neuroprotection at the nanolevel—part i : introduction to nanoneurosurgery

Neuroprotection at the Nanolevel—Part I

Introduction to Nanoneurosurgery

RUSSELL J. ANDREWS

NASA Ames Research Center, Moffett Field, California, USA

ABSTRACT: Nanoneurosurgery demands a departure from the tradi-tional “excise what you can see and touch” role of neurosurgeons. More-over, there is a conceptual leap necessary for neuroscientists as wellas neurosurgeons in developing and applying nanotechniques to neuro-surgery at the nanolevel. After introducing the realm of nanotechnologyand some unique properties of nanomaterials, I review several of thenanotechniques in development that are most likely to affect neuropro-tection at the nanolevel. These techniques include quantum dot “nano-barcode” labeling of cellular and subcellular entities, as well as nanotech-niques for following enzymatic reactions in real time. Nanoscaffolds offermechanical enhancement of neurorepair; carbon nanotube electrode ar-rays can provide nanolevel electrical and chemical enhancement. Eventraditional “cut and sew” surgery is being taken down to the micron, ifnot nano, level for single axon repair, and the technology can use capillar-ies to deliver therapeutics to virtually any portion of the nervous systemwith greater than pinpoint accuracy. In this report, I use these nanotech-niques to introduce the multiplex nanodevices under development.

KEYWORDS: carbon nanotubes; nanoelectrode arrays; nanoscaffolds;nanotechnology; neuromodulation; neuroprotection; quantum dots

INTRODUCTION

Nanotechnology for neuroprotection presents two challenges for neurosur-geons. The first challenge began with the use of techniques such as neuroen-doscopy, where the three-dimensional world loses the dimension of visualdepth. The tactile feedback of direct open surgery is also reduced or lost asmicroinstruments become elongated—and finally flexible catheter driven—towork in spaces where the human finger cannot reach. Instead of “cutting thingsout” (e.g., tumors, ruptured discs) or “implanting devices” (e.g., spinal fusionhardware, deep brain stimulation electrodes), today’s neurosurgeon is armed

Address for correspondence: Russell J. Andrews, M.D., 50 E. Hamilton Ave., Ste. 120, Campbell,CA 95032. Voice: 408-374-0401; fax: 408-866-8842.

[email protected]

Ann. N.Y. Acad. Sci. 1122: 169–184 (2007). C© 2007 New York Academy of Sciences.doi: 10.1196/annals.1403.012

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170 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES

with techniques that are truly “no see, no touch.” One example is stereotacticradiosurgery, in which hundreds of radiation beams converge on a target to de-stroy (“with surgical precision”) the tumor or other abnormality while leavingthe surrounding healthy tissue unharmed.

The second challenge is comprehending the nanoworld itself. The “macro”neurosurgeon, when contemplating an operation such as brain tumor excision,considers the effects of the operation on the organ (e.g., the brain, spinal cord,fifth cranial nerve), not to mention such concerns as the patient’s overall qualityof life. The “nano” neurosurgeon must begin to think like an atom or molecule,not like someone about to operate on an organism, although the effects of theintervention will be on the organism as a whole. Indeed, the definition ofnanotechnology is generally attributed to Norio Taniguchi in 1974:

“Nano-technology mainly consists of the processing of, separation, consoli-dation, and deformation of materials by one atom or one molecule.”3

The paradigm shift1 or quantum leap in technique from macro- to nanoneu-rosurgery is accompanied by a new set of risks and benefits for the patient.For example, many years ago, when surviving brain surgery was problematic,death might be considered the primary risk. Now the concept of a surgicalcomplication is extended to an adverse event within 30 days of surgery (e.g.,an early postoperative infection such as pneumonia, or a pulmonary embolism,or a myocardial infarction, all presumably related to the decision to performan operation). With other interventions such as radiation therapy and drugs,the risks may take years after treatment to appear (e.g., radiation necrosis orradiation-induced cancers). The damage inflicted on the nervous system by ascalpel blade may be the easiest to predict and may also be one of the easiestto treat with nanotechniques, as we will see in Part II. Medical nanotoxicologyis a burgeoning field.

Richard Feynman, Nobel Prize laureate (physics, 1965), is usually creditedwith the concept of the nanoscale and nanotechnology. In 1959, his talk titled“There’s Plenty of Room at the Bottom” for the American Physical Societyincluded the following:

“I want to talk about the problem of manipulating and controlling things ona small scale . . . It is a staggeringly small world that is below. In the year2000, when they look back at this age, they will wonder why it was not untilthe year 1960 that anyone began seriously to move in this direction.”2

“Nano,” Greek for “dwarf,” was attached to “technology” by Norio Taniguchi15 years later as a term for one-billionth: 1 nm = 10−9 m.

FIGURE 1 graphs and illustrates macro-, micro-, and nanosized objects.In nanomedicine, perhaps the greatest contribution to date has been made

by another Nobel Prize laureate (chemistry, 1996), Richard Smalley—whotogether with Robert Curl, Jr., and Harold Kroto discovered the C60 “buckyball”

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FIGURE 1. Length scale 1 m to 1 nm. The region of nanoscience/nanomedicine (1–100 nm) is expanded.4

(0.7-nm diameter). Although Smalley died in October 2005, of non-Hodgkin’slymphoma, he predicted the following in 1999:5

“Twenty years ago, without this crude chemotherapy, I would already bedead. But 20 years from now, nanoscale missiles will target cancer cells inthe human body and leave everything else blissfully alone. I may not live tosee it. But I am confident it will happen.”

Smalley’s words capture the paradigm shift or quantum leap ofnanomedicine: treating cellular-level disorders with cellular-level (i.e., nano-sized) techniques. No longer will macro-, or even micro-, techniques be appro-priate for all but the few macro-sized neurosurgical problems, such as evacu-ation of intracranial hematomas and removal of penetrating foreign bodies.The following overview of some nanotechniques relevant to neurosurgeryshould convince the reader of the prescience of Smalley’s words. By 2020,such nanotechniques—imaging, electrical and chemical monitoring, mechan-ical manipulation, electrical and chemical modulation, as well as surgery atthe subneuron or subcellular level—will in all likelihood have become main-stream in the world of clinical medicine. But perhaps more important than theclinical applications for nanomedicine and nanosurgery is the opportunity tounderstand, at the neuronal and subneuronal level, the electrical and chemicalworkings of the nervous system in both health and disease.6–8


TABLE 1. Density, tensile strength, and Young’s modulus of various materials

Density Tensile Young’s modulusMaterial (g/cm3) strength (GPa) (stiffness) (GPa)

Spider silk 1.3 1.3 275Kevlar 1.4 3 125Carbon fiber 1.8 5 150Carbon nanotube 2 200 >1000Glass 2.5 4 75Diamond 3.5 1.2 >1000Titanium 4.5 1 110Steel 7.8 0.5 200

NANOPROPERTIES, NANOFABRICATION,AND CARBON NANOTUBES

Nanofabricated materials can be as strong as naturally occurring materials(TABLE 1). Carbon nanotubes (CNTs) have a density just over half that ofdiamond, yet CNTs have a comparable Young’s modulus (a measure of stiffnessor elasticity, i.e., the slope of the stress–strain curve) and a tensile strengthnearly 200 times as great.

A major benefit of nanodevices for nervous system electrochemical mon-itoring is their cellular/neuronal level size. With a measuring device whosesize is comparable to what is being measured, whether it is a neurotransmittermolecule (e.g., dopamine in the synaptic cleft) or electrical charge (e.g., actionpotentials or neuronal conduction), the small size of nanomonitors (comparedeven with microelectrodes) presents great advantages (FIG. 2). Furthermore,the small size permits tagging of intracellular processes and allows processessuch as enzymatic reactions to be followed.

Basic to the fabrication of nanodevices such as CNTs is the concept of“bottom-up” rather than “top-down” construction. Indeed, those CNTs thathave yet to be modified after being produced by a bottom-up technique arecalled “as-grown” CNTs (FIG. 3).

However, the electrochemical properties of CNTs and other nanostructuresare particularly useful for applications in neuroprotection and nanoneuro-surgery. I will discuss specific properties of CNTs relevant to neuromodulationboth here and in the companion report.

NANOIMAGING FOR NEUROPROTECTION ANDNEUROSURGERY: SUBCELLULAR TRACKING

Over the last decade, several nanoimaging techniques for tracking cellsand subcellular entities (e.g., proteins, receptors) have been developed andare undergoing constant refinement. Here I have chosen to review quantum

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FIGURE 2. (A) Why nanoelectrode arrays? Reducing the electrode size greatly im-proves spatial and temporal resolution as well as signal-to-noise ratio. (B) Comparison ofmacro/microelectrode and nanoelectrode.


FIGURE 3. Bottom-up fabrication of CNT arrays. CVD = chemical vapor deposition;TEOS = tetraethylorthosilicate; CMP = chemical–mechanical polishing; EC = electro-chemical measurements.

dots (Qdots) and Forster (or fluorescence) resonance energy transfer (FRET)because of their potential for biomedical applications, but other promis-ing nanotechniques for following enzymatic activities, such as surface-enhanced Raman spectroscopy, are likely to be important in nanomedicineas well.

Qdots are nanocrystals with a core (usually <10 nm in diameter) of, forinstance, cadmium selenide (CdSe), which is encapsulated by a shell of, say,zinc sulfide (ZnS). The Qdot fluoresces when excited by light of a specificwavelength, with the frequency (i.e., color) of the fluorescence depending onthe size of the nanocrystal (FIG. 4).9

Advantages to using Qdots for labeling cellular and subcellular entities in-clude the following:

• As the size of the nanocrystal is increased, the wavelength of the fluo-rescence increases; thus, many different-sized Qdots can be used to tagvarious entities (FIG. 4).

• Because Qdots fluoresce much more brightly than organic dye molecules(i.e., have a higher extinction coefficient), they are much more readilyimaged in vivo. Indeed, Qdots have been nicknamed “nanobarcodes” be-cause of their versatility for labeling.

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FIGURE 4. Qdots.9 Depending on the size of the Qdot, the emission wavelength (i.e.,color) varies: larger diameter correlates with longer wavelength.

FIGURE 5. Glycine receptors on spinal cord neuron dendrites labeled with red Qdots.10

For example, Qdots can be conjugated to receptor antibodies to locate re-ceptors (e.g., FIG. 5), where the Qdots then identify glycine receptors on spinalcord neuron dendrites.10

The potential uses of Qdots are evolving rapidly, such as in contrast agents.In FIGURE 6A, Qdots have been modified to serve as a water-soluble contrastagent for magnetic resonance imaging (MRI); in FIGURE 6B, Qdots are usedfor capillary angiography.11,12


FIGURE 6. (A) Qdots as an MRI contrast agent.11 Qdots are encapsulated in a para-magnetic/PEGylated shell to serve as a contrast agent in fluorescent imaging and MRI. (B)Capillary angiography in vivo using water-soluble Qdots.12 Panel A, Water-soluble Qdotsare injected through the tail vein of mice; capillaries are visible at a depth of 100 �m in thedermis. Panel B, Line scan of blood flow velocity (∼10 �m/s) across the capillary in panelA. Undulations in capillary wall are caused by heartbeat (enlarged image at right). Panel C,Capillary structure in adipose tissue surrounding mouse ovary. Scale bars: panels A and B,20 �m; panel C, 50 �m.

Although the use of Qdots to localize and track receptors, microtubules,and other subcellular entities is valuable, the ability to locate and track eventssuch as enzymatic reactions is probably more important. Qdots have beencombined with FRET, the fluorescent emission that occurs when donor (e.g.,a Qdot) and receptor fluorophores interact. A major application of FRET todate has been DNA detection (FIG. 7)11,13; however, FRET can also be used tofollow various protein interactions in cells such as monitoring multiple proteinkinase activities.14,15

Qdots, FRET, and other such nanolevel imaging techniques are greatly en-hancing our understanding of intra- and interneuronal entities and events. Suchnanoimaging techniques are a crucial first step in greater understanding of thecellular- and neuronal-level events involved in nervous system injury and neu-rodegeneration.

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FIGURE 7. FRET.11 When the targeted reaction occurs (here, conjugation of the Qdotand the DNA), FRET emission occurs (in addition to the Qdot emission present beforeconjugation).

MECHANICAL NANONEUROMODULATION(NANOSCAFFOLDS)

Nanoscaffolds address a fundamental set of problems that occur after trau-matic injury. Many events inhibit neuronal-level nervous system repair in theadult:

• Scar formation after tissue injury• Phagocytosis resulting in gaps in the central nervous system tissue after

injury• Lack of axonal regrowth in the adult central nervous system, caused by

both intrinsic mechanisms and exogenous inhibitors.

To investigate axonal regeneration at the neuronal level, various micron-sized models have appeared recently.16 Beyond the study of axonal regener-ation, nanoscaffolds have been fabricated to address the issues noted above,which inhibit axonal regeneration. For example, electrospun nanoscaffolds ofpoly(L-lactic acid) may augment axonal growth17; such electrospun nanoscaf-folds can also be modified for the timed release of substances such as diclofenacsodium.18

Dramatic results from using a nanoscaffold in vivo have recently been re-ported by Ellis-Behnke et al. (FIG. 8).19 Transection of the optic tract in thesuperior colliculus of hamsters (1.5 × 2.0 mm) was treated either with saline(control) or with a self-assembling peptide nanofiber scaffold (SAPNS). TheSAPNS is composed of positively and negatively charged L-amino acids thatself-assemble into interwoven nanofibers (∼10-nm diameter). Either the con-trol (saline) or the SAPNS (volume, 10 �L) was injected into the wound inthe superior colliculus. Significant repair of the tissue injury occurred over


FIGURE 8. SAPNS repair of optic tract transection in hamster midbrain.19 (A) Dorsalview of hamster midbrain; left is rostral. Oblique line indicates optic tract transectionin SC. (B) Parasagittal view of midbrain; left is rostral. Position and depth of surgicalincision in SC indicated. (C–G) Dark-field composite parasagittal photos. Day 1—(C)control, (D) treatment; day 30—(E) control, (F) treatment; day 60—(G) treatment. (H)Bright-field photo. Day 60—treatment, showing minimal residual tissue disruption. IC,inferior colliculus; LGB, lateral geniculate body; LP, lateral posterior nucleus; MGB, medialgeniculate body; PT, pretectal area; SC, superior colliculus. Scale bars: panel B, 500 �m;panels C–H, 100 �m.

2 months (FIG. 8).19 Axonal regeneration was confirmed by both histologicaland behavioral examination, with the SAPNS hamsters showing sufficient re-covery of vision to orient toward a small object. Visual recovery was correlatedwith axonal regeneration.

NANONEUROMODULATION AND ELECTROCHEMICALNANONEUROMONITORING

Neurons in the nervous system communicate by a combination of electricaland chemical means. Understanding these electrical and chemical (neurotrans-mitter) neuronal (and neuromuscular) communications has had challenges:

• Our limited ability to monitor electrical activity in vivo at the level ofsingle neurons or small ensembles of interconnected neurons in neuralnetworks. Although the electroencephalogram and the electrocorticogramallowed macroscale continuous electrical monitoring, there have been nocomparable chemical monitoring techniques for neurotransmitters.

• Extended continuous real-time electrical or chemical monitoring, at thelevel of the single neuron or the synaptic cleft, has not been possiblewith our present techniques. Permanently implanted microelectrode ar-rays for monitoring brain electrical activity in paralyzed patients, neuro-motor prostheses, represent a recent step toward this goal.20,21

Nanotechniques for neuromonitoring and neuromodulation can addressthese limitations. With nanosized monitoring techniques, the detection de-vice is on the same scale (submicron) as the object being measured (e.g., a

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FIGURE 9. Upper panel: Multiwalled CNTs (MWCNTs) as nanoelectrodes. (A, B)Transmission electron micrograph of MWCNT from Iijima’s original publication.21 (C, D)Computer models of MWCNT, showing the bamboo or stacked cup structure of a defectiveMWCNT. Lower panel: CNTs.


FIGURE 10. I. Single-axon cutting.23 (A) Axon to be cut in center of field; knife attop. (B) Knife positioned over axon by micromanipulator. (C) Knife lowered for cutting.(D) Resulting cut axon. (E) Another axon before cutting. (F) Same axon after cutting.(G) Mouse sciatic nerve axons (top, myelinated; bottom, unmyelinated) after cutting. Scalefor panels D–G, 10 �m. II. Noncontact DEP manipulation of axons.23 Enzyme cocktailused to release individual sciatic nerve axons. DEP electrodes: pair of 10-�m-wide metaltraces (black horizontal and semicircular bars) deposited onto glass. (A) Arrows point totwo parallel axons before DEP. (B) After DEP, axons move away from horizontal electrode(superior and to left). (C) After DEP discontinued, axons return to original position. Axonsmoved 10 �m in 1–2 s. Scale bar, 20 �m. DEP, dielectrophoresis. III. Axon electrofusionwith spread of GFP between axons.23 (A) Two bundles of GFP axons. (B) Bright-fieldpicture of panel A with arrow pointing to unlabeled axon. (C) GFP is apparent in sameaxon 20 min after electrofusion. (D) Bright-field picture of panel C. (E) GFP-labeled axons.(F) Bright-field picture of panel E. Arrow points to unlabeled axon. (G) Arrow points toGFP-labeled axon within 1 min of electrofusion. (H) Arrow points to same axon as in panelG 15 min after electrofusion. Scale bar, 10 �m. GFP, green fluorescent protein.

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FIGURE 10. Continued

dopamine molecule) (FIG. 2). Perhaps most promising for neuromodulation isthat appropriately configured CNTs can monitor both electrical activity andchemical activity at the single neuron/synaptic cleft level for extended periods.

CNTs, first described by Iijima in 1991,22 have a rapidly expanding fieldof potential applications. FIGURE 3 shows a typical bottom-up fabrication ap-proach for CNTs. Both single-walled and multiwalled CNTs can be fash-ioned in many configurations, possessing favorable characteristics for nano-electrodes (FIG. 9).

The companion piece discusses the properties and potential of CNT nano-electrode arrays with regard to electrical and chemical/neurotransmitter mon-itoring. The focus is on the application of such CNT nanoelectrode arrays fordeep brain stimulation (neuromodulation) as used in clinical neurosurgery forepilepsy and movement disorders such as Parkinson’s disease.


NANOINTERVENTIONAL NEUROSURGERY

A survey of neuroprotection and nanoneurosurgery should consider twotechniques that, although not strictly nanoscale (<100 nm), represent a ma-jor transition from conventional microneurosurgery toward nanoneurosurgery.The first might be termed nanorobotic neurosurgery; the second, interventionalnanoneuroradiology (in line with the term interventional neuroradiology).

The operating microscope, used for more than 30 years in standard clinicalneurosurgery (with ongoing refinements), can magnify brain tissue up to 40times. The adaptation of industrial robots for neurosurgery and other surgicalspecialties has a clinical history about half that long but has evolved quickly.Most devices in clinical use today use “robotic assistance” rather than trueindependent robotic surgery. That is, the surgeon manipulates hand controls andthe robot performs the actual surgical maneuvers through a linkage, possiblydigital, to remove physiological tremor and potentially increase precision. In2001, two teams performed gall bladder surgery with the surgeon in New YorkCity and the surgical robot and patient in Strasbourg, France.

Extreme microneurosurgery and robotic neurosurgery have recently beencombined by Sretavan et al.23 A prototype platform has been fabricated thatcombines (1) a 5- to 10-�m cutting blade, (2) electrokinetic manipulation oftissue (e.g., axons), and (3) cell fusion. The repair of traumatized axons is theinitial goal of the platform. Doing so requires excision of the damaged portionfollowed by direct repair (if sufficient axons can be mobilized) or insertion ofan axonal graft (if the traumatized portion is lengthy). FIGURES 10A–C illustrateeach component: axon cutting, axon manipulation by dielectrophoresis, andaxon electrofusion.23

Interventional nanoneuroradiology will probably prove to be a short-livedterm. It is neither in the province of the neuroradiologist, nor does it rely onradiological imaging techniques. However, interventional nanoneuroradiologycaptures the concept of using the cerebral vasculature—down to the capillarylevel—to gain minimally invasive entry to all regions of the brain. One exampleuses the cerebral vasculature to place nanowire electrodes in the capillariesnear ensembles of neurons for electrical recording and/or stimulation.24 Suchinterventional nanotechniques using capillaries could precisely deliver, forexample, anticancer agents or neuroregenerative agents (in acute stroke).

A fascinating recent review,25 which addresses too many issues to be pre-sented here, examines the issues involved in, and the potential for, nanoroboticsin medicine.

CONCLUSION

The evolution of nanotechniques with potential application to neurosurgeryand neuroprotection/neurorepair has been impressive over the last 15 years.

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Virtually none of the nanotechniques considered here existed in other thanrudimentary form, if at all, 15 years ago. The late Richard Smalley predictedthat by the year 2020 nanotreatment would target cancer cells individually,sparing adjacent normal cells. We appear to be roughly on schedule, giventhe progress to date in nanomedicine, and we will probably keep a similartimetable for dramatic advances in neuroregeneration and neurosurgery withnanotechniques.

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neuroprotection at the nanolevel—part i : introduction to nanoneurosurgery

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