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

前交叉韧带（ACL）断裂在生活方式更活跃的年轻人群中越来越普遍。据估计，仅在美国，其年发生率为1/3000，转化为超过100，000例介入手术以恢复关节稳定性。目前最佳实践的外科重建技术涉及使用自体或同种异体替代ACL移植物，但这些移植物具有缺点，包括初始坏死、变性和缓慢结合。此外，ACL重建与骨关节炎的发生有关，研究发现ACL重建膝关节的关节炎患病率更高。克服这些缺点的工程创新包括开发和优化具有受控功能性能标准的再生置换移植物，以更好地恢复关节稳定性。脱细胞生物组织，如人骨-髌腱-骨（hBPTB）[由大学专利工艺生产]，提供了一种令人兴奋的替代方法来替代受损的骨，而没有自体移植物和同种异体移植物的缺点。这些移植物来自天然组织，但细胞和DNA被移除以防止患者的“排斥”。此外，它们在制造生物过程中提供灵活性，以定制生物力学特性，以匹配不同的患者人群（年龄，性别，活动等）。然而，为了优化它们的使用并预防退行性变化（包括骨关节炎）的发生，需要对其开发、实施和性能进行进一步研究。手术实施和相关的功能评估，与工业（NHS血液和移植组织和眼科服务）和临床（盖伊先生，顾问整形外科医生）合作伙伴。核心目标是：1.通过群体特异性和分层方法确定去细胞化hBTB的精确生物力学性质要求。虽然其他参数，如年龄和身体质量指数影响人体骨骼的属性，但个体的性别仍然是与生物力学性能最密切相关的参数。提案的这一部分将允许通过操纵生产生物工艺对男性和女性人群的脱细胞hBTB产品进行分层。确定植入这些产品时涉及的正确固定方法（例如螺钉、悬吊装置）和张力，并优化产品/主机界面。基于CT成像评估脱细胞hBTB固定对周围骨环境原位结构特性的影响，并使用生物力学测试评估稳定性。临床见解将由项目团队的顾问外科医生提供。开发工具，以评估开发产品的生物力学功能和实施策略，参考原生ACL结构，其旨在通过访问工业合作伙伴的组织库服务来替代当前的金标准替代移植物（同种异体移植物）。该提案与EPSRC为未来研究补助金资助确定的“制造未来”战略主题内的“21世纪产品”优先领域非常一致。该研究还涉及EPSRC“医疗保健技术”主题中的“开发未来疗法”和“优化治疗”领域。此外，有了工业合作伙伴，翻译研究结果的机会很高，在学生期间产生的证据可以用于未来的影响案例研究。

BackgroundRupture 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 & objectivesThe 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 opportunitiesThe 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.