Nanotechnology has become a rapidly growing field with potential applications ranging from electronics to cosmetics. Richard Feynman introduced the concept of nanotechnology in his pioneering lecture “There’s plenty of room at the bottom” at the 1959 meeting of the American Physical Society. However, only recently has our ability to harness the properties of atoms, molecules and macromolecules advanced to a level that can be used to build materials, devices and systems at the nanoscale.

 The term “nanotechnology” varies greatly based on the specific definition that is used. National Science Foundation and the National Nanotechnology Initiative define nanotechnology as understanding and control of matter at dimensions of 1–100 nm where unique phenomena enable novel applications. In this manuscript, we use a similar definition; however, we also discuss molecular structures, materials and devices with dimension of 1–100 nm in one of their dimensions. This includes miniaturization approaches that generate nanofabricated structures such as nanopatterns and nanotextures. Interestingly, much of what we know about bulk properties of materials breaks down at these length scales. For example, nanomaterials such as carbon nanotubes and gold nanoparticles have physical properties that are different from their bulk counterparts. Therefore, such technologies generate new opportunities and applications. Nanoscale materials and devices can be fabricated using either “bottom-up” or “top-down” fabrication approaches. In bottom-up methods, nanomaterials or structures are fabricated from buildup of atoms or molecules in a controlled manner that is regulated by thermodynamic means such as self-assembly (1). Alternatively, advances in micro technologies can be used to fabricate nanoscale structures and devices. These techniques, which are collectively referred to as top-down nanofabrication technologies, include photolithography, nano molding, dip-pen lithography and nano fluidics (2, 3). It is perhaps because of the breadth of different approaches in the synthesis and fabrication of nano-molecules and nano-devices that chemical engineers are playing a key role in advancing the field of nanotechnology. On one hand, chemical engineers possess the skills to understand molecular events through modeling and simulation as well as thermodynamic and kinetic calculations; while on the other hand, they have the ability to understand systems, device miniaturatizaion and fluidics associated with top-down fabrication strategies. Nanomaterials and devices provide unique opportunities to advance medicine. The application of nanotechnology to medicine is referred to as “nanomedicine” or “nanobiomedicine” and could impact diagnosis, monitoring, and treatment of diseases as well as control and understanding of biological systems. In this review, we discuss the use of nanotechnology for medical applications with focus on its use for drug delivery and tissue engineering. Specifically, we discuss bottom-up and top down nanofabrication technologies and their use in various drug delivery and tissue engineering applications.

Nanotechnology for drug delivery
Controlled drug-delivery strategies have made a dramatic impact in medicine. In general, controlled-release polymer systems deliver drugs in the optimum dosage for long periods, thus increasing the efficacy of the drug, maximizing patient compliance and enhancing the ability to use highly toxic, poorly soluble or relatively unstable drugs. Nanoscale materials can be used as drug delivery vehicles to develop highly selective and effective therapeutic and diagnostic modalities (4–6). There are a number of advantages with nanoparticles in comparison to micro particles. For example, nanoscale particles can travel through the blood stream without sedimentation or blockage of the microvasculature. Small nanoparticles can circulate in the body and penetrate tissues such as tumors. In addition, nanoparticles can be taken up by the cells through natural means such as endocytosis. Nanoparticles have already been used to deliver drugs to target sites for cancer therapeutics (7) or deliver imaging agents for cancer diagnostics (8). These vehicles can be engineered to recognize biophysical characteristics that are unique to the target cells and therefore minimize drug loss and toxicity associated with delivery to non-desired tissues. In general, targeted nanoparticles comprise the drug, the encapsulating material and the surface coating (Figure 1a). The encapsulating material could be made from biodegradable polymers, dendrimers (treelike macromolecules with branching tendrils that reach out from a central core) or liposomes (spherical lipid bilayers). Controlled release of drugs (such as small molecules, DNA, RNA or proteins) from the encapsulating material is achieved by the release of encapsulated drugs through surface or bulk erosion, diffusion, or triggered by the external environment, such as changes in pH, light, temperature or by the presence of analytes such as glucose (6). Controlled-release biodegradable nanoparticles can be made from a wide variety of polymers including poly (lactic acid) (PLA), poly (glycolic acid) (PGA), poly (lactic co-glycolic acid) (PLGA) and olyanhydride. PGA, PLA and their co-polymer PLGA are common biocompatible polymers that are used for making nanoparticles. Since PGA is more susceptible to hydrolysis than PLA, by changing the ratio of these two components, PLGA polymers can be synthesized with various degradation rates. Current research into novel nanomaterials is aimed at improving the properties of the materials such as biocompatibility, degradation rate and control over the size and homogeneity of the resulting nanoparticles. In order to control the targeted drug delivery of intravenously delivered nanoparticles, nanoparticle interactions with other cells, such as macrophages must be controlled. Various approaches have been developed to control these interactions, ranging from changing the size of the particle to changing nanoparticle surface properties. To remove nonspecific protein adhesion and decrease uptake by macrophages, nanoparticles can be functionalized using protein replant materials, such as poly(ethylene glycol) (PEG) (7) and polysaccharides (8, 9). Non adhesive surface coatings increase the circulation time of the nanoparticles (7) and reduce toxic effects associated with non-targeted delivery (10, 11). More recently, novel approaches aimed at conjugating small molecules on nanoparticles using high-throughput methods have yielded nanoparticle libraries that could be subsequently analyzed for their targeted properties (12). Also, noncovalent approaches have been used to surface modify nanoparticles.

For example, the layer-by-layer deposition of ionic polymers has been used to change surface properties of nanoparticles, such as quantum dots (13). Layer-by-layer methods alter the surface charge of nanoparticles, which has been shown to regulate nanoparticle biodistribution. For example, increasing the charge of cationic pegylated liposomes decreases their accumulation in the spleen and blood, while increasing their uptake by the liver and tumor vessels (14). To eliminate the need for surface modification schemes, amphiphilic polymers may be synthesized by covalently linking biodegradable polymers to PEG prior to formation of nanoparticles. For example, Nanoparticles can be synthesized from amphiphilic copolymers composed of lipophilic (i.e., PLGA or PLA) and hydrophilic (i.e., PEG) polymers. Upon formation of these nanoparticles, PEG migrates to the surface in the presence of an aqueous solution forming pegylated nanoparticles (7). To target nanoparticles to the desired tissues, a number of methods have been developed. These include physical means such as controlling the size, charge and hydrophobicity of the particles. In addition, targeting molecules, such as antibodies and peptides, that recognize specific cell surface proteins and receptors, can be conjugated to the nanoparticle surface to specifically target specific cell types. Antibodies and peptides have been successfully used to target nanoparticles to a number of desired cell types and provide powerful means of directing controlled-release nanoparticles to specific sites in the body. Potential disadvantages of antibody- and peptide-based targeting include their batch-to-batch variation and their potential immunogenicity. Aptamers, a class of DNA- or RNA-based ligands, may overcome some of the limitations associated with antibody- and peptide-based drug delivery. Aptamers have been conjugated to nanoparticles to generate nanoparticles that can target prostate cancer cells (15, 16). Current research in targeting the delivery of Nanoparticles involves validating the in vivo efficacy of the various targeting approaches and developing methods of enhancing the targeting of the particles without side effects. Future generations of nanoparticles promise to not only deliver drugs to the desired sites within the body, but to do so in a temporally regulated manner. For example, nanoparticles have recently been generated that can be used to sequentially deliver drugs to cancer cells so that each drug is delivered at the proper time to induce cell death as well as to prevent angiogenesis (17). It is envisioned that the development of “smart” nanoparticles could be a powerful means of further enhancing the functionality of these nanoparticles. In addition to polymeric nanoparticles, other types of nanomaterials have also been used for medical applications. For example, quantum dots, nanoparticles with novel electroluminescent properties and magnetic resonance imaging (MRI) contrast agents have been used to image cancer cells. Also, carbon nanotubes, nanowires and Nanoshel have also been used for various therapeutic and diagnostic applications (18). Each of these materials provides unique physical, chemical and biological properties that are based on the nanoscale size and structure of the materials. For example, quantum dots are more stable than chemical fluorphores, have tighter emission wavelengths and can be engineered to emit at specific wavelengths by changing its size. Thus, the targeted delivery of these materials could potentially lead to significant medical breakthroughs. Top-down nanofabrication and microfabrication approaches based on integrated circuit processing may be used to fabricate controlled-release drug delivery devices. Using photolithographic and integrated circuit processing methods, silicon-based microchips have been fabricated that can release single or multiple chemicals on demand using electrical stimuli (19) (Figure 1b). These engineered microdevices can be used to maintain biological activity of the drugs and facilitate the local, accurate and controlled release of potentially complex drug-release profiles. In addition to silicon-based devices, polymeric-based micro fabricated devices have been made that can release drugs based on the degradation
of polymeric reservoir covers (20). Micro fabrication techniques have also been used to develop transdermal drug delivery approaches based on micro needles (21). These micro fabricated needles, which are much smaller than hypodermic needles, may be used to deliver drugs in a painless and efficient manner. By penetrating through the outer 10–20 μm of skin, micro needles can deliver drugs without activating sensory nerves of the tissue, thus providing a painless method of delivering drugs. Although the above examples have been performed using micro scale resolution, the current state- of the- art in top-down nanofabrication approaches can generate features that are less than 100 nm in resolution. Therefore, the fabrication of nanoscale devices using these approaches is theoretically possible and may be advantageous for specific drug-delivery applications in which miniaturized nanoscale devices are desired. Interestingly, bottom-up and top-down approaches have merged to optimize drug-delivery vehicles. For example, micro fabricated approaches have been used to develop microfluidic devices that mimic the body’s vasculature and can be used to test and optimize the interaction of targeted nanoparticles with the cells that line the cancer blood vessels (15). By changing parameters such as shear stress and geometry of the channel, as well as nanoparticle properties such as size, and surface properties optimized nanoparticle formulations can be obtained before performing costly animal and clinical experiments.

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