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The birth of nanotechnology, defined by the Oxford English Dictionary as the branch of technology that deals with the manipulation of individual atoms and molecules, is usually dated to a 1959 lecture give by Richard Feynman to the American Physical Society entitled "There's plenty of room at the bottom".1-3 However, interest in the field was properly awakened at the start of the millennium, and the massive potential of the technology is now being exploited in almost all areas of science.
The presence of nanotechnology is increasingly felt in everyday applications such as surface coatings, outdoor paints and varnishes, packaging, clothing and fuel additives.4 The Project on Emerging Nanotechnologies estimates that in August 2009, over 1000 nanotech products were publicly available, representing a growth of 379% over the preceding three years.4 Of these products, the majority (605) fell into the category of "Health and Fitness" (Figure 1).
Figure 1. A: Number of publically available nanotechnology products by category (2009); B: Number of products per sub-category within the "Health and Fitness" category. Adapted from The Project on Emerging Nanotechnologies,4 reproduced with permission
The study of medicine is a particularly exciting application of nanotechnology, and nanoparticles are currently being developed for diagnostic and therapeutic purposes as well as biomedical tools for research.2,5,6 An enormous array of nanotechnology platforms, including fullerenes, nanotubes, quantum dots, nanopores, dendrimers, liposomes, magnetic nanoprobes and radio-controlled nanoparticles, are being developed for all manner of medical applications ranging from targeted drug delivery to tissue regeneration, cell culture and biosensors.2 So far, it seems, we are only scratching the surface of what the technology can achieve.
Insert figure to describe different types of nanoparticle
Nanotechnology has started to find important application within the field of surgery, particularly in surgical implants and tissue engineering, including bone replacement.7-9 These applications are particularly suited to the field of plastic surgery, and considerable research effort is currently being devoted to this specific area. The following article is a broad overview of the some of the ongoing research within the field of nanotechnology that may be of particular interest to plastic surgeons. Much of the research is in its infancy, but this review offers a glimpse of how this technology may come to revolutionize techniques in plastic surgery over future years.
2. Nanotechnology and reconstructive surgery
Regenerative medicine, which aims to repair and replace lost or damaged tissues or organs by initiating the natural regeneration process,10 has an obvious relevance to plastic surgery. Biomaterials which are able to mimic the characteristics of the extracellular matrix (ECM) at the nanometer scale can serve as temporary scaffolds to guide neo tissue formation and organization. For example, nanofibrous biomaterials can mediate protein interactions and cell function, mimicking the nano fibrillar structure of the natural ECM;11-13 nanocomposite biomaterials offer excellent mechanical and biological properties by mimicking the composition and structure of mineralized tissues;14-16 while nanospheres or nanoparticles can be incorporated into 3D scaffolds for controlled delivery of biological molecules, which mimic the signaling cascades in natural repair mechanisms. Even one of the earliest types of nanomaterials, carbon nanotubes (CNTs), can be used as tissue scaffolding materials to enhance organ regeneration. 7
A number of techniques have emerged over recent years for the synthesis of nanomaterials suitable for supporting tissue regeneration. Electrospinning is a simple, elegant technique to fabricate polymeric nanofibres, 11 while in cell sheet technology, autologous cells are grown and collected as a contiguous sheet of cells which can be used to reconstruct multifunctional 3D tissues in vitro, which can then be transplanted to replace and regenerate a defective tissue.17
2.1 Small vessel synthesis
While grafts for large diameter vessels (> 6mm) have been successfully engineered from polymeric materials, the synthesis of artificial grafts suitable for small vessels remains problematic due to frequently occurring occlusion.18
There is growing recognition that synthetic nanofibers that are biocompatible and structurally similar to natural ECM could be excellent scaffolds in small vascular tissue engineering. 18 Synthetic poly-L-lactic acid (PLLA) nanofibers made by electrospinning combine the advantages of synthetic biodegradable polymers, with nanometer-scale dimension and a defined architecture that closely replicates the vascular structure.19 PLLA nanofibers of this type appear to represent an ideal tissue engineering scaffold, especially for blood vessel engineering.18-20 Another promising line of research involves the formation of nanocomposite microvessels, which not only provide a thrombus-repelling surface with optimal permeability characteristics but are also able to simulate arterial pulsations.21 Researchers believe that these microvessels could become an effective alternative to vein grafts in microsurgery and ultimately allow the construction of more complicated microvascular networks.21
2.2 Bone reconstruction
Orthopaedic implants have traditionally been made from a number of materials, from metals to ceramics and polymers. However, it seems that all these materials may be improved through the application of nanotechnology,22 with the corresponding nanomaterials demonstrating vastly superior properties.22 Since bone is a hierarchical material with the lowest level falling in the nanoscale range, nanomaterials are able to mimic the natural nanostructure of our tissues and improve osseointegration and the osseous healing response. Nanoscale structures have numerous applications in bone reconstruction including nanostructured scaffolds for bone repair, the controlled modification of surface topography and composition, delivery of osteogenic agents and biomicroelectromechanical systems.23
Bone reconstruction has particular relevance for plastic surgeons, particularly in the field of craniofacial surgery, as discussed later.
3. Nanotechnology and nerve regeneration
Much has been written recently about the potential of nanotechnology in the field of nerve generation.24-32 This must represent one of the most exciting areas of research in nanomedicine and has tremendous relevance and application to plastic surgery.
The value of being able to reconnect nerves has been recognized for centuries, but remains highly problematic. The focus of most recent research has been targeted at axon repair with the aim of achieving sufficient regrowth of injured axons to re-establish synaptic contacts and regain neurological function.27 Nanotechnology, with its ability to organize and deliver biologically active compounds at a nanoscale, can provide an ideal environment to regulate axon regeneration,27 while nanostructured scaffolds achieve an intimate contact with neurons and enable more precision with individual neuritis on a single neuron.24,33 Other promising nanotechnology strategies for axon regeneration include the use of scaffolds with functionalized cell-binding domains, the use of guidance channels with cell-scale internally oriented fibers, and the possibility of sustained release of neurotrophic factors.26
In a recent study, CNT-based networks which naturally mimic the structure of the ECM were developed as biomimetic cues to control the directional growth of neurites.31 It was found that the neurites selectively grew along CNT patterns and the resulting cultured neuronal networks closely resembled in vivo neural circuit structures, suggesting exciting potential for this technique. Bionanocomposites may also have a role to play in nerve regeneration in the future. Preliminary research into a biodegradable nanocomposite suggests that it may be possible to use this material to form a biofunctionalized multichannel nerve conduit that will allow nerve regeneration over longer nerve gaps than is currently possible.29
An alternative approach to axon repair involves the direct 'surgical' repair of severed axons to achieve structural integrity.27 This approach has not traditionally been successful due to the practical difficulties of operating at
subcellular scale on axons. However, technological advances in nanoscience are beginning to provide the tools necessary for such an intervention, and some researchers believe we may be on the verge of a breakthrough in this area.27 If successful, direct axon surgical repair would offer a number of advantages over axon regeneration, including rapid functional recovery and the maintenance of existing patterns of neural and synaptic circuitry.27
4. Nanotechnology and craniofacial surgery
Many advances have been made in craniofacial surgery over the past decade.34 Notably, the use of distraction osteogenesis and endoscopic procedures combined with advances in 3-dimensional imaging, computer simulation, and intra-operative navigation have created many more opportunities for the management of craniofacial disorders.
One area of research attracting much attention among craniofacial surgeons is in the development of improved bone graft substitutes. Strategies being pursued include gene therapy and nanotechnology; with nanotechnology at a more advanced stage. A number of hydroxyapatite/polymer composite scaffolds are currently being fabricated using nanotechnology to maximize both strength and osteoconversion.35
Nanotechnology also has potential application in the field of dentistry. Some experts predict that emerging technologies such as salivary diagnostics and high-resolution imaging in combination with nanotechnology and other new tools will lead to efficient and effective personalized dental treatments.36 For example, it may become possible to administer nanomaterials that are able to deliver biologically based therapies that promote natural remineralization in places where the enamel shows early signs of demineralization.36 This early treatment will have a profound impact on the standard of dental care in the future.
Research is also being conducted into the development of cell-based strategies to regenerate enamel and other dental tissues in adulthood.37 During tooth development, ectoderm-derived ameloblast cells create enamel by synthesizing a complex protein mixture serving to control cell to matrix interactions and the habit of hydroxyapatite crystallites. Investigations into the effect of artificial bioactive nanostructures on ameloblasts with the long-term goal of developing cell-based strategies for tooth regeneration have so far proved promising, although any practical application remains some way off.
Finally, cancer of the head and neck represents a major challenge to craniofacial specialists. Surgical resection is problematic due to the proximity of important structures such as the carotid artery, eye, and brain, meaning that residual tumor often remains near vital structures and necessitating the use of adjuvant treatments. Adjuvant therapy in head and neck cancer is limited to radiotherapy, with its high failure rates and toxicity, and supporting chemotherapy. Nanotechnology is poised to create a paradigm shift in the diagnosis and management of head and neck cancer by offering the potential of molecular diagnostic probes and novel therapeutic devices, such as photothermal and magneto-thermal probes, drug- and gene-delivery vectors, and radiation enhancers.38 Plasmonic gold nanoparticles appear particularly interesting because of their facile surface chemistry, relatively limited toxicity, and novel optical properties useful for concurrent imaging and therapy.38
5. Nanotechnology and burns and wounds
Wound healing is one clinical application that has so far received the greatest benefit from nanotechnology, and is one of the most well established applications of the technology.39 The overuse of antibiotics and poor infection control have over recent years contributed to substandard wound care, leading to increased mortality and morbidity. Thus, antimicrobial therapy that is able to control colonization and proliferation of microbial pathogens, including multi drug-resistant organisms, is a major target in wound care.
Silver has been used for centuries as a highly effective bactericidal agent. However, the use of silver nanoparticles increases the rate of silver ion release and dramatically improves the antimicrobial properties of standard silver. Silver nanoparticles have been shown to destroy Gram-negative bacteria more effectively than Gram-positive bacteria, to exhibit good antifungal activity, synergism when associated with commonly used antibiotics such as ceftazidime, additive effects when associated with streptomycin, kanamicin, ampiclox, polymyxyn B, as well as antagonistic effects with chloramphenicol.39 Interestingly, silver nanoparticles even exhibit good anti-inflammatory properties, further promoting wound healing. Animal studies suggest that silver nanoparticles are able to increase the rate of wound closure through promoting proliferation and migration of keratinocytes and by driving the differentiation of fibroblasts into myofibroblasts.40
The superior wound healing properties of nanocrystalline silver dressings have been evaluated in randomized controlled trials. In one trial of 166 burns in 98 patients, nanocrystalline silver dressings significantly decreased wound healing time by an average of 3.35 days and increase bacterial clearance from infected wounds compared with conventional silver sulfadiazine.41 A newer type of nanocrystalline dressing incorporating chitosan has also been developed, and early results look extremely promising.42-44 Indications are that dressings of this type may also improve cosmetic appearance in addition to facilitating wound healing - a feature of particular interest for plastic surgeons.
Nitric oxide radicals are also effective in wound repair and as an antimicrobial agent; however, storing the small gaseous free radical has been a technical challenge.45 Using nanotechnology, it is possible to trap NO within a dry matrix where it is kept stable. Once exposed to moisture, NO is released from the nanoparticle over an extended period of time at a relatively fixed concentration. This sustained release distinguishes nanoparticles from other vehicles, such as injections, that release a large concentration of the drug with a rapid return to baseline.45 The efficacy and safety of NO-nanoparticles has been demonstrated in numerous animal studies,46-48 suggesting that this technology may ultimately offer an effective alternative in the treatment of cutaneous infections.
Finally, nanofibers, which mimic collagen fibrils in the ECM, also have many properties that may be beneficial in burn care, including a large surface-area-to-volume ratio, high porosity, improved cell adherence, proliferation and migration, and controlled in vivo degradation rates.49 As a result of these characteristics, nanofiber scaffolds have immediate applications as dressings for burn wounds, and potential for drug delivery, including antibiotics, analgesics, and growth factors. Nanofiber scaffolds may eventually have the potential to create an unlimited supply of durable tissue engineered skin for large burn wounds.49
6. Cosmetic/aesthetic applications of nanotechnology
Solid lipid nanoparticles and nanostructured lipid carriers have a well-documented protective action of on the skin, with their benefit mainly related to their small size and lipid composition.50 Known properties of these nanoparticles include adhesiveness, occlusion and skin hydration; lubrication, smoothness and emolliency; and the ability to control of pH and osmotic effects. 50 Consequently, nanotechnology has found significant outlet in a number of areas in the cosmetic industry.
The first cosmetic products based on nanostructured lipid-carrier technology, NanoRepair Q10 cream and NanoRepair Q10 Serum, were introduced to the market in 2005 by Dr Rimpler GmbH in Germany as anti-ageing products.51
Nanostructured lipid carriers represented an improvement on the earlier generation of solid lipid nanoparticles, and the products achieved some success. Nanostructured lipid carriers now appear in a number of cosmetic products worldwide.
One common application of lipid nanoparticles is as vehicles for molecular sunscreens. These nanoparticles have a synergistic effect of the UV scattering and therefore allow the concentration of the molecular sunscreen to be reduced.50 This has the advantage of reducing potential side effects, as well as the costs of formulation of expensive sunscreens. In addition, lipid nanoparticles can be used to formulate sunscreen products with lower and medium sun protection factors.
Nanotechnology is also being exploited to achieve prolonged release of perfumes, creating a once-a-day application with a sustained effect over several hours. By incorporating fragrances in a solid lipid nanoparticles instead of an oil droplet, release of the perfume can be considerably slowed.50 The same technology can also be used for the delivery of insect repellents to be applied onto the skin.
Finally, manufacturers are beginning to use solid lipid nanoparticles and nanostructured lipid carriers to make cosmetic products look more visually appealing in the bottle.50 Components that are either permanently colored or that become colored during the shelf life can be incorporated into solid lipid nanoparticles and nanostructured lipid carriers to create an effective whitening effect. This makes the product much more appealing to the customer from a marketing point of view.
Some media attention has been devoted to the issue of the safety of nanotechnology. Nanoparticles have the potential to cause varied pathologies of the respiratory, cardiovascular and gastrointestinal systems.2 In addition, nanoparticles are able to enter the central nervous system and to cross the blood-brain barrier.
However, no studies to date have confirmed any specific danger to human health from the technology. Recent studies have demonstrated that titanium oxide nanoparticles from sunscreen do not penetrate the dermis,52 and that these nanoparticles cause no damage to the DNA in human peripheral blood lymphocytes.53 All ongoing research is proceeding with adequate evaluation of its risk and safety factors.2
7. Quantum dots
Semiconductor nanoparticles, often referred to as "quantum dots", are fascinating particles with exceptional photophysical properties.54-56 Owing to the effects of quantum confinement, QDs are highly photostable, with broad absorption, narrow and symmetric emission spectra, slow excited-state decay rates and broad absorption cross-sections. Their emission color depends on their size, chemical composition and surface chemistry and can be tuned from the ultraviolet to the visible and near-infrared wavelengths.56
A full discussion of quantum dots is beyond the scope of this article. However, these nano semiconductors have attracted a great deal of interest recently in the biological sciences and medicine for a number of reasons, including their potential for cellular and molecular imaging. Near infrared light penetrates deep tissues with minimal scatter, exciting quantum dots that emit in the near infrared range. The fluorescence from these dots can be detected by an near infrared camera, and used to anatomically locate the exact position of the quantum dots.56 Breast cancer surgery may become one of the major clinical applications this type of imaging technique.
8. Conclusions and future directions
Nanotechnology is an exciting and rapidly advancing field. Its reach touches almost all branches of science and its applications can be found in an increasing number of everyday products. The applications described in this review are those considered to be of greatest relevance to those with an interest in plastic surgery. These applications range from reconstructive surgery and nerve regeneration to use in wound and burn care and cosmetics applications. While some applications are well established, such as the use of nanoparticles in wound management, much of the research described is at an early stage. However, the enormous potential of this technology for plastic surgery is evident.
The future for nanotechnology in plastic surgery looks very exciting. Nanodentristy will make possible the maintenance of comprehensive oral health, and even tooth repair and regeneration, while dentists may be able to use nanorobots to perform nanoscale operations or alter nerve impulse traffic in individual nerve cells.3 Nerve and small vessel regeneration will become a real possibility, allowing surgeons to restore function to hands and limbs, while advances in tissue regeneration may allow the formation of facial bones and tissues. The use of quantum dots also looks likely to have a significant impact on medical practice over the coming years, with exciting scanning techniques promising to revolutionize the way that surgery is conducted.