A Treatment Paradigm for Femoracetabular Impingement (FAI)

摘要：只有不到1/5患有活动受限的年轻髋关节骨性关节炎(OA)患者选择 接受全髋关节置换(THR)手术，而不是进行症状处理。尽管他是 髋关节骨性关节炎的标准护理，全髋关节置换对于年轻患者来说不是一个理想的手术，因为他们会 需要在其生命周期中进行多次翻修手术，每次迭代都会带来额外的并发症，速度更快 植入失败，总体满意度下降。而在这一年轻人群中，疾病的病因是 不同的、明确的干预目标是髋臼撞击(FAI)，它直接导致 关节内的骨软骨(OC)损伤。目前，还没有针对OC病变的有效治疗方法。 由FAI引起，因此这些关节继续退化，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，以及需要最初的关节 替补。我们的技术恢复了关节的功能，而只替换了表层的，病变的 组织。我们植入物的技术基础是3D编织支架，设计成模仿机械 关节软骨的性能，然后将其热结合到工程设计的刚性印刷基板上 用来长出骨头。为了在体内长期发挥作用，植入物必须填充能够 强大的组织合成能力。在此背景下，与骨髓间充质干细胞(MSCs)预培养 可能需要临床使用。然而，显然需要证明高度的软骨形成潜力。 临床使用前的可变MSC批次。这种直接到第二阶段SBIR应用的目标是 因此，首先设计一种快速筛选同种异体骨髓间充质干细胞成软骨潜能的方法 在目标1中使用RNA测序，然后在目标2中，对基于MSC的关节表面进行组织工程 植入修复FAI(CAM型)绵羊模型中较大的OC髋臼缺损，在通常 与这名年轻病人有关。所有动物都将接受骨软骨成形术以缓解 然后随机分为以下组之一：1)对照组，仅清创；2)去细胞 “仅植入”对照；以及3)基于同种异体间充质干细胞的组织工程化植入。结果衡量标准是 选择用于纵向跟踪研究期间的跛行、疼痛和功能。因为核磁共振成像是 临床评估，所有动物都将在研究开始和牺牲后接受核磁共振检查，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 也将根据国际标准化组织10993-11进行评估。我们希望，积极的结果将使我们能够推动这一进程。 技术更接近临床实践，最终目标是开发治疗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.