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Nanotechnology in medicine and the biosciences

At first sight, there would seem to be little connection between nano- technology, on the one hand, and medicine/biology on the other. However, from its emergence in the microelectronics and semiconductor industry, nanotechnology is begin- ning to be successfully exploited in other disciplines, including the bio- sciences and medicine. In conjunc- tion with scanning-probe micro- scopes (SPMs), which are capable of imaging and manipulating structures at the atomic level, nanotechnology now offers the biological/medical researcher the prospect of working directly at subcellular or molecular dimensions - the fundamental level from which the architecture and operation of biological systems orig- inates.

This exciting new area was the subject of a recent conference*. The participants included academic and industrial researchers from a wide variety of disciplines, ranging from engineering and physics, through biochemistry, biomedicine and bio- physics, to clinicians and surgeons. The overall aim of the conference, which was opened by Sir Eric Ash (University College London, London, UK), was to explore the areas in which nanotechnology, as currently practiced by microengin- eers and physicists, could be usefully transferred to biological and medical research. The meeting concentrated on four themes:

Biocompatible materials Richard Coombs (1Loyal Post-

graduate Medical School, London, UK) summarized the challenges of clinical orthopaedic medicine to which nanotechnology might offer solutions, and described the surgical limitations of current prosthetic implants. He advocated the need for further biocompatible materials for joint surfacing and restructuring. He concluded that such materials should

*'The UK National Symposium on Nano- technology in Medicine and the Biosciences' was held at the Royal Postgraduate Medical School, Hammersmith Hospital, London, UK, 16-18 March 1994.

mimic the natural material and sur- faces and have a life span in excess of 30 years.

William Bonfield (Queen Mary and Westfield College, London, UK) reported recent success in making a synthetic material that mimicked the ultrastructure of natural bone, and which could replace the steel-based alloys that are currently used. The mechanical properties of this new material, a lattice ofhydroxyapatite - the major component of natural bone - reinforced with polyethylene composite, met the requirements for modulus matching (i.e. had a similar strength and density index to that of natural bone), fracture toughness and strong binding to natural bone. This biocompatible material shows poten- tial for use in orthopaedic prostheses.

Other papers reported the poten- tial of vapour-deposited diamond, diamond-like carbon and sol-gel ceramics for medical use, all of which show high biocompatibility and low cell adhesion.

Biological systems Tony Atkinson (University of

Warwick, Coventry, UK) described the challenge faced by protein and nucleotide chemists in exploiting proteins (enzymes, irnmunoglobu- lins, etc.) fully, and in understanding biological molecular-surface archi- tecture and charge distribution at the atomic level. Saul Tendler (Univer- sity of Nottingham, Nottingham, UK) described scanning probe mi- croscopy (SPM), a technique that enables images of the topography of a surface to be generated. He illus- trated his presentation with recent data on proteins at <4nm resolution obtained using SPM. He described the key problems of sample defor- mation and substrate artefacts, which can mislead the inexperienced user, and described methods to overcome these problems.

Chris Wilkinson (University of Glasgow, Glasgow, UK) described studies on nerve cells placed on elec- tronic arrays, which have enabled the firing of nerve cells to be observed noninvasively. This method has the potential to replace the traditional invasive technique of piercing nerve

cells with fine electrodes, which causes artificial firing of the nerves.

Nerve cells are also being used to investigate how cells migrate and grow along surfaces. Nerve cells have been shown to align along nano- machined grooves in an insulating layer (10 Ixm wide and 3 Ixm deep). Potentially, this may lead to (1) thin, flexible 'grooved' bandages, along which severed nerve cells or tendons could align and grow; and (2) neural networks in electronics.

Bob Cart (Centre for Applied Microbiology and Research, Porton Down, UK) described how laser- illuminated apertures (70 nm diam- eter) in metallized optical wave- guides were being used to detect, in real time, binding events between individual antibodies and antigens labelled with 30 nm gold particles. Other talks on this subject area covered the electrochemical fabri- cation ofnanolayer sensors for appli- cation in DNA-sequence analysis, and the use of SPM in chromosome analysis.

Analytical techniques Many speakers described tech-

niques that used nanotechnology to interrogate biological materials. Vari- ous optical interferometric methods have been applied to measuring bone stress, measuring the length of the eyeball and fibre-optic-mediated measurement of clinical body tem- perature and blood pressure.

John Burt (Universi W of Wales, Bangor, UK), showed how the analy- sis of the electrical/electrodynamic properties of individual cells could be achieved by analysing their motion and rotation in dipole-inducing non- uniform electric fields (dielec- trophoresis and electrorotation, respectively). This method used nanolithographic techniques to make microelectrodes of a particular shape, which could trap and manipulate the cells electrically.

In an extension of this technology, changes to the frequency and phase of alternating electric fields applied through combs of electrodes enabled the differential electromigration and subsequent separation of different cell types. For example, Micrococcus spp. could be separated from blood erythrocytes, and viable cells could be distinguished from nonviable cells.

Richard Simmons (Kings College, London, UK) described experiments in which the forces associated with the interaction between individual molecules of the muscle proteins,

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actin and myosin, attached to small beads, were determined using optical tweezers (finely focused laser beams capable of trapping and moving single particles) to pull the linked beads apart.

Peter Luckham (Imperial College, London, UK) used a surface-force apparatus to determine, to nano- metre resolution, the electrostatic potential of films of blood plasma proteins adsorbed onto mica surfaces, and the effect that thrombogenic agents have on such films.

Tim Fell (University of Oxford, Oxford, UK) gave an update on progress in the development of auto- mated DNA-sequence analysis, in which arrays of tens of thousands of different oligonudeotides, hybridized separately to individual micron-sized pixels within the array, might be used in a future, single-step, solid-state DNA-sequence analysis device.

Peter Wells (Bristol General Hos- pital, Bristol, UK) described how air bubbles of a defined diameter, of the order of a micrometer, could be used as contrast agents to enhance ultra- sonic imaging in medical applications.

Alan Griftlths (University of Glasgow, Glasgow, UK) demon- strated how specific enzymes, linked to fine electrodes (200 nm wide) on a biosensor, can be used to detect and study compounds produced by indi- vidual cells. He described the appli- cation of this technology to the detection of glutamate and super- oxide anions.

A novel technique to detect early stages of cell abnormalities was de- scribed by Richard Tweedie (Uni- versity of Dundee, Dundee, UK). As cells contain a large number of dif- ferent biomolecules, each with its own dielectric potential, encased in a semipermeable membrane, the interaction of the conductivity and polarization of the complex dielectric material creates a distinctive, measur- able impedance. The group at Dundee have shown how this impedance alters as a result of the onset o(~ disease in a cell, and thus offers the potential of detecting early stages of diseases such as cancer or vascular problems.

Future trends Bob Davies (University of

Nottingham, Nottingham, UK) reviewed the possibility of particle engineering and the use of micro- spheres in drug delivery. Particle- mediated drug targeting, introduced by injection, could be made specific

(through different particle size, ma- terial, coating, etc.) for particular organs (for example, the liver) or cell types (endothelial or tumour cells). Three papers from Davies' group described work currently under way at Nottingham on the optimization of protein adsorption to particles, the differential rates of uptake by differ- ent tissues/organs (particularly the regional lymphatic system) as a func- tion of particle surface hydrophilicity or hydrophobicity and, finally, the importance of size (200-300nm diameter) on the uptake of particles by the spleen.

The general theme of improving the interaction of living/cellular systems with artificial nanoscale structures (made by electron-beam writing) was taken up by Colin Humphries (University of Cambridge, Cambridge, UK). He conjured up images of a future in which silicon chips [for example, read-only- memory (ROM) devices] might act as brain implants that are able to be accessed by neuronal connecfons for memory enhancement and other funcfons aimed, perhaps, at the treat- ment of Alzheimer's or Parkinson's diseases.

A review of the current state-of- the-art fabrication techniques was given by Ron Lawes (Rutherford Appleton Laboratories, Oxford, UK). The power of UV excimer lasers and energy-beam milling promise to be of significant value in the future in the construction of complex three-dimensional micro- machines, whose moving parts are only nanometres in size, and which could be employed in biosystems.

Derek Matheson (Heriot Watt University, Edinburgh, UK) indi- cated how the powering of small devices could be achieved using microfluid actuators, and described the development of 100 Ixm cutting blades powered by microflnidics for use in eye surgery.

Keith Bowen (University of Warwick, Coventry, UK) and Dennis Robinson [Science and Engineering Research Council (SERC), London, UK], in summing up, emphasized that lowering the technical language barrier is crucial to facilitating cross- disciplinary communication. A sig- nificant feature of the conference was the importance of surface-molecule interactions, particularly in biocom- patibility and the response of the body to foreign materials. Nano- technology is particularly well suited to such surface characterization and

modification, particularly in con- junction with the well-established techniques of SPM.

There is, undoubtedly, a great deal of interest in the subject of nano- biotechnology. International sym- posia are beginning to take place, and journals that are dedicated to the subject have emerged. Japan and the USA are investing heavily in nano- technology, and it cannot be too long before biological applications for the technology become com- monplace. The UK has managed to secure a strong position in this area through the SERC and Department of Trade and Industry (DTI) Nano- technology Initiatives, but its con- tinued presence will require substan- tial funding.

The technology for fabricating at the nanoscale is expensive. Never- theless, just as the fields of micro- electronics and materials science have experienced a near-exponential and worldwide growth in interest in, and publications involving, nanotech- nology and its applications over the past decade, it is expected that the same will happen in the bioscience and medical fields. It is clear that researchers working in the bio- sciences who wish to keep abreast of exciting new developments that are certain to impact in their field in the future would be well advised to keep a close eye on this emerging subject.

Jonathan Murphy The Chimaera Group, 6 Bedford Road,

Salisbury, Wilts., UK SP2 7LW.

Bob Carr Centre for Applied Microbiology and Research,

Porton Down, Salisbury, Wilts., UK SP4 0JG.

Tony Atkinson Department of Biological Sciences, University of

Warwick, Coventry, Warwick, UK CV4 7AL.

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