilia interactions, Bi oph ys. J. , 74, 1658-1676,1998.

[50] Michael E.J. H olwill, Peter Satir, II.4 G eneration of Propulsive Forces by C ilia andFlagella, in J. Bereiter-H ahn, O.R . Anderson, W.-E. Reif, eds., C ytom echanics: T he M echanical Basis of Cell For m and Str uctu re , Springer-Verlag , Berlin, pp. 120-130, 1987

[51] S.F. G oldstein, N.W. C haron, Motility of the spirochete Leptospira, Cell Motil .Cytoskeleton , 9, 101-110, 1988.

[52] D.R Pitelka, C.N Schooley, The fine structure of the flagellar apparatus inTrichonympha, J. M orph. , 102, 199-246, 1958.

[53] D. Bray, Cell M ovements , 2nd ed., G arland Publishing, New York, 259-261, 2001.[54] J. G ray, Ci liary M ovement , C ambridge University Press, 1928.[55] M.A. Sleigh, T he Biol ogy of the Cili a and Flagella , Pergamon Press, 1962.[56] H. Lodish, et al, M olecular Cell Biol ogy , Scientific American Books, 1998.[57] S. M. Block, Fifty Ways to Love Your Lever: My osin Mo tors, Cell , 87 , 151-157, 1996.[58] M . Shwa rtz, Walking proteins need to ro ck and roll, study finds, Stanfor d Report , July

11, 2001, htt p://new s-service.sta nfo rd .edu/new s/2001/july11/kinesin-711.ht ml.[59] J. Edd, S. Pay en, B. Rubinsky, M .L. Stoller, and M . Sitti, Biomimetic Propulsion for a

Swimming Surgical Micro-Robot, I EEE/RSJ I ntelligent Robo ti cs and Systems Conf erence , Las Vegas, USA, O ct., 2003, http: //w w w .me.cmu.edu/fa culty1/sitti/nano/publica -tio ns/iros03_last.P D F.

[60] A. Na jafi, R. G olestanian, Simple Sw immer at Low Reynolds Number: Three LinkedSpheres, Phys. Rev. E , 69, 062901, 2004.

[61] S. G uo, Y. Ha segaw , T. Fukuda, and K. Asaka, Fish-like underwa ter microrobot w ithmulti DOF, I nternation al Symposium on M icromechatr onics and H uman Science ,Piscataway, NJ, USA, 2001.

[62] S. G uo, T. Fukuda, and K. Asaka, A new type of fish-like underwa ter microrobot,I EEE/A sme Transactio ns on M echatr onics , 8, 136-141, 2003.

[63] G . Laurent and E. Piat, Efficiency of Swimming Microrobot s using Polymer Meta l Com-posite Actuators,I EEE Robotics and Automation Conf erence , Seoul, Korea, 2001.



29/29

[64] J-B. M athieu, S. Ma rtel, L. H . Yahia, G . Soulez, G . Beaudoin, Preliminary studies forusing ma gnetic resonance imaging systems as a means of propulsion for M icrorobots inblood vessels and evaluation of ferromagnetic artefacts, CCG EI 2003 , Montral, May,2003, http://w w w .nano. polymtl.ca/Articles/2003/MR -Sub%20CC ECE%2003%20v7.pdf.

[65] T. Morita , M. K. Kurosaw a, and T. Higuchi, Cy lindrical shaped micro ultrasonic motorutilizing PZ T thin film (1.4 mm in dia meter and 5.0 mm long stato r transducer), Sensors and Actu ator s, A:Physical: The 10t h In ternat ion al Conf erence on Sol id-State Sensors and Actuators TRA N SD UCERS 99 , Jun 7-Jun 10 1999, vol. 83, no.1. May, pp. 225-230,2000.

[66] O. Vyshnevskyy, S. Ko valev, J. Mehner, Coupled tangential-axial resonant modes ofpiezoelectric hollow cylinders and their application in ultrasonic motors, IEEE Trans Ul trason Feroelectr Freq Cont rol , Jan, 52 (1), 31-6, 2005.

[67] Z. C hang, Y. Bar-Cohen, Piezopumps using no physically moving parts, N D EAA Tech- nologies, Jet Propulsion L aboratory , 1999, http: //eis.jpl.nasa.go v/ndeaa /ndeaa -pub/pumps/Piezopump-99-w orkshop. pdf.

[68] Z. Chang, Y. Bar-Cohen, Piezoelectrically Actuated Miniature Peristaltic Pump, - Proceedin gs of SPI E s 7th A nnu al In ternat ion al Symp osium on Smart Str uctur es and

M aterials , Newport, 1-5 March, 2000.CA. Paper No. 3992-103 SPIE, http://eis.jpl.na sa.gov/ndeaa /ndeaa -pub/SPIE-2000/paper-3992-102-Piezopump. pdf .[69] R. Liang et al, A novel piezo vibration platfo rm for probe dynamic performa nce calibra-

tion, M eas. Sci. T echnol. , 12, 1509-1514, 2001, http://w w w .iop.org/EJ/abstract/0957-0233/12/9/318.

[70 ] W. Xudong, S. Jinhui, L. Jin, L.W. Z hong, D irect-Current Na nogenerator Driven byUltrasonic Waves, Science , 316 (5821), 102-105, 2007.

[71] P. M ela, N. R . Tas, J. E. ten Elshof, A. van den Berg, Na nofluidics , E ncyclopedia of N anoscience and N anotechnology, American Scientific Publishers, 2004.

[72] R. Q iao a nd N.R . Aluru, Transient Analysis of Electroosmotic Flow in Na no-diameterChannels, Beckman Inst itute for Advanced Science and Techno logy,htt p://w w w .cr. org /publicat ions/M SM2002/pdf /196.pdf .

[73] J. Alam, J.C. Bowman, Energy-Conserving Simulation of Incompressible Elec-

tro-Osmotic and Pressure-Driven Flow, Theoret. Comput. Fluid Dynamics, 16,133150,2002.[74] R.A. Freitas, Nanodentistry , J A m D en t A sso c, 131, 1559-1565, 2000,

ht tp: //jad a.a da .o rg/cgi/repr int /131/11/1559.pdf .[75] W.B. Sherman, N.C . Seeman, A Precisely Controlled DN A Biped Walking Device,

N ano Lett . , 4 (9), 1801-1801, 2004.[76] K.-Y. Kw on, K. L. Wong, G . Paw in, L. Bartels, S. Stolbov, T. S. Ra hman, Unidirectional

Adsorbate Motion on a High-Symmetry Surface: Walking Molecules Can Stay theCo urse, PRL 95, 166101, 2005

[77] K.L. Wong, G. Pa w in, K.-Y. Kw on, X. Lin, T. Jiao, U. Solanki, R.H .J. Faw cett, L. Bartels,S. Stolbov, T.S. Ra hman, A Molecule Carrier, Science , 315, 1391, 2007.

[78] F. Faris, et al., Non-invasive in vivo near-infrared optical measurement of the penetrationdepth in the neonat al head, Cl in . Phys. Physiol. M eas. , 12, 353-358, 1991.

[79] Chance B., Nioka S., Kent J. , M cCully K., Fountain M., Greenfield R., H oltom G ., Time-Resolved Spectroscopy of Hemoglobin and Myoglobin in Resting and IschemicMuscle, A nalyti cal Biochemistr y , 174, 698-707, 1988.

[80] J. La demanna, H . Richtera, U.F. Schaeferb, U. Blume-Peytavia, A. Teichmanna, N.Ot berga, W. Sterrya, H air Follicles - A Long-Term Reservoir fo r D rug D elivery, Skin Pharmacol. Physiol . , 19(4), 232-236, 2006.

[81] R. Alvarez-Rom n, A. Naik, Y.N. Kalia , R.H . Guy, H . Fessi, Skin penetration and distri-bution of polymeric nanoparticles, Jour nal of Cont rol led Release , 99, 53-62, 2004.

References 421

sch-ch15 second proof

Documents