Over the last decades manufacturing in UK regions has been exposed to intense global competition, particularly as a consequence of trade liberalisation. At the same time, there is an increasing recognition that regions play a central role in national development, and there are mounting pressures on regions' ability to independently strategise and interconnect globally. These trends are particularly visible in the redistribution of power and funding from national to local government currently occurring through the so-called devolution deals, and through the emergence of Local Enterprise Partnerships that since 2010 have succeeded Regional Development Agencies. The renaissance of industry and manufacturing and the recognition that industry plays a central role in job creation, growth, and regions' economic recovery is also a priority in the policy agenda, with the 'Northern Powerhouse' strategy dominating the political lexicon, and setting the ambition to deliver business and enterprise growth with economic benefits for local communities. However, without adequate technology foresight and the identification of emergent technologies that may lead to innovations in practice, industrial manufacturing regions face the challenge of industrial stagnation and the threats of global outsourcing. Therefore, it is critical for regions to overcome the debilitating problem of poor innovation capabilities reinforced by the frequent overspecialisation of the knowledge infrastructure in these areas. It is also necessary to identify the technology enablers that may lead to opportunities for development and growth: the upgrading or revitalisation of businesses; the development of new business activities in areas related to the existing industries; or new industries based in new technologies. Focusing on Sheffield City Region as an internationally recognised manufacturing hub, and on the Advance Manufacturing and Materials sector, this project will generate new knowledge and procedural solutions to the extremely important issue relating to the enhancement of a region's ability to identify and exploit knowledge of technological innovations, in order to maximise competitiveness and sustainability. Working closely with firms, local enterprise partnerships, policy makers and innovation experts, the project focuses on the understanding and development of concrete regional practices and processes for identifying, transferring and integrating technological innovations. This set of practices and processes includes the identification of relevant emergent technologies, the production of visions concerning their applicability (e.g. ability to generate product, processes or business innovations), and the contextualisation and application of the knowledge produced (brokerage activities) to allow exploitation and use in practice by firms.

Osteoarthritis (OA) affects about 10% of the global population. It has a major impact on a patient’s quality of life; with pain and physical function being worse than chronic obstructive pulmonary disease or even cardiovascular disease. Its prevalence is increasing, by 2020 it will be the 4th leading cause of disability. OA is caused by ‘wear and tear’ and currently only symptoms are treated using pain killers until major surgery is needed, then the joint is replaced. Although joint replacements have improved and often last over 30 years, they do fail with about 10% of all joint replacement operations being to fix a failed implant. In this project JRI is working with University Medical Center Utrecht (UMCU), The Netherlands and the Cell and Gene Therapy Catapult (CGT), UK, to develop a new treatment of OA in the hip and take it to market. This involves catching the disease early when it appears as a distinct lesion. JRI has developed Hummingbird, a system that can get into the complex anatomy of the hip and precisely cut out patches of diseased tissue. Then treating these patches with a cell-based treatment developed by UMCU and successfully used to treat OA in the knee. JRI believes that this treatment can be provided at a competitive price and at a scale to meet the global market. However, to do this they will need to build a robust business case and define in detail the regulatory pathways to the markets in Europe and USA. They will do this by working with CGT. This Feasibility Study is the first phase of this work. With CGT, JRI will define: the regulatory pathway, the cost of providing the treatment, the reimbursement methods and the likely market share. The second phase will be in the first-in-human study and a critical step in both meeting the regulations and defining the benefits to this cell-based treatment being applied to the hip. This treatment may not cure OA, but should delay major joint surgery and, in time, may allow some to avoid it all together.

Osteoarthritis (OA) is a degenerative joint disease caused by loss of hyaline articular cartilage. Given the spread of OA in elderly patients and the desirability of avoiding extensive surgery, there is strong interest in developing minimally-invasive cell-based therapies to replace damaged articular cartilage. It is well-recognised that bone marrow-derived mesenchymal stem cells (MSC) can readily differentiate to chondrocytes in vitro, and are thus a promising source for OA cell therapy. However, there are two major challenges facing MSC-based therapies: firstly, it is difficult to direct MSC to differentiate to hyaline cartilage, and secondly, future therapies would require the development of a biocompatible material scaffold capable of maintaining the phenotype of MSC-derived chondrocytes following transplantation. Differentiation of hyaline chondrocytes: MSC chondrogenesis in vitro is poorly controllable, with the resulting chondrocytes resembling the transient hypertrophic chondrocytes that serve as a template for bone formation, rather than the permanent hyaline chondrocytes required for the normal functioning of joints. The laboratory of the lead academic supervisor (PM) has recently shown that novel biomimetic material substrates containing specific fibronectin-based motifs can induce the differentiation of bone marrow-derived MSC to nascent chondrocytes, without the need for additional growth factors (see above, PM research experience). The chondrocytes that form under these conditions express markers of early differentiating chondrocytes, such as N-cadherin, Sox9 and collagen II, which are expressed in the progenitors of both hypertrophic and hyaline chondrocytes. Recently, much progress has been made towards elucidating the mechanisms that regulate the differentiation of these two chondrocytic cell types in vivo. Interestingly, the formation of hyaline cartilage is not only dependent on factors with chondrogenic activity, such as the TGF-b family member, Gdf5, but is also dependent on the activity of anti-chondrogenic factors, such as Wnt9a. Biomaterials for chondrocyte transplantation: Although some progress has been made towards the development of biomaterial scaffolds for transplantation of primary hyaline chondrocytes, a major problem is that over time, the transplanted chondrocytes fail to maintain their phenotype and tend to form fibrocartilage. A likely reason for this is that following transplantation, the chondrocytes are no longer exposed to the culture medium components that help maintain their phenotype in vitro. Various approaches have been taken to improve the performance of biomaterial scaffolds, many of which involve incorporating signalling molecules or peptidic motifs into the scaffold matrix. However, it has proved difficult to achieve the correct density of ligands/motifs needed to elicit the required cellular response. The group of the academic co-supervisor (OM) has developed a novel self-assembling protein co-polymer (termed ZT) with proven bottom-up functionalization capabilities that holds high promise to overcome many of these problems (see above, OM research experience). Project Aims: [1] To establish culture conditions capable of directing the differentiation of nascent chondrocytes derived from MSC to hyaline, rather than hypertrophic cartilage. [2] To test if the growth factors identified in 1 can be replaced by small molecular weight mimetics or peptidic motifs. [3] To fabricate molecularly engineered variants of the ZT biomaterial scaffold to incorporate the key motifs/peptide motifs identified in 2. [4] To determine if the molecularly engineered biomaterials fabricated in 3 are able to maintain the phenotype of MSC-derived hyaline chondrocytes in vitro. [5] To implement a commercialisation strategy for culture conditions, media compositions and engineered biomaterials derived from this work that are capable of maintaining the phenotype of hyaline chondrocytes.

Template-assisted electrohydrodynamic atomisation (TAEA) spray-patterning is a novel, recently patented, method which allows the production of interlocked bioactive coatings on flat metallic substrates. The pattern geometry can be varied by simply changing the template geometry and dimensions. The process is based on stable jetting of a flowing liquid/suspension subjected to an electric field and is carried out at the ambient temperature and pressure. It is easy to control this rapid process using the applied voltage, the flow rate and the working (collection) distance between the flow nozzle and the substrate. Because of the interlocking of the bioactive coating with a patterned buffer layer coating, previously deposited via TAEA, this method of bioactive patterning also allows better adhesion of the coating. Also, the biological response to TAEA patterned bioactive deposits by cellular entities has proven to be more favourable. These factors compare very favourably when considering the fact that conventional plasma spraying, which is usually used to just plainly cover-coat bioactive materials on metallic substrates, is carried out at extremely high temperatures (about three orders of magnitude higher) and is difficult to control especially when it comes to the preparation of thin coatings. According to industry sources, economic loss due to malfunction and shutdown time involved with plasma spraying is very significant and the industry is looking to uncover and implement alternatives. This project proposed is concerned with investigating the use of TAEA bioactive patterning on curved surfaces in order that the process is ideal for the preparation of clinical inserts and implants, especially for the orthopaedics sector which is the business of the industrial project partner. This will ensure that the process can be implemented in many real implants which have both flat and curved surfaces. The project work endeavours to systematically investigate TAEA spraying of bioactive nanostructured hydroxyapatite onto curved biometallic substrates, such as orthopaedic titanium alloys, starting from well-characterised suspensions and solutions - the viscosity, surface tension and electrical conductivity of which affect stable jetting. Convex and concave titanium alloy substrates of different diameter will be prepared, together with a variety of fitting curved copper mesh-templates which allow different patterns to be deposited - lined, hexagonal and square. One key difference between flat and curved surface TAEA will be the varying working distance encountered as spraying takes place. This can result in uneven coating thicknesses and inhomogeneties. In order to counteract this, an automated conveyer system which will enable the substrate to be held and moved in and out and/or rotated will be put in place, and the design, construction and implementation of this strategy will be a key part of the project. The microstructures of the curved surface TAEA coatings produced will be studied mainly by electron microscopy. Adhesion and mechanical properties of the coatings will be fully assessed using scratch- and nano-indentation techniques; evaluating adhesion, hardness/scratch hardness and the generation of load-displacement data from which the elastic modulus and the yield strength will be estimated. An attempt will also be made to calculate fracture toughness and residual stresses using any indentation cracks which might be present on the coatings. The coatings will also be subjected to cell culture tests in order to ascertain bioactivity. Two other aspects will also be investigated: Firstly, using an improved and simpler on-line heat treatment to consolidate the titania buffer layer on the substrate will be tried out. Secondly, we shall attempt to do co-axial (co-flow) TAEA which will pave the way for composite polymer-ceramic bioactive deposits or bioactive deposits doped with other ingredients like antibiotics and growth factors.