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International Journal of Surgery (2005) -, -e-

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EDITORIAL

Nanotechnology, nanomedicine and nanosurgery

An exciting revolution in health care and med-ical technology looms large on the horizon. Yet theagents of change will be microscopically small,future products of a new discipline known asnanotechnology. Nanotechnology is the engineer-ing of molecularly precise structures e typically0.1 mm or smaller e and, ultimately, molecularmachines.

Nanomedicine1e4 is the application of nano-technology to medicine. It is the preservationand improvement of human health, using molecu-lar tools and molecular knowledge of the humanbody. Present-day nanomedicine exploits carefullystructured nanoparticles such as dendrimers,5 car-bon fullerenes (buckyballs)6 and nanoshells7 totarget specific tissues and organs. These nanopar-ticles may serve as diagnostic and therapeutic an-tiviral, antitumor or anticancer agents. But as thistechnology matures in the years ahead, complexnanodevices and even nanorobots will be fabri-cated, first of biological materials but later usingmore durable materials such as diamond toachieve the most powerful results.

Early vision

Can it be that someday nanorobots will be able totravel through the body searching out and clearingup diseases, such as an arterial atheromatousplaque?8 The first and most famous scientist tovoice this possibility was the late Nobel physicistRichard P. Feynman. In his remarkably prescient1959 talk ‘‘There’s Plenty of Room at the Bottom,’’Feynman proposed employing machine tools tomake smaller machine tools, these are to beused in turn to make still smaller machine tools,and so on all the way down to the atomic level,noting that this is ‘‘a development which I thinkcannot be avoided.’’9

1743-9191/$ - see front matter ª 2005 Surgical Associates Ltd. Pudoi:10.1016/j.ijsu.2005.10.007

Feynman was clearly aware of the potentialmedical applications of this new technology. Heoffered the first known proposal for a nanoroboticsurgical procedure to cure heart disease: ‘‘A friendof mine (Albert R. Hibbs) suggests a very interest-ing possibility for relatively small machines. Hesays that, although it is a very wild idea, it wouldbe interesting in surgery if you could swallow thesurgeon. You put the mechanical surgeon insidethe blood vessel and it goes into the heart andlooks around. (Of course the information has to befed out.) It finds out which valve is the faulty oneand takes a little knife and slices it out. .[Imag-ine] that we can manufacture an object thatmaneuvers at that level!. Other small machinesmight be permanently incorporated in the body toassist some inadequately functioning organ.’’9

Medical microrobotics

There are ongoing attempts to build microrobotsfor in vivo medical use. In 2002, Ishiyama et al. atTohoku University developed tiny magneticallydriven spinning screws intended to swim alongveins and carry drugs to infected tissues or even toburrow into tumors and kill them with heat.10 In2003, the ‘‘MR-Sub’’ project of Martel’s group atthe NanoRobotics Laboratory of Ecole Polytechni-que in Montreal tested using variable MRI magneticfields to generate forces on an untethered micro-robot containing ferromagnetic particles, develop-ing sufficient propulsive power to direct the smalldevice through the human body.11 Brad Nelson’steam at the Swiss Federal Institute of Technologyin Zurich continued this approach. In 2005, theyreported the fabrication of a microscopic robotsmall enough (w200 mm) to be injected into thebody through a syringe. They hope that this deviceor its descendants might someday be used to de-liver drugs or perform minimally invasive eye

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2 Editorial

surgery.12 Nelson’s simple microrobot has success-fully maneuvered through a watery maze using ex-ternal energy from magnetic fields, with differentfrequencies that are able to vibrate different me-chanical parts on the device to maintain selectivecontrol of different functions. Gordon’s group atthe University of Manitoba has also proposed mag-netically controlled ‘‘cytobots’’ and ‘‘karyobots’’for performing wireless intracellular and intranu-clear surgery.13

Manufacturing medical nanorobots

The greatest power of nanomedicine will emerge,perhaps in the 2020s, when we can design andconstruct complete artificial nanorobots using rigiddiamondoid nanometer-scale parts like moleculargears (Fig. 1) and bearings.14 These nanorobotswill possess a full panoply of autonomous subsys-tems including onboard sensors, motors, manipula-tors, power supplies, and molecular computers.But getting all these nanoscale components tospontaneously self-assemble in the right sequencewill prove increasingly difficult as machine struc-tures become more complex. Making complexnanorobotic systems requires manufacturing

Figure 1 A molecular planetary gear is a mechanicalcomponent that might be found inside a medical nanoro-bot. The gear converts shaft power from one angular fre-quency to another. The casing is a strained silicon shellwith predominantly sulfur termination, with each ofthe nine planet gears attached to the planet carrier bya carbonecarbon single bond. The planetary gear shownhere has not been built experimentally but has beenmodeled computationally. Copyright 1995 Institute forMolecular Manufacturing (IMM).

techniques that can build a molecular structureby what is called positional assembly. This will in-volve picking and placing molecular parts one byone, moving them along controlled trajectoriesmuch like the robot arms that manufacture carson automobile assembly lines. The procedure isthen repeated over and over with all the differentparts until the final product, such as a medicalnanorobot, is fully assembled.

The positional assembly of diamondoid struc-tures, some almost atom by atom, using molecularfeedstock has been examined theoretically14,15 viacomputational models of diamond mechanosyn-thesis (DMS). DMS is the controlled addition of car-bon atoms to the growth surface of a diamondcrystal lattice in a vacuum-manufacturing environ-ment. Covalent chemical bonds are formed one byone as the result of positionally constrained me-chanical forces applied at the tip of a scanningprobe microscope apparatus, following a pro-grammed sequence. Mechanosynthesis using sili-con atoms was first achieved experimentally in2003.16 Carbon atoms should not be far behind.17

To be practical, molecular manufacturing mustalso be able to assemble very large numbers ofmedical nanorobots very quickly. Approaches un-der consideration include using replicativemanufacturing systems or massively parallel fabri-cation, employing large arrays of scanning probetips all building similar diamondoid product struc-tures in unison.18

For example, simple mechanical ciliary arraysconsisting of 10,000 independentmicroactuators ona 1-cm2 chip have been made at the Cornell Nation-al Nanofabrication Laboratory for microscale partstransport applications, and similarly at IBM for me-chanical data storage applications.19 Active probearrays of 10,000 independently actuated micro-scope tips have been developed by Mirkin’s groupat Northwestern University for dip-pen nanolithog-raphy20 using DNA-based ‘‘ink’’. Almost any desired2D shape can be drawn using 10 tips in concert. An-other microcantilever array manufactured by Proti-veris Corp. has millions of interdigitated cantileverson a single chip. Martel’s group has investigatedusing fleets of independently mobile wireless in-strumented microrobot manipulators called Nano-Walkers to collectively form a nanofactory systemthat might be used for positional manufacturingoperations.21 Zyvex Corp. (www.zyvex.com) ofRichardson, TX has a $25million, five-year, NationalInstitute of Standards and Technology (NIST) con-tract to develop prototype microscale assemblersusing microelectromechanical systems. This re-search may eventually lead to prototype nanoscaleassemblers using nanoelectromechanical systems.

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Editorial 3

Respirocytes and microbivores

The abil ity to build compl ex diamondo id medi calnanoro bots to mole cular pre cision, and the n tobuild the m cheaply enough in sufficient ly largenumbers to be useful thera peuticall y, will revo lu-tioniz e the pra ctice of medi cine and surger y. 1 Thefirst theoreti cal de sign study of a compl ete medi-cal nanorobo t ever publish ed in a peer-rev iewedjournal (in 1998) described a hy pothetica l artifici almecha nical re d blood cell or ‘‘re spirocyt e’’ madeof 18 b illion preci sely arr anged structur al atom s.22

The resp irocyte is a bloodborne spheri cal 1- m m di-amo ndoid 1000-atm osphere pressure vess el withrevers ible molec ule-selec tive surface pumps pow-ered by end ogenous serum glucos e. This nanoro botwould deliver 236 times more oxygen to bod y tis-sues per unit volume tha n nat ural red cells andwould ma nage carbo nic acidity, cont rolled by gasconc entratio n sensors and an onboard nanoco m-puter. A 5-cc thera peutic dose of 50% resp irocytesaline suspen sion conta ining 5 trillio n nano robotscould exactly repl ace the gas car rying capaci ty ofthe patient ’s entir e 5.4 l of blood.

Nanor obotic artifi cial phagocyt es called ‘‘micro-bivores ’’ (Fig. 2) could patro l the bloodstrea m,seekin g out and diges ting unwant ed pat hogens in-clud ing bacte ria, virus es, or fungi. 23 Micro bivoreswould achie ve compl ete clearan ce of even themost severe septicem ic infections in hours orless. This is far bett er than the weeks or monthsneed ed for ant ibioti c-assisted natu ral phagocyt icdefen ses. The nanorobo ts do not increas e the riskof seps is or septic shock because the pathoge nsare completel y digested into harmle ss sugars, ami-no aci ds and the like, which are the only effluent sfrom the nanorobot.

Figure 2 Nanorobotic artificial phagocytes called ‘‘mi-crobivores’’ could patrol the bloodstream, seeking outand digesting unwanted pathogens. Copyright 2001Zyvex Corp.; designer Robert Freitas, artist Forrest Bishop.

Surgical nanorobotics

Surgica l nano robots could be intr oduce d into thebody through the vascul ar system or at the ends ofcathe ters into vario us vessels and other cavi ties inthe human body. A surgica l nanorobo t, pro-gramm ed or guided by a human surgeon, couldact as a sem i-auton omous on-site surgeon insidethe human bod y. Such a device could performvariou s fun ctions such as searchi ng for patho logyand then diagnosi ng and cor recting lesions b ynanoma nipulati on, coor dinated by an onboa rdcomput er while ma intaining c ontact w ith thesupervi sing surgeo n via code d ultra sound signals.The earli est for ms of cellular nanos urgery arealready being explored today. For example, a rap-idly vibrating (100 Hz) micropipette with a <1-mmtip diameter has been used to completely cut den-drites from single neurons without damaging cellviability.24 Axotomy of roundworm neurons wasperformed by femtosecond laser surgery, afterwhich the axons functionally regenerated.25 Afemtolaser acts like a pair of ‘‘nano-scissors’’ byvaporizing tissue locally while leaving adjacent tis-sue unharmed. Femtolaser surgery has performedthe follo wing: (1) localized nanosu rgical abla tionof focal adhesions adjoining live mammalian epi-thelial cells,26 (2) microtubule dissection insideyeast cells,27 (3) noninvasive intratissue nanodis-section of plant cell walls and selective destruc-tion of intracellular single plastids or selectedparts of them,28 and even (4) the nanosurgery ofindividual chromosomes (selectively knocking outgenomic nanometer-sized regions within the nu-cleus of living Chinese hamster ovary cells29).These procedures do not kill the cells upon whichthe nanosurgery was performed. Atomic force mi-croscopes have also been used for bacterium cellwall dissection in situ in aqueous solution, with26 nm thick twisted strands revealed inside thecell wall after mechanically peeling back largepatches of the outer cell wall.30

Future nanorobots equipped with operatinginstruments and mobility will be able to performprecise and refined intracellular surgeries whichare beyond the capabilities of direct manipulationby the human hand. We envision biocompatible31

surgical nanorobots that can find and eliminateisolated cancerous cells, remove microvascularobstructions and recondition vascular endothelialcells, perform ‘‘noninvasive’’ tissue and organtransplants, conduct molecular repairs on trauma-tized extracellular and intracellular structures,and even exchange new whole chromosomes forold ones inside individual living human cells.

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References

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16. Oyabu N, Custance O, Yi I, Sugawara Y, Morita S. Mechanicalvertical manipulation of selected single atoms by soft nano-indentation using near contact atomic force microscopy.Phys Rev Lett 2003;90:176102.

17. Freitas Jr. RA. A simple tool for positional diamond mecha-nosynthesis, and its method of manufacture. U.S. provision-al patent application no. 60/543,802, filed 11 February2004, U.S. patent pending; 11 February 2005. Also

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21. Martel S, Hunter I. Nanofactories based on a fleet of scien-tific instruments configured as miniature autonomousrobots. In: Proceedings of the third international workshopon microfactories. 16e18 Sep 2002, Minneapolis, MN, USA;2002. p. 97e100.

22. Freitas Jr RA. Exploratory design in medical nanotechnol-ogy: a mechanical artificial red cell. Artif Cells BloodSubstit Immobil Biotechnol 1998;26:411e30. Also avail-able from: http://www.foresight.org/Nanomedicine/Respir-ocytes.html.

23. Freitas Jr RA. Microbivores: artificial mechanical phago-cytes using digest and discharge protocol. J Evol Technol2005 Apr;14:1e52. Also available from: http://jetpress.org/volume14/Microbivores.pdf.

24. Kirson ED, Yaari Y. A novel technique for micro-dissection ofneuronal processes. J Neurosci Methods 2000;98:119e22.

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31. Freitas Jr RA. Nanomedicine, Vol. IIA: Biocompatibility.Georgetown (TX): Landes Bioscience; 2003. Also availablefrom: http://www.nanomedicine.com/NMIIA.htm.

Robert A. Freitas Jr.Institute for Molecular Manufacturing,

555 Bryant Street,Suite 354, Palo Alto,

CA 94301, USAE-mail address: rfreitas@rfreitas.com