International Journal of Surgery (2005) 3, 243e246

www.int-journal-surgery.com

EDITORIAL , and nanosurgery

An exciting revolution in health care and med- Feynman was clearly aware of the potential ical technology looms large on the horizon. Yet the medical applications of this new technology. He agents of change will be microscopically small, offered the first known proposal for a nanorobotic future products of a new discipline known as surgical procedure to cure heart disease: ‘‘A friend nanotechnology. Nanotechnology is the engineer- of mine (Albert R. Hibbs) suggests a very interest- ing of molecularly precise structures e typically ing possibility for relatively small machines. He 0.1 mm or smaller e and, ultimately, molecular says that, although it is a very wild idea, it would machines. be interesting in surgery if you could swallow the Nanomedicine1e4 is the application of nano- surgeon. You put the mechanical surgeon inside technology to medicine. It is the preservation the blood vessel and it goes into the heart and and improvement of human health, using molecu- looks around. (Of course the information has to be lar tools and molecular knowledge of the human fed out.) It finds out which valve is the faulty one body. Present-day nanomedicine exploits carefully and takes a little knife and slices it out. .[Imag- structured nanoparticles such as dendrimers,5 car- ine] that we can manufacture an object that bon fullerenes (buckyballs)6 and nanoshells7 to maneuvers at that level!. Other small machines target specific tissues and organs. These nanopar- might be permanently incorporated in the body to ticles may serve as diagnostic and therapeutic an- assist some inadequately functioning organ.’’9 tiviral, antitumor or anticancer agents. But as this technology matures in the years ahead, complex Medical microrobotics nanodevices and even nanorobots will be fabri- cated, first of biological materials but later using There are ongoing attempts to build microrobots more durable materials such as diamond to for in vivo medical use. In 2002, Ishiyama et al. at achieve the most powerful results. Tohoku University developed tiny magnetically driven spinning screws intended to swim along veins and carry drugs to infected tissues or even to Early vision burrow into tumors and kill them with heat.10 In 2003, the ‘‘MR-Sub’’ project of Martel’s group at Can it be that someday nanorobots will be able to the Laboratory of Ecole Polytechni- travel through the body searching out and clearing que in Montreal tested using variable MRI magnetic up diseases, such as an arterial atheromatous fields to generate forces on an untethered micro- plaque?8 The first and most famous scientist to robot containing ferromagnetic particles, develop- voice this possibility was the late Nobel physicist ing sufficient propulsive power to direct the small Richard P. Feynman. In his remarkably prescient device through the human body.11 Brad Nelson’s 1959 talk ‘‘There’s Plenty of Room at the Bottom,’’ team at the Swiss Federal Institute of Technology Feynman proposed employing machine tools to in Zurich continued this approach. In 2005, they make smaller machine tools, these are to be reported the fabrication of a microscopic robot used in turn to make still smaller machine tools, small enough (w200 mm) to be injected into the and so on all the way down to the atomic level, body through a syringe. They hope that this device noting that this is ‘‘a development which I think or its descendants might someday be used to de- cannot be avoided.’’9 liver drugs or perform minimally invasive eye

1743-9191/$ - see front matter ª 2005 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijsu.2005.10.007 244 Editorial surgery.12 Nelson’s simple microrobot has success- techniques that can build a molecular structure fully maneuvered through a watery maze using ex- by what is called positional assembly. This will in- ternal energy from magnetic fields, with different volve picking and placing molecular parts one by frequencies that are able to vibrate different me- one, moving them along controlled trajectories chanical parts on the device to maintain selective much like the robot arms that manufacture cars control of different functions. Gordon’s group at on automobile assembly lines. The procedure is the University of Manitoba has also proposed mag- then repeated over and over with all the different netically controlled ‘‘cytobots’’ and ‘‘karyobots’’ parts until the final product, such as a medical for performing wireless intracellular and intranu- nanorobot, is fully assembled. clear surgery.13 The positional assembly of diamondoid struc- tures, some almost atom by atom, using molecular Manufacturing medical nanorobots feedstock has been examined theoretically14,15 via computational models of diamond mechanosyn- The greatest power of nanomedicine will emerge, thesis (DMS). DMS is the controlled addition of car- perhaps in the 2020s, when we can design and bon atoms to the growth surface of a diamond construct complete artificial nanorobots using rigid crystal lattice in a vacuum-manufacturing environ- diamondoid nanometer-scale parts like molecular ment. Covalent chemical bonds are formed one by gears (Fig. 1) and bearings.14 These nanorobots one as the result of positionally constrained me- will possess a full panoply of autonomous subsys- chanical forces applied at the tip of a scanning tems including onboard sensors, motors, manipula- probe microscope apparatus, following a pro- tors, power supplies, and molecular computers. grammed sequence. using sili- But getting all these nanoscale components to con atoms was first achieved experimentally in spontaneously self-assemble in the right sequence 2003.16 Carbon atoms should not be far behind.17 will prove increasingly difficult as machine struc- To be practical, molecular manufacturing must tures become more complex. Making complex also be able to assemble very large numbers of nanorobotic systems requires manufacturing medical nanorobots very quickly. Approaches un- der consideration include using replicative manufacturing systems or massively parallel fabri- cation, employing large arrays of scanning probe tips all building similar diamondoid product struc- tures in unison.18 For example, simple mechanical ciliary arrays consisting of 10,000 independent microactuators on a 1-cm2 chip have been made at the Cornell Nation- al Nanofabrication Laboratory for microscale parts transport applications, and similarly at IBM for me- chanical data storage applications.19 Active probe arrays of 10,000 independently actuated micro- scope tips have been developed by Mirkin’s group at Northwestern University for dip-pen nanolithog- raphy20 using DNA-based ‘‘ink’’. Almost any desired 2D shape can be drawn using 10 tips in concert. An- other microcantilever array manufactured by Proti- veris Corp. has millions of interdigitated cantilevers on a single chip. Martel’s group has investigated using fleets of independently mobile wireless in- strumented microrobot manipulators called Nano- Figure 1 A molecular planetary gear is a mechanical Walkers to collectively form a nanofactory system component that might be found inside a medical nanoro- that might be used for positional manufacturing bot. The gear converts shaft power from one angular fre- operations.21 Zyvex Corp. (www.zyvex.com)of quency to another. The casing is a strained silicon shell Richardson, TX has a $25 million, five-year, National with predominantly sulfur termination, with each of the nine planet gears attached to the planet carrier by Institute of Standards and Technology (NIST) con- a carbonecarbon single bond. The planetary gear shown tract to develop prototype microscale assemblers here has not been built experimentally but has been using microelectromechanical systems. This re- modeled computationally. Copyright 1995 Institute for search may eventually lead to prototype nanoscale Molecular Manufacturing (IMM). assemblers using nanoelectromechanical systems. Editorial 245

Respirocytes and microbivores Surgical nanorobotics

The ability to build complex diamondoid medical Surgical nanorobots could be introduced into the nanorobots to molecular precision, and then to body through the vascular system or at the ends of build them cheaply enough in sufficiently large catheters into various vessels and other cavities in numbers to be useful therapeutically, will revolu- the human body. A surgical nanorobot, pro- tionize the practice of medicine and surgery.1 The grammed or guided by a human surgeon, could first theoretical design study of a complete medi- act as a semi-autonomous on-site surgeon inside cal nanorobot ever published in a peer-reviewed the human body. Such a device could perform journal (in 1998) described a hypothetical artificial various functions such as searching for pathology mechanical red blood cell or ‘‘respirocyte’’ made and then diagnosing and correcting lesions by of 18 billion precisely arranged structural atoms.22 nanomanipulation, coordinated by an onboard The respirocyte is a bloodborne spherical 1-mm di- computer while maintaining contact with the amondoid 1000-atmosphere pressure vessel with supervising surgeon via coded ultrasound signals. reversible molecule-selective surface pumps pow- The earliest forms of cellular nanosurgery are ered by endogenous serum glucose. This nanorobot already being explored today. For example, a rap- would deliver 236 times more oxygen to body tis- idly vibrating (100 Hz) micropipette with a <1-mm sues per unit volume than natural red cells and tip diameter has been used to completely cut den- would manage carbonic acidity, controlled by gas drites from single neurons without damaging cell concentration sensors and an onboard nanocom- viability.24 Axotomy of roundworm neurons was puter. A 5-cc therapeutic dose of 50% respirocyte performed by femtosecond laser surgery, after saline suspension containing 5 trillion nanorobots which the axons functionally regenerated.25 A could exactly replace the gas carrying capacity of femtolaser acts like a pair of ‘‘nano-scissors’’ by the patient’s entire 5.4 l of blood. vaporizing tissue locally while leaving adjacent tis- Nanorobotic artificial phagocytes called ‘‘micro- sue unharmed. Femtolaser surgery has performed bivores’’ (Fig. 2) could patrol the bloodstream, the followings: (1) localized nanosurgical ablation seeking out and digesting unwanted pathogens in- of focal adhesions adjoining live mammalian epi- cluding bacteria, viruses, or fungi.23 Microbivores thelial cells,26 (2) microtubule dissection inside would achieve complete clearance of even the yeast cells,27 (3) noninvasive intratissue nanodis- most severe septicemic infections in hours or section of plant cell walls and selective destruc- less. This is far better than the weeks or months tion of intracellular single plastids or selected needed for antibiotic-assisted natural phagocytic parts of them,28 and even (4) the nanosurgery of defenses. The nanorobots do not increase the risk individual chromosomes (selectively knocking out of sepsis or septic shock because the pathogens genomic nanometer-sized regions within the nu- are completely digested into harmless sugars, ami- cleus of living Chinese hamster ovary cells29). no acids and the like, which are the only effluents These procedures do not kill the cells upon which from the nanorobot. the nanosurgery was performed. Atomic force mi- croscopes have also been used for bacterium cell wall dissection in situ in aqueous solution, with 26 nm thick twisted strands revealed inside the cell wall after mechanically peeling back large patches of the outer cell wall.30 Future nanorobots equipped with operating instruments and mobility will be able to perform precise and refined intracellular surgeries which are beyond the capabilities of direct manipulation by the human hand. We envision biocompatible31 surgical nanorobots that can find and eliminate isolated cancerous cells, remove microvascular obstructions and recondition vascular endothelial cells, perform ‘‘noninvasive’’ tissue and organ Figure 2 Nanorobotic artificial phagocytes called ‘‘mi- transplants, conduct molecular repairs on trauma- crobivores’’ could patrol the bloodstream, seeking out tized extracellular and intracellular structures, and digesting unwanted pathogens. Copyright 2001 and even exchange new whole chromosomes for Zyvex Corp.; designer Robert Freitas, artist Forrest Bishop. old ones inside individual living human cells. 246 Editorial

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