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Introduction to Nanotechnology and Its Applications to Medicine

Gabriel A. Silva, M.Sc., Ph.D. Departments of Bioengineering and Ophthalmology, Whitaker Institute for Biomedical Engineering and Neurosciences Program, University of California, San Diego, LaJolla, California

Silva GA. Introduction to nanotechnology and its applications to medicine. Surg Neurol 2004;61:216 20.

Nanotechnology can be dened as the science and engineering involved in the design, synthesis, characterization, and application of materials and devices whose smallest functional organization in at least one dimension is on the nanometer scale or one billionth of a meter. At these scales, consideration of individual molecules and interacting groups of molecules in relation to the bulk macroscopic properties of the material or device becomes important, since it is control over the fundamental molecular structure that allows control over the macroscopic chemical and physical properties. Applications to medicine and physiology imply materials and devices designed to interact with the body at subcellular (i.e., molecular) scales with a high degree of specicity. This can potentially translate into targeted cellular and tissuespecic clinical applications designed to achieve maximal therapeutic affects with minimal side effects. In this review the main scientic and technical aspects of nanotechnology are introduced and some of its potential clinical applications are discussed. 2004 Elsevier Inc. All rights reserved.

anotechnology and nanoengineering stand to produce signicant scientic and technological advances in diverse elds including medicine and physiology. In a broad sense, they can be dened as the science and engineering involved in the design, syntheses, characterization, and application of materials and devices whose smallest functional organization in at least one dimension is on the nanometer scale, ranging from a few to several hundred nanometers. A nanometer is one billionth of a meter or three orders of magnitude smaller then a micron, roughly the size scale of a molecule itself (e.g., a DNA molecule is about 2.5 nm long while a sodium atom is about 0.2 nm). To give an appreciation of just how signicant an order of mag-

Address reprint requests to: Dr. Gabriel A. Silva, University of California, San Diego (UCSD), Jacobs Retina Center, 0946, Room 204, 9415 Campus Point Drive, La Jolla, CA 92093-0946. Received July 27, 2003; accepted September 24, 2003. 0090-3019/04/$see front matter doi:10.1016/j.surneu.2003.09.036

nitude is, let alone three orders when going from micron to nanometer scales, consider that no one would ever walk from New York to San Diego, but with a single order of magnitude change in speed (the equivalent of changing speed from walking to driving), you would get to San Diego across the United States in about 2 days. Flying, which would be two orders of magnitude faster than walking, would get you across the United States in a few hours and in a supersonic plane (or three orders faster than walking), it would take you minutes. (Walking a straight line between the two cities would take about 42 days at an average speed of 3 miles per hour.) The potential impact of nanotechnology stems directly from the spatial and temporal scales being considered: Materials and devices engineered at the nanometer scale imply controlled manipulation of individual constituent molecules and atoms in how they are arranged to form the bulk macroscopic substrate. This, in turn, means that nanoengineered substrates can be designed to exhibit very specic and controlled bulk chemical and physical properties as a result of the control over their molecular synthesis and assembly. For applications to medicine and physiology, these materials and devices can be designed to interact with cells and tissues at a molecular (i.e., subcellular) level with a high degree of functional specicity, thus allowing a degree of integration between technology and biological systems not previously attainable. It should be appreciated that nanotechnology is not in itself a single emerging scientic discipline but rather a meeting of traditional sciences such as chemistry, physics, materials science, and biology to bring together the required collective expertise needed to develop these novel technologies. In this review, the main synthetic and assembly approaches used in nanotechnology are intro 2004 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010 1710

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duced, and emerging technology being developed for biological and medical applications is reviewed. The rst section will give a brief overview of the main synthetic methods of nanotechnology and will attempt to give a feel for how one goes about manipulating matter on such a small scale. The second section will focus on some of the unique engineering challenges imposed by such small spatial (and temporal) scales. The third section will describe some general applications of nanotechnology to medicine and biology that are currently being developed. This article represents an introduction to this emerging science. Future articles in Surgical Neurology will focus and expand on the potential of nanotechnology aimed at treating central nervous system (CNS) disorders and discuss the unique challenges that the CNS presents.

Synthetic and Assembly Approaches

Different methods for the synthesis of nanoengineered materials and devices can accommodate precursors from solid, liquid, or gas phases and encompass a tremendously varied set of experimental techniques that are beyond the scope of a short introductory review. In general, however, most synthetic methods can be classied into two main approaches: top down and bottom up approaches and combinations thereof. Top down techniques begin with a macroscopic material or group of materials and incorporate smaller-scale details into them. The best known example of a top down approach is the photolithography technique used by the semiconductor industry to create integrated circuits by etching patterns in silicon wafers [12]. This process generally starts by covering a piece of silicon with some kind of photoresist, a photochemicalsensitive polymer that hardens upon exposure to laser light of specic wavelengths. Patterns are then drawn into the photoresist-coated silicon with a laser so that the untreated photoresist can be washed away and the exposed silicon treated so it can act as an electrode. Aluminum wires are then placed down in the etched patterns after removing the hardened photoresist to yield transistors. A similar approach has been used to develop microscale connected wells in agar using poly(dimethylsiloxane) molds to study neuron-astrocyte communication. Cell cultures are set up where neurons are in one well and astrocytes in an adjacent well connected by a channel that allows the diffu-

sion of soluble factors [33]. This is an example of a lithographic technique applied to cell biology. Other types of nanolithographic techniques such as dip pen nanolithography [16,17] and electrostatic atomic force microscope nanolithography [19], where individual molecules are deposited or moved, respectively, into desired congurations are able to produce true nanoscale features in various materials. Bottom up approaches, on the other hand, begin by designing and synthesizing custom-made molecules that have the ability to self-assemble or self-organize into higher order mesoscale and macroscale structures [12,20,21,29,31]. The challenge is to synthesize molecules that spontaneously self-assemble upon the controlled change of a specic chemical or physical trigger, such as a change in pH, the concentration of a specic solute, or the application of an electric eld. The physical mechanisms that produce self-assembly, that is, the driving forces that push these molecules to selfassemble into organized structures, are due to thermodynamics and competing molecular interactions including hydrophobic/hydrophilic forces, hydrogen bonding, and van der Waals interactions that aim to minimize energy states for different molecular congurations. The trick is to design systems that self-assemble into macroscopic higherorder structures that display desirable chemical and/or physical properties not displayed by the constituent molecules themselves. A related synthetic approach relevant to biological applications are templating or scaffolding techniques which use pre-existing structures to guide the nucleation and growth of a nanostructured material. Good examples of this are biomineralizationtype applications such as the growth of articial bone biomimetics [30,32]. This is achieved by inducing the formation of organoapatite on (surgically implantable) titanium structures such as foils; meshes; or porous cylinders by the preadsorption onto the bare metal of poly-L-lysine or polyL-glutamic acid, which when in contact with the metal form a polyionic bilayer. It is thought that the capture of tiny embryonic crystals and subsequent nucleation of these seed crystals are what lead to the actual growth of the apatite on the metal. Other techniques are attempting to mimic the ultrastructure of bone without the requirement of deposition on pre-existing metal structures by inducing the self-assembly and formation of molecular nanobers interspaced with mineralized hydroxyapatite crystals, structures that are similar in spirit to the collagen ultrastructure of bone [8]. As these technologies develop, it is expected that these ad-

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vanced materials will not only provide desirable mechanical properties but also incorporate functional cell signaling properties such as neurotrophic support or anti-inammatory effects (see [1]). In addition to various orthopedic applications, this may be of interest to the neurosurgeon when spinal fusions are indicated, for example.

Spatial and Temporal Considerations

It is important to appreciate that the principle scientic and engineering obstacles involved in developing nanotechnology applications stem from the inherent size and time scales being considered, from a few to about a hundred nanometers spatially and from nanosecond to femtosecond time scales if atomic bond oscillations need to be taken into account, for example. (A femtosecond is 6 orders of magnitude smaller then a nanosecond, a billionth of a nanosecond or 10 15 seconds, an incomprehensibly small unit.) Because the molecular building blocks being manipulated are on such a small scale, these substrates have spatial and/or temporal levels of organization that span several orders of magnitude, with different levels nested within higherorder levels (e.g., 6 orders of magnitude for a device that has a nanoscale ultrastructure but a millimeter macroscopic structure). Therefore, to study and explore these rich and complex systems, highly sophisticated theoretical and experimental tools are required. In particular, the visualization, characterization, and manipulation of materials and devices require sophisticated imaging and quantitative techniques with spatial and temporal resolutions on the order of 10 6 (the size of a microna red cell is 7 microns in diameter) and below to the molecular level. In addition, these techniques are critical for understanding the relationship and interface between nanoscopic and mesoscopic/macroscopic scales, a particularly important objective for biological applications. As such, further nanotechnological advances will necessitate parallel progress of these physical characterization techniques. Examples of important tools available at the moment include (a) highly focused (i.e., 12 m) synchrotron X-ray sources for X-ray diffraction and related techniques that provide detailed molecular structural information by directly probing the atomic arrangement of atoms [10]; (b) scanning electron and scanning tunneling microscopy that allow three-dimensional-type topographical views of nanoscale structures [9,22,28,34,38,41]; and (c)

in situ monitoring techniques that allow the monitoring and evaluation of building block assembly and growth, such as reection high-energy electron diffraction (RHEED) [23]. The principle behind RHEED is a high-energy electron beam that is directed at a sample at a grazing angle and subsequently picked up by detectors as it bounces off the sample. The atomic structure of the material being investigated disrupts the path of the high-speed electrons, which produces differing patterns of electron streaks on a phosphor screen detector. It is these patterns of streaks that are then interpreted to yield the atomic structure of the material being investigated. Ultimately, these and other techniques are required not just to probe the structure of the materials themselves but also to study the interface between these materials and the cells and tissues they are designed to interact with because they are the only means we have of looking at what is happening at these extremely small scales.

Applications to Biology and Medicine

Recent advances in tissue engineering that have occurred at levels larger than the nanoscales described above include microelectromechanical systems (MEMS) and biocompatible electronic devices that have a signicant potential for improving the treatment of many disorders [3,4,25,36,37,40]. However, despite this potential, these approaches all depend on bulk molecular engineering or chemical manipulation of macromolecular (mostly polymer) structures, which lack the ability to manipulate the nanoscale structure. Nanoengineered materials and devices designed to interact with cells and tissues or carry out biologically specic functions should offer a much greater degree of integration between technology and physiological systems. In turn, this should eventually translate into novel clinical applications and treatment options. At present, applied nanotechnology to medicine and physiology is in its infancy, with most of the research at the basic science stage as the eld attempts to organize itself. As such, viable clinical applications are still years away, but despite this the breadth and pace of current research is impressive. One example of such an application includes novel drug delivery systems (specically for the blood brain barrier in some cases) using nanoparticles [7,15,18] or highly porous self-assembling bilayer tubule systems [26,27]. Another class of applications being developed is chemically func-

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tionalized dendrimers, highly branched molecules with a tree-like branching structure that can be used as molecular building blocks for gene therapy agents or as magnetic resonance imaging (MRI) contrast agents [14,35]. Dendrimers are attractive molecules for gene therapy applications because they are a nonviral delivery vehicle for DNA (an important clinical consideration), which tends to wrap itself in the dendrimer branches. Dendrimer-based MRI contrast agents have been shown to produce increased relaxivity, the induced spin relaxation time of surrounding water protons, which translates into higher contrast images. Specialized membranes for the separation of lowweight organic compounds from aqueous solutions have been developed by lling the pores of microltration or ultraltration membranes (i.e., pore sizes on the order of microns and smaller) with functional polymeric molecules that have an afnity for the compounds to be ltered [11]. This nanomembrane may allow very selective ultraltration of physiologic toxic compounds, for example. In addition, much research is going into biologically inspired functional nanodevices, such as the development of DNA/polymerase chain reaction or protein-based molecular computers [2,6], which encode information in the nucleotide sequences of DNA molecules or in the tertiary structures of proteins and carry out computations by following different biochemical reaction pathways. Another area of interest are biomimetic self-assembling molecular motors [13,24,39], such as the agella of bacteria [13,24], or the mechanical forces produced by RNA polymerase during protein transcription [39]. These molecular motors provide excellent examples of naturally occurring biological self-assembly, since they are composed of different molecular parts that self-assemble to produce the functional structure and are important targets to study and emulate to develop synthetic nanomotors that can interact with biology, for example. These applications represent just a few examples of emerging nanotechnology research aimed at medicine and physiology. Developing nanotechnologies are being pursued for general cellular processes such as ubiquitous signaling pathways that may benet numerous physiological systems, as well as being targeted toward the particular challenges of specic disorders such as diabetes mellitus or arteriosclerosis. Ultimately, every pathophysiological process has a molecular origin, and it is from this basic fact that the tremendous potential of nanotechnology applications to medicine arises.

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ife cycle changes occur as you move through life. They include things like changing family demands or reduced energy with

age. Generational differences, on the other hand, persist throughout the life cycle changes and characterize members of a common age cohort.
The Physician Executive November December 2003