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

Lead Research Organisation: University of Bristol
Department Name: Mechanical Engineering

Abstract

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.

Planned Impact

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.

Publications

10 25 50
 
Description Practically validated methods
- A new improved, robust and more user friendly set-up of Bristol's Transverse Dynamic Force Microscope (relating to Objective 1)
- Development of a high speed x-y stage and positioning control (Objectives 1 and 2)
- Creation of a robust controller for non-contact scanning based on a secondary z-height signal (Objective 2)
- Improved control robustness after a redesign of existing controllers (Objective 2)
- Development of several practical procedures for creating a family of dynamic ordinary differential equations characterising the behaviour of the TDFM cantilever, starting from an accurate spatio-temporal approach (partial differential equations) and using measurements captured at a high sampling frequency from the TDFM rig. This is significant for easy design of advanced control-engineering based estimators and control laws. (Objectives 2 and 4)
- Creation of a real-time capable algorithm for the estimation of unmeasurable shear forces resulting from the cantilever interacting with a fluid layer above the specimen (Objective 4)
- Real-time identification of viscosity and elasticity coefficients within the fluid layer above the specimen to identify material parameters in real-time scans at nano-precision (Objective 4)
- Real-time large scale scans to estimate shear forces, viscosity and elasticity coefficients within the fluid layer above the specimen to identify material parameters (Objective 4, carried out PhD student Kaiqiang Zhang)

In addition several other new methods have been validated in simulation (and possess solid theoretical underpinnings) but have not yet been implemented on the TDFM:
- Non-raster scanning approaches (relating to Objective 4)
- Robust control methods for real-time large scale scans (relating to Objectives 2 and 5, carried out PhD student Kaiqiang Zhang)
- An adaptive approach for cantilever amplitude control which allows implicit estimation of the tip-to-sample distance (relating to Objectives 2 and 5)

Journal papers are under review or are being prepared with currently available results. We have addressed in our work all the 5 originally planned objectives.
Further work on Objective 5 (Enhanced robust and adaptive control of the HS-TDFM cantilever system using observer based methods) has been carried out by the PhD student Kaiqiang Zhang. Objective 5 is the most challenging and the most 'blue sky' of all the objectives. A slight change to the original objective, to the more general theme of 'nonlinear robust multi-variable control methods', was needed, as we understand now all requirements for control better.
Note that the completion of the project was delayed for more than one year in 2012 by the extended construction work on a major building next to the Nano-science and Quantum Information (NSQI) Centre of the University of Bristol. The NSQI houses the experimental system, as it is, in the UK and world-wide, one of the most advanced nano-science research centres with its vibration reduced working environment. Much of the initial work in 2012 (although intense) was preparatory and directed towards redesign of the force microscope, while learning practical skills necessary for the effective use of the force microscope started only in 2013. This unplanned delay has certainly had an effect on the morale of the team. Moreover, the resignation of a researcher at the University of Bristol during that initial period in 2013 was not beneficial. (This researcher left for personal reasons.) It should be understood that the transverse dynamic force microscope is a probe microscope built from first principles. Thus, the hardware and in particular the control software has also been built in house using the most powerful FPGA-based control implementation equipment system on the market at the time of start of the project. Complete practical realization of objective 5 will require additional, upgraded FPGA-equipment, but very promising results have been achieved by Kaiqiang Zhang. This fact has made the project challenging and exciting. Thus, in any respect, the team is very happy to have achieved the majority of the targeted objectives (while addressing them all), of which many additional results are to be published soon.
Exploitation Route Mr Kaiqiang Zhang, who worked as a research intern on this project, has successfully (co-)authored then 5 conference and journal papers for this project. As a result, he obtained a PhD studentship from the University of Bristol (update of status as of 12 March 2019: 4 journal and 4 conference papers). He started his PhD research in March 2015 on advanced nonlinear control algorithms for Bristol's nano-precision devices such as the Transverse Dynamic Force Microscope under the supervision of Dr Herrmann, Professor Miles and Dr Massimo Antognozzi. His PhD-viva will be on 29 April 2019.

In preparation of further impact and the application for new funding, further actions on outcomes of the project are: The Transverse Dynamic Force Microscope has been successfully used for analysis of artificially engineered proteins (SAGE - Self-assembled peptide cages). This has been our first collaboration with the Department of Chemistry: Professor Dek Woolfson is working on Protein design and its application in bionanotechnology and synthetic biology. This has been a result of discussions in a funding oriented multi-disciplinary, cross university initiative at the University of Bristol (Long-term BristolBridge initiative), but also with the Physics and Astronomy Group at the University of Exeter: The objective is to use the transverse dynamic force microscope for non-contact scanning of biological specimens and specific elements of the cell interior.

Further discussions with the Infection and immunity research group, in the School of Cellular and Molecular Medicine, University of Bristol have been carried out. For instance, the sliding-mode based shear force detection method is a relatively generic approach with many other potential application areas and could be used in a larger scale device for viscosity and elasticity characterisation of viscous fluid layers. This has potential for investigating joint fluids in animals. This is still a more speculative outcome of the discussions at the BristolBridge event.

As a separate device, the development of the x-y stage for the force microscope has created a significant pool of expertise and knowledge in the design of electro-mechanical x-y stages, the use of laser-interferometry for position x-y measurements and the design and implementation of related controllers. First steps have been actively explored to use this knowledge for projects targeting a higher technology readiness level. This has been currently delayed due to the need to review the team, involved in the discussions. Moreover, the University of Bristol Principal Investigator, G Herrmann, is about to change affiliation.
Sectors Education,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Dissemination of the results on both a formal and informal level within the two universities (University of Bristol and University of Exeter), has led to extended interest. In particular, the Institution of Mechanical Engineering (IMECHE) supported a talk at the University of Bristol on 19 March 2015 and generated the first significant impact on engineers within the region of Bristol and Bath and other researchers within the Faculty of Engineering and university wide. Moreover, public talks at schools have created further interest in STEM subjects.
First Year Of Impact 2015
Sector Education
Impact Types Societal

 
Title FPGA-based control and estimation algorithms 
Description Implementation of robust nano-precision H_infinity-based-control algorithms and of nonlinear estimation algorithms in a fixed-point format on FPGA systems at high-implementation frequency of up to 4 MHz. This is to achieve high bandwidth for estimation or control in a real-time environment subject to limited computational resources. 
Type Of Material Computer model/algorithm 
Year Produced 2017 
Provided To Others? No  
Impact (1) Nano-precision control has enabled the non-contact scanning of bio-specimen (2) Fast real-time estimation has enabled real-time identification of shear forces, viscosity and elasticity coefficients within the fluid layer above the specimen to identify material parameters in real-time scans at nano-precision 
 
Description IMECHE Public Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact "Engineering and its impact on biomedical research at nano-scale", 11 March 2015 19:00 - 20:00, talk held by Dr Guido Herrmann (P-I), Dr Toshiaki Hatano (Postdoctoral Researcher) & Gavindu De Silva (Research Intern)
This activity was part of the public talks organised by the Institution of Mechanical Engineering (IMECHE) within the region of Bristol and Bath.
https://nearyou.imeche.org/near-you/UK/Western/Bath---Bristol-Area/event-detail?id=10247
http://research-information.bristol.ac.uk/en/activities/engineering-and-its-impact-on-biomedical-research-at-nanoscale(897b4958-7567-40ed-aa66-68f27411154d).html
These talks are usually attended by engineers working and living within the region of Bristol and Bath. In addition, post-graduate and post-doctoral researchers, undergraduate students, members of other faculties within the University of Bristol attend. This is an ideal way of disseminating the research outcomes. This talk has sparked discussions across the Faculty of Engineering and the University.
Year(s) Of Engagement Activity 2015
URL https://nearyou.imeche.org/near-you/UK/Western/Bath---Bristol-Area/event-detail?id=10247
 
Description Talks on STEM subjects and current engineering research, e.g. the transverse dynamic force microscope, to primary, secondary and A-level students 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Professor Stuart Burgess, one of the co-investigators, has been highly active in disseminating engineering and engineering research to schools to increase the interest in STEM and in particular in engineering subjects among primary, secondary and A-level students. During the following talks, the work on the high precision control and mechanical design problems for the Transverse Dynamics Force Microscope have been particularly mentioned:

- St Mary's, http://www.stmaryscalne.org, a secondary / A-level girls' school, SN11 0DF, Calne, Wiltshire, 28 Jan 2014
- Clifton High School, http://www.cliftonhigh.bristol.sch.uk, a primary, secondary & A-level school, BS8 3JD, Bristol, 10 March 2014
- forthcoming: Emmaus School, http://www.emmaus-school.org.uk, a primary school, BA14 6NZ, Wiltshire, 23 June 2014


Professor Stuart Burgess has been very successful with these presentations at schools. As a result, he has hosted summer placement students within the Faculty of Engineering at the University of Bristol. It is expected that similar summer placement activities will take place in the near future.
Year(s) Of Engagement Activity 2014