Ligament repair in the ankle for restoration of function: exploring the application of decellularised grafts.

该博士学位将结合联合收割机新的实验测试和成像方法，以检查踝关节韧带和潜在的替代生物材料的机械性能，并确定潜在的组织损伤机制。使用和开发独特的体外测试设备将检查单个踝关节韧带的机械行为及其对正常功能的贡献。该多学科项目将使用先进的成像技术来识别组织内胶原结构的损伤模式。骨固定在踝关节的局限性的评价将导致新的工程方法来解决这个复杂的临床challenge.Research ObjectivesThe主要目的，这个项目是调查的潜力的脱细胞移植踝关节韧带损伤的修复。这将通过以下目标实现：1）天然踝关节韧带及其插入点的表征2）了解关节韧带失效的机制a）识别生物学损伤B）了解由此产生的机械性能变化3）识别所需支架几何形状a）韧带与解剖结构和生物力学功能的对齐B）仅需肌腱或复合骨-肌腱支架c）选择合适的猪韧带组织4）研究合适的固定方法5）与临床医生和患者合作，了解特定的临床需求背景全球范围内，对修复和替换患病或受损的肌肉骨骼组织的干预的需求日益增长。世界卫生组织最近的一份报告表明，地球仪上有20%-33%的人患有疼痛的肌肉骨骼疾病，2011年这种疾病的费用为2130亿美元。足部和踝关节的许多状况对活动性、疼痛和生活质量有显著影响。基础疾病和急性损伤可导致足部和踝关节的功能变化。慢性踝关节不稳定（CAI）影响正常的生物力学功能，并且是高达22%的踝关节骨关节炎（OA）病例发展的一个因素。CAI被认为是踝关节外侧韧带复合体的功能不全，通常由单一创伤事件或初次创伤后的再损伤引起。通过修复踝关节韧带治疗CAI的新方法可以预防或延迟相关OA的发作，并改善患者的生活质量。CAI的修复方法包括解剖（韧带的重新附着）或非解剖（用另一种材料修复，如肌腱）重建。CAI中受损的组织可以用供体组织重建以恢复正常功能。供体组织可以来自患者（自体移植物）或已故供体（同种异体移植物）。同种异体移植物中的供体细胞可以引发免疫反应，导致延迟愈合或组织排斥。重要的是，正常的机械功能是由组织特异性细胞外基质（ECM）介导的，而不需要细胞本身。去细胞化过程从ECM中去除细胞和细胞碎片。所得到的支架提供结构和机械支持，而不会引起不良的免疫反应。利兹大学医学和生物工程研究所已经开发了一系列获得专利的去细胞化方法（利兹方法）。利兹方法涉及开发组织特异性去细胞化过程;组织特异性ECM的使用确保生物学和生物力学特性适合于应用。本研究将深入了解天然韧带的特性及其损伤机制，确定合适的支架尺寸和潜在的固定方法，并确定潜在的失效机制，以建立对CAI修复支架的信心

This PhD will combine novel experimental testing and imaging methods to examine the mechanical performance of ankle ligaments and a potential replacement biomaterial and identify potential tissue damage mechanisms. Use and development of unique in vitro testing equipment will examine the mechanical behaviour of individual ankle ligaments and their contribution to normal function. The multidisciplinary project will use advanced imaging to identify damage patterns in collagen structures within the tissues. Evaluation of the limitations of bony fixation in the ankle will lead to novel engineering approaches to address this complex clinical challenge.Research ObjectivesThe primary aim of this project is to investigate the potential of a decellularised graft for the repair of ankle ligament injury. This will be achieved through the following objectives:1) Characterisation of native ankle ligaments and their insertion points2) Understanding mechanisms of failure of ligaments in the joint a) Identify biological damage b) Understand resultant changes in mechanical properties3) Identification of required scaffold geometriesa) Alignment of ligament with respect to anatomy and biomechanical functionb) Need for tendon-only or composite bone-tendon scaffoldsc) Selection of suitable porcine ligamentous tissue 4) Investigation of suitable fixation methods5) Working with clinicians and patients to understand specific clinical needsBackgroundGlobally, there is a growing need for interventions to repair and replace diseased or damaged musculoskeletal tissues. A recent report by the World Health Organisation suggests that 20%-33% of people across the globe live with a painful musculoskeletal condition, with such conditions costing the US$ 213 billion in 2011. Many conditions in the foot and ankle impact significantly on mobility, pain and quality of life. Underlying disease and acute injury can cause functional changes in the foot and ankle. Chronic ankle instability (CAI) affects normal biomechanical function and is a factor in the development of up to 22% of ankle osteoarthritis (OA) cases. CAI is regarded as insufficiency in the lateral ankle ligament complex, usually caused by a single traumatic event or re-injury after initial trauma. New methods to treat CAI by repairing ligaments in the ankle could prevent or delay the onset of related OA and improve patient quality of life. Repair methods for CAI include anatomical (reattachment of the ligament) or non-anatomical (repair with another material, such as tendon) reconstruction. Damaged tissues in CAI may be reconstructed with donor tissue to restore normal function. Donor tissues can be from the patient (autograft) or a deceased donor (allograft). Donor cells within allografts can trigger an immune response, resulting in delayed healing or tissue rejection. Importantly, normal mechanical function is mediated by the tissue-specific extracellular matrix (ECM) and the cells themselves are not required. Decellularisation processes remove cells and cellular debris from the ECM. The resulting scaffolds provide structural and mechanical support without provoking an adverse immune response. A series of patented decellularisation processes (the Leeds approach) have been developed in the Institute of Medical and Biological Engineering at the University of Leeds. The Leeds approach involves developing a tissue-specific decellularisation process; the use of tissue-specific ECM ensures that the biological and biomechanical properties are appropriate for the application. A recently developed process produces a porcine bone-tendon scaffold which may be a suitable for ligament repair.This project will develop a detailed understanding of the properties of natural ligaments and their injury mechanisms, identify appropriate dimension and potential fixation methods for the scaffolds and identify potential failure mechanisms to build confidence in the scaffolds for CAI repair