Hip and knee replacements are very commonly performed surgeries. Joint replacements involve removing the painful portion of bone and replacing it with an implant. More and more patients wish to return to high-impact activities, like running, after a joint replacement. However, high-impact activities are discouraged by surgeons, for fear that they will harm the new joint implant and the surrounding bones - thus, requiring a second surgery. A second surgery is more expensive than the first and riskier for the patient. This project will be the first to quantify the loads experienced by the implants and surrounding bones in high-impact activities after a joint replacement. It is very hard to conduct a 5 to 25-year study following patients over time and precisely measuring how many activities they are doing over these periods. However, computer models can allow us to precisely and efficiently measure the short- and long-term safety of high- and low-impact activities. Our three sub-projects will address this. In our first sub-project, we will recruit individuals with hip and knee replacement who have successfully returned to high-impact activities. All participants will attend a single session of testing. Participants will complete a survey to gather information about their health and activity levels. We will capture motion and force measures and muscle activation patterns, while they will perform short bouts of walking, running, jumping, landing, hopping, and change of direction running. Lastly, participants will wear a small sensor for a week, to measure how much walking and running is done. The objective of this first sub-project is to understand how people move during high- and low-impact activities following a joint replacement. We also want to determine the volume of high- and low-impact activities undertaken by people after a joint replacement in their daily lives. The second sub-project's objective is to determine how different types of activities (high-impact alone, lower-impact alone, or a mixture), different volumes and different movement techniques influence the amount that the new joint implant will wear out. This is crucial to understanding the safety of returning to running, because even though running exerts a higher impact than walking, it is done less frequently, and different running techniques can be used to potentially maximise its long-term safety. We will create computer models of the joints using information from the first sub-project, and create models that mimic many years of performing walking and running, and study the speed and amount of wear on the implants. The objective of the final sub-project is to determine how different types of activities and movement techniques, influence the load experienced by the bone surrounding the new joint implant. By knowing how much load is applied and where it is concentrated, we can determine if these loads can result in bone breaking, or potentially be beneficial to build stronger bones. We will create another set of computer models of the joints to determine if the loads exerted by different activities will exceed the strength of the bone, causing breakage. As joint replacements become more common and people live longer, more patients receiving a joint replacement will wish to return to some form of high-impact activities. High-impact activities have many physical and mental health benefits, like making bones stronger, which cannot easily be achieved by low-impact activities. Additionally younger patients are now receiving joint replacements. Not knowing if and by how much, high-impact activities are harmful, automatically removes the possibility to reap many health benefits from such activities. This will reduce patient satisfaction with the surgery. This project will provide crucial information that clinicians and patients can use to make informed healthcare decisions about the safety of returning to different activities after a joint replacement.

Biological tissues and organs undergo a constant state of dynamical structural and chemical changes with time, which can range from our joint tissues elastic recoil during walking to the slow tissue breakdown as we age, to the very rapid secretion and reaction of proteins by cells in response to sensed mechanical forces. Biological tissues are hierarchical in both structure and function, with protein and DNA architecture at the nano scale leading up to cells and fibrous extracellular matrices at the micron scale to organs at the largest scale. The way such organs operate in a dynamic environment cannot be inferred solely from the gene, but must take into account the processes happening at multiple levels. A classic example is how our joints deteriorate with age, which is - at the molecular level - governed by how proteins levels and composition, at one level higher how they aggregate differently into fibres with poorer elasticity, at a level higher still (microscopic) in how cells react to external loads by changing what proteins they secrete, and finally at the level of the whole organ in how the cell/tissue array becomes less resilient and breaks down with time. A grand challenge is to understand both what this hierarchy of dynamical processes are as well as how they affect tissue functioning, growth and disease. Currently, however, physical-science and engineering methods used in the biomedical field lack the capacity to image these processes dynamically, in a condition close to the living tissue and at multiple levels simultaneously. However, this is potentially possible, due to recent advances in physical-science based high energy imaging methods at central research facilities (like synchrotrons) in specialist methods like 3D X-ray imaging, microfocus diffraction, laser-scanning methods and the use of free-electron lasers to watch molecules vibrate at speeds many orders of magnitude faster than was previously possible. The challenge is coupling these with physiologically realistic environments to enable the imaging of dynamics of biophysical/chemical processes, bridging the huge temporal and spatial scales of these processes, and finally translating these technologies first to the laboratory and then into the clinic. In this network, we will work to make this potential a reality by bringing together leading physical-science and engineering researchers in the UK with biomedical researchers to attack the engineering and biological challenges in a team-effort. We will focus on three areas: i) developing experimental setups using these high energy methods which keep the tissue/cell/organ in a native state ii) devising methods to cross-correlate the information across techniques and iii) linking information obtained at different length scales into a unified picture. Our projects will focus on musculoskeletal degeneration at multiple scales, but we will seek to develop methods that are as widely applicable to other conditions as possible. We will run several short-term proof of concept projects which will allow these teams to test new ideas and whether they work, and fund researchers to spend short-term visits in each other's labs which will help transfer from the physical to the biological sciences. If these results show promise, they will lead to full-scale projects where a biomedically or clinically relevant application can be developed in full. We will hold a range of activities to explore and identify challenges (sandpits and workshops) and to present and analyse the results (annual conferences). The methods and tools we develop will be made widely available to the general academic community to bring them sooner to benefit the general public. Our network, in short, will provide the key proving-ground where the most advanced high energy techniques to analyse complex matter, available only at central facilities, are adapted and made applicable to solve critical questions in the life- and medical-sciences.

The aim of this project is to evolve current unicondylar knee replacement (UKR) design paradigms based on contemporary knowledge of natural knee kinematics. The design concepts shall consider implants specific for knees with varus and valgus deformity, and an all polymer configuration that would remove metal from the replaced joint entirely. To achieve these aims, a large dataset of computed tomography scans of normal, varus and valgus knees will be generated. The geometry and morphology of these data will be analysed using principal component analysis and multivariate statistical methods such that key relationships are identified. These data shall be used to generate implant design concepts for normal, varus and valgus knees that can recreate the natural anterioposterior constraint of the medial tibiofemoral articulation during flexion. Design concepts shall be assessed for implant stress, bone strains and interface micromotion using an experimentally validated finite element (FE) protocol previously generated in our group. Once the FE gives acceptable values, rapid prototypes of the designs shall be manufactured and implanted in cadaver knees by an experienced surgeon. The kinematics during flexion shall be measured using established methods in our laboratory and compared to the natural knee to prove the concept of the prototype design. Successful delivery of the proposal will lead to the development of a UKR with significant advantages over existing devices including more natural kinematics and soft tissue tension, morphology to suit common deformities, and potentially lower cost materials and manufacturing methods. By supporting the final design concepts, the proposed research can be used to support clinical trials of the device or any subsequent regulatory submission. The proposed research is highly likely to succeed due to the close relationship our lab has with orthopaedic surgeons, our track record of commercialising concepts and the support of a well respected industry partner. The environment in which the proposed research will be conducted will therefore allow the project to thrive.

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.

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.