Multicenter Cartilage Repair Preclinical Trial in Horses

描述（由申请人提供）：骨关节炎（OA）是导致残疾的主要原因。需要新的临床策略来改善受损关节软骨的评估、修复和再生，以预防或延迟致残性疼痛和OA的发作。该提案的目标是进行综合的多学科大型动物研究，以推进美国关节软骨损伤和退化的临床治疗和评估。微骨折是一种从软骨下骨获取修复细胞的简单且微创的技术，是该国最广泛使用的软骨修复程序。然而，微骨折是不一致的，并且产生耐久性差的纤维到纤维软骨修复组织。尽管许多研究表明，通过处理骨髓以选择和植入多能细胞组分以及一些国际人类病例报告，可以改善基于BMC的软骨修复的一致性和质量，但这种治疗策略尚未转化为美国的临床研究，部分原因是缺乏确定的一年大型动物研究。该提议测试了中心假设，即当与临床前大型动物模型中的微骨折相比时，增加递送至软骨伤口的骨髓来源的多能细胞的浓度将改善所得修复组织的结构和生物力学性质。将使用两种不同的策略来选择和浓缩用于体内软骨修复的多能骨髓细胞。第一种方法将采用单步离心程序，以生成最低限度处理的骨髓穿刺浓缩液（BMAC）。第二种方法将使用通过ficoll密度梯度离心和经典地描述为间充质干细胞（MSC）的培养扩增来增加骨髓来源的多能细胞的数量的技术。这两种策略将在马软骨损伤模型中研究一年。将使用关节镜以及新型无损成像技术（如关节镜光学相干断层扫描（OCT）和3T和7T下的高分辨率定量MRI）评估所得修复软骨。修复组织的生物力学质量将通过压痕测试和限制压缩进行评估，而修复和宿主软骨之间界面的完整性将通过拉伸测试进行评估。新的成像、生物力学和生物标志物评估将与组织学、免疫组织化学和生化分析进行比较。这项研究的结果将确定添加浓缩BMC是否能改善软骨修复，还将提供有关在大型动物模型中识别和验证软骨损伤、修复和早期退变的生物化学和成像生物标志物的信息。这些活动对于开发和评估骨关节炎的新疾病修饰疗法至关重要。该提案对长期改善公共卫生和最终降低关节疼痛和骨关节炎的医疗保健相关成本的潜在影响是重大的。

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is a leading cause of disability. New clinical strategies to improve evaluation, repair, and regeneration of damaged articular cartilage are needed to prevent or delay the onset of disabling pain and OA. The goal of this proposal is to perform the integrated multi-disciplinary large animal studies needed to advance clinical treatment and assessment of articular cartilage injury and degeneration in the United States. Microfracture, a simple and minimally invasive technique to access repair cells from the subchondral bone, is the most widely used cartilage repair procedure in this country. Microfracture is, however, inconsistent and generates a fibrous to fibrocartilaginous repair tissue of poor durability. Despite numerous studies that have shown that the consistency and quality of BMC based cartilage repair can be improved by processing the bone marrow to select and implant pluripotential cell fractions as well as some international human case reports, this treatment strategy has not been translated into clinical study in the US in part due to the lack of definitive one year large animal studies. This proposal tests the central hypothesis that increasing the concentration of bone marrow derived pluripotential cells delivered to the cartilage wound will improve the structural and biomechanical properties of the resulting repair tissue when compared to microfracture in a preclinical large animal model. Two different strategies to select and concentrate pluripotential bone marrow cells for in vivo cartilage repair will be used. The first will employ a single-step centrifugation procedure to generate a minimally processed bone marrow aspirate concentrate (BMAC). The second method will use the technique of increasing the number of bone marrow derived pluripotential cells through ficoll density gradient centrifugation and culture expansion of what has been classically described as mesenchymal stem cells (MSC). Both strategies will be studied for one year in an equine cartilage injury model. The resulting repair cartilage will be assessed with arthroscopy, as well as novel nondestructive imaging technologies such as arthroscopic optical coherence tomography (OCT) and high resolution quantitative MRI at 3T and 7T. The biomechanical quality of the repair tissues will be assessed by indentation testing and confined compression, while the integrity of the interface between repair and host cartilage will be assessed by tensile testing. Novel imaging, biomechanics and biomarker assessments will be compared to histology, immunohistochemistry and biochemical analyses. The results from this study will define whether the addition of concentrated BMC improves cartilage repair, and will also provide information on the identification and validation of biochemical and imaging biomarkers of cartilage injury, repair and early degeneration in a large animal model. These activities will be critical to the development and assessment of new disease modifying treatments for osteoarthritis. The potential impact of this proposal on generating long-term improvements to public health and eventual reduction in health care related costs from joint pain and osteoarthritis are major.