In this research, I will develop a cyber-physical system (CPS) for the diagnosis and treatment of lung diseases. My project is motivated by three facts: 1) Lung cancer treatment is most successful when it is found at an early stage. Treatment of early-stage cancer offers 73% chance of survival, whereas in late-stage this is reduced to 13%. However, the current methods for early diagnosis of peripheral lung lesions using bronchoscopic biopsy are challenging with varying diagnostic yield. Thus, there is a need to develop new technologies for reliable diagnosis of cancer in the lung periphery. 2) At present, surgical resection of malignant nodules (Tumours<3cm diameter) in the lung is the treatment modality of choice. However, most patients are not suitable surgical candidates, thus prompting the need for other therapeutic options. An emerging less invasive treatment option is bronchoscopic ablation of lung cancer via delivering physical therapy to lesions in the lung (cryotherapy/photonic ablation). Bronchoscopic ablation is not widely used to treat lung cancer, primarily due to the limited depth of penetration and small range of motion of the bronchoscope. 3) The overall in-hospital mortality rate for patients in ICU with ventilator associated events approaches 30%. New pulmonary infiltrates are a diagnostic challenge and due to the poor sampling methods available, patients are often initiated on non-targeted therapies. Bronchoscopy and sampling of the distal lung in diffuse diseases is not standardised and lacks repeatability and requires expert operators. The key aim of this research is to democratise ICU bronchoscopy and develop a platform using vision computing, EMT and external registration to enable non-skilled operators to sense, sample and diagnose pathology in vivo in situ. To this end, I propose a CPS that addresses the unique issues of bronchoscopic diagnosis and treatment of lung diseases using novel mechatronic systems, control algorithms, and image guidance. The CPS has the potential to deliver unified diagnosis and treatment platform for early-stage lung cancer and on-site differential diagnosis of diffuse lung diseases by enhancing the current bronchoscopic technology in two specific ways: 1) Manipulation augmentation: I will design and develop a mechatronic device comprised of an active mini-bronch and a user interface for steering. The active mini-bronch is made of a flexible robot equipped with an endoscopic camera, fibre-optics for molecular imaging/sensing of tissue. It also provides a working channel that can be used for ablation of cancerous tissue or tissue sampling. The proposed mechatronic device can be used in two scenarios: (1) Autonomous tissue sampling in intensive care units: The mini-bronch uses control algorithms to navigate to lung subsegments and take multiple samples for diagnosis, (2) Semi-autonomous tissue diagnosis/treatment: the operator uses the user interface to navigate the mini-bronch to the periphery of the lung, characterise, sample and detect cancerous tissue, and then ablate . My control algorithms will provide unprecedented capabilities in terms of dexterity, safety, and ease of operation. 2) Visual augmentation: A key goal is to develop algorithms that employ emerging molecular imaging techniques to provide an imaging technology for in-vivo diagnosis of lung diseases. I postulate that the proposed CPS will enable rapid on-site evaluation of lung diseases and successful bronchoscopic detection and therapy.

The unique properties of light have made it central to our high-tech society. For example, our information-rich world is only enabled by the remarkable capacity of the fibre-optic network, where thin strands of glass are used to carry massive amounts of information around the globe as high-speed optical signals. Light also impacts areas of our society as diverse as laser-based manufacturing, solar energy, space-based remote sensing and even astronomy. One area where the properties of light open up otherwise-impossible capabilities is medicine. In ophthalmology for example, lasers are routinely used to perform surgery on the eye through corneal reshaping. This involves two different lasers. In the first step, a laser producing very short pulses of infrared light cuts a flap in the front surface of the eye to provide access. In the second step, another laser producing longer pulses of ultraviolet (UV) light sculpts the shape of the cornea and correct focusing errors. The flap is then folded back into place so that the cornea can heal. The two very-different laser systems in that example illustrate an important point: the effects of light on human tissues are highly-dependent on the specific properties of both the light and the tissues involved. To sculpt the cornea, the laser wavelength of 193 nm is in the deep UV region of the electromagnetic spectrum, much shorter than the visible range (380 - 740 nm) we are familiar with. This is because (unlike visible light) it is very efficiently absorbed by the cornea, so that essentially all the energy of the light is deposited at the surface. Thus only a very thin layer of tissue (a few microns thick) is removed, or "resected", with each pulse of light, facilitating very-precise shaping of the cornea and accurate adjustment of its focusing properties. 193 nm light can be generated by an ArF excimer gas laser, a >40 year-old technology producing a poor-quality low-brightness beam of light. This is suitable for corneal reshaping, but not for a range of other important therapies requiring higher-quality deep UV beams. Unfortunately, alternative ways to generate such short wavelengths are non-trivial, resulting in complex and expensive laser systems not suitable for widespread clinical uptake. U-care aims to address this gap by exploiting cutting-edge techniques in laser physics. We will develop new sources of deep UV light which will be highly compact, robust and low cost. We will develop ways to deliver this light precisely to tissues, and work to understand in detail the biophysical mechanisms involved. Our efforts will focus on new therapies that target some of the biggest challenges facing medicine: cellular-precision cancer surgery, and the emergence of drug-resistant "super-bugs". Importantly, U-care will involve engineers and physical scientists working in close collaboration with clinicians and biomedical scientists to verify that the therapies we develop are effective and safe. By doing so in an integrated manner, we will drive our deep-UV light therapies towards healthcare impact and widespread use in the clinic by 2050.

In the 1980s it began to be possible to produce potentially unlimited quantities of human proteins by placing the gene defining them in a simple organism such as yeast. From this grew a new kind of medicine capable of treating conditions such as severe arthritis, haemophilia, growth deficiency, and some cancers that previously had no satisfactory treatments. As well as having great clinical value the resulting technology has become the basis of a new and fastest growing part of the pharmaceutical industry, described as biopharmaceuticals. Because the molecules involved are proteins, they are orders of magnitude larger and more complex than conventional drugs such as aspirin and their processing is much more demanding. They are also so complex that they cannot in general be characterised with precision except in relation to the methods by which they are made. That means the capacity to precisely define such processes is critical to clinical safety and commercial success. Full scale trials of the processes are so costly they can only be conducted once clinical promise is established but, given the number of factors governing processing of even first generation products, there have often been hold-ups so extensive as to delay availability to patients. UCL has pioneered micro scale methods that are sufficiently good at predicting efficient conditions for large scale performance that far fewer and better focussed large scale trials suffice. That resolves part of the problem but an even greater challenge is now emerging. The early biopharmaceuticals were in general the easiest ones to produce. The final scales were also relatively modest. Now, the next generation of biopharmaceuticals are more complex materials and with rising demand the scales are far larger so that processes push the boundaries of the possible. The combined complexity of the product and the process with so many variables to consider means that the managers need better systematic means of supporting their decisions. Already the cost of developing a single biopharmaceutical can exceed 0.7 billion and take 10 years. With more advanced biopharmaceuticals these figures tend to rise and yet the world's governments are facing a healthcare cost crisis with more older people. They therefore exert pressure on companies to reduce prices. Because the public wishes to have medicines that do not pose risks, regulations become ever more stringent so they are a major factor in defining the bioprocess. This also adds to the need for managers to have sector-specific decisional-support aids well grounded in the detailed engineering of the processes. Finally, it is now possible to apply molecular engineering to proteins and vaccines to enhance their therapeutic properties but this can also cause serious bioprocessing problems. The research vision developed with detailed input from UK industry experts will apply these methods as the foundation for another step change whereby much faster and lower cost information can be gathered and integrated with advanced decisional techniques to give managers a better foundation on which to base their policies. The academic team from leading UK universities provides the necessary continuum of skills needed to assess the ease of manufacture of novel drugs, the costs of processing and of delivery to patients. We will work with companies to test the outcomes to ensure they are well proven prior to use on new biopharmaceuticals. This will cut costs so that all the patients who might benefit can receive them and at the earliest possible date achieved within the severely restricted budgets now available to the NHS.

The broad theme of the research training addresses the most rapidly developing parts of the bio-centred pharmaceutical and healthcare biotech industry. It meets specific training needs defined by the industry-led bioProcessUK and the Association of British Pharmaceutical Industry. The Centre proposal aligns with the EPSRC Delivery Plan 2008/9 to 2010/11, which notes pharmaceuticals as one of the UK's most dynamic industries. The EPSRC Next-Generation Healthcare theme is to link appropriate engineering and physical science research to the work of healthcare partners for improved translation of research output into clinical products and services. We address this directly. The bio-centred pharmaceutical sector is composed of three parts which the Centre will address:- More selective small molecule drugs produced using biocatalysis integrated with chemistry;- Biopharmaceutical therapeutic proteins and vaccines;- Human cell-based therapies.In each case new bioprocessing challenges are now being posed by the use of extensive molecular engineering to enhance the clinical outcome and the training proposed addresses the new challenges. Though one of the UK's most research intensive industries, pharmaceuticals is under intense strain due to:- Increasing global competition from lower cost countries;- The greater difficulty of bringing through increasingly complex medicines, for many of which the process of production is more difficult; - Pressure by governments to reduce the price paid by easing entry of generic copies and reducing drug reimbursement levels. These developments demand constant innovation and the Industrial Doctorate Training Centre will address the intellectual development and rigorous training of those who will lead on bioprocessing aspects. The activity will be conducted alongside the EPSRC Innovative Manufacturing Research Centre for Bioprocessing which an international review concluded leads the world in its approach to an increasingly important area .

It is now widely accepted that up to ten years are needed to take a drug from discovery to availability for general healthcare treatment. This means that only a limited time is available where a company is able to recover its very high investment costs in making a drug available via exclusivity in the market and via patents. The next generation drugs will be even more complex and difficult to manufacture. If these are going to be available at affordable costs via commercially viable processes then the speed of drug development has to be increased while ensuring robustness and safety in manufacture. The research in this proposal addresses the challenging transition from bench to large scale where the considerable changes in the way materials are handled can severely affect the properties and ways of manufacture of the drug. The research will combine novel approaches to scale down with automated robotic methods to acquire data at a very early stage of new drug development. Such data will be relatable to production at scale, a major deliverable of this programme. Computer-based bioprocess modelling methods will bring together this data with process design methods to explore rapidly the best options for the manufacture of a new biopharmaceutical. By this means those involved in new drug development will, even at the early discovery stage, be able to define the scale up challenges. The relatively small amounts of precious discovery material needed for such studies means they must be of low cost and that automation of the studies means they will be applicable rapidly to a wide range of drug candidates. Hence even though a substantial number of these candidates may ultimately fail clinical trials it will still be feasible to explore process scale up challenges as safety and efficency studies are proceeding. For those drugs which prove to be effective healthcare treatments it will be possible then to go much faster to full scale operation and hence recoup the high investment costs.As society moves towards posing even greater demands for effective long-term healthcare, such as personalised medicines, these radical solutions are needed to make it possible to provide the new treatments which are going to be increasingly demanding to manufature.