Robustness and adaptivity: advanced control and estimation algorithms for the transverse dynamic atomic force microscope

Observing the dynamic behaviour and interactions of single biomolecules is a long-standing goal to facilitate bio-medical research. Standard practice is to use one of several scanning probe microscopes (SPMs), principally atomic force microscopy (AFM). The principle of an AFM is simple: a horizontally oriented cantilever with a very sharp tip is moved across the object of interest, allowing the capture of a three dimensional topographical image. However, the low forces and fast timescales of the fundamental inter-molecular events of interest in bio-medical sciences, generally lie far outside the operational range of commercial AFMs, which typically require several minutes per image. Thus, while AFMs can provide sub-molecular resolution of biomolecules under physiological conditions (cf. electron microscopy which uses a vacuum) there are two significant disadvantages of AFMs still to be overcome.- slow imaging rates: A typical 256x256 pixel image takes 60 seconds to produce.- excessive interaction forces during imaging: A significant challenge to imaging biomolecular interactions is that the forces typically present between the probe and the sample disturb or even damage the biomolecules.To counter these issues, we will combine the latest advances in control theory with the novel SPM instrumentation, currently in development in Bristol, to produce a new scanning probe microscope capable of imaging these fragile samples without damaging them: Thus, Bristol's transverse dynamic force microscope (TDFM) will represent a breakthrough in both SPM instrumentation and the study of biomolecules.In Bristol's TDFM, the probe is aligned perpendicularly to the sample surface (rather than parallel to it, as in AFMs) and oscillates in the plane of the sample. The amplitude of oscillation decreases as the tip-sample separation distance decreases. The amplitude of the probe oscillation can be used as a measurement signal to control the probe-sample separation with sub-nanometer precision. When using this control method, at no point during scanning should the probe come into contact with the sample surface.Novel control methods will create a high-speed TDFM (HS-TDFM) by-controlling the fast movement of the cantilever height (z-motion)-controlling the fast placement of any (biological) specimen to be observed (x-y-motion)-estimating sample-cantilever forces, e.g. Van-der Waals forces, to better understand the wealth of measured information for faster and simpler fusion & processing of data obtained from the HS-TDFM.Before any of this is possible, the TDFM will be redesigned to incorporate highly precise sensor technology and to obtain the best possible dynamic behaviour. The modern control approaches will include linear robust control approaches, nonlinear sliding mode control, nonlinear adaptive (neural network) control, modern estimation/observer techniques using sliding modes, and adaptive principles.The challenges will be to-achieve practical control at bandwidths above 1MHz;-understand & exploit the nonlinear HS-TDFM dynamics for better data interpretation;-develop novel estimators/observers combining the paradigms of adaptive and sliding mode methods, for signal and parameter identification;-incorporate novel estimation and control approaches for improving the control system of the HS-TDFM.The resulting HS-TDFM will be a true non-contact imaging technique capable of comparable spatial resolution and lower interaction forces than AFMs. The HS-TDFM will display pico-Newton force-sensitivity and provide a wealth of information from direct observation of the interacting biomolecules. It will collect multiple images per second as required for observing biological processes. This will not only benefit life-sciences but also support SPM users in material science, producers of nano-sized systems, and in nano-electronics, e.g. microprocessors.

The high speed transverse dynamic force microscope (HS-TDFM) developed at Bristol has the potential to become a world-leading research tool with which to probe biological interactions and the dynamic behaviour of single molecules. This will allow the real-time visualization, for example, of protein motion. This can have implications on research into drug delivery, cancer or bio-material science. Thus, the novel HS-TDFM can help create a significant leap forward in understanding in life & biological sciences. The HS-TDFM will significantly improve on commercial products available from scanning probe microscope (SPM) producers. In fact, the HS-TDFM together with the novel control and nonlinear estimation techniques will resolve the three important issues raised by major SPM-providers: -Performance (Resolution + Speed): the fastest high resolution video-rate results will be provided, guaranteed by high bandwidth & high performance control. -Useful Information: The HS-TDFM approach is a direct force measurement technique. Combined with the novel estimation methods, it will allow direct use of the collected information without ambiguity. -Productivity: Direct provision of video-rate data, without further processing, will allow 'instant' use. AFMs are often regarded as research tools, and typically high levels of training are required to operate them. The advancements in accuracy and user-friendliness resulting from the control and estimation approaches in this proposal, will benefit general users of SPMs (e.g. in the areas of material science, producers of nano-sized systems, and in nano-electronics). The control methods which will be developed will also be applicable to other nano manipulation-systems such as optical nanotweezers (where again the Nano-science group in Bristol has world leading capabilities). The estimation problems considered in this project can also form the basis of observer methods for condition-monitoring or fault-detection. Hence this field of engineering would also benefit from the proposed research, (fault detection methods are important in the aerospace and automotive industry for example). The training of all project participants and the dissemination of the results is of significant importance. Publication of the results at topical, high standard conferences has the additional benefit of training & engagement. Nano and biophysics conferences and specific control conferences are targeted for publication. High impact journals such as the IEEE Transactions on Control Systems Technology, Mechatronics and Nanotechnology will be targeted for archive journal publication. Regular talks & training sessions at Bristol will provide all researchers with a vibrant opportunity for engagement and training. All members of the group in Leicester & Bristol will be fully integrated via weekly meetings using teleconferencing, shared web-workspace access, three extended research periods at Bristol and a website. This will guarantee high efficiency, immediate impact & communication with fellow scientists and the public. Moreover, it is of interest to present the positive aspects of nano-technology to the wider public: two formal events, taking the form of presentations to members of the IMechE and the IET, will be held. This will be complemented by a less formal event at the Science Caf in Bristol allowing discussions with a wider audience. In addition, a website will provide an introduction both in laymen's terms & at a scientific level. Thus far, development and exploitation has been largely through start-up companies, licensing arrangements & patent assignment sale. An example is Bristol's highly successful nano-science spin-out company, Infinitesima Ltd, producing SPMs developed in the Miles-Group. We will choose the most appropriate route after discussion with the technology transfer officer.