REVIEW 1 Most Journal of 5–12 4 3 Vol.2, 1–25, 2005 Burgeoning interest in the 3 Computational and Theoretical Nanoscience The NIH Roadmap’s new Nanomedicine 5 and could approach $1 billion in next year’s staffed by a highly interdisciplinary scientific 2 with annual nanotechnology investment worldwide 3 In December 2002 the U.S. National Institutes of broadly, nanomedicine is theing, process and of preventing diagnosing, disease treat- anding traumatic pain, injury, and of reliev- ofusing preserving molecular and improving toolshuman human and body. health, molecular knowledge of the medical applications ofemergence of nanotechnology a new has field led called nanomedicine. to the reaching approximately $3wide billion market for in nanoscaleing 2003.The devices should and world- grow molecular2002 28%/year, model- to $1.37 rising billion in fromin 2007, revenues $406 with from a million 35%/year biomedical growth nanoscale in rate devices. Initiatives, firstthis released cutting-edge inmedical area late benefits of 2003, aswill research begin early “envision will with as “establishingCenters that begin a 10 handful yielding years ofcrew Nanomedicine from including now” biologists, and physicians, mathematicians, Health announced ananotechnology 4-year program in for medicine. nanoscience and budget.The European Commission haslion set euros aside 1.3bil- 2006, for nanotechnology research during 2003– FY 2004 1546-198X/2005/2/1/025/$17.00+.25 doi:10.1166/jctn.2005.01 Robert A. Freitas, Jr. Medical Nanorobotics reaching $849 million in Institute for Molecular Manufacturing, Palo Alto, California, USA 1 Assembly, Nanomaterials, Nanorobot, Nanorobotics, Nanotechnology. Current Status of Nanomedicine and Keywords: Nanomedicine is the process ofrelieving diagnosing, pain, treating, and and of preventing disease preservingknowledge and of and traumatic the improving injury, of human humantant health, body. In medical using problems the molecular by relatively tools using nearmanufactured and nanoscale-structured term, today, molecular materials including nanomedicine and can the simpleIn address nanodevices interaction that many the of can impor- mid-term, be nanostructuredmedicine biotechnology materials and will with biobotics, biological make includingterm, microbiological systems. possible biorobots perhaps even or 10–20 more engineeredmay years remarkable organisms. join from In advances the the in today, medical longer conquer the armamentarium, molecular human earliest finally disease, giving molecular ill-health, physicians and machine the aging. systems most and potent tools nanorobots imaginable to Copyright © 2005 AmericanAll Scientific rights Publishers reserved Printed in the United States of America Molecular Imprinting ...... 3 Scaling Studies ...... 18 NANOMEDICINE Acknowledgments ...... References 21 ...... 21 2.1.Nanopores ...... 2.2. 2 Artificial Binding Sites and 2.3.Quantum Dots and Nanocrystals ...... 2.4.Fullerenes and Nanotubes ...... 3 2.5.Nanoshells and Magnetic Nanoprobes 4 Nanoparticles2.6.Targeted ...... and Smart Drugs2.7.Dendrimers and 4 Dendrimer-Based ...... Devices2.8.Radio-Controlled ...... Biomolecules 5 ...... 6 7 4.1.Early Thinking in Medical Nanorobotics4.2.Nanorobot Parts and ...... Components ...... 4.3.Self-Assembly and Directed Parts 9 Assembly4.4.Positional Assembly 9 ...... and Molecular Manufacturing4.5. 12 ..... Medical Nanorobot Designs 14 and J. Comput. Theor. Nanosci. 2005, Vol. 2, No. 1 1.NANOTECHNOLOGY AND Annual U.S. federalexceeded $500 funding million in for 2002 nanotechnology R&D CONTENTS 1.Nanotechnology and Nanomedicine ...... 2.Medical Nanomaterials and Nanodevices 1 ...... 2 3.Microscale Biological Robots ...... 4.Medical Nanorobotics ...... 8 9 REVIEW is hrpuial sflnnmdcldevices, ear- nanomedical the Desai of useful one therapeutically 1997 considered liest be nanopores.In could what or created Ferrari holes, and sur- with a is perforated nanomaterials medical face simplest the of one Perhaps Nanopores 2.1. NANOMATERIALS 2.MEDICAL engineering in processes and vocabulary—lexicon— parts of terms”. biological kind define new “a to who develop built” also are will machines molecular how scientists about information computer and engineers Nanorobotics Medical and Nanomedicine of Status Current hsicue h neato fnnsrcue materi- nanostructured systems. of biological interaction with 2). als (Section the today includes manufactured simple This be and can materials that nanoscale-structured nanodevices prob- using medical by important lems many address can nanomedicine e oksAlac o aoeia Technologies. Nanomedical for Alliance York’s New otptn ol mgnbet oqe ua disease, human 4). (Section conquer aging to and imaginable ill-health, the tools physicians potent giving most join finally may armamentarium, ear- nanorobots medical the and the today, systems from machine years molecular 10–20 liest 3).In perhaps (Section term, longer organisms remark- the engineered more or biobotics–micro- robots even and biological medicine molecular possible in advances make able will biotechnology ml nuht meetepsaeo uhlarger much are of and but immunoglobulins passage as pass, the such to molecules impede insulin system molecules to immune and small enough glucose, allow diameter. small to oxygen, in enough as nanometers large such 20 are as pores small uni- These of as density high nanopores a form present membranes to micromachined filter are envi- silicon which biological polycrystalline wafers.The surrounding through the silicon ronment with crystalline interface single chambers cell-containing tiny within fabricate chambers to micromachining bulk ing 2 nterltvl ertr,oe h et5years, 5 next the over term, near relatively the In N NANODEVICES AND 13 vnsaefne rgashv eu,sc as such begun, have programs state-funded Even ieai efRpiaigMcie 20) nte rto-t-idtcncltreatise. technical co-authored first-of-its-kind recently another most (2004), and ref- Machines chapters, 25 book Self-Replicating published contributed Kinematic has several systems.He and factory publications and journal machine ereed Bioscience. in assemblers Landes self-replication molecular and machine by pathways), nanofactories, molecular experimental 2003 and and design, and (theory nanorobotics 1999 mechanosynthesis medical in diamond nanomedicine, systems, published include: were first interests series the research 4-volume nanorobotics; the His this medical of of discussion and technical volumes nanotechnology book-length journal.More molecular two from first of biomedical the applications mainstream J.D. of Nanomedicine, of medical peer-reviewed of study analysis potential a author a design the feasibility and technical in is detailed NASA published Freitas 1974 first recently, ever 1980 the in nanorobot the authored College medical 1996 co-edited in a Mudd 1979.Freitas and factories Harvey in Corp.(Richard- space Zyvex from Clara self-replicating at Santa Psychology B.S. Scientist received of and Research 2000-2004.He University Physics during a company, in was nanotechnology and molecular degrees first California, the Alto, Texas), Palo son, in (IMM) ing Jr. Freitas, A. Robert 7 vrtenx –0years, 5–10 next the Over ahrn extensive gathering 15 employ- sSno eerhFlo tteIsiuefrMlclrManufactur- Molecular for Institute the at Fellow Research Senior is 14 mlne eet h kno oedaee patients. diabetes some of be skin cells—could the islet beneath piglet implanted reject.Microcap- cells— easily-harvested Langerhans and likely of most attack islets replacement cells normally containing foreign sules would the of it for unaware while pores which remains healthy the system remain through immune out and the back nutrients insulin secreting receive weeks, may pancre- cells rat atic encapsulated this immunoisolated behind barrier, ensconced artificial particles.Safely virus graft-borne ilmembranes, cial o pumps, ion oycudas eavlal a otetohrenzyme other treat to diseases, way deficiency valuable hormone a or be the also to serious could cells new at body encapsulated patient infection.Supplying powerful the for glu- for leave risk need can delicate the that body’s without immunosuppressants loop the feedback restore control cose temporarily could This htdtcscagsi hmclcnetainof concentration chemical in changes detects that separations, drug perform to xenlyregulated. externally Parkin- or Alzheimer’s for treatment diseases. future son’s a of possi- part be neurotransmitters, as then bly release and to brain the stimulated in electrically implanted be could which neurons rcs oto fintasotwt infiatmolecu- significant with efforts transport recent specificity.Martin’s ion lar achieve of to constraints control charge and precise shape, can size, pore ions gat- with voltage ing positive combine only may nanodevices mem- voltage, similar negative pass.Future the a membrane.When receives the brane ions through negative only positively transported and are are excluded tubules are as the ions When positive diameters charged, nanometers. inside 1.6 with as nanotubules small gold cylindrical of oeua aoiv a arctdb atnadcollea- and Martin by gues fabricated was nanosieve molecular biocatalysis. nietenntbsa ciebooia nanosensors, DNA biological and active proteins as other nanotubes antibodies, the inside enzymes, as agents such molecular-recognition biochemical immobilizing at h o fmtrastruhnnprscnas be also can nanopores through materials of flow The 19 n19.atnsmmrn otisa array an contains membrane 1995.Martin’s in 24 23 otg-ae aooe meddi artifi- in embedded nanopores voltage-gated tesaeivsiaigsnhtcnanopore synthetic investigating are Others 25 .Cmu.Ter aoc.2 1–25, 2, Nanosci. Theor. Comput. J. n nincanlsic biosensor switch channel ion an and 18 h rtatfiilvoltage-gated artificial first The 22 23 17 nldn encapsulated including n oalwselected allow to and 20 aebe directed been have ∼ Freitas 10 2005 − 18 26 21 16 . REVIEW 3 47 and vas- Quan- 48 52 live cell 51 for cancer gene map- 50 44 40 Quantum dots 41 39 immunocytochem- 42 54–56 On the research front, the abil- 38 gene expression studies, and many other applications. intracellular organelle markers, 38 49 medical diagnostics and drug screening, 43 46 and other methods. 45 35 53 Current Status of Nanomedicine and Medical Nanorobotics Quantum Dot Corp. (www.qdots.com), the manufac- cell detection, computationally using time-dependenttheory density functional labeling, tum dot physics has been studied theoretically are being investigated as chemical sensors, ity to simultaneouslyand tag inside multiple cells biomolecules couldplex both allow cellular scientists on changes to andproviding watch events valuable the associated clues com- withpharmaceuticals disease, for and therapeutics.Quantum the dotsful development for are of studying use- genes, future cells, proteins tissue specimens, and and drug living animals. targets in single ping and DNA microarray analysis, cular imaging, ical probes, SNP (Single Nucleotide Polymorphism) genotyping, 2.3. Quantum Dots and Nanocrystals Fluorescent tags are commonplaceogy, found in medicine in andthat everything image biol- from the HIV innermolecules tests functions to must of experiments be cells.Butlasers different are used dye needed forcolors to each tend get to color, eachuse.“Quantum bleed color-matched dot” dye together nanocrystals to have and nonecomings.These fluoresce, of fade these dots and quickly short- are dye afterfew tiny one nanometers particles across, measuringmolecule about only the or a same anearly size short as unlimited sequence a palette ofcan protein of DNA.They be sharply-defined come customized colors in bytion.Particles changing a which can particle be sizelight, excited or can to composi- fluorescence besensitive with linked probes white to tothousand biomolecules identify to times specific form brighter compoundsmany long-lived than biological up tests, conventional to andsimultaneously dyes a can tagging used track each in biologicaldifferent biological events proteins by component or DNA (e.g., specific sequences) color. with nanodots of a turer, believes this kindand of easy flexibility way could toof offer a screen a number a of cheap also blood different give viruses sample physicians at a for the fast diagnosticpresence the same tool time.It of presence to could a detect, say, particular the cates set a of person proteins iscellular that having cancer a strongly markers. heart indi- attack or to detect known polymers have limitations,removal, such broad guest as affinitiesmass incomplete and transfer.Imprinting template selectivities, inside and dendrimersmay slow (Section allow quantitative 2.7) templateneous removal, binding nearly sites, solubility homoge- inand common organic amenability solvents, togroups. the incorporation of other functional and is an 27 35 34 By 1998, Bran- and investigating experiments with 32 possibly eventually 29 32 2005 33 Nanopore-based DNA- understanding the unzip- 32 But molecularly imprinted polymer block was created. 30 3 37 recognition elements in biosensors and biological and receptor mimics and the recognition of folded DNA 36 37 31 through nanopores are in progress. 28 Molecular Imprinting Finally, Daniel Branton’s team at Harvard University Molecularly imprinted polymers could be medically new 3–10 nm silicon-nitride nanopores, ton hadrapidly shown discriminate that betweenments pyrimidine the and (the purine nanopore twogle seg- types RNA could of molecule.In bethe nucleotide 2000, ability the bases) used to scientists alonglar to demonstrated distinguish a length between sin- and DNAsequence.Current composition chains research that of differfabricating is simi- only pores directed in withgeometries toward base specific at pair reliably diameters high and precision, repeatable the benefits ofto adding pores electrically to conductingthe improve single-base electrodes longitudinal level resolution for “possibly DNA”. to existing technique inmonomers which interacts reversibly a with a cocktailonly target molecule noncovalent of using forces.The functionalized complex isand then polymerized cross-linked in apolymer casting with procedure, recognition leaving sitesget behind complementary molecule a to in thesite both tar- constitutes shape an andof induced functionality.Each molecular selectively such “memory,” binding capable ment the involving an target amino species.Incial acid binding one derivative site target, experi- per one (3.8 artifi- nm) including artificial antibodies (plastibodies)ing or biomimick- enzymes (plastizymes). molecules passing through the pore, has conducted an ongoingelectric series field of to experimentsmers drive using through an a the variety centralprotein of nanopore RNA of channel an andthe mounted alpha-hemolysin DNA outer in poly- membrane a of lipid a bilayer living cell. similar to Chiral separations, enzymatic transitionhigh state receptor activity, affinities and have been demonstrated. useful in clinicalrelease, drug applications monitoring such devices,arations quick and as biochemical assays, controlled sep- drug sequencing devices could allowtially per-pore read up rates to poten- 1000 bases per second, and chemosensors, diffusion providing a low-costrapid genome high-throughput sequencing. method for very 2.2. Artificial Binding Sites and Another early goal oflogical nanomedicine molecular is receptors toficial work, study and binding how then bio- sitesspecific to on medical build a arti- results.Molecular made-to-order imprinting basis to achieve ping of double-strandedthrough the DNA pore as one strand is pulled J. Comput. Theor. Nanosci. 2, 1–25, Freitas Molecular dynamics theoretical studies of viscosity REVIEW hlscruaetruhtebd ni hyaccumulate they until body the through body.The the layers. circulate into constituent injected shells tumor- and the drug-containing polymer a of is hydrogel in targeted size resonance embedded relative optical are nanoshells whose the The coating, of core gold function a a a and with silica nanospheres of dielectric-metal are nanoshells rlslrss(L rLuGhi’ disease) Gehrig’s Lou lat- or amyotrophic (ALS for sclerosis treatments eral include may which agents pdapafr o aocl rgdlvr aldthe called delivery drug nanoscale for devel- nanoshell. have platform Houston in a University oped Rice at West and Halas Nanoprobes Magnetic and Nanoshells 2.5. biosensor. hybridization DNA electrochemical an as and glucose, biosensors, detect as to investigated example being for are nanotubes carbon anticancer and C as such fullerenes of derivatives Soluble Nanotubes and Fullerenes 2.4. Nanorobotics Medical and Nanomedicine of Status Current aoaoymdli tlattoyasaway. years neu- two a least cancer, in at in testing is though role model conditions, a laboratory other play and nucleus. that disease cell rological genes used defective the be target day on one to in might nanodevice home nanocrystal simple nanoparticles This the vectors, viral help like can which, as the proteins, such scaffolding, off or dioxide peptides titanium snips navigational the to x-rays attached oligonucleotides be or can besides light molecules gene.Other to defective nanoparticle of exposure bound whereupon defec- the its strand, with DNA binds complementary DNA the tive attached into defective the nanoparticle where the a nucleus introduce matches cell then that cell, DNA a of within gene strand semiconduc- a the scaffolding to attach tor would x-rays). acid researchers or example, nucleic light pos- For light-inducible to exposed also a when of (separating importantly endonuclease property unique more the but sess DNA, oligonucleotide eso lgncetd DNA. oligonucleotide tita- of snip- with pets biocompatible attached covalently of semiconductor dioxide nanocrystals “nanodevice” nium hybrid 4.5-nm a of created composed have Laboratory National o’ disease.Single-walled son’s hs aoopstsntol eanteitiscpho- intrinsic TiO the of retain capacity only tocatalytic not nanocomposites these peroxide, eimtuberculosis terium hyhv lobe netgtdcomputationally investigated been also have they 4 satvrlaet ms oal gis HIV, against rela- notably serve (most at may agents even compounds antiviral toxicity dosages.Fullerene as have low high (www.csixty.com), and tively trials biocompatibility clinical good in derivatives, agents.These already pharmaceutical many as utility great niatra gns( agents antibacterial eerhr rmNrhetr nvriyadArgonne and University Northwestern from Researchers 71 75 eetdpoen uha immunoglobulins, as such proteins selected 76 67 niecro ulrns h lgtylarger slightly the fullerenes, carbon Unlike hrpe,atoiat n anti-apoptosis and antioxidants therapies, , 64 .coli E. t.,pooyai antitumor photodynamic etc.), , 2 62 57 69 n h iatvt fthe of bioactivity the and Streptococcus 70 72 xeiet hwdthat showed Experiments 74 n multi-walled and ethanol, 60 58 68 , 63 74 aeshown have n Parkin- and Mycobac- hydrogen 59 where 60 71–73 65 61 70 69 66 ), n,aditgae eeto n treatment. and detection imag- noninvasive integrated fast and imaging, ing, site.Nanoshells detailed earlier more specific treatments: and detection, cancer a polymer traditional at over the advantages payload offer melt drug frequencies, selec- their virus) IR release polio the a the absorb than laser, tively larger infrared slightly an (each with nanoshells heated cells.When tumor near hl lo eywl,s ti notmlwavelength optimal an is immunoassay. it penetrates blood so which light whole well, to for near-infrared very light of blood respond; color whole the nanoshells of tuning the precise allow shell ei irpril rbscae ihtre protein- a with target probes with nanoparticle 13-nm coated plus antibodies probes binding microparticle netic trials clinical human begin to 2006. permission in for and FDA tests the human designing ask start to plans BioSystems Triton few a in cells tumor to the particles killing iron degrees, seconds. the 170 to heats than (similar machine) more machine MRI field miniaturized magnetic a from alternating generated portable field magnetic bio- a a with hours, covered several after is probes micrometastases) tumor antibodies or the visible membranes.Once the (whether cell whereupon tumor body, to bind the selectively inside injected circulate are 40 probes and about inert chemically nanobioprobes long.The into nanometers antibodies monoclonal nanoparticles iron and bond to is (www.tritonbiosystems.com) lk.etsbet eln anfo h etgenerated. nanoparticles heat the and from pain residue no feel cellular subjects alike.Test removes system tion iswsahee nsln,srm n hl lo in blood whole and serum, saline, minutes. in 10–30 achieved immunoglobu- was of lins quantities sub-nanogram-per-milliliter muosa sn nioynnpril ojgtsof nanoshells. conjugates gold antibody-nanoparticle blood using insulin- whole researchers point-of-care immunoassay the a Rice remove of for mid-2003, development and the and tri- 2006.In announced 2004 clinical by find by system start treatment to delivery cancer to the surgeons hopes for company for als scalpel.The small a can- too with of MD cells aggregates the tiny cer micrometastases, at specif- Texas, targeting of studies University ically technology. the develop- at animal Center nanoshell is Cancer conducting Anderson West, of is and applications Nanospectra Halas commercial by ing started company vate the in remain could months. for system times body nanoshell-polymer several of the taken pulse day, a are a release which to from injections, polymer heat where insulin.Unlike the a injected.The cause skin use been would the would had nanoshells heat patient polymer nanoshell a to the insulin, laser of infrared injection ballpoint-pen-size diabetes.Instead an treating taking in useful of prove also could nique iknsgopa otwsenUiest ssmag- uses University Northwestern at group Mirkin’s BioSystems Triton by pursued approach alternative An aopcr isine wwnnsetacm,apri- a (www.nanospectra.com), Biosciences Nanospectra 80 neteclsaedsryd h oysexcre- body’s the destroyed, are cells the Once 78 .Cmu.Ter aoc.2 1–25, 2, Nanosci. Theor. Comput. J. 78 ayn h hcns ftemetal the of thickness the Varying 79 ucsfldtcinof detection Successful 77 hstech- This Freitas 2005 80 REVIEW 5 Pseu- “different 90 separate the target- 87 “The selectivity of the 89 Other stimulus-responsive bacteria are present.But if 91 wound infections, was success- Suzuki started with the common 90 , a Gram-negative bacillus that causes P. aeruginosa This targeted drug molecule turns lethal only 88 Current Status of Nanomedicine and Medical Nanorobotics A further improvement in enzyme-activated drugs are Enzyme-activated drugs, first developed in the 1980s “smart” hydrogels are being studied,composite including membrane a hydrogel- co-loadedoxidase with enzyme insulin that and exhibitsrelease glucose a twofold rate increase when instrating immersed insulin in “chemically glucose stimulated solution, demon- controlled release” and antibiotic molecule gentamicin andusing bound a it newly to developed acleaved peptide hydrogel linker.The by linker a candomonas be proteinase aeruginosa enzyme manufacturedinflammation by and urinaryotitis tract externa infection, in humans.Tests folliculitis, onhydrogel and rats is show applied that toreleased when the a if wound no site,any bacteria the of antibiotic this isenzyme type not that are the present,linker microbes then and the naturally the proteolytic produceria.“If gentamicin the cleaves is proteinase the specific released,can to killing each be bacterium the used [species] bacte- for the signal,” wrote Suzuki, spectra of antibioticsdressing could material, depending be onIn released the subsequent from strain work oftem the an bacterium.” triggered alternative same antibiotic byStaphylococcus release thrombin aureus sys- activity,fully which tested accompanies as atrolled high-specificity drug stimulus-responsive con- release system. ing and activationdirected functions.For enzyme-triggered prodrug instance, cancer an therapydeveloped is by antibody- being researchers at theGermany. University of Gottingen in damage still dependsthe on right antibody’s cells, and ability onbody to the that absence hook also of activate onto other the enzymes prodrug.” in the “smart drugs” thatcific become circumstances medically and active in onlyYoshihisa an Suzuki in at inherently Kyoto localized spe- University manner. hasdrug designed a molecule novel thatence releases of antibiotic an only infection. in the pres- when it reachesinside cancer healthy cells cells.Inwith tests, while mice human remaining previouslyenzyme harmless tumors that implanted sticks only are toring human tumor healthy given cells, mouse mostly igno- an cells.Theninjected.In its the activated activating antitumor state, this moleculemolecule fungal-derived targeted is antibiotic is athat highly-strained is ring apt to of burstwreaks three open, havoc becoming carbon a among atoms reactive the moleculefor nucleic that normal acid cell moleculesa function.But essential prodrug–an the antibiotic molecule lackinga is the sugar injected strained safety-catch.Once ring as the andpreviously sugar with positioned is targeted clipped enzyme,rearranges off the itself by drug into the molecule aactive.Notes three-atom chemist ring, Philip becoming Ball: lethally and still under active investigation, 84 82 include the 83 2005 However, drug speci- 86 with promising preliminary results against After the target protein in the test sample 85 81 Targeted radioimmunotherapeutic agents ficity is stillchosen no antibody, better and there than is significanting the mistargeting, to lead- targeting unwanted accuracy side of effects. the FDA-approved “cancer smart bombs”killing that radioactive deliver yttrium tumor- attached (Zevalin) to or a lymphoma-targeted iodine (anti-CD20) (Bexxar) antibody. is captured by thethe microparticles, complexed microparticle magnetic probes separationby and dehybridization of of PSA the is bar-codenanoparticle followed oligonucleotides probe on surface, the allowingthe the presence determination of PSA of released by identifying from the the bar-codechain sequence nanoparticle reaction probe.Using on polymerase PSA the to oligonucleotide bea bar detected million at times codes more 3accepted allows sensitive conventional attomolar than assays concentration, comparable fortein clinically about detecting target. the same pro- 2.6. Targeted Nanoparticles and Smart Drugs Multisegment gold/nickel nanorods areLeong’s being group explored by at Johns Hopkins School of Medicine advanced ovarian cancer in mice. J. Comput. Theor. Nanosci. 2, 1–25, Other antibody-linked agentsas are being the investigated such molecules alpha-emitting that actinium-based useto penetrate internalizing “nanogenerator” the monoclonalspecifically cell kill antibodies leukemia, and lymphoma, breast, haveroblastoma, ovarian, been neu- and shown, prostateocurie) in cancer levels, vitro, cells to at becquerel (pic- as tissue-targeted carriers for“can gene simultaneously delivery bind intotargeting cells compacted ligands that DNA in plasmids a“precise spatially and control defined of manner” composition, andity size allow of and the multifunctional- trodeposited gene-delivery system.” into The theof nanorods cylindrical an are 100 elec- alumina nmsegment membrane, diameter and joining pores a aalumina 100 100 template nm nm is length lengthtionalized etched nickel gold away, by segment.After the attaching the nanorodsments DNA are and plasmids transferrin, func- to asegments, the cell-targeting nickel using protein, seg- to molecularto the linkages gold only that one selectively metalnanorods bind and in thus a impart spatiallyextra biofunctionality segments defined to could manner.Leong the be notesple added that to to the bind nanorods, additionalsomolytic for biofunctionalities agent, exam- such or magnetic asallow segments an manipulating the could endo- nanorods be with added anfield. external to magnetic Freitas similar coating butcode” including DNA a sequencedetecting unique protein hybridized as analytes “bar- angen such (PSA). ultrasensitive as prostate-specific method anti- for REVIEW N srlae n irtst h ulu hr it where nucleus the to 6 the migrates inside, and interior.Once released cell’s the is which into DNA bub- dendrimer admitted tiny the then encloses a is vesicle into vesicle.The which deforms or in membrane ble, endocytosis outermost called cell’s process a the a of trigger dendrimers size cell, trans- certain living for a today encountering employed fection.Upon commonly response, vectors immune for an viral triggering hooks unlike can avoiding which as while DNA, a cells serve as form enter such that molecules, to groups useful other molecular made attaching of be spheroidal field can in dense nanometers layer few peripheral a size diameter.The typically exact particles, the dictating the “generations” of number or the steps with nanometer, synthetic by of nanometer form from that outward core emanating a structure molecules branching regular synthetic a tree-shaped with are dendrimers Starburst chemically- a as pancreas.” function artificial to synthesized systems such of potential “the Nanorobotics Medical and Nanomedicine of Status Current aoatce ihabooptbeplehln glycol polyethylene biocompatible oxide detection coating. a iron early silica-coated with using the cancer, nanoparticles brain for of nanodevices therapy and molecular development Uni- the novel is the of goal at current group Michigan.Their Kopelman’s of versity Raoul by developed being ilta a onfidiswyit eia therapeutics. medical into way its find soon may that rial Dendrimers Devices Dendrimer-Based and Dendrimers 2.7. of indications.” treatment disease cardiovascular and and imaging cancer targeting, in core provide flexibility that the ultimate components provides interchangeable platform with nanosome technology “the company, to the According Ther- Dynamic as (www.moleculartherapeutics.com). Molecular apeutics to the commercialized license under called being “nanosomes” therapeutic nanodevices, now lab, (Fig.1), these Kopelman’s vis- in Nano-Platform on not postdoc sometimes working a are Yan, range is sep- hence surgeons.Fei can locations site, to in tumor cells ible grow microns— the may tumor 50 from and type, as arate each microns small cancer 5–50 as the from cells also on a tumor but depending see brain cells to small chemother- MRI cancerous few allow traditional kills cells.Nanoparticles unlike which healthy destroys cells radiation destructive and laser sick the apy on subsequent concentrating only the tissue, effect during brain dur- effect of visible irradiation killing highly also the con- particles particles of (MRI).The enhance to the imaging nanopacket resonance makes adheres a magnetic ing with that that affixed agent molecule are trast tracer and cancer other cells, a by cancer or to damaged attached antibody severely are cell be particles otherwise surgery.The would invasive of that areas brain into penetrate the to them allow nanometers—should aoatce iha vngetrrneo cinare action of range greater even an with Nanoparticles 93 h iicl ieo h particles—20–200 the of size miniscule The 94 ersn e nte aotutrdmate- nanostructured another yet represent 92 95 oilylrenme fnndvcscnb synthesized. be can nanodevices combina- of number a large which torially from smart components a a dendrimeric built of to has library necessary group (Fig.2).Baker’s function each nanodevice a therapeutic types, perform different to of designed type modules a dendrimer additional surrounded dendrimer from by core single components. up a dendrimer have Tecto-dendrimers built single-molecule multi-component of tecto-dendrimers of number synthesis called the to nanodevices work this extending types has cell technique mammalian of genome.The variety a cell’s on the tested been of part becomes rights. all reserve who E.Monson, Inc. Eric Therapeutics, photo illustrator Molecular targeted and of to sensing courtesy therapy.Image biological from cancer functions dynamic of may elements number contrast a which and enable technology, control to optical the and magnetic of incorporate extensions eventually proposed shows “nanosome” 1. Fig. endn nsm edie-ae nanoparticles. dendrimer-based some on done also been have simulations pre- anti- simian-HIV.Computational in dendrimer-based successful venting been their has of the product 2003, microbicide.Their trials HIV by July human for cells.In branches cleared FDA natural outer U.S. was the the (www.starpharma.com) of to instead Starpharma adhere decoys the to membrane, of acid particles cell sialic virus mammalian the the causing in mimics found that normally surface groups a present dendrimers oesriso nunavrsparticles. deactivate virus and influenza trap of to strains used done.Glycodendrimer some been be also to have remain “nanodecoys” therapy gene drimer nmlmodels, animal Photodynamic ae ae’ ru tteUiest fMcia is Michigan of University the at group Baker’s James Core Matrix Molecules hsilsrto fteDnmcNn-ltom(N)or (DNP) Nano-Platform Dynamic the of illustration This Oxygen Species Beacon/Sensing Reactive Molecules 97 .Cmu.Ter aoc.2 1–25, 2, Nanosci. Theor. Comput. J. 98 huhciia ua raso den- of trials human clinical though Super-Molecules 99 Antenna 100 Magnetic/Constant Molecular Targets Nano-particles h glyco- The EMonson PEG Coat Cloaking 96 101 n in and Freitas 102–106 2005 106 REVIEW 7 Says 109 The researchers sep- 1 GHz radio-frequency 111 ∼ have attached tiny radio-frequency 108 “You can even start to think of differ- 110 Current Status of Nanomedicine and Medical Nanorobotics The long-term goal is to apply the antennas to living The gold nanocrystals can be attached to proteins as Gerald Joyce: arated an RNA-hydrolyzing enzyme called ribonuclease antennas—1.4 nanometer gold100 nanocrystals atoms—to of DNA.Whenmagnetic less a field than is transmittednating into eddy the currents tiny inducedhighly antennas, in alter- localized the nanocrystals inductivestranded produce DNA heating, to causing separateseconds into the in two a double- strands fullyleaves in neighboring reversible a molecules dehybridization matter untouched. process of that systems and control DNAity (e.g., to gene expression, turn the genesing.This abil- on requires or attaching off) goldoligonucleotides via nanoparticles which, remote to when added electronic specific would to switch- a bind sample to ofthe complementary DNA, activity gene of sequences,off.Applying those the blocking rf genes magnetic field andticles, then effectively causing heats the turning their goldturning them par- attached the DNA genes fragmentsmaceutical back to on.Such researchers a detach, apotential tool way drugs could which to give also simulate phar- turn the genes on effects and of off. ential receivers–different radio receiversferently that to respond different dif- frequency, frequencies.By you dialing can turn innot on other the tags tags.” right on one part ofwell DNA as but DNA,frequency opening up biology the electronicallyplex possibility biological controlling of processes more future suchtein as radio com- folding enzymatic activity, andJacobson pro- announced biomolecular that assembly.Incal his control late team over 2002, proteins had as achieved well. electri- caspase-3, one oflular the suicide first or enzymessign apoptosis released of (programmed during aone cell cel- component death), radiation-damaged that one cell.Thesugar identifies so device the that includes dendrimerwhite the blood as nanodevice cell, a andcence is blood resonance a readily energy second transfer absorbed componentclosely (FRET) into that using bonded employs a fluores- two molecules.Beforesystem apoptosis, stays the boundremains together FRET dark and uponand the caspase-3 illumination.Once white is apoptosis cell released,the the begins interior white bond blood is cellnal quickly is awash broken scanning in and device fluorescentinside light.If measuring a an the reti- astronaut’s body levelcounteracting reads of drugs above can fluorescence a be certain taken. baseline, 2.8. Radio-Controlled Biomolecules While there areattached already to many biological examplesthe systems of same nanocrystals for nanoparticlesmeans biosensing are for directly now purposes, controllingson being biological processes.Jacob- and investigated colleagues as a 107 105 2005 The same cell-surface pro- 106 105 The standard tecto-dendrimer device, which may be composed Image courtesy of James Baker, University of Michigan. 106 NASA and the National Cancer Institute have funded tein recognition-targeting strategy could bevirus-infected applied cells against and parasites.Molecularbeen modeling has used toifications determine optimal for dendrimervices the surface and mod- function totargeting. of suggest surface tecto-dendrimer modifications nanode- that improve Baker’s lab to producecan dendrimer-based detect nanodevices that andexposure report in cellular astronauts damage on due long-term to space radiation missions. J. Comput. Theor. Nanosci. 2, 1–25, By mid-2002,device the to lab detect had and report built the a intracellular presence dendrimeric of nano- At least a halfassociated dozen with cancer at celling least types dendrimers one have could unique already use been and protein to identify as which the the target- cell genomicproteins as cancerous, revolution unique progresses to it eachthus is kind allowing likely of that Baker cancerfor will to each be design identified, type a of recognition cancer. dendrimer Fig. 2. of monitoring, sensing,les. therapeutic, and other useful functional modu- The initial libraryform contains the components following(2) which diagnosis tasks: will of (1) disease per- state,ing diseased (3) location, drug cell delivery, and (4) recognition, using report- (5) this reporting modularapeutic outcome architecture, of nanodevices an therapy.By For array can instance, of once be apoptosis-reporting, smart contrast-enhancing, and created ther- chemotherapeutic-releasing withmade dendrimer and little attached modules to effort. thesible are core to dendrimer, it make shoulda be large pos- starting quantities material.This of frameworktomized this structure to tecto-dendrimer fight can a as beany particular cus- cancer one simply of by“targeting” many substituting dendrimers, possible creating distinct ato nanodevice cancer destroy customized recognition a specific or sparing cancer the healthy type normal and cells.Inthesized no three nanodevices using other, syn- while an also dendrimer ethylenediamine of generation core 5, polyamidoamine withmethotrexate folic covalently acid, attached fluorescein, to and targeting, the imaging, surface and to intracellular drug provide ties, delivery the capabili- “targeted delivery improved theof cytotoxic response the cells to methotrexate 100-fold over free drug.” Freitas REVIEW itdsedpBte oesaeceryneeded. clearly wild are than models faster pre- the 31% pre- speedup.Better confirm grow was to dicted to failed that experiments phage unfortunately, permutation the type; allow genome to new dicted one orders element found genetic altered and with mutants T7 teriophage asd ol esu ih ntastbtwudopen would but cancer transit targeted viral in entering so after tight blood, gates shut than redox-controlled their be potential inte- redox could cellular higher potential; capsids a redox have by control riors allow to neered eetees obntra xeiet nwl yeT7 type others wild by on experiments combinatorial Nevertheless, Endy example, fruit.For much borne al. yet et not have but devices. biological artificial new, create bacteria—to viruses and biological nat- systems—microscale engineer nanomachine to is ural nanorobotics to shortcut convenient One ROBOTS BIOLOGICAL 3.MICROSCALE the inactivating protein, larger the enzyme. with on, S-peptide assembling switched the prevented the field from nanoparticles rf field, the spinning external rapidly rf the turn the with the to RNAase but of the active, switch and absence remains conformation a usual the their as adopt off—in S-peptide S-peptides particles and of on the end enzyme used the protein.Jacobson’s to and the nanoparticles of strands gold mouth linked the in the group of unless sits up inactive called strand is strand made small enzyme 18-amino-acid segment RNAase small protein S-peptide.The a the large and acids a amino pieces: 104 two into S Nanorobotics Medical and Nanomedicine of Status Current htrslsfo eesbesrcua rniin nthe in transitions structural reversible complete virus. from a mechanism results gating make that a to exploiting virion nanodevice, tumor-killing artificial the re-engineering eoedltdadwihrpiaetiea ata wild as their fast as of twice 12% replicate type. which have and which deleted genome variants T7 indistinguishable hs uo-agtn atce osrea tumor-selective agents. 180 as contrast allowing serve of MRI capsid, to incorporation can- viral particles the breast tumor-targeting 28-nm and these each of coat, into types viral atoms many the gadolinium generously to of cells) protein surface cer lamanin-binding the on for 11 expressed peptide site lamanin docking of (a addition the functional includes surface-exposed groups.This of cage engineering protein allow viral to (CCMV) surface virus mottle chlorotic Cowpea at ftegnm hthv oaprn function.” apparent no have that eliminating genome and the usage, manipulation of codon parts easy reclaiming for parts, allow various genes. to of or 56 sites “adding and restriction include: Kbp removing process 40 redesign about the bacterio- of in a size Considerations T7, genome a generation with next phage the building is ology.org) 8 fot tprl ainlvrsdsg r underway are design virus rational purely at Efforts on n Douglas and Young 112 117 120 opttoal iuae h rwhrtso bac- of rates growth the simulated computationally h ytei ilg a tMT(syntheticbi- MIT at Lab Biology Synthetic The h aua ia aeo CVhsbe reengi- been has CCMV of gate viral natural The 115–117 aepoue e u immunologically but new produced have 119 118 h eerhr aeinvestigated have researchers The aeceial oie the modified chemically have 113 114 iial oi,wyt gtmtsaie cancer. metastasized fight to yet way powerful, toxic, capsids— minimally potentially engineered a and delivery—represent the transport, controlled drug of targeting, cell capabilities imaging, high-sensitivity four prin- the agents.In therapeutic ciple, of payload their releasing cells, eunigfm,adHmlo .mt,aNbllau- Nobel a O.Smith, announced Hamilton reate, and fame, sequencing tasks. mechanical useful detri- perform intracellular to even indigestible or or tus, toxins, poisons, substances and harmful as absorb products such selectively end to harmless a into or which metabolize deficient, in was cytokines body or patient’s enzymes use- hormones, produce to vitamins, designed ful be could genome medicine, biorobots in a artificial length.Used these by in bases specified nucleotide be 150,000 only chassis—could cellular microbe— basic chemical synthetic a minimal environmental a replicating.Thus to and cues, responding functions molecules, so and biomolecules, salts other or transporting dozen damage, cellular repairing the energy, life—manufacturing generating perform for to life, func- able required be a for gene would minimal for required set this genome be containing organism possible may microbe.An tional minimum that the all constituting are genes conserved sued.Mushegian three-year a possible.In be repli- eventually project viral synthetic should completely of design cators, manufacture rational lead- the sequences, the to viral ing artificial and completely today, of synthesis possible and already is cators el,wihte ietdtesnhsso opee(and complete particles. of virion synthesis polio the infectious) fully directed from a taken then proteins into which of RNA cells, mixture synthetic a artifi- the containing the broth injecting cell-free of then copy strand, in RNA DNA sequence cial an genetic creating viral enzymatically known DNA, labora- the the synthesizing in by scratch” tory “from manufactured rationally was eevd“h rt[patent] first “the received environment. the if into die escape to to designed manage and does infecting confined strictly it of be incapable will it and render people, will to cell hobbled the safety, deliberately abil- ensure be reproduce.To its for and survive tested be to then ity will which into cell, inserted hollowed-out be the will chromosome artificial life.The sustain al curn hoooeta hyhp ilcontain will of hope number natu- they minimum a that resembling the chromosome material occurring genetic removing synthesizing of rally then are string organism, scientists artificial the the an from material people, genetic the 25 all with of Depart- starting staff Energy organism, research minimalist the genitalium a from Mycoplasma create a grant to received three-year ment had million, (IBEA), $3 Alternatives Energy Biological nNvme 02 .ri etr fhmngenome- human of Venter, J.Craig 2002, November In nierdbceil“irbt”aeas en pur- being also are “biorobots” bacterial Engineered repli- viral chimeric of synthesis and design rational The n20,Ee isine (www.egeabiosciences.com) Biosciences Egea 2003, In 121 umntn n20,te70-aeplovirus polio 7500-base the 2002, in culminating .Cmu.Ter aoc.2 1–25, 2, Nanosci. Theor. Comput. J. 123 122 htternwcmay nttt for Institute company, new their that ocue hta e s30highly 300 as few as that concludes irogns.okn iha with microorganism.Working .genitalium M. 124 oicuebodcam for claims broad include to 121 ee eddto needed genes 119 Freitas 2005 REVIEW 9 ab 126 suggesting 128 the first known proposal for a on medical nanorobotics. 7 “Our ability to model molecular 127 5 126 laying the foundations for molecular machine sys- structural analysis and molecular dynamics simula- 126 Current Status of Nanomedicine and Medical Nanorobotics The vision behind Feynman’s remarks became a serious Molecular bearings are perhaps the most convenient that it mightparts, nanodevices be that possible couldhuman inspect being to the and construct, cells carryfollowed of from on a a repairs biological living decade withinbook them.This later was by Drexler’s seminal technical 4.2. Nanorobot Parts and Components 4.2.1. Nanobearings and Nanogears In order to establishturing, the it feasibility of is molecularsible first manufac- designs necessary to forin create nanoscale principle, and mechanical be to manufactured.Because partscannot analyze these that yet pos- components be could, physicallynot built be in 2004,validation.Designers subjected such are designs to forced can- initio rigorous instead to experimental relytions.Notes testing upon Drexler: and nanomedical procedure to curemine heart (Albert disease: R.Hibbs) “A friend suggestsbility of a for relatively very small interesting machines.Heit possi- says is that, although aif very you wild could idea, swallowsurgeon the it surgeon.You inside put would the the be blood mechanical and interesting vessel looks around.(Of in and course it surgery theout.) goes information It into has finds to the out be heart little which fed knife valve and is slices the itpermanently out.Other faulty incorporated small one machines in and might the takes be equately body a to functioning assist organ.” somein Later inad- 1959, in Feynman his urgedconnection historic us with biological to lecture cells, consider “thatan the we object can possibility, that manufacture in maneuvers at that level!” area of inquirywhile two still decades a later, graduate student whenof at K.Eric Technology, the published Massachusetts Drexler, Institute a technical paper tems and molecularFreitas’ manufacturing, technical and books subsequently by machines (systems and devices) ofin specific kinds, part designed for easemake of them.Design calculations modeling, and has computationalments far experi- enable outrun the our theoretical ability studiespendent of to of these the devices, technologies inde- needed to implement them.” class of components tooperation design is because their fairlyexamples structure is straightforward.One and Drexler’s of overlap-repulsion bearing the design, simplest shown with endusing views both ball-and-stick and and explodedThis space-filling bearing representations. views has in 206 atomshydrogen, Figure of and carbon, 3 silicon, is oxygenwithin composed and a of ring a sleeve small measuring shaft 2.2 that nm rotates in diameter. The potential medical applicationswas of proposing.After the new discussingleague, technology Feynman his offered he ideas with a col- — 125 126 7 5 , which Egea 4 − 10 ∼ 2005 The patent recites one 125 from one thousand 100-mers. Feynman was clearly aware of the surgery on individual human cells. 127 in vivo preferred embodiment ofof the “a gene invention of as 100,000 bp the synthesis The overlap betweencleotides ‘pairs’ is of plus 75In and bases, this minus leaving method, oligonu- corresponding a a pairs 25 combinatorial of base approachcleotides partially are is pair hybridized complementary used in overhang. the oligonu- where hybridization first step.A then second is round of undertakenplementary with pairs appropriately of com- process products is from repeatedhybridization the a reducing first total round.This theLigation of number of 10 of thewould times, products products be each by then a round half. strandlong is enough of of performed.” to DNA The make 100,000 a result base very pairs simple in bacterial genome. length, calls “word processing for DNA”. The ability tobers design, of construct, microscopic andpossible. medical deploy nanorobots large will num- make this 4.1. Early Thinking in Medical Nanorobotics In his remarkably prescientRoom 1959 at talk the “There’sP.Feynman Bottom,” proposed Plenty the of employing late machinesmaller Nobel machine tools tools, to physiciststill these make Richard smaller to machine beto tools, used the and in atomic so turn level. on to all make the way down takes as itsmechanical purview systems thebiotechnology engineering for extends the of medical range complexoptions and available applications.Just efficacy nano- from of nanomaterials, the treatment as ular advent of nanotechnology molec- willeffectiveness, precision again and expand speedments of enormously while future at medical the the treat- risk, same cost, time and significantlyperform invasiveness.MNT reducing direct will their allow doctors to J. Comput. Theor. Nanosci. 2, 1–25, 4.MEDICAL NANOROBOTICS The third major developmentmolecular pathway nanotechnology of (MNT) nanomedicine— or nanorobotics Freitas the chemical synthesisgenes of comprising a entire genome,ing the genes organisms.” ‘operating and Egea’s system’ proprietary of networks GeneWriter™tein liv- and Programming™ of Pro- technology has: (1)of produced libraries more thanduced 1,000,000 over programmed 200duced proteins, the synthetic largest (2) gene genes ever16,000 pro- chemically and bases, synthesized (4) of proteins, over engineered(5) proteins (3) improved for protein pro- novel expression functions, tion, through and codon (6) optimiza- ufacturing developed in custom specificresearchers genes host to for cells.Egea’s author protein softwarepany’s new man- allows DNA hardware sequences can thatwith the a then com- base-placement manufacture error to of only specification REVIEW 10 sleeve Merkle strained-shell and 2808-atom Drexler a by designed of pro- bearing shows view that 4 rotation.Figure exploded combination shaft an to a barriers symmetry, energy low 14-fold while vides symmetry, has 6-fold a ring in arranged the are shaft the of atoms bearing. 3. Fig. Nanorobotics Medical and Nanomedicine of Status Current xml,DelradMerkle design-ahead.For and manufacturing Drexler molecular example, for system os n.sdwt permission. with Inc.Used Sons, n s43n ndaee n . mi egh with length, molec- in a nm nm and 33.458 4.4 daltons of 51,009.844 and volume of diameter ular weight in molecular nm parts views a moving 4.3 twelve exploded is has and assembly and end, entire 5.The side, Figure in in shown gear, planetary lntr er,rttn rudtecnrlsat are shaft, central the around rotating small slowly.The rapidly gears, rotating rotating shaft planetary output shaft peripheral central the the and shows simulation puter osd,o ipaei naydrcin(xetailrota- axial resistance. (except strong very encounter direction smooth) a side any extremely from is in it displacement it structure. rock wherein tion, or displace stiff down, or very or side, up a to shaft making the bob sleeve, to interlock the Attempts shaft on the ridges on with surface.Ridges modi- (100) a diamond from fied derives an which energies features interface lengths, strain interlocking-groove bearing and bond 4.8-nm diameter distances, reasonable.This that Waals are ensure der van to angles, fields bond force mechanics ular oeua er r nte ovnetcomponent convenient another are gears Molecular 126 n iw n xlddveso 0-tmoverlap-repulsion 206-atom a of views exploded and views End (b) (c) (a) mg oreyo .rcDelr©19,Jh ie & Wiley John 1992, Drexler.© K.Eric of courtesy Image exploded view axial view 129 side view 1 nm 3 A nmto ftecom- the of animation .An 126 einda3557-atom a designed 126 206 atoms shaft sn molec- using sleeve mg oreyo .rcDelr©19,Jh ie os Inc. Sons, & Wiley John 1992, permission. Drexler.© with K.Eric Used of courtesy Image 5. Fig. oxy- with CH than structures planet rather hexasterane gen the multiple to surface; related resemble structure (100) gears in a diamond sul- is proper oxygen-terminated planets gear with sun in shell an the the silicon move termination; strained holds atom components a fur is all that gear that ring gear fashion.The ensures ring and a place by Inc. surrounded Sons, & Wiley John 1992, permission. Drexler.© with K.Eric Used of courtesy Image 4. Fig. planet carrier (b) (a) n- ie,adepoe-iwo 57ao lntr gear. planetary 3557-atom a of exploded-view and side-, End-, bearing. sleeve strained-shell 2808-atom a of view Exploded (a) planet bearing planet gear .Cmu.Ter aoc.2 1–25, 2, Nanosci. Theor. Comput. J. 2 rde ewe h aallrns and rings; parallel the between bridges (c) ring gear sun gear 1 nm 3,557 atoms exploded view 2808 atoms 1 nm (b) Freitas 2005 126 126 REVIEW 11 By Image 133 136 132 nano.xerox.com g all by self-assembly.In a microscopic 135 modified a natural biomotor to incorporate 134 ht 1 MM and Xerox www.imm.or Side views of a 6165-atom neon gas pump/motor. g ri Current Status of Nanomedicine and Medical Nanorobotics py On the experimental pathway, Montemagno and Co engineering a secondary binding site tailored to a cell’s video presentation, dozens oflike bars a could field be of seenmolecular tiny spinning motor propellers.The group’s ranper first for second, integrated but 40 subsequenthours motors minutes continuously have at by been providing operated 3–4 amagno for surplus is revolutions of also ATP.Monte- tryingular to motor-driven build autonomous aenergy nanodevice, solar-powered, wherein is biomolec- light convertedfuel source into for ATPswitching the which motor, his and then hybrid also serves motors a as chemical on means a and of off reliably: courtesy of K.Eric(www.imm.org). Drexler.© Institute for Molecular Manufacturing nonbiological parts,nanomotor.Using creating the the toolsadded of first metal-binding genetic artificial engineering, aminoubiquitous they acid hybrid enzyme residues whosetein moving to shaft part ATPase, (or is a in rotor, a response in central electric-motorthe to pro- terms) molecule’s electrochemical three thatelectromagnets reactions proton rotates channels in with (comparable theEach each to stator motor the of molecule coilpedestals bonded of prepared tightly by an to electronoriented beam electric nanoscale motor lithography.Properly nickel motor). molecules 12then nanometers in attached diameter to were theing pedestals 15 with nanometers, ananometers and precision long approach- a wasmotor silicon bound molecule, to nitride the bar rotor a subunit hundred of each which allows the designcomplete and nanomachines testing of andlibraries large the of structures compilation molecular or designs.Future oftions nanosystem growing may simula- requireexplicitly, 1–100 demanding million further improvements atoms inmolecular to present-day dynamics be methodologies considered whichtively have recently only entered rela- the multi-million atom range. Bachand Fig. 6. . 3 xy 132 130 found 80 GHz 131 10 m/sec ∼ < plane cannot be suggested that an xy 2005 131 C bonded bearings. 1 GHz for < -direction, we may develop a z -direction as the teeth contact in the z reported that preliminary molecular dynamics 131 A rotational impulse dynamics study of this first- 400 K.Only when the100 GHz gear did was significant instabilities severely appear, overdriven although to the -direction nestles within a Vee notch in the race to retain plane.This design would make nogear sense system for since a the macroscopic gearrace.However, could for never a be placed molecular insidethat system the the one gear could is imagine constructedall and except that for the a last racebled joining is and unit.The constructed parts then couldcomplete be the assem- the final design.” connections on the face made4.2.2. to Nanomotors and Power Sources Another class ofdesigned is theoretical a nanodevice gas-powered that molecular motor has or been pump. that at the normalcomponent operational rotation was rates designed forinterfacial which (e.g., velocities), this the gear workednot as overheat.Started intended from room and temperature, did a the gear few took cycles∼ to engage, then∼ rotated thermally stablydevice at still did not self-destruct.One run at showed excess kineticto energy oscillate up causing tothe gear 450 ongoing temperature K design above effort, baseline.Commenting Goddard on simulations of the device showedtion that it as could indeed a func- so pump, further although refinement itAlmost of is all this not such initialnology very design design is energy-efficient research is restricted in warranted. to molecular theory nanotech- and computer simulation, The device couldatoms serve or (if either run backwards)pressure as as into a a rotary motor power.The to pump helical convertcylindrical rotor neon bearing for has gas surface at a neon each grooved end,threaded gas supporting cylindrical a screw- segment inrotation the of middle.In the operation, tudinal shaft grooves moves inside aenough the for helical pump small groove gas housing.There moleculescross, past is only where and longi- room facing these grooves the crossing other as points the moveGoddard shaft from turns, moving one the side neon atoms to along. optimal configuration couldplanetary have gear the butdifferent might functionality have from of an the a example: appearance “Because macroscopic completely a system, gearatomically tooth and smooth in offered the in the an Vee design so thatz the Vee shape ofstability the in gear the tooth in the generation planetary gear Goddard and colleagues J. Comput. Theor. Nanosci. 2, 1–25, The pump and chambercontains wall segment 6165 shown88,190.813 in daltons and atoms Figure a molecular 6 volume of with 63.984 nm a molecular weight of Freitas the planet carrier isarray adapted created from a bylinked to Lomer R.Merkle the dislocation planet and gears using L.Balasubramaniam, C REVIEW h iigcl ocnrlnndvcsipatdwithin implanted nanodevices of control system cell. sensory to the the cell use living to plans the he cascade, signaling Nanorobotics Medical and Nanomedicine of Status Current un h rtcmeca oeua lcrncdevices electronic molecular commercial first the suing n Leigh, and a sMvodssgroup path- Mavroidis’s bio-nano is deliver the way and as following synthesize such would agents.Also they cells, chemotherapy where specific tumors, to of these targeted those that be speculates could cells.He nanofactories living inside operating ries pn hnilmntdb oa nryb Feringa. by energy solar by illuminated when spins aocl eois sn ehnclyitrikdring catenanes, interlinked called mechanically molecules in using employed memories, be could nanoscale room- first that reversible switches the molecular effort monitor completely temperature produced of collaborative Packard properly demonstration a Hewlett laboratory to 2000, and UCLA work.In physician between their a control allow onboard and require to may nanorobots computers medical effective Truly Nanocomputers 4.2.3. mix to used devices. be could microfluidic rotor in spinning liquids the to or up gigahertz, few possibly a oscillations frequency microwave generate group, a and throw exerting rotaxane-based chemically-powered motor in a linear 139 synthesized Kelly, by motor 1999 rotating chemically-powered atom blood- chemically-powered 4.3.2). the (Section operated nanomotors medicine travel have DNA-based in that Others tasks industry.” systems unprecedented and other the perform up or stream “make protein the “pave viral later assemblies” will nanorobotic a and complete that produce of development 2007, to for by way grant prototype NSF nanomotor four-year linear M $1 a eetpors ihnntb-adnnrdbsdmolec- nanorod-based electronics. and ular nanotube- with progress recent osi reyaon h ne aoue sanal fric- nearly a as nested nanotubes the inner bearing. of the tionless rotor around wall attached freely outer and spin nanotube to the outer broke a the stators allowing making and the nanotubes, degrees, rotor to 20 jolt the to electrical jerked up strong forth oscillator.A and gold torsional the back current, were rocked direct stators of rotor volts the 50 provide rotor.When with to charged the alternately etched for selectively nanotubes, clearance was the sufficient surface to cho- the rotor which the the after annealing around then stators nanotubes, rotor, opposing lithog- sen gold and beam nm sur- 110–300 anchors, electron a oxide using nanotube pattern then silicon simultaneously wafer, to flat silicon raphy the a of on face number nanotubes a depositing multiwalled first of by nanomotor wide 550-nm ered n20,teZtlgroup Zettl the 2003, in 12 te xeietlnnmtrrsac nldste78- the includes research nanomotor experimental Other 140 137 Vdie aeaebsdrn oo yWong by motor ring catenane-based UV-driven a 141 otmgoevsostn hmclfacto- chemical tiny envisions Montemagno n natfiil5-tmmtrmlcl that molecule motor 58-atom artificial an and ∼ 146 5 e otato yl yStoddart’s by cycle contraction sec 250 144 147 h siltn oo ih eue to used be might rotor oscillating The eea rvt opne r pur- are companies private Several ∼ 0 No oc iha19nm 1.9 a with force of pN 100 143 138 145 rae neetial pow- electrically an created hc nlt 03received 2003 late in which n hr a enmuch been has there and 142 Also lrsrcue ytecodnto fmlclsto molecules of monomolec- coordination ordered the form by surfaces, which structures sys- those ular molecular include self-assembling tems best-known the Perhaps Parts Mechanical of Self-Assembly 4.3.1. Assembly Parts Directed and Self-Assembly 4.3. biology-based low-speed of 4.3.4). possibility (Section nanocomputers the digital and also self-assembly, is of there techniques using components nanocomputers computational of other and memories including ofrainlsice a lo h self-assembly structures.Saitou the mechanical allow complicated quite can of switches conformational vs.orientation energy of tools. modeling development minima– the energy local mechanical necessitating undesirable any a avoid the to as added making is are challenge acts machine, types component that state more flexure enzyme.As the allosteric mechanical in a ‘switch’ has the machine mechan- inter- state poly-fluorodecalin.The an ical and water at between floating face while “mechanical self-assembles pro- that simple machine grammatically state a mechanical 2-bit presents analog–a enzyme” emulate and that allostery, components enzymatic dynamic including by assembly efasmln iii ielsadvesicles, and films, micelles Langmuir-Blodgett lipidic or self-assembling films thin self-assembling facmoetTemdli efasmln automa- self-assembling a inspired explicitly is ton model in component.The changes a systems conformational of specify self-assembling that conformational as rules of written switches—local are model instructions assembly a which presented has fprscnpouetemtn fadsrdpi of pair desired a of mating the assortment produce random from a parts.Griffith can drawn contains parts parts initially of of which of process pair bin a random parts a which a of in mating picking” sequential bin random “sequential sebyo ml ehnclprst vi ietparts direct avoid to parts mechanical grasping, small of assembly eajse o01n ycnrligtesrcueo the of of to to control structure dimensions although axis in-plane the monolayer, vertical allows controlling the by comprising surface the molecules 0.1-nm a in to to composition adjusted affixed be and molecules thickness of both layer single a raiignanostructures. organizing ihebde switches. embedded parts triangular with self-assembling Hosokawa’s by and blocks rwn eerhae.e n Smith and area.Yeh research growing a rcs fflii efasml foteetoi devices, optoelectronic of self-assembly fluidic of process fsl-sebigatmt a lob ple oself- to applied 3-dimensions. or be 2- also in can assembly automata self-assembling of h rgamn fegnee eune fsuch of sequences engineered of programming The eea tepshv enmd oaheeself- achieve to made been have attempts Several Guided 148 154 161–164 aldsl-sebe ooaes(SAMs), monolayers self-assembled called 155 157 n Saitou and rdirected or .Cmu.Ter aoc.2 1–25, 2, Nanosci. Theor. Comput. J. ugssepnigtetobxo self- of toolbox the expanding suggests 156 < ytePenrose the by 0 mi eaieydifficult. relatively is nm 100 152 160 165–167 156 153 atuclaims Saitou ie ipeeapeof example simple a gives nmn fteesystems, these of many In efasml a become has self-assembly 154 159 aedsrbda described have self-replicating 156 151 i model his n self- and Freitas 156 2005 150 149 158 REVIEW 193 13 Alberti 7 nm sep- 194 ∼ 13 sec per cycle. ∼ and reported the design synthesized another DNA 25 kD, there are several synthesized a 30-nm long 192 0 198 < 197 has focused on a continuously run- 199 synthesized a sequence-dependent DNA 1 nm separation in ∼ 195 have made a single-DNA-molecule inchworm 30 kD tRNAs), the spliceosome, the ribosome, 196 200 ∼ Current Status of Nanomedicine and Medical Nanorobotics In other labs: sequence-specific DNA hybridization 3 kD.Molecules even larger than this are manipulated A special “removal” strand,strand when and added, binds pulls to itMore the away, recent fuel opening the work nanotweezers again. and Mergny aration to a actuator using three single strandswhen of artificial placed DNA together, which, and find self-assemble their to complementary formmouth a partners of V-shaped this structure.The nanotweezer open cana be special made “fuel” to close strandDNA by which adding dangling binds from toers the the single-stranded and ends of zips the them arms closed, of moving the from tweez- a and constructionmight of serve as 2-dimensional templates DNA for nanomechanical arrays assembly. which motor, and Shu and Guo chimeric pRNA (DNA-packaging)strands motor of made RNA from surroundingthe six a presence of center ATP, the strandin RNA of succession, strands DNA—in spinning push the itforce.Yurke DNA and around axle Turberfield producing 50–60 pN of 4.3.3. Protein-Directed Assembly While mostulating enzymes in smallclasses cells molecules of are enzymescovalently involved involved bound in in moleculescofactors, manip- manufacturing such complex antibiotics, as∼ and vitamins, toxins enzyme by tRNA-synthetase with (aulates masses 40–100 kD up enzyme to that manip- Seeman is nowcomputational collaborating chemists with to genetic achievecation engineers “the of and practical design nanoscale andprogress devices” in fabri- and demonstrating “to DNA makeincluding based rapid nanoscale “sequence-dependent devices,” devices [that]the can diversity provide of structures necessary for nanorobotics.” is used to bend silicon microcantilevers, ning DNA nanomotor.Reif’s groupDNA has tiles devised X-shaped that linkstrands up consisting in of aand sections square shorten of grid with DNA bywhose some that 6.8 mesh of can nm size the lengthen control. can like expand tiny or pistons, contract making under chemical a net “piston” composed of aplays 21-base a oligonucleotide 5-nm that two-strokeand linear dis- Tan motor type movement, Li region to beture to converted the from unusualarms Z-DNA the structure.The shift normal free position ends B-DNAreversible of by structural struc- the 2–6 conversion, like nanometersclosing.A a large during version hinge of this opening theelbow, fully and device while might smaller function as devicesBy an could 2002, serve Seeman’s ascal group finger DNA-based joints. had rotary demonstrated motor a mechani- 169 184 190 the the- or “silicon “offer more 185 182 173 181 1 mm in diame- 172 ∼ 2005 and shape-selective self- The mechanism has two have impressed electrical 171 first demonstrated capillary- By the mid-1990s, Seeman 191 170 have described a tile assem- Two decades ago, Seeman rec- 175 189 168 then a truncated octahedron con- 187 and some of this work has since 174 188 176 and the computational modeling of self- including “micro-origami” 186 as well as mesoscopic nucleic acid analogs. 156 183 177–180 154 In 1999, Seeman reported the construction of a mechan- sophisticated strategies forrical the networks fabricationunit.”) incorporating of Whitesides et more asymmet- al. than one repeating could fabricate nanoscale DNA stickregular figures geometric of shape, almost by any the billions per batch. force drivenstructures assembly from millimeter-scale of components,static and a self-assembly, electro- simple circuit and other ory ofstructures, designable self-assembling molecular machine assembly processes are beginning to be addressed. 4.3.2. DNA-Directed Assembly Early mechanical nanorobots mightin be assembled, part, at least fromnanoscale objects DNA.The has idea beenat pioneered New of by York University. Nadrian using Seeman DNA to build origami”, ognized that aa strand construction of material.First, itmer.Its DNA intermolecular is has interaction a many with relativelybe advantages readily other stiff predicted as poly- strands and can complementarity programmed due of to the nucleotides,ing base-pair the blocks of fundamentalassemble.Arbitrary genetic build- sequences material.DNA are alsousing readily tends conventional biotechnological to manufactured techniques,is self- and DNA readily manipulatedber of and enzymes.During modifieddevelop the strands by 1980s, of ainto Seeman DNA more large worked that and num- then to would more three-dimensional complex zip shapes—first themselves stick-figure480 tiny nucleotides up cubes each, squares, comprised of rigid double-stranded DNAthat arms a can few beintroducing nanometers a made long positively charged to cobaltsolution rotate compound surrounding into between the the fixed molecules, positions causing by the bridge been extended toparts, the fluidic self-assembly of microscale assembly using lock-and-key structures ter, then inducedspecified these 3-D octahedra electricalby to co-melting networks self-assemble of ofthat into opposing hierarchical up self-assembly solder to spots.(Gracias 12 notes devices circuits includingpolyimide LEDs truncated on octahedra each the surfaces of copper- ical DNA-based device thata might nanoscale serve robotic as actuator. the basis for taining 2550 nucleotides. bly model for pseudocrystalline self-assembly, Breivik J. Comput. Theor. Nanosci. 2, 1–25, The dynamics of Brownian self-assembly, Freitas Rothemund and Winfree has designed and patented apolymers, set and of self-replicating Gracias physical et al. REVIEW n ells rcsls hn1n pr noacopper a onto apart nm precipitat- bacterium 1 the chemically train than to by less base) (created tracks cellulose film ing grooved a used gold, size, in nm equilat- 200 as to up such hexagons, shapes and geometric triangles specific eral in silver pure molecu- ( in AG259 bacteria of employed stutzeri strain be fabrication.One parts also lar might microbes Artificial Assembly Virus-Directed and Microbe- 4.3.4. mRNA. interior enzyme produce the translo- to through a order DNA as feed in act to that ratchet II cation polymerase helix RNA bridge in and or clamp mechanisms the insertion” as “parts such employ maneuvers, “threading” manipulators complex.Many protein replication these DNA of the and proteosome, the Nanorobotics Medical and Nanomedicine of Status Current enue oasml ivr n gold-particle-based already and have silver- prions assemble cell to yeast nanowires, used of variant been genetic cial edslcnmicrocantilevers. can silicon specificity con- protein/nucleic bend binding exemplar to a biostructure.Protein-protein scaffolds as acid DNA camshaft molecular to a proteins struct fusion of addressing rudtencso udn eilsadsqueezing, well- and endocytosis—is wrapping vesicles cellular during budding spirals, known. off, of or them necks pinching rings the into around self-assembles which n asn hmt ec,eepiyn protein-directed exemplifying the ribozymes react, alignment assembly.(RNA-based as to parts proper then, them into and causing parts envision and these solution can bringing a folds, we in enzyme acids, parts synthetases,” molecular amino “nanopart grabbing synthetic called using be possibly might which enzymes nain yoi,adlclmcaia stress. ori- mechanical be and local guidance and can contact hypoxia, characteristics entation, factors, chemotactic network by cell ECM altered fibroblasts, natural and in functionality stochastic is positioning strand nw nbiology, in known reactions.) some for proteins than suited ter a“oaetprsjiig yeo prto) n can and operation), lattice. of collagen fibers type collagen joining” apply crosslinking parts a “covalent of at genetically (a capable track be prepared can are microns/minute.Fibroblasts the engineered, 4 along of cellulose rate of ribbons neat n desmcnutrqatmdt 45n)into nm) (4.5 dots quantum arrays. nm) semiconductor nanoscale 10 or CdSe 5, (1.4, nanoparticles and can gold of molecules) assembly the (chaperone direct templates protein chaperonin 14 nrai tutrscmoe fbismuth, of composed synthesize structures and materials inorganic accumulate can microorganisms sfrmcoedrce at seby od tal. et Kondo assembly, parts microbe-directed for As ace-cinpoenbsdmlclrmtr r well- are motors molecular protein-based Ratchet-action 213 ∼ 205 0 Nfre hl meddi 3-dimensional a in embedded while forces pN 100 magnetite, 204 Smith n h Taednmnmechanoenzyme— dynamin GTPase the and skont arct igecytl of crystals single fabricate to known is ) 216 208 206 212 203 lhuhEM(xrclua matrix) (extracellular ECM Although a sdmethyltransferase-directed used has 214 ofrainlcsae faspe- a of cascades conformational silica, ctbce xylinum Acetobacter 201 207 212 ydsgigsynthetic designing By n silver. and eeial engineered Genetically 202 a rv bet- prove may 210 212 Pseudomonas CdS, oexude to 209 211 and 212 215 hmclcnetainflswti rslce bounds. the preselected when within protein falls fluorescent concentration a chemical on turn and surroundings its icista a ucina switches as function can that circuits iigcl oosfrpms avs n ovyrbelts. conveyor and colleagues valves, and pumps, Turner for motors form cell to living devices (MEMS) systems microelectromechanical tal. et ns htcnasml oeua tutr ywa is what by structure molecular a mech- a assemble design can to that sense right anism more non- makes the complex it in structures, build getting periodic difficult.To self-assemble increasingly complex, spontaneously is to more sequence parts become the structures all machine As Molecular and Assembly Positional 4.4. assembly.Belcher vroeo h rtiswsi t o state hol- low flashing like its lights.” cells in iday twinkling gently was of population proteins when- of a active the was test became of one protein one loop—in fluorescent ever a “a in system, connected their inverters three with ici in circuit ytesrn osato h ESstructure. MEMS the of constant spring the contracts by a cell at “walk” of muscle to speed structure the pre- mechanical the prosthesis.When solution, causing tiny repeatedly, glucose a like with cell sented muscle attached cardiac is a wide to microns 230 lithographically- structure a U-shaped 2003, produced in experiment mechan- one cell-powered motors.In create ical to structures MEMS isolated cfod o h ietdnnasml fnanoparticles dots, of quantum nanoassembly as directed such the for scaffolds n ytei nlg. noeexperiment, one proteins In by analogs.” directed novel synthetic properties with and magnetic phases and inorganic electronic nonbiological of synthesis oi lmnssc sAD AD n O ae are al. gates et NOR Gardner and 2000 investigation.In NAND, active AND, under as such elements logic hnapidtefimisd iytbs hruo the diffu- as whereupon fast as tubes, twice alone.Montemagno tiny fluids sion blend inside along, arms film bacterial beads gyrating the the carry applied to then appendages rotating microbes’ marcescens tia eue ssaflsfrnnmtrassynthesis nanomaterials for scaffolds as 72- can used proteins and be a coat ordering viral assembles domains.Engineered nanoscale nanocrystals micron-sized having sulfide film zinc ZnS-containing for recog- specific moiety a nition with bacteriophage M13 engineered cally r o hc h uptpoeno ahi h nu pro- input the is Leibler each and of other.Elowitz protein the of output tein the which for ers an to device memory a self-assembly, oetbihdgtlcnrloe irognss genetic microorganisms, over control digital establish To atracnsrea hsclsse components.Tung system physical as serve can Bacteria ia hlsas rvd sfltmltsfrnanoscale for templates useful provide also shells Viral Manufacturing 222 r tepigt noprt iigbcei into bacteria living incorporate to attempting are ∼ .coli E. 6mcosmnwt eeiinrt controlled rate repetition a with microns/min 46 220 228 y20,Weiss 2002, By .Cmu.Ter aoc.2 1–25, 2, Nanosci. Theor. Comput. J. atraot iybas loigthe allowing beads, tiny onto bacteria nldn efasmldmonolayers. self-assembled including htcuddtc pcfi hmclin chemical specific a detect could that 165 225 225 223 .coli E. 224 mly iu asdsel as shells capsid virus employs 226 aeafie l of film a affixed have a obndlvn el with cells living combined has napoeso “biomimetic of process a in atru sn w invert- two using bacterium 221 a rae five-gene a created had 219 217 aea oscillator an made rcomputational or 225 224 h result the geneti- a 218 227 Serra- Freitas added 2005 and 118 220 REVIEW 242 15 used for the 236 positional 126 247 235 234 A method for the precise manufacture of but most especially in various electron- Nanotube-based nanotweezers have since optics, radiology, biochemical synthesis employ redox probe microscopy (RPM) in 243 have reviewed recent progress in using scan- 233 244–246 241 237 239 240 238 Current Status of Nanomedicine and Medical Nanorobotics The ultimate goal of molecular nanotechnology is to In contrast to high-pressure diamond synthesis and Precise positional covalent attachment of molecules to precise manufacture of diamondthesis structures.Mechanosyn- aimsby to inducing achieve chemical transformationstional site-specific controlled systems chemical operating by with posi- the synthesis atomic-scale precision tip (e.g., of a scanning probe microscope or SPM), thus a palladium-coated SFM (Scanningto Force Microscope) chemically tip modifyorganosiloxane-coated surface terminal to functional createassemblies biotin-streptavidin groups in on patterns with an Diaz minimum et 33 al. nm line widths. mechanosynthesis has been proposed by Drexler ning tunneling microscopy (STM)thesize to individual manipulate molecules. and syn- develop a manufacturingsively manufacture most technology arrangements of that atomsspecified that in can can molecular be detail—including inexpen- ments complex arrange- involving millionsuct or object, billions of as(Section atoms 4.5). in This per the willing prod- provide technology hypothesized the in medical ultimatelow terms cost.Two manufactur- nanorobots central of mechanisms itsachieve have these been precision, goals proposed flexibility, at to positional and the assembly molecular scale: includingstructures programmable fabrication using of molecular diamondoid massive feedstock parallelism (Section 4.4.1), ofcesses and all (Section fabrication 4.4.2). and assembly pro- 4.4.1. Diamond Mechanosynthesis There is widespreadties interest of in diamond—ithigh the thermal has conductivity, low exceptional extreme frictionalical coefficient, proper- hardness chem- and inertness, strength, tions and have been a driven byfor wide the diamond many bandgap.Recent in emerging MEMS applications devices, investiga- mechanical and electromechanical been reported by others. microscopic and nanoscale diamond structurestremendous would utility have in science and industry. low-pressure gas-phasevia diamond synthesis chemical of vapor diamond deposition or CVD, ics devices. and medicine, surfaces is also being pursued.Blackledge et al. which an SFMals, tip whereupon is the modified interactionsbate with between or tip redox-active and between materi- anelectrode tip adsor- potential.This and system amicrotweezer has surface to also are manipulate been and modulatedRieder used position by objects.Hla as the and a were only 25 nanometers apart,nanotweezer. making a better-controlled capable of 229 used standard 232 2005 created the first general-purpose 231 230 Kim and Lieber One of the leading proponents of positional assembly providing linear two-dimensional1.5 nanometers, movement the width in ofThe about steps 9 core bonded of carbon of atoms. ear the micromover motor is that aleft does or stepper not front actuator rotate, to ormicrometers but back.The lin- in platform instead can each steps traveleach right direction a micrometer total to in of 2.5 is 30 micromover milliseconds; would made take since approximately up 20,000verse steps of 30 to tra- micrometers, 1,000 awidth nanometers, distance of the which a single isworked human about on hair.Martel’s half group a the NanoWalker. at similar MIT nano-positioning has device called the micromachining processes tosilicon carve an from array ofbe a cantilevered opened tiny micro-pliers and slab whichelectron closed could of beam electrically.Boggild then tofrom used grow the an a end of tiny each carbon cantilever, nanotweezer angled arm so that the tips nanotweezer whose workingcontrolled end carbon is nanotubes made a fromwalled pair a carbon of bundle nanotubes.To of operate electrically multi- age the is tweezers, applied a across volt- arm the to electrodes, develop causing a one positiveto electrostatic nanotube charge develop and a the other cessfully negative charge.Kim grasped and organelle-sized Lieberof 500-nanometer polystyrene have clusters spheres, suc- andtor have wire removed 20 awires, semiconduc- nanometers using wide tweezer arms from4 about a microns 50 long, mass nanometers butfield of wide the at and entangled technique the creates tweezermanipulated.In tips a 2001, which large can electric Boggild’s alter group the objects being J. Comput. Theor. Nanosci. 2, 1–25, Freitas called positional assembly—thatmolecular is, parts.A picking device capable andwould of placing work positional much assembly cars like on the automobile robotrobot assembly arms manipulator lines.In that picks this uppiece, manufacture approach, installs a the it, part, then moveswith repeats it many the to procedure different the overassembled. parts and work- until over the final product isat fully the molecular scalethe is first Zyvex engineering Corp.using firm (www.zyvex.com), positional to assembly espouse tocise manufacture an structures, atomically explicit pre- orfabrication goal of tool more capable specifically,structures of “a with creating 3-dimensional user-controlled cally molecularly capability viable manner.” precise in Zyvex anability has to already economi- positionally demonstrated the assemblescale large parts, numbers and of hasindependently-controlled MEMS- inch-long demonstrated robotic the arms ability toulate manip- to tiny carbon use nanotubes three inwatchful three eye dimensions, of under the amonitor scanning objects electron andat microscope motions near-video that scan as can rates.Agilentan small Laboratories ultra-high-precision has micromover as platform created 6 nanometers REVIEW 16 includ- placement researchers Srivastava, dimer) many (or involved Goddard, theoret- Cagin, atom has lattice.The ing carbon diamond crystal of growth on diamond the analysis to the atoms ical carbon of of addition surface controlled the is sur- the of area lowered mechanosynthesis. defined is during precisely face a which in barrier, reactions activation surface of the for dependence on exponential the rates on reaction relies surface methods activate of these to selectivity all introduced tip reaction deliv- be the (3) (mechanosynthesis).The then or from reactions reaction, can energy desired mechanical which of ering to catalyst region tip the a into the as precisely of chemi- act chemistry a it the activate to make manipulating to field (2) surface reac- electric reaction, a chemical an cal of delivering direct region (1) to sub-nanometer by: SPM a surface an the of on use tions manipulate the meth- proposed involve to many and ods ability atom, by an atom micro- structures demonstrated on surface electron has sites (STM) tunneling reaction scope scanning of workpiece.The selection the positional direct enabling Nanorobotics Medical and Nanomedicine of Status Current rwltaetr eg,icuiga90 a with- including appropriate (e.g., an trajectory using the tip drawal provided tool of functional) mechanosynthetic removal the density appropriate.Subsequent is B3LYP trajectory approach and set based basis results place computational to take on (according can barrier insertion surface model no latter to with a cluster surface.The 9-atom into a diamond using carbene the surface C(100) controlled a inser- positionally on the posi- dimer a and a dimer, of of that insertion tion into a surface, carbene C(111) controlled of a tionally placement onto dimer including carbon reactions, mechanosynthetic olt ra the break to tool fidwt C C a diamond with ified reconstructed a from of removed terrace selectively upper be could the dimer carbon bonded tm ftonihoigsraedmr sattached, is dimers C surface a neighboring else two or with of bonds atoms forming locations C four-fold the onto deposited ylpnee sbogtu oteC10 ufc,either surface, C(100) the to aC up brought is cyclopentene) h n a ftetpWe lnrC planar tip.When the of cap end the rC10 imn ufc tseicstswsiniti- Walch of was work sites computational Merkle. C(111) the specific a by and at on first surface atoms supported ally carbon diamond hydrocarbon of C(100) small clusters or small atoms, or carbon species, individual inserting yDeiek tal. et simulations dynamics Dzegilenko molecular position by bridged dimer.Classical the in the atom carbon on single a leave to dicted 2 h rnia hleg ndaodmechanosynthesis diamond in challenge principal The × binitio ab 3 oeywt w oe tm ftetpinitially tip the of atoms C lower two with moiety H 1 ufc yacro aouetpceial mod- chemically tip nanotube carbon a by surface 248 249 248 4 H Mann, 253 acltosuigGusa iha63 G 6–31 a with Gaussian using calculations 2 n Walch. and 2 abn aia pce togybne to bonded strongly species radical carbene Drexler, rgeti dobdao w atoms C two atop adsorbed is fragment ac n ekeaaye several analyzed Merkle and Walch 252 249 odo h obebn)i pre- is bond) double the of bond Merkle, 126 248 hwdta igeweakly- single a that showed 253 Dzegilenko, 250–254 h esblt fprecisely of feasibility The Peng, 6 H  249 2 oaino the of rotation (methenylidene 251 Freitas, 252 Saini, 100 250–252 249 − h i rjcoy n aiu loe u neie tip undesired but allowed various and rearrangements. distances, trajectory, tip-surface tip initial outcome the the reaction upon the critically with depending dimers, surface neighboring of tm otetp rtpligteaosoftesurface back the them re-inserting off then atoms and the silicon face pulling crystal bind Si(111) first to a sur- tip, used of (111) been the the have to from sample.STMs atoms atom a germanium of single face a extract to synthesis. 7. Fig. Vaosaepr ftosbtttdaaatn (C adamantane substituted two group of supporting part dimer.The are atoms (CC) IV proposed carbon-carbon bound the weakly the more so to progressively be carbon, likewise will to tooltips forms bonds elements of weaker series this (sili- progressively lead), atoms or supporting tin, IV group germanium, dimer.Consider- two con, to CC bonded the the dimer to a and make ing they stability biadaman- bond their IV-substituted the evaluate of group Gaussian strength and specific structures with tooltip on theory tane focus site.Their functional to specific a dimer— density 98 at CC used surface atoms—a diamond analysis employed carbon growing two be a of to onto placement intended the tools for mechanosynthetic of ily ieyb eurds htteatv i ol ehl and held structure.Initial be could handle tip rigid would active a the molecule via that this positioned so of required version be appa- larger likely mechanosynthetic somewhat full a a tool.In ratus, complete the a only (Fig.7).The of is apex them dicarbon, bi-silaadamantane orient a molecule, and tooltip position that frameworks al sn cnigpoemcocp is n18 Becker 1985 Golovchencko in experimen- tips, and demonstrated microscope probe been scanning yet using tally not has dimers carbon Ge the of temperatures. operation room successful at the tooltip confirmed has tips tool sequent n20,Mrl n Freitas and Merkle 2003, In lhuhpc-n-lc fidvda abnaosor atoms carbon individual of pick-and-place Although C6S ie lcmn oltpfrdaodmechano- diamond for tip tool placement dimer DCB6-Si 250 binitio ab 03 ap .ekeadRbr .ria,Jr. A.Freitas, Robert and C.Merkle Ralph 2003, © 249 .Cmu.Ter aoc.2 1–25, 2, Nanosci. Theor. Comput. J. oeua yaissmltoso these of simulations dynamics molecular 255 iSi Si sdvlaeple na T tip STM an on pulses voltage used 250 rpsdanwfam- new a proposed 252 n sub- and Freitas 10 2005 H 16 REVIEW 271 TM 272 17 /device, 3 to arrays would be 268 and by 1998 to 263–266 70 microns from in which a single ∼ 269 275 26,000 micron 274 ∼ and microscale SPMs 10 cantilevered tip array fabricated in fabricated an experimental piezoelectric 262 Similarly, by 1997 MacDonald’s group × 20 nm/volt–for instance, 0.3-nm resolution microcantilever array of ten tips on a sin- 267 ∼ 261 270 2 -axis actuator for the whole array, and at least one “electronic nose” microcan- z -axis (e.g., vertically) up to near their mechani- z 273 -on-SiO Current Status of Nanomedicine and Medical Nanorobotics 2 Yet another alternative is Zyvex’s patented Rotapod and each of thein devices the could becal resonance operated frequencies independently of 145–147sensitivity of KHz at an actuation at 125 KHz.Parallel probebeen scanning achieved and by lithographyple was Quate’s piezoresistive microcantilever group, arrays with progressing100 5 from tips microns spaced sim- apartonly and one 0.04-nm resolution at 1 KHz but most convenient.Force-sensing devices such astric, piezoelec- piezoresistive and capacitive microcantileverspossible make to it constructan microscale external AFMs deflection onand sensor.For chips colleagues example, without in 1995 Itoh with integrated sensorsimaging and and actuators lithography thatcontrol with of allow each feedback of parallel and up3 to independent mm/sec 16 tips, using with a scanning piezoresistive speeds sensor, up to order to fabricateassemblies, large massively parallel numbers scanning of probe(SPM) microscopes nanoparts arrays and nano- robotic arm on afacing wafer surface makes by picking aproduced up second micron-size parts—carefully robotic lithographically- laid armthe on out right a in locations so advanceand the in tiny assembling robotic exactly arm them.Thetwo can two find more them— robotic robotic armssurfaces.These arms, four then one robotic make then on arms, make each two four of onues more the each with robotic two surface, the arms.This facing number process of contin- robotic arms steadily increasing arrays of 50–100tips independently mounted controllable AFM inincluding probe 2-D a patterns 10 closely with spaced 60 rows KHz usinga single throughwafer resonances, chip. interconnects on gle silicon chip.Each cantilever tip lay its neighbor, and measuredwide 150 and microns long, 3.5 50 microns microns thick, or exponential assembly design concept, had built and testedface an of array an oftilever ordinary 150 micro-STMs silicon microns on chip, long thethe with with largest sur- each 3-D prototype tip sensing arraysquare on and had consisting a of control— 144 can- 12 probes,vidual rows arranged probe of needles in 12 about probes a 200in each, microns with apart.Researchers the indi- Millipedeoratory project used at IBM’s conventionalscanning Zurich microlithography probe Research to tip Lab- to fabricate arrays achieve terabit-per-square-inch of data storageMirkin’s up densities, group to constructed an 1024 arraytips individual of with 10,000 tips each microscope others, capable of acting independently from the ZnO tilever array has beenitated fabricated cantilevers with on millions a of single interdig- chip. × 258 21 7) unit × ta1GHz , on a crys- 2 would use a in volume, then to 3 2005 260 and segments of individual dimer volume of molecularly precise prod- 3 257 256 have demonstrated the first repeatable site- 259 ea1cm Massively parallel manipulator arrays These results, both theoretical and experimental, sup- individual simple molecular components—even a operating frequency, serialof atom-by-atom a manufacturing singleclearly object not would economically takefacturing, viable.But many vast with thousands numbers parallel of ofprocessed manu- simultaneously, molecular years, reducing batch components processingto can times days, be hours, orfor even performing massively less.At parallel least positionalbeen two assembly have such identified: techniques (1) massivelyand (2) parallel self-replicating manipulator systems. arrays very large arraydevices of (e.g., scanning independently probe actuated tips,cess robot manipulation a arms, etc.) very tonents pro- large simultaneously number to build of a molecular larger precise product compo- object.In manufactur rows of silicon atoms haveface been extracted to from the create Si(100) and structures lateral features with that atomically are straight only edges one dimer in width. cell, as well as theatom mechanosynthetic on deposition of a a created single surface vacancy. 7) surface, themechanosynthesis involving first the solely experimental mechanical removal of demonstration a of selected silicon pure the atom surface from without its equilibrium otherwise position perturbing at the (7 tal surface, albeitnear electrically-mediated.Most contact recently, a atomictemperature force has been microscopeof used operated selected for at single the low- vertical silicon manipulation atoms from the Si(111)–(7 uct requires the assembly of 1000 billion billion (10 port the generalations feasibility that of can molecularremoving modify positional small hydrocarbon a oper- clusters diamondeven on that workpiece, adding workpiece and adding or removingappropriate or single vacuum atoms conditions.Repeatedthese or application basic dimers operations under of and should atomically allow precise building molecular structures, upmanufacture permitting of complex the a widetures range with of atomically nanoscale precise diamond features. struc- 4.4.2. Massively Parallel Manufacturing Massively parallel assemblyviability is of the key molecularperhaps to the manufacturing.Biology the best provides allelism economic example in of assembly, the(multiple such power ribosomes as of translatingsimultaneously).The polysomes massive difference between in a par- serial and living singleprocessing parallel is cells similarly mRNA crucial in strand where molecular the manufacturing, basic partslarly are precise simple very component small.If is a 1 nm typical molecu- J. Comput. Theor. Nanosci. 2, 1–25, Ho and Lee Freitas into the crystal, specific mechanosynthetic covalent bonding operationdiatomic of carbon-containing a molecule, Fe(CO) REVIEW n ytm nte14sad1950s, and replicat- 1940s of the studies in systems theoretical ing Neumann’s von for John ever unnecessary since per- manufacturing.Nevertheless, is correct parallelism macroscale the percep- massive traditional (2) such erroneous and that difficulty, but technical ception widespread least great of the at tion for (1) manufacturing reasons: pur- macroscale two been in not have explicitly but sued systems widely biological are natural systems in found itself.Self-replicating than of rather copies objects, would product more useful population produce to manipulator redirected the be enough, was large copies, systems systems. manipulator deemed of replicated further number of total population fabricate the the in Once to increase themselves, rapid a copies of in resulting copies those fabricating allowing by then first assembly allel NM)frpooyennsaeassemblers. nanoscale systems prototype for nanoelectromechanical (NEMS) and (MEMS) systems microelectromechani- cal using assemblers pro- microscale develop National Advanced to totype five-year, contract (NIST) government Technology million, Program and Technology $25 Standards a of 2001, Institute awarded operations.In was desired manufacturing Zyvex the manipu- undertake parallel large subsequently single massively a can build a which to array arms).Thus parts lator com- robotic man- supplied are some uses tiny surfaces until manipulator with etc., both 64, (e.g., covered 32, reached 16, pletely is 8, 4, limit 2, ufacturing 1, pattern the in Nanorobotics Medical and Nanomedicine of Status Current hoeia n xeietl nmcaia (nonbiolog- machines. both mechanical self-replicating programs, on ical) experimental, research and university there theoretical process.Today ongoing simple several fundamentally are a be can tion usd htgiei,se yse,i sebigasec- a assembling in of step, number by some the manipulator.After step remote-controlled from it, ond remote- guide instructions a that component. essence, receiving outside replicating in manipulator the becomes, to controlled replicator means physical several broad- The of the broadcast any is is information approach by control flexible wherein not and architecture, will safe cast inherently example information an replicators.One of of nanomechanical storage by onboard required that be the likely future is foreseeable in the it for operating that domain.Note replicators size nanoscale to mechanical beginning study just seriously are communities engineering molecular 90NS niern td fsl-elctn lunar self-replicating of study factories, engineering NASA 1980 neeti h hleg fmcaia self-replicating mechanical of challenge systems, the in interest between. in remote-controlled, combinations fully various or be autonomous, that noting fully can worth is systems arms.It that robot self-replicating Prefecture make to Yamanashi arms nearly robot in uses Fanuc’s factory self-replicating robot Fujitsu fully “unmanned” the notably of most goal factory—including the toward progressing 18 efrpiaigsystems Self-replicating ntels e er hr a enrnwdresearch renewed been has there years few last the In 278 277 npr u oteraiainta replica- that realization the to due part in auatrn uoainhsbe slowly been has automation manufacturing ol civ asvl par- massively achieve would 278 h itcnlg and biotechnology The 276 n h well-known the and ieyrvee yFetsadMerkle. and Freitas by exten- reviewed are to manufacturing sively molecular sent for instructions designs devices.Concep- system prod- of manipulator tual useful replicated stream of of the population numbers altering the identical large by assemble of objects to uct number used large be can a then manipulators is manipulators.These result remote-controlled the cycles, repeat u oo,otubrn u iseclsams e to ten almost cells tissue our one. outnumbering through swim colon, microbes single-celled our human instance, trillion the nanodevices.For 40 actually such than but more with odd, teems bit a already seem body might nanorobots us self-powered of autonomous inside placing of idea The and Designs Nanorobot Medical 4.5. ln ouehsmdfidAPs oos(eto 4.2.2) (Section motors ATPase modified his use to plans vessels. propulsion blood of the means in a microrobot as a system for of Res- Magnetic (MRI) Laboratory a Imaging use onance will NanoRobotics Montreal in the Polytechnique Ecole of project “MR-Sub” for intended microrobots n ehp 0mcosi size. measur- in trillion each microns lymphocytes, a 10 and perhaps than neutrophils ing more as white and such of fibroblasts cells bod- population called cell.Our nanodevices a bacterial biological motile the maintain of also outside between biologi- ies the differences 30-nanometer and pH a inside by by the powered nanomotor driven ionic is cal that flagellum, or os n kroos rpsdb huc tal. et Chrusch by proposed “karyobots” and bots” ncesbe”Ohrapoce oMM-ae micro- literature, still MEMS-based for are intended to which robots approaches vessels out made carry blood Other to robot the inaccessible.” “possible a in fur- it applications create “to making medical to parts,” goal nanometric and long-term for of system a up rules the with design miniaturize microrobot, ther define of to type gath- this information blocked currently is necessary of project reopening ering biopsies.The the taking or release, arteries, drug might targeted prototype generation include first human the the through of device body.Applications small develop a to direct pro- to able power propulsion particles, sufficient of ferromagnetic system miniaturized containing magnetic a robot viding a a generate would on field force magnetic MRI variable a ovrosogn o ipslfo h body. the them from transporting disposal for and organs particles various microbes, foreign to us, up invading gathering of attacking and inside tissues, around damaged crawling repairing constantly are nanorobots eal ehooisFreape Montemagno example, fore- currently technologies.For using constructed seeable be could that nanorobots surgery. intracellular wireless performing hr r non tepst ul MEMS-based build to attempts ongoing are There hr r rlmnr rpsl o yrdbio- hybrid for proposals preliminary are There 5 cln Studies Scaling aybcei oeb hpigaon iytail, tiny a around whipping by move bacteria Many 280 nldn h antclycnrle “cyto- magnetically-controlled the including .Cmu.Ter aoc.2 1–25, 2, Nanosci. Theor. Comput. J. nvivo in nvivo in s aebe ecie nthe in described been have use 5 hs eeca natural beneficial These s.o xml,the example, use.For 279 278 nti approach, this In 7 281 Freitas 282 2005 for 283 REVIEW ) 2 (at 19 this 2 7 Designer Robert 285 and unload CO 2 therapeutic dose of 50% ) and carbon dioxide (CO 2 fa5cc An artificial red cell—the respirocyte. Current Status of Nanomedicine and Medical Nanorobotics Each respirocyte can store and transport 236 times the lungs), oronboard nanocomputer vice and versa numeroussure chemical (at sensors and the enable pres- reprogrammable tissues) complex by device (Fig.9).An theacoustic behaviors physician signals. remotely via externally applied as muchSo gas the perrespirocyte injection unit saline o suspension, volume aual total as nanorobots, of into a 5replace trillion the natural individ- the human gas red bloodstream5.4 can carrying liters cell. exactly capacity of blood.sion of could If the safely up be patient’s added to to entire 1 the human liter bloodstream, of respirocyte suspen- could keep a patient’s4 tissues hours safely in oxygenated the forbeating, event a up even heart in to attack the causedical absence the applications of heart of to respiration.Primary stop blood respirocytes med- substitution; will partial include treatmentneonatal transfusable for and anemia, perinatal/ lungcular/neurovascular disorders; procedures, tumor enhancement therapiesnostics; of and prevention diag- cardiovas- of asphyxia;variety artificial of breathing; sports, and veterinary, a battlefield and other uses. 4.5.2. Microbivores An artificial mechanicalcalled white a cell “microbivore,”destroy of has microscopic microbiological as size, pathogens its found primary in function the to human molecules.Later on, thesethe gases tank can inular a be pumps.Respirocytes controlled released mimic mannerral from the using hemoglobin-filled action the red ofsensors same blood the on molec- cells.Gas natu- the concentration know outside when of it each device is let time the to nanorobot load O A.Freitas, Jr.© 1999, Forrest Bishop.Used with permission. Fig. 8. in a diamondoidof pressure up tank to 3 that billion can oxygen be (O pumped full 285 two 285–288 but the develop- 2005 284–288 5–7 7 The greatest power of nanomedicine will emerge in a There are many possibilities of which arestudies summarized are briefly not below.Noteing that intended design these to forpurpose produce a is future an merely nanomedical actual toconstraints, product.Rather, engineer- examine scaling the issues, a and setwhether reference of designs or appropriate to not design assess determine the key basic limitations ideato of might biocompatibility such of be designs.Issues medicaldiscussed feasible, related nanorobots elsewhere. and are extensively to ment pathway will bescaling long studies and are arduous.First,ity.These used theoretical initial to studies assess woulddetailed basic then computational be concept followed simulations feasibil- bycomponents of more and specific assemblies, nanorobot simulations, and all thoroughly ultimately integrated fullulations with systems additional of sim- from massively start parallel to finishengineering manufacturing consistent philosophy.Once processes with a molecularcapabilities design-for-assembly become manufacturing available,progress from experimental component efforts fabricationponent and may assembly, testing, and to finally com- ufacture, to prototypes ultimately and mass leadingprogress man- in to medical clinicalconcept nanorobotics feasibility trials.In stage—since remains 1998, 2004, largelylished the four at author theoretical has nanorobot the pub- scaling studies, J. Comput. Theor. Nanosci. 2, 1–25, is aatmosphere bloodborne pressure spherical vesselpowered 1-micron (Fig.8) with by diamondoid active endogenous236 pumping 1000- serum times glucose, morethan able oxygen natural to red to cells deliver nanorobot and the is to tissues manage made carbonic of per acidity.The 18 unit billion volume atoms precisely arranged 4.5.1. Respirocytes The artificial mechanical red blood cell or “respirocyte” Freitas to create a nanorobotby that entering a acts cell, asthat grabbing a proteins will “pharmacy produced in notneeded by a the be later cell” cell by used,a the and tiny patient.The nickel storing device drum, wouldical them attached consist motor, until to of which the theythe is target ATP-powered are biolog- molecules, coated whereupon withmolecules an to electric antibodies a field that storage pulls chamber the adsorb and holds themdecade in or two place. when weplete learn to artificial design and nanorobotsscale construct com- using parts diamondoidmanipulators, and nanometer- power subsystems plants,we and including make molecular sensors, the computers.If day motors, reasonable be assumption able thatnanorobots to we build (Sections will these 4.2cheaply some- complex and enough diamondoid 4.4.1), and medical useful and in therapeutically to sufficiently (Section build largemedical 4.4.2), implications? them numbers then to what be are the REVIEW i.10. Fig. nanorobots gulp.The any be single large virtually a would from in is species microbe which bacteremic single major cycle, a internalize 30-second to per enough material organic of protocol. discharge and digest a using bloodstream 9. Fig. Nanorobotics Medical and Nanomedicine of Status Current .ria,J. lutao ors ihp©20,ZvxCorp. Zyvex 2001, Bishop.© Forrest Jr., illustrator A.Freitas, rpe irbsa aiu hogpto micron 2 of throughput maximum a digesting at up completely microbes while consume power trapped may continuous device of pW The 200 picograms. to 12.2 of mass dry 20 tm nagosgoercvlm f1. micron 12.1 of volume minor geometric its gross structural along a arranged in diameter precisely atoms billion in its 610 microns of along consisting 2.0 axis, diameter and device axis in nanomedical major 3.4microns spheroidal measuring oblate (Fig.10) an is microbivore Bar Code Product Pattern nenlctwyve frsioyeeutra lf)adplr(ih)view. (right) polar and (left) respirocyte—equatorial of view cutaway Internal Computer diameter) natfiilwiecl—h microbivore. cell—the white artificial An (124 nm, ∼ Chamber Oxygen Gas 0tmsmr fceta hgctcagents phagocytic as efficient more times 80 Oxygen Rotors Gas Oxygen Rotors Gas Sensors Oxygen Gas Chamber (Ballast) Water Water Rotors Water Rotors EQUATOR Glucose Glucose Engine Engine Chamber (Ballast)

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Dioxide Carbon n m 286 einrRobert Designer Dioxide Carbon Rotors Dioxide Carbon Rotors 3 286 Chamber n a and Equatorial Dioxide Carbon Bulkhead The Gas/Water Bulkhead 3 EQUATOR n,temreltdrmiso h elaepsoe into pistoned are micron cell 2 the separate of a remains morcellated minc- the mechanical ing, sufficient chamber.After morcellation reversible species-specific via sites. flypaper, binding micro- on bloodborne fly the a of like surface bivore the to bound is bacterium infections. poten- dense of locally range including entire threats, the bacterial to tial physician therapeutic the the extend of to biologi- competence able antibiotic-assisted and defenses, or phagocytic natural cal unaided either to complete than up bloodstream.Hence be achieve the to to from appear microbivores bacteria months target or of weeks antibiotics— clearance require by often aided can natural when whereas defenses—even hours, to phagocytic eliminate minutes natu- in fully infections would larger than septicemic cells.Microbivores far phagocytosis blood have white for would ral capacity and lifetime agent, maximum phagocytic unit per of digested volume/sec volume of terms in macrophages than icagdbc notebodtemtruha exhaust an through harmlessly bloodstream then the into are back molecules discharged simple sim- and sugars.These acids fatty ple amino free monoresidue glycerol, progressively to mononucleotides, suc- acids, times, ultimately morcellate are six the enzymes extracted reducing and engineered injected 40 cessively of sequence grammed hr h ahgncl sitraie noa2micron 2 device a the into of internalized front is the the cell transport at pathogen port the then anchorage ingestion where membrane, secure the plasma establish to pathogen microbe’s surface, the device to the in silos uigec yl fnnrbtoeain h target the operation, nanorobot of cycle each During Computer diameter) (124 nm, 285 96 oetAFets Jr. A.Freitas, Robert 1996, © 5 eecpn ooi rplseeg from emerge grapples robotic Telescoping .Cmu.Ter aoc.2 1–25, 2, Nanosci. 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Freitas port at thedigestion rear of cycle.This theis “digest device, conceptually completing and similar thetion discharge” 30-second to process protocol the practicedthe by internalization natural artificial and phagocytes, process diges- For except should example, that be it muchbiologically is faster well-known active and that cleaner. compounds macrophages during release bacteriophagy, REVIEW 22 Nanorobotics Medical and Nanomedicine of Status Current 56. 55. 62. 61. 60. 59. 58. 57. 63. 64. 66. 65. 69. 68. 67. 72. 71. 70. 73. 74. 76. 75. 78. 77. 80. 79. 81. 82. .gt .udc,YSa n J.R.Chelikowsky, Lett. and Y.Saad R.Burdick, S.Ogut, 1056 M.Lieberman, and B.Isaksen, C.S.Lent, niirb gnsChemother. Agents H.Y.Lei,Antimicrob. and C.K.Chou T.Y.Luh, P.P.Kanakamma, N.Tsao, M.E.Tuckerman, 1326 and D.I.Schuster, Z.Zhu, M.Prato, I.Bonin, and G.Stefancich, S.Miertus, S.Castellano, Ros, T.Da G.L.Marcorin, niirb gnsChemother. F.Wudl, Agents and Antimicrob. 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