A Treatment Paradigm for Femoracetabular Impingement (FAI)

翻译后摘要：少于1/5的年轻患者患有活动限制髋关节骨关节炎（OA）选择 接受全髋关节置换术（THR），而不是选择症状管理。尽管是 髋关节OA的标准治疗，THR不是年轻患者人群的理想手术，因为 在其一生中需要多次翻修手术，每次迭代都会造成额外的并发症， 植入物失效和总体满意度下降。虽然这一年轻人群的疾病病因是 多种多样，一个明确的干预目标是股骨髋臼撞击（FAI），它直接导致 关节内的骨软骨炎（OC）损伤。目前，没有有效的治疗OC病变 所以这些关节会继续退化，最终需要THR。因此，有一个关键的 需要新的干预措施来延缓或阻止FAI疾病的进展， 更换.我们的技术可以恢复关节的功能，同时只替换表面的病变， 组织.我们植入物的技术基础是一种3D编织支架，旨在模拟机械 关节软骨的特性，然后将其热粘合到刚性印刷基底上， 促进骨长入为了在体内长期发挥作用，植入物必须填充有能够在细胞中表达的细胞。 稳健的组织合成。在这种情况下，预培养与骨髓来源的间充质干细胞（MSC） 可能需要临床使用。然而，显然需要证明高密度聚乙烯的软骨形成潜力。 在临床使用前，对不同MSC批次进行了检测。此直接进入第二阶段SBIR应用程序的目标是 因此，首先设计一种用于快速筛选同种异体MSC的软骨形成潜力的方法， 在目标1中使用RNA测序，然后在目标2中使用RNA测序，以组织工程化基于MSC的关节表面置换 在FAI（CAM型）绵羊模型中植入修复大OC髋臼缺损的植入物， 与年轻病人有关所有动物将接受骨软骨成形术， 撞击，然后随机分配至以下组之一：1）对照组，仅清创; 2）无细胞 “仅植入物”对照;和3）同种异体的基于MSC的组织工程化植入物。结局指标为 在研究期间选择纵向跟踪跛行、疼痛和功能。因为MRI是诊断的黄金标准， 在临床评估中，所有动物将在研究开始时和处死后接受MRI，这些 扫描将与关节组织的组织学和生物力学特性相关。全身毒性试验 还将根据ISO 10993-11进行评估。我们期待积极的成果将使我们能够推动这一进程， 技术更接近临床实践，最终目标是制定治疗FAI和其他疾病的策略。 软骨相关疾病

Abstract: Fewer than 1 in 5 young patients suffering from activity limiting hip osteoarthritis (OA) choose to undergo total hip replacement (THR) surgery, opting instead for symptom management. Despite being the standard of care in hip OA, THR is not an ideal procedure for the young patient population because they will require multiple revision surgeries in their lifetime, each iteration posing additional complications, quicker implant failures, and overall decreased satisfaction. While the etiology of disease in this young population is diverse, one clear target for intervention is femoroacetabular impingement (FAI), which directly leads to osteochondral (OC) damage within the joint. Currently, there are no effective treatments for the OC lesions caused by FAI, so these joints continue to degenerate and eventually require a THR. As such, there is a critical need for new interventions that delay or halt the progression of FAI disease and the need for that initial joint replacement. Our technology restores the function of the joint while only replacing the surface-level, diseased tissue. The technological basis of our implant is a 3D woven scaffold, engineered to mimic the mechanical properties of articular cartilage, which is then thermally bonded to a rigid printed substrate, which is engineered for bone ingrowth. In order to function long-term in vivo, the implant must be populated with cells capable of robust tissue synthesis. In this context, preculture with bone marrow derived mesenchymal stem cells (MSCs) may be required for clinical use. However, a clear need exists to prove the chondrogenic potential of highly variable MSC lots prior to their use clinically. The goals of this Direct to Phase II SBIR application are therefore to first devise a method for rapidly screening the chondrogenic potential of allogeneic MSCs using RNA sequencing in Aim 1, and then in Aim 2, to tissue-engineer a MSC-based joint resurfacing implant to repair a large OC acetabular defect in an ovine model of FAI (CAM-type), at a site often implicated in the young patient. All animals will receive an osteochondroplasty procedure to relieve impingement and then be randomized to one of the following groups: 1) Control, debridement only; 2) acellular ‘implant only’ control; and 3) allogeneic MSC-based, tissue-engineered implant. Outcome measures are selected to longitudinally track lameness, pain, and function during the study. As MRI is the gold standard for clinical assessment, all animals will receive an MRI at the beginning of the study and after sacrifice, and these scans will be correlated to histological and biomechanical properties of joint tissues. Systemic toxicity testing will also be assessed according to ISO 10993-11. We expect that positive outcomes will enable us to move this technology closer to clinical practice, with the ultimate goal of developing strategies to treat FAI and other cartilage-related disease.