develop decellularised hBPTB grafts scaffolds that reduce the risk in developing osteoarthritis in ACL reconstructed knees.

Background
Rupture of the anterior cruciate ligament (ACL) is becoming increasingly prevalent in younger populations with more active lifestyles. It has been estimated to occur at an annual rate of 1 in 3000 in the US alone, translating to over 100,000 interventional surgeries to restore joint stability. Current best practice surgical reconstruction techniques involve using autologous or allogeneic replacement ACL grafts, but these have drawbacks including initial necrosis, degeneration and slow incorporation. Additionally, ACL reconstruction has been associated with the onset of osteoarthritis with studies finding a greater prevalence of arthritis in ACL reconstructed knees. Engineering innovations to combat these drawbacks include the development and optimisation of regenerative replacement grafts with controlled functional performance criteria to better restore joint stability.
Decellularised biological tissues such as human bone-patellar tendon-bone (hBPTB) [produced by University patented processes] offer an exciting alternative approach to replace damaged ACLs without the disadvantages of autografts and allografts. These grafts are derived from natural tissue but the cells and DNA are removed to prevent 'rejection' by the patient. Furthermore, they offer flexibility in their manufacturing bioprocess to tailor the biomechanical properties to match different patient populations (age, gender, activity etc.). However, further research in their development, implementation and performance is required in order to optimise their use and prevent the onset of degenerative changes including osteoarthritis.
Aims & objectives
The aim of this PhD proposal is therefore to develop decellularised hBPTB grafts scaffolds that reduce the risk in developing osteoarthritis in ACL reconstructed knees through optimisation of the graft manufacturing processes, surgical implementation and associated functional assessment, in collaboration with industrial (NHS Blood and Transplant Tissue and Eye Services) and clinical (Mr Guy, consultant orthopaedic surgeon) partners. The core objectives are:
1. Determining the precision biomechanical property requirements of decellularised hBTBs through a population specific and stratified approach. Although other parameters such as age and body mass index affect the properties of human ACLs, the sex of the individual remains the parameter most strongly associated with biomechanical properties. This segment of the proposal will allow for the stratification of decelluarised hBTB products for male and female populations by manipulation of the manufacturing bioprocess.
2. Identifying the correct fixation methods (e.g. screws, suspension devices) and tensioning involved in implanting these products and optimising the product/host interface. To assess the effects of decellularised hBTB fixation on the in-situ structural properties of the surrounding bone environment based on CT imaging and the stability using biomechanical testing. Clinical insight will be provided by the consultant surgeon on the project team.
3. Developing tools to assess the biomechanical function of the developed product and implementation strategy with reference to the native ACL structure it is intended to replace and current gold standard replacement grafts (allografts) through access to the industrial partner's tissue banking service.
Strategic alignment with funding opportunities
The proposal is exceptionally well aligned to the "21st Century Products" priority area within the strategic theme of "Manufacturing the Future" identified by the EPSRC for future research grant funding. The research also addresses the "Developing Future Therapies" and "Optimising treatment" areas within the EPSRC's "Healthcare Technologies" theme. Furthermore, opportunities to translate findings are high with an industrial partner in place and evidence generated in the studentship can be utilised for future impact case studies.