UCL Centre for Nanotechnology

Case for Support: Scientific Rationale

1. Introduction

2. Experiments on chips and tips

3. Theory and modelling

4. Fabrication research -
photon assisted processing

5. Novel electronics

6. Strongly interacting electrons
in reduced dimensions

7. Nanomagnetism

8. Nanofluids

9. Nanobiology

References

1. Introduction

UCL currently hosts a wide spectrum of world-class activities in materials research, ranging from exploration of the thermodynamics of exotic metals to the force microscopy of biological tissues. The aim of the activities is to address key intellectual issues, make discoveries, and develop novel applications. Even while many traditional academic disciplines are involved, the methods of materials research are becoming increasingly shared between the disciplines. In addition, the methods are becoming increasingly quantitative and expensive. All of these factors make it advantageous to form multidisciplinary centres with a common methodology as focal point. One particular methodology undergoing rapid evolution both in its capabilities as well as range of applications is nanotechnology. Nanotechnology entails the suite of techniques for nanoscale fabrication and characterisation developed for semiconductor electronics. It most famously includes lithographies for writing metallic patterns on silicon and scan-probe microscopies which are now being used to image an ever larger range of phenomena on the submicron scale. In light of the extraordinary growth in this area, and its central role in materials research, we are proposing to create a unique Nanotechnology Centre at UCL.

Fig. 1: UCL Nanotechnology Centre. The schematic shows the role that the Centre will play as a focus for interdisciplinary nanoscale materials and device research at UCL. By acting as bridge between biomedical, physical and electrical sciences, the Centre will cross the chip-to-cell interface: an essential step if the UK is to remain internationally competitive in biotechnology.

Figure 1 shows the basic structure of the Centre, at whose heart are the fabrication and characterisation technologies which motivate and enable the remaining activities. The heart is surrounded by various scientific endeavours, which, as we proceed outwards, are further removed from microelectronics, the traditional driver of nanotechnology. Thus, closest to the core we find development of new fabrication methods, followed by research on new devices, mesoscopic phenomena in hard condensed matter, nanomagnetism, fluids in confined geometries, and finally applications to the biomedical world. Cross-cutting themes are summarised by the phrases 'laboratories on chips and tips' and 'theory and modelling'. The former denotes the ability to integrate on a single silicon wafer the stimulus, probe, and sometimes even the sample itself for a particular experiment. Similarly, a cantilever to be mounted on a scanning probe microscope can contain in its tip a sophisticated measuring device such as a magnetic field sensor relying on the Hall effect. 'Theory and modelling' refers to the ever-increasing power of numerical techniques as tools for understanding phenomena on the 'mesoscopic' length scales between the atomic and macroscopic. Over the next decade, the techniques are likely to become indispensable design aids for nanodevices as well as the processing required to fabricate the devices.

The Centre draws together co-applicants from the Departments of Electronic & Electrical Engineering, Physics & Astronomy, and Medicine. They are experts in the nanoscale characterisation of biological cells and molecules, in the theory and modelling of mesoscopic processes and phenomena, in novel growth and deposition routes for electronic materials, in the properties of confined fluids, and in magnetic and electrical measurements on a wide variety of materials from magnetic clusters to high temperature superconductors. The purpose of the Centre is to make this expertise, along with a unique physical infrastructure, available to a much broader community of scientists at UCL. The many letters of support attest to the tremendous need for the Centre as a focal point for the scientific exploitation of nanotechnology.

Each co-applicant has an active research program that already uses or advances nanotechnology, and to maintain competitiveness over the next decade, will need the state-of-the-art facilities as well as the strong interdisciplinary interactions that the Centre will provide. At least one co-applicant is responsible for each theme area in Fig.1, and the remainder of this document is devoted to sections describing the new science that will emerge from the theme areas, in order of increasing distance from the microelectronics-driven heart. Before proceeding to these more detailed descriptions, it is important to point out that even though we are thinking about the Centre and its scientific case in terms of Fig. 1, this figure is merely a snapshot of nanotechnology as it stands today. In the future, we expect that the development of nanotechnology will be much more guided by activities that are far from traditional microelectronics. Indeed, the key driver in 10 years time may well be biomedical, which presently seems to be at the periphery. One of the great opportunities of forming such an interdisciplinary Centre at UCL now is to redraw the map shown in Fig.1, especially with the input and demands that the large and accomplished biomedical community at UCL will inevitably make.

2. Experiments on chips and tips

The concept of a scientific experiment as a process embedded on a chip represents as profound a change for experimental science as the microprocessor has represented for computation, control, and telecommunications. Even more radical is the notion that such miniature experimental apparatus can be moved with ångstrom precision over the sample being examined. The economic and political leaders of the developed world now recognise that research organisations which do not exploit these two ideas, across all disciplines, will lose their viability over the next decade. UCL has also recognised this. Even though its current infrastructure is inadequate, many of the Centre co-applicants have made pioneering contributions which exploit the inevitable trend towards laboratories on chips and tips.

Fig. 2: Laboratories on chip fabricated as part of UCL research program. An array of microcalorimeters deposited on Si. Each comprises a heater and two thermometers, allowing the heat capacity of milligram size samples to be measured. This technology is in its infancy but is proliferating rapidly. The new Centre will allow UCL to maintain its leadership role in this area.

Fig. 3: Temperature-dependent magnetic force imaging. Data show magnetic contrast near artificial (straight vertical line) and natural (clustered around oblique line) grain boundaries in a manganite film, deposited by pulsed laser deposition, exhibiting colossal magnetoresistance. Above the nominal Curie point (350 K) for the film (far left), the grain boundaries still display a magnetic moment whose magnitude and spatial decay length into the grains shrink as the temperature is raised above 360 K (far right).

Figure 2 shows an array of 300 microcalorimeters fabricated on a 4" Si wafer. Its construction was originally motivated by interest in rare earth and actinide magnetism, although it is clear that the applications are far wider. The technology was transferred to Oxford Instruments, who now market it as a turnkey calorimeter system. Figure 3 shows another example from a co-applicant's laboratory,¹ where the tip of an atomic force microscope is used to explore temperature-dependent magnetic phenomena with high spatial resolution. As is characteristic of qualitatively new experimental technologies, as soon as the modified commercial microscope entered operation, we were able to make a significant discovery which explained bulk anomalies that had previously been unaccounted for. Equally interesting is the sample - a thin magneto-resistive manganite film deposited via pulsed laser deposition on a bicrystal substrate - which represents a type of nanoengineering that will become increasingly common over the next decade and which could be performed entirely in-house within the new UCL Centre.

In the new Centre, we propose to build on our existing expertise in the development of 'experiments on chips and tips' for all of UCL science. Examples of directions we are especially interested to pursue are:

Nanocalorimeter arrays, to be fabricated in the new clean room and based on our group's success with the microcalorimeter array in Fig. 2.
The manipulation of bioparticles is dependent on their dielectric constant.^2,3 We will fabricate a chip-based method, based on our thermal expansion cell, to measure the dielectric constant of bioparticles.
A miniature integrated diamond anvil cell, exploiting our interdisciplinary group's expertise in carbon devices and physical measurements at high pressures.

3. Theory and modelling

Alongside the nanofabrication revolution, which is leading to a new approach to experimental science, another revolution is occurring in the theoretical sciences. This involves the widespread application of computing to the modelling and understanding of physical processes over an enormous range of time- and length scales. The new approach has been particularly important in the opening up of mesoscale and nanoscale phenomena to theoretical understanding,⁴ since such phenomena involve large numbers of particles, yet cannot be simplified by a bulk continuum description.

Fig. 4: UCL theory and modelling of atomic and electronic motion at the nanoscale. An atomic force microscope tip leaves self-forming 'nanostrings' of atoms as it is pulled away from a surface (left), while an electron moving coherently through a nanowire is predicted to couple to the atomic vibrations, lowering the band gap locally as it moves along (right).

We are now entering a particularly exciting period, in which the length scale of systems that can be accurately modelled and simulated is the same as the scale on which systems can be imaged (and indeed fabricated) using the new experimental scanning probe techniques. This JIF proposal is focussed on experimental facilities, but we intend that theory and modelling will play a central role in the scientific programme across all the sub-themes, as indicated schematically in Fig. 1. This commitment is shown by the presence as co-applicants on the proposal of two representatives of the large and active UCL theory and modelling group (more than 30 researchers, including 7 academic staff).

Our current research spans many aspects of the theory of nanoscale phenomena. We study the theory of probe microscopy, with a view towards understanding the fundamental mechanisms of image formation in atomic force microscopy^5-8 and scanning tunnelling microscopy.^9-12 Calculations are being performed on the formation, electronic properties and dynamics of nanostructures such as quantum dots and wires.^13-17 New approaches to nanoscale simulations are being explored: in UCL's Virtual Matter Laboratory, we can calculate properties from first principles (using only the atomic numbers of the elements concerned) with an effort which scales only linearly with the size of the system.^18,19, allowing simulations of nanostructures containing thousands or millions of atoms. We are also developing methods to compute the quantum properties of systems in nanoscale environments,²⁰ and have discovered new approaches to the thermodynamics of the nucleation of clusters during aerosol growth and surface deposition.^21-23 Finally, we are determining the principles of local nanoscale modification of materials by electronic excitation^24-26 and studying the processes limiting the growth and performance of thermal oxide films on silicon.²⁷

Ultimately, the role of theory is to explain and motivate experiment, and to serve as a design tool for technology. The Centre will promote a much closer coupling between theory and experiment because its state-of the-art nanofabrication and characterisation techniques are well matched to the modelling group's expertise and will enable much faster turnaround between experiment and theory. Beyond those listed above, research areas that will grow out of our current expertise and the much stronger interactions with UCL experimentalists in the new Centre include:

The thermal, rheological, magnetic, and electrical properties of solids and fluids in confined geometries.
Tip design for scan probe microscopy, particularly for soft materials and cells.
Fabrication process design. Today, etches, heat treatments, exposures to light and electrons, and deposition routines employed for nanofabrication are optimised largely via expensive trial and error. We aim to develop software tools which will give experimentalists a more restricted parameter space when searching for the best strategies to create particular nanostructures. The development of credible software is possible only in conjunction with in-house experimental benchmarking.
Gaining insight into the relationship between structure and function in biomolecules, in the light of new experiments measuring the chemical and electrical activity of such molecules interfaced with inorganic substrates and measured with scanning probes.

4. Fabrication research - photon assisted processing

Because of the large potential payoff for the UK industrial base, and to gain a competitive edge, there is an obvious need for state-of-the-art fabrication and for new processing routes. A major theme here is the minimisation of thermal budgets. One research approach towards this involves photon-based processing.^28,29 UCL has been most active in this area over the past 15 years, through contributions in photon-oxidation of Si and SiGe, photo-etching of III-V materials, direct-write repair of VLSI devices,^30-32 and extensive development of pulsed laser deposition (PLD), where the first UK laboratory was established in 1988.³³ PLD has evolved into a powerful technique for producing good quality multicomponent thin films, many of which cannot be prepared by any other route. Many unique high T^c superconductors and Giant Magneto-Resistive (GMR) structures have been made by PLD, enabling studies of atomic substitution in up to 7 atom systems that cannot be made any other way.³⁴ Thus, as a tool for research into non-standard multi-element 'difficult' thin films, PLD is indispensable.

Fig. 5: UV fabrication methods at UCL. Copper microstructures formed directly on AlN via direct VUV irradiation of palladium acetate with an excimer lamp system constructed at UCL. The irradiated zones result in the creation of Pd clusters which act as nucleation sites during subsequent Cu deposition. The figure indicates the ability to readily process conventional chip-sized area. No fundamental limits are foreseen for the larger areas and finer linewidths to be explored in the new Centre.

UCL has also pioneered the development and application of new ultraviolet (UV) and vacuum UV light sources based upon the silent discharge of excimer mixtures.^35,36 These offer wavelengths from the short visible down to 126 nm, which can be applied to a wide range of photo-chemical processing steps. Recently, such sources have been used to initiate ultra-thin oxide and nitride growth, as well as to induce surface roughening leading to improved adhesion, surface nucleation, metallisation, selective etching, and sol-gel processing. This technology thus promises much in the drive towards low temperature production of ultrathin layers. It can also enhance more conventional fabrication routes, such as MBE, or CVD, by providing direct photochemical chemical pathways in addition to those already in operation. An example of this is VUV dissociation of oxygen to provide extra radical species during PLD of perovskites. The 126 nm radiation could potentially also directly photodissociate nitrogen molecules and enable direct nitridation.

Key projects which the new Centre will allow us to pursue include:

Fabrication, using a new state-of-art PLD system, of the new films, from magnetic multilayers to bio-compatible coatings, described elsewhere in this proposal. The current system in the UCL EE department still uses one of the first 10 Hz, 1 J excimer lasers in the UK. It is more than 12 years old, has high operating costs, requires constant repair, and is extremely unreliable.
The first 6" VUV processing facility in the world, capable of providing a choice of processing wavelengths selectable for a range of reactions. One major advantage of the new silent-discharge excimer lamps, in addition to their almost unlimited lifetime, is that they can form the basis for a large area processing facility.
Miniature excimer lamps, fabricated as on-chip UV sources. Otherwise undetectable chemicals can be dissociated by using UV-induced photochemical reactions, so that their more detectable by-products can be sensed by detectors and allied electronic circuitry fabricated on the same chips. Another application is for on-chip optical processing, e.g. for modification of circuitry in the field or for purging sensor elements. The power required is expected to be low, permitting battery power for portability. The underlying mechanisms for radiation generation at low rare-gas pressures within micron-order discharge gaps will be investigated, and the trade-offs for the realisation of high-performance UV sources and integrated sensors, as well as the controlling photochemical reaction steps and kinetics, will be addressed.

5. Novel electronics

Once at the nanometre scale, the electronic, optical and physical bases of current device designs will need to be superseded by those which account for quantum and other effects that emerge at these dimensions. It is notoriously difficult to gain acceptance of new electronic materials in the microelectronics arena; in contrast there are no established means for the mass production of nanoscale devices on a commercial basis, thus opening the way for innovative research in this area. Hence, the principal emphasis of the Centre's device work will be on the use of novel materials to engineer nanoscale electronic, optoelectronic and electro-mechanical devices for applications in electronics and sensing environments.

Fig. 6: Diamond electronics. AFM image (left) of a 2mm x 2mm section of highly oriented diamond nuclei grown by microwave plasma-assisted CVD. The (100) grains are oriented with respect to the Si(100) substrate and mis-aligned to each other by less than 4%. Diamond optoelectronic devices (right) produced at UCL are now commercially produced by UK industry under licence.

At UCL we have an established 'Diamond Electronics' group which has been acknowledged to be at the forefront of this activity within the world.³⁷ Current activities encompass the use of crystalline diamond and diamond-like carbon, for the formation of electronic, optoelectronic and sensing devices. Within the new Centre work with carbon nanotubes and silicon carbide will be added. Diamond has a superlative set of optical, electronic and physical properties and has long been heralded as potentially the 'ultimate semiconductor'. The advent of chemical vapour deposition (CVD) methods for the formation of large area diamond films at modest cost has enabled the use of this wide band gap material within commercial products to be realistically considered. However, problems with the control of defects and difficulty with doping have hindered its development as a serious electronic material. Despite this, exciting progress is now occurring with, for example, the UCL group developing high performance, visible blind, diamond UV photodetectors which are commercially produced by UK industry under licence from us. New dopants are emerging (hydrogen as a shallow p-type dopant, sulphur and phosphorus for n-type character), defect passivation treatments have been developed and the field is set for a period of rapid growth. Initial work on diamond-based micro-electro-mechanical systems (MEMS) has also been very encouraging. The wide range of amorphous but fully constrained carbon materials known generally as diamond-like carbons (DLCs, Eg ~ 2-3 eV) has also begun to make an impact on device technology. These materials can be effective dielectrics, and are suitable for integration in MEMS. They can also perform as high efficiency cold cathodes.

Important projects in new materials-based electronics at the new Centre include:

Ultra-thin SiC films. Silicon carbide (Eg ~ 3 eV) has begun to establish itself as an effective wide band-gap semiconductor. Device quality layers are commercially available, although problems with micropipe-based defect densities persist. Following the discovery of fullerenes, in which the UK played a leading role, the potential uses of both ball-like and 'nanotube' forms of this type of carbon have begun to be explored; their use as nanoscale transistors and field emitters are of particular interest at UCL.
Nanoscale diamond, diamond-like carbon and SiC structures, formed via 'top-down' (laser machining, laser chemical etching, reactive ion etching) and 'bottom-up' (pulsed laser deposition, molecular beam epitaxy, chemical vapour deposition, reactive sputtering, plasma enhanced CVD) methods. On this scale the problem associated with polycrystalline growth of diamond when non-diamond substrates are used can be avoided, since individual nuclei can be developed into single crystal nanometre features. In the case of nanotube formation, a 'bottom-up' approach will be explored, where metallic nuclei are created with the aim of anchoring, and aligning, nanotubes onto the substrate surface. A combination of top-down and bottom-up processes will be used to fabricate composite nanostructures from these materials. Many of the nanostructures will be designed for research, in collaboration with other Centre co-applicants and UCL faculty. Particularly interesting applications are for miniature high-pressure environments and nanobiology, where the chemical stability and hardness of diamond may make it the material of choice for sensors as well as micromachines, perhaps injected into the bloodstream to engage in clinical cutting tasks.
'High-k' dielectrics, which are binary oxides such as Ta₂O₅ and ZrO₂, and complex oxides such as Zr-Al-O, SrTiO₃ and various silicates. The need to shrink MOSFET dimensions, including the gate thickness, places a strain on SiO₂ as ultra-thin gate layers of this material become leaky and unreliable. High-k dielectrics offer a solution to this problem. The EE department at UCL has a long established record of innovative work on silicon dioxide deposition and is well placed to move into the formation of higher-k dielectrics. The formation of such layers with nanometre thicknesses will be explored using the MBE, PLD and plasma enhanced CVD in the Centre.

6. Strongly interacting electrons in reduced dimensions

One of the most lively areas of condensed matter physics in the last decade has been concerned with strongly interacting electrons, which increasingly appear to violate the tenets of the conventional band theory (also called 'Fermi liquid theory') of solids which accounts so well for the behaviour of ordinary metals and semiconductors.^38,39 Materials containing strongly interacting electrons are becoming more ubiquitous, and today include rare-earth and uranium based intermetallic compounds, as well transition metal oxides and compounds. The most celebrated among the transition metal oxides in this class are the layered cuprates, whose normal (metallic) state properties are just as mysterious as their high-temperature superconductivity. Some of the rare earth intermetallics have equally spectacular properties, most notably effective electron masses more than three orders of magnitude in excess of the free electron mass, and are thus commonly referred to as heavy Fermion systems.

Fig. 7: Strongly correlated Fermi system. Phase diagram for (Mn,Fe,Co)Si. Colours in top frame represent electrical conductivity, those in bottom frame correspond to low field magnetisation. While MnSi is a classic metallic ferromagnet and CoSi a diamagnetic metal, FeSi is a non-magnetic small gap insulator, which, when doped, becomes a low carrier density heavy fermion metal. Depending on the sign of the carriers (holes or electrons), the metal can remain a Pauli paramagnet or what seems to be a fully polarised, ferromagnetic electron gas. A curious fact is that even though FeSi and CoSi are both non-magnetic, most intermediate mixtures of the two isostructural compounds are magnetic. Quantum interference effects appear to account for the entire magnetotransport to temperatures above 50 K. At the new Centre such effects will be followed into the mesoscopic regime.

Several of the co-applicants have well-established research programs in the area of strongly interacting electrons, having focussed primarily on electrical and thermodynamic properties as well as magnetic correlations measured using neutrons and bulk susceptometry.^40-50 One of the important conclusions of the research is that non-Fermi liquid behaviour as well as the heavy Fermion phenomenon are generally found near quantum critical points, phase transitions scanned at zero temperature by tuning the strength of quantum rather than thermal fluctuations. Another emerging theme is that anomalous superconductivity, such as seen in the cuprates and certain cerium and uranium intermetallics, is frequently found where there are also quantum critical points and non-Fermi liquid behaviour.⁵¹

At the present moment, there is no accepted explanation for the panoply of anomalous properties of materials containing strongly interacting electrons, and there are no obvious applications that exploit these properties, high temperature superconductivity excepted. Furthermore, the transport (e.g. electrical resistivity), thermodynamic, magnetic and spectroscopic characteristics of such systems on short length scales and near surfaces are essentially unknown (although see Fig. 3 for an exception). As a consequence, new experiments are needed to reveal both low dimensional and finite-size effects^52,53 as well as the quantum interference effects at the heart of the bulk anomalies, and which might simultaneously provide the conceptual underpinnings for future device applications. That there probably exist such interference effects, analogous to those found in conventional doped semiconductors, emerges from experiments,⁵⁴ represented by Fig. 7, carried out on alloys of the very common elements iron, cobalt, silicon, and manganese. The experiments that we have in mind will address such interference phenomena using:

Low dimensional and other small structures, which we will prepare by a combination of lithographic techniques and pulsed laser deposition and by ion beam milling of oriented single crystals.
Scan probe microscopy, at low temperatures and as a function of external magnetic field, on well prepared surfaces of materials containing strongly interacting Fermions.

7. Nanomagnetism

Strong efforts are currently devoted to new nanocrystalline soft and hard magnetic alloys. The trend towards high-density magnetic recording presents another great challenge to materials scientists working in nanomagnetism, as areas per bit reach towards the nanometre scale. Nanoparticulate magnetic dispersions, in either a solid or a liquid matrix, also have important applications in ferrofluids, magnetic refrigeration and granular giant magnetoresistance materials. In other cases, the magnetism conveys important information about composition and nanostructure, or serves as a tracing element, as in catalysts, magnetic resonance imaging agents, geological and archaeological materials.

Fig. 8: Nanomagnetism. AFM image of an aminosilane coated iron oxide magnetic fluid deposited on a glass slide (350 x 350 x 10 nm³). These biocompatible fluids could be the basis of a new magnetic separation based technology for protein purification, and a means of enzyme immobilisation and assaying.

Over the last five years, several applicants have collaborated on a UCL nanomagnetism research programme. The work has included the chemical reduction synthesis of 5-10 nm transition-metal-boron alloys;^55-59 characterisation of superparamagnetism and intermediate range dipolar interactions in nanoscale granular alloys and in matrix-dispersed iron oxides;^60-67 the optimisation of biocompatible magnetic fluids for protein purification;⁶⁸ and studies of thin film giant and colossal magnetoresistive materials.^69,70 Building on the experience gained through this work, and exploiting the capabilities afforded by the new clean room with its MBE, PLD and FIB systems, we will be able to fabricate and examine nanomagnets as individuals rather than as polydisperse aggregates.

Specific research programmes to be undertaken include:

Patterned magnetic media. The combination of PLD and FIB will enable the preparation of patterned oxide and boride films, including Fe-based oxides and perovskites, hard magnets such as NdFeB, the CMR manganites, high transition temperature superconductors, metal/metal-oxide composites, and variations thereof. This opens the door to a huge range of possibilities ranging from magnetoelectronic device arrays through biological assay chips to model systems for statistical and quantum physics.
Single-dot science. The idea is to examine the size, shape, and material dependence of classical and quantum mechanical domain reversal phenomena in single magnetic dots. The resulting science has implications not only for magnetic recording, but also for much more futuristic endeavours such as quantum computing and biological applications. The research will need the nanofabrication facilities as well as the low temperature laboratory, especially the high-field/low temperature scan probe microscope.
Self-assembling arrays of magnetic nanoelements. The plan is to exploit magnetic interactions together with Centre expertise in UV-induced nucleation and nanofluidics to create densely packed assemblies with novel and tuneable superstructures, which could themselves have non-magnetic as well as magnetic applications.

8. Nanofluids

Nanofluidics is exciting because it underpins future developments of assays and processes in chemical engineering, biology, and medicine. It also shows considerable promise for the development of new nanofabrication schemes. The Centre will establish new programmes to understand and control solvent-mediated interactions between nanoparticles. The research will depend on the sample preparation, structural characterisation, surface probe, fabrication and modelling facilities within the Centre. It will also bridge the boundaries between biology, physics and engineering. There will, of course, be particularly strong synergy with our nanobiology theme.

Fig. 9: Nanofluids: A snapshot of a hydrated vermiculite clay, in which the clay layer spacing is 4nm. The colour coding is: blue-O, white-H, black-Si/Mg, green-N, red-C. Our neutron diffraction studies of this system have provided a uniquely detailed picture of aqueous structure at a charged solid surface, in the so-called electrical double layer. The data reveal two layers of highly structured water molecules at each clay surface. More surprisingly, the distribution of propyl-ammonium counter-ions reaches a maximum at the centre of the interlayer region. The combined X-ray reflectometer/uniaxial stress cell in the new Centre will allow interfacial structure to be directly related to forces between surfaces. The new understanding of confined liquids and solid-liquid interfaces will form the basis for our research into 'chip-cell-probe' systems.

The opportunities that we have identified for nanofluidics build on our current standing as an internationally recognised centre for experiment and theory on liquids. Our existing programmes are unravelling many fundamental questions concerning aqueous and non-aqueous solvents,^71-74 as well as the solvation of hydrophobic particles,^75-79 (bio)organic molecules,^80-84 ions and electrons.^73,74 We are also making major contributions to the understanding of confined fluids.^85-94 Together, these programmes lead us naturally to the projects we aim to pursue in the new Centre:

Solid-liquid interfaces. We will focus on well-characterised layered systems, such as clays and graphite intercalation compounds.^90-94 The Centre will open up major new opportunities in this field. Importantly, it will provide a unique facility to measure simultaneously interfacial structure (within the electric double-layer region) and surface-surface forces, under non-ambient conditions. This will be achieved by mounting a temperature-controlled uniaxial stress cell on a θ-θ geometry X-ray reflectometer. This new technique will be complemented by scan probe microscopy, using a non-ambient liquid cell. The relevant imaging modes include tunnelling, (pulsed) force, capacitance, and electrical force/potential. Quantitative interpretation and prediction will be aided by state-of-the-art theoretical studies.
Fluids in confined geometries and on patterned substrates. Research into confined fluids will underpin our 'chip-cell-probe' theme. It will exploit our unique ability to fabricate substrates in the clean-room facilities, and to examine them using the imaging and nano-oscillator tools of our colleagues in hard condensed matter science.
Molecule-substrate interactions. Interactions between molecules and surfaces in aqueous solution depend critically on the chemical nature and temperature of the solvent.⁷² However, many of the processes of interest that involve through-solvent interactions are characterised by a longer length scale (for example protein molecules can have diameters of several tens of ångstroms).⁷¹ We therefore propose to exploit temperature-controlled wet AFM techniques to measure directly the through-solvent forces between well-characterised substrates and coated tips. Reflectometry will also be used to characterise the composition of substrate-solvent interface as a function of distance from the surface.
Fluid-phase nanofabrication. We will develop sub-ångstrom control of particle-particle separation and morphology in the fluid phase as a route to fabrication. We have already shown that for clay-hydrates, the liquid film thickness is fully controllable down to 3.5 Å, and that one can therefore create stacks of ~107 regularly spaced flat solid surfaces.⁹¹ Solvent-based control of solid carbon particles, such as graphene and fullerene, promises a full suite of planar, spherical and tubular geometries. Aqueous and aromatic solvents have already been investigated in this context. However, metal-amine solutions are potentially much more desirable, due to the high solubility of the solid particles.^93,95 We have recently achieved a break-though in the preparation and containment of metal-ammonia solutions.^73,74 The structures will be characterised by X-ray scattering and a posteriori probe microscopy.

9. Nanobiology

The ability to create and exploit devices on the nanoscale is beginning to have a major and practical impact upon biomedicine. For instance, the development of chemical and biological sensors (e.g., the IBM 'NOSE' project) will make real-time diagnostics possible and eventually enable personal therapeutic regimens to be developed. Likewise, the ability to examine biological processes at a scale below that of visible light will yield a new biology - 'mesophysiology' - that operates between high-resolution molecular imaging and the bulk biochemical and physiological techniques of traditional biology. The programme of work in the nanobiology section of the Centre will build upon the innovation and expertise of the medical co-applicant and his collaborators in the field. A requirement for success will be the ability to interact with the existing skills of mainstream physical measurement methodologies and the new nanofabrication techniques which will become available as part of this proposal. An interdisciplinary approach is essential to capture the wealth of UCL physics and electrical engineering expertise for the benefit of medicine and nanobiology.

Fig. 10: Development of AFM systems for biology. The results are images of surface and intracellular structures of living cells (at left, live cells on glass with prominent cytoskeletal fibres) and maps of physical properties - e.g. receptor binding forces - of cell materials. We have also integrated a confocal microscope with the AFM to accomplish simultaneous fluorescence analysis (at right, a 3D isosurface reconstruction of bone cells on a mineralised substrate (blue) labelled in two colours (red, green) to independently demonstrate the distribution of two membrane proteins). The future lies in developing the bio-AFM further and introducing a range of more sophisticated physical techniques, electrophysiological applications and micromanipulation methods. Each image measures 50 x 50 μm².

Recently, we have developed several of the technologies that will enable nanoscale analysis of processes in living cells.^96-100 We have designed and built a life science optical interface between a commercial AFM and inverted microscope and modified the z-piezo controller to allow imaging and analysis over the large heights required for use with living cells which have a large, irregular and moving surface landscape. Finally, we have combined confocal microscopy,¹⁰¹ time lapse image capture and patch clamping with the modified AFM to measure real time cell signalling responses by optical and electrophysiological methods. This work has been made possible by 'blue-skies' pharmaceutical industry support and collaboration with instrument manufacturers - we believe that this collaborative approach will be essential for long term exploitation of our findings.

The outcomes from this engineering/development programme have been: (i) the first estimates of single molecule ligand-receptor binding forces in cells using integrin cell adhesion receptors as a paradigm in cells;⁹⁶ (ii) generalisation of these techniques to other receptors and binding molecules;⁹⁷ (iii) development of mapping techniques to demonstrate the combined location of active receptors with 3-D topography in cells;^97,98 (iv) micromanipulation and signalling experiments: introduction of a few ligand molecules to a cell using the AFM cantilever at defined positions and under known and controlled mechanical forces with simultaneous recording of signal processes such as intracellular calcium levels, kinase enzyme activation, and induction of apoptosis;^99,100 and (v) use of an AFM to analyse the material properties of cells and of associated ion channels, some of which are activated by the tip itself.

Based on the above, the first research areas to be pursued in nanobiology in the new Centre will focus on the further development and utilisation of life sciences force microscopy. This will include work on: (i) AFM tips with special shapes and coatings, to be made using the clean room facilities of the Centre, and designed taking advantage of the Centre staff's combined expertise in fabrication and modelling of tip interactions with soft surfaces; (ii) the continuation of our work on the study of cellular signalling events ensuing from receptor activation via reactive ligands on AFM tips; (iii) the analysis of the biomechanics of cellular mechanotransduction;^102,103 and (iv) the design and manufacture of an AFM-based 'cell scraper'¹⁰⁴ which we will use to study total cellular interaction forces between cells and newly fabricated materials for use in tissue engineering (with members of the UCL Tissue Engineering Centre and the Eastman Dental Institute) and 'lab on a chip' applications within the Centre.

The activities just described will eventually be only a very small part of the nanobiology activities in the Centre. We will be working with a large number of collaborators to further the development of SPM for biology and medicine, as well as to fabricate special purpose chips and even micromachines for assays and eventually even disease treatments. To illustrate this commitment, specific collaborations that we are planning include:

Surface and intracellular properties of cells and their inhomogeneities (e.g., lipid rafts and polarised cell domains^105,106) by such methods as surface electrochemical properties (Prof. David Williams, Dept. of Chemistry UCL), ion conductance imaging¹⁰⁷ (Prof. Chris Pitt, Dept. of Electronic & Electrical Engineering UCL), electrophysiology (Prof. Jonathan Ashmore FRS, Dept. of Physiology UCL), cell thermal imaging, and X-ray reflectometry.
Development of new probe techniques such as: single molecule FRET (fluorescence energy transfer) at the tip-cell/macromolecule interface;¹⁰⁸ near-IR scanning near-field optical microscopy using microfabricated devices;^109-112 magnetic property imaging; probing electron transport in cells (Prof. David Delpy FRS, Dept. of Medical Physics UCL).
Sequence analysis of receptors 'fished' from cells using specific ligand-derivatised AFM tips made in the Centre (Prof. Tony Segal FRS, Dept. of Medicine UCL in the Wellcome Trust proteomic facility).
AFM imaging and structure of 2D crystals and proteins in artificial lipid bilayers (Prof. Helen Saibil, Birkbeck Crystallography and BBSRC Biomolecular Structure Centre); and analysis of structure of process-engineered plasmids, proteins and other biomolecules (Prof. Peter Dunnill, ACBE UCL). The hope here is to learn about proteins occurring in or near membranes, where their conformations may be quite different than in the crystals required for traditional (X-ray) protein structure determination.
Large-scale sensor arrays for diagnostics of biological fluids. The arrays in question can consist of a wide variety of devices, ranging from micromechanical cantilevers, each with a slightly different chemical binding property, to microcalorimeters (see Fig. 2) to measure energy released upon chemical reactions with different molecules resident within each calorimeter (Prof. David Williams).
Electronic properties and exploitation of biomolecules. Although the electrical characteristics of biomolecules may not generally be relevant to their biological function, they do represent a fascinating class of new materials for possible use in electronics. We plan to use scanning tunnelling microscopy (STM) as well as special-purpose substrates prepared in the nanofabrication facility to measure and eventually to make use of these characteristics (Prof. David Delpy FRS).

Our biological research programme is absolutely dependent upon unfettered access not only to the nano-fabrication facility, but also on the presence in a single location of scientists with expertise in theory, hard and soft condensed matter physics, and electrical engineering. All of these will be available in the Centre, and as can be seen from the previous sections of this proposal, are keen to pursue applications of their work in nanobiology. What the Centre will therefore provide is much more than the essential new physical infra-structure, but the unique interdisciplinary environment needed for meeting the challenges of nanobiology.

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