Multicenter Cartilage Repair Preclinical Trial in Horses

马的多中心软骨修复临床前试验

• 批准号: 7854800
• 负责人: CONSTANCE R CHU
• 金额: $ 102.57万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7854800
• 关键词: Affect; American; Animal Model; Animals; Arthralgia; Arthroscopy; Aspirate substance; Beds; Biochemical; Biochemistry; Biological Markers; Biomechanics; Bone Marrow; Bone Marrow Cells; Cartilage; Cartilage injury; Case Study; Cell Fraction; Cells; Centrifugation; Clinical; Clinical Research; Clinical Treatment; Country; Defect; Degenerative polyarthritis; Density Gradient Centrifugation; Development; Disease; Doctor of Philosophy; Early Diagnosis; Equus caballus; Evaluation; Fibrin; Ficoll; Funding; Goals; Healed; Healthcare; Histology; Human; Image; Imaging technology; Immunohistochemistry; Implant; Individual; International; Lubrication; Magnetic Resonance Imaging; Mesenchymal Stem Cells; Methods; Modeling; Natural regeneration; Optical Coherence Tomography; Orthopedic Surgery procedures; Pain; Procedures; Process; Property; Public Health; Research; Resolution; Scientist; Stifle joint; Structure; Techniques; Technology; Testing; Thick; Translating; United States; Validation; Work; Wound Healing; articular cartilage; base; bone; burden of illness; cost; disability; experience; healing; implantation; improved; in vivo; injury and repair; migration; minimally invasive; novel; pre-clinical; preclinical study; prevent; repaired; scaffold; treatment strategy; wound

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.

描述（由申请人提供）：骨关节炎（OA）是致残的主要原因。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，以防止或延迟致残性疼痛和OA的发生。本提案的目标是进行综合多学科大型动物研究，以推进美国关节软骨损伤和退变的临床治疗和评估。微骨折是一种从软骨下骨获取修复细胞的简单微创技术，是国内应用最广泛的软骨修复手术。然而，微骨折是不一致的，产生的纤维到纤维软骨的修复组织耐久性差。尽管许多研究表明，通过处理骨髓来选择和植入多能细胞片段可以提高BMC软骨修复的一致性和质量，以及一些国际人类病例报告，但由于缺乏确定的一年大型动物研究，这种治疗策略尚未在美国转化为临床研究。在临床前大型动物模型中，与微骨折相比，增加骨髓来源的多能细胞的浓度递送到软骨伤口将改善修复组织的结构和生物力学性能，这一提议验证了中心假设。两种不同的策略来选择和浓缩多能骨髓细胞用于体内软骨修复。第一种方法将采用单步离心程序产生最低限度处理的骨髓抽吸浓缩液（BMAC）。第二种方法是通过ficoll密度梯度离心和经典间充质干细胞（MSC）的培养扩增来增加骨髓来源的多能细胞的数量。这两种策略将在马软骨损伤模型中进行为期一年的研究。由此产生的修复软骨将通过关节镜以及新的无损成像技术进行评估，如关节镜光学相干断层扫描（OCT）和3T和7T高分辨率定量MRI。修复组织的生物力学质量将通过压痕测试和受限压缩来评估，而修复与宿主软骨之间界面的完整性将通过拉伸测试来评估。新的影像学、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。本研究的结果将确定添加浓缩BMC是否能改善软骨修复，并将在大型动物模型中为软骨损伤、修复和早期退变的生化和成像生物标志物的鉴定和验证提供信息。这些活动将是至关重要的发展和评估新的疾病修饰治疗骨关节炎。这一提议对长期改善公众健康和最终减少由关节疼痛和骨关节炎引起的医疗保健相关费用的潜在影响是重大的。