Organ failure and tissue loss are challenging health issues due to widespread aging population, injury, the lack of organs for transplantation and limitations of conventional artificial implants. There is a fast growing need in surgery to replace and repair soft tissues such as blood vessels, stent, trachea, skin, or even entire organs, such as bladder, kidney, heart, facial organs etc. The high demand for new artificial implants for long-term repair and substantially improved clinical outcome still remains .Our well-publicised successes in using tissue-engineering to replace hollow organs in cases of compassionate need have shown the world that an engineering approach to hollow organ replacement is feasible, as well as serving to highlight those areas where more work is required to provide bespoke manufactured tissue scaffolds for routine clinical use Being able to replicate a functional part of one's body as an exact match and therefore to be able to replace it 'as good as before' is familiar in science fiction. Most implants will share limitations that are associated with either the materials used or the traditional way in which they have been made. With the advancement of additive manufacturing technology, 3D printing, biomaterials and cell production, printing an artificial organs is becoming a science and engineering fact and understandably can save lives and enhance quality of life through surgical transplantation of such printed organs produced on-demand, specifically for the individual of interest. The project seeks to addresses the unmet need in traditional implants by exploiting our proprietary polymer nanocomposites developed at UCL and advanced digital additive manufacturing with surgical practice. we aim to develop a 3D advanced digital bio-printing system for polymer nanocomposites in order to manufacture a new-generation of synthetic soft organs 'on-demand' and bespoke to the patient's particular needs. Our extensive preclinical and on-going preclinical study on the nanocomposite-based organs will ensure the construct is able to induce angiogenesis and to perform function of an epithelium. Here we take these experiences in the compassionate case, and take trachea as an exemplar to develop a manufacturing method of producing bespoke tubular organs for transplantation with nanocomposite material. This proposal will allow us to develop; a) a customer made 3D bioprinter with multi-printing heads and an environmental chamber which can print 'live' soft organs/scaffolds with seeded cells to meet the individual patients needs; b) a series of polymer nanocomposites suitable for 3D printingorgan constructs/host scaffolds; c) a formulations of bio-inks for printing cells, proteins and biomolecules. d) a printed artificial tracheal constructs using their radiographic images with optimised biochemical, biophysical and mechanical properties. e) Establishment of in-vivo feasibility data through observation of restoration of respiratory function and normal tissue integration of pig models which will be surgically transplanted

Micromachining materials such as ceramics and polymers for use in the medical implant or electronics industry is becoming an increasingly important activity for UK industry. Creating features on the micron scale or depositing coatings on the nanoscale has enabled the above industrial sectors to develop new solutions to such applications as: the acceptance of implants by the human body or patterning of thin conduction layers on touch-screen displays at a high resolution, allowing the phone's owner to watch movies while travelling. All of these breakthroughs in medical devices and microelectronics, are made possible by the creation of small features. Laser Induced Micro Plasma Processing (LIMP2) will be an enabling tool allowing the production of features smaller than the actual laser spot which can be as less than 10 um. LIMP2 would also allow lasers to be used on materials that up to now have been impossible to machine by laser. The aim of the project is to develop an understanding of how a plasma, a highly energetic hot gas, and laser beam interact at the surface of different substrates such as polymers, glass, metals and ceramics. It will attempt to answer such questions as "Can we control the plasma-laser beam interaction using electrical and magnetic fields and in so doing create interesting effects that will allow the plasma to be pinched into an area that is smaller than the laser spot diameter"? In so doing LIMP2 will allow a relative inexpensive laser system to machine directly on the nanoscale. LIMP2 will introduce a new manufacturing technology that will be employed in the manufacturing of high value high performance electronic goods. This will benefit the UK suppliers of laser sources into the electronics production machine market. The other benefit that the general public will see in terms of healthcare. An important application in the medical field is microstructure texturing of medical implants such as stents and artificial joints. LIMP2 can be used to create novel microstructures that have the property of being able to control how a living cell interacts with the surface of the implant. The structures will allow one type of cell to grow while suppressing other types that would prove detrimental to the patient's health, causing swelling of a joint and possible rejection of the implant. The UK companies who are supporting the project will also gain immediate benefits from a successful conclusion of the project. Two laser companies are working together to support the project, one based in the Midlands the other in the South West of England. LIMP2 would open new markets for their laser systems allowing them to compete in the competitive microelectronics market in the Far East. Two of the projects supporting companies Biomer Technology and MicroSystems plan to use LIMP2 in medical devices market but on very different materials. Biomer Technology produces a polymeric coating that they use to coat medical devices. Biomer is interested in LIMP2 micro-machined surfaces that can control cell growth. MicroSystems on the other hand produce micro-moulds for major pharmaceutical companies. MicroSystems see LIMP2 being used on their micro-moulds to produce surfaces that are hydrophilic, (likes water) or hydrophobic, repels water molecules. This type of control over a surface property is very useful not only in the medical device sector but in other sectors such as aerospace, electronics, and the defence industry.

Over 3 million people in the UK suffer from cardiovascular disease causing over 150,000 premature deaths in people under the age of 75. Restriction of blood flow and blockage of blood vessels surrounding the heart leads to interruption of the blood supply to the heart muscle causing heart cells to die. The oxygen shortage, if left untreated can cause damage or death of the heart muscle resulting in heart attack or complete heart failure. Narrowing of the blood vessels in the legs can lead to blockage, amputation and limb loss if left untreated. Patients requiring amputation face a diminished quality of life and severe disability. The primary goal is to restore at least one straight line of blood flow by using a stent depending on the degree of obstruction. The application of stenting is carried out using a minimally invasive approach. A stent is a small mesh tube that is inserted using a catheter, and is deployed at the same time as a balloon is inflated across the diseased vessel wall. The stent acts as a scaffold to hold open the artery to restore blood flow. However, severe healthcare concerns have been raised with current stents, which release drugs through localised allergic reactions, chronic swelling (inflammation) and repeat episodes of thrombosis (or blood clotting), which requires a lifetime prescription of anti-platelet and blood thinning medication causing unwanted side effects followed by repeat surgery. To overcome the current problems with stenting, we plan to build upon our knowledge and expertise to deliver a new generation of stents by developing two products: 1) a novel surface coating with tiny particles embedded in a polymer or plastic coating called nanocomposite polymers, and 2) inclusion of capture antibodies (present on the surface of cells) in to the coating layer to capture stem cells from the circulating blood and converting it to endothelial cells from shear flow, the endothelial is type cells cover entire our cardiovascular system , to protect from blood thrombosis. The nanocomposite polymers have already undergone extensive testing in the laboratory, and in animals demonstrating that the polymer can be potentially used safely in humans. For example, we developed a range of surgical implants using nanocomposite polymers with a number of successful outcomes, such as the world's first synthetic wind pipe over 2.5 years ago and the patient is doing very well, 6 tubes that drain the tears (lacrimal duct) have been carried out in patients to date, and coronary artery bypass graft using same materials has started at Heart Hospital, heart valves at the preclinical. We have already optimised the polymer coating for stents, and in this study our plan is to carry out a final assessment of coated stents and compare them with currently used stents (as product 1). Pre-clinical animal studies will be used to evaluate their effectiveness application in humans. The development of product 2 is at the proof-of-principle stage. Here, we carry out preliminary tests using antibodies (raised against circulatory stem cells in the blood) incorporated in to the polymer coating for capturing stem cells from the blood, and perform tests to obtain sufficient data to apply for funding towards pre-clinical studies. This proposal will enable us to test polymer coated stents in preparation for first-in-man studies after consultation with the MHRA (UK regulatory agencies) and FDA. We will then be in a strong position to apply for funding towards clinical trials, which can be implanted in humans. The development of a new generation of nanocomposite polymer coated stents, which prevent thrombosis along with the inclusion of stem cell capture technology to enhance endothelisationcells would have a significant impact on the global economy, as individuals affected will be active in the workforce for longer, enjoy a greater quality of life and reduce the strain on vital healthcare resources.

Soft tissue related diseases (heart, cancer, eyes) are among the leading causes of death worldwide. Despite extensive biomedical research, a major challenge is a lack of mathematical models that predict soft tissue mechanics across subcellular to whole organ scales during disease progression. Given the tremendous scope, the unmet clinical needs, our limited manpower, and the existence of complementary expertise, we seek to forge NEW collaborations with two world-leading research centres: MIT and POLIMI, to embark on two challenging themes that will significantly stretch the initial SofTMech remit: A) Test-based microscale modelling and upscaling, and B) Beyond static hyperelastic material to include viscoelasticity, nonlinear poroelasticity, tissue damage and healing. Our research will lead to a better understanding of how our bodies work, and this knowledge will be applied to help medical researchers and clinicians in developing new therapies to minimise the damage caused by disease progression and implants, and to develop more effective treatments. The added value will be a major leap forward in the UK research. It will enable us to model soft tissue damage and healing in many clinical applications, to study the interaction between tissue and implants, and to ensure model reproducibility through in vitro validations. The two underlying themes will provide the key feedback between tissue and cells and the response of cells to dynamic local environments. For example, advanced continuum mechanics approaches will shed new light on the influence of cell adhesion, angiogenesis and stromal cell-tumour interactions in cancer growth and spread, and on wound healing implant insertion that can be tested with in vitro and in vivo systems. Our theoretical framework will provide insight for the design of new experiments. Our proposal is unique, timely and cost-effectively because advances in micro- and nanotechnology from MIT and POLIMI now enable measurements of sub-cellular, single cell, and cell-ECM dynamics, so that new theories of soft tissue mechanics at the nano- and micro-scales can be tested using in vitro prototypes purposely built for SofTMech. Bridging the gaps between models at different scales is beyond the ability of any single centre. SofTMech-MP will cluster the critical mass to develop novel multiscale models that can be experimentally tested by biological experts within the three world-leading Centres. SofTMech-MP will endeavour to unlock the chain of events leading from mechanical factors at subcellular nanoscales to cell and tissue level biological responses in healthy and pathological states by building a new mathematics capacity. Our novel multiscale modelling will lead to new mathematics including new numerical methods, that will be informed and validated by the design and implementation of experiments at the MIT and POLIMI centres. This will be of enormous benefit in attacking problems involving large deformation poroelasticity, nonlinear viscoelasticity, tissue dissection, stent-related tissue damage, and wound healing development. We will construct and analyse data-based models of cellular and sub-cellular mechanics and other responses to dynamic local anisotropic environments, test hypotheses in mechanistic models, and scale these up to tissue-level models (evolutionary equations) for growth and remodelling that will take into account the dynamic, inhomogeneous, and anisotropic movement of the tissue. Our models will be simulated in the various projects by making use of the scientific computing methodologies, including the new computer-intensive methods for learning the parameters of the differential equations directly from noisy measurements of the system, and new methods for assessing alternative structures of the differential equations, corresponding to alternative hypotheses about the underlying biological mechanisms.