Photo-Initiated Cartilage Crosslinking as a Preventative for Post-Traumatic Osteoarthritis

 描述(申请人提供)：拟议工作的总体目标是评估一种保护急性损伤的关节软骨的光引发交联剂治疗。 从进展到创伤后骨关节炎(PTOA)。PTOA的发生是因为急性创伤的机械和生物效应削弱了软骨组织。虚弱的组织承受机械负荷的能力较差，因此即使是正常的活动也会产生异常磨损。相反，我们和其他人之前已经证明，胶原交联会增加健康软骨的硬度、强度以及对机械磨损和生化降解的抵抗力。我们进一步表明，胶原交联剂增加了被冲击破坏的软骨的耐磨性，而光引发的交联剂技术也提高了软骨的耐磨性，而不影响细胞的活性。这项拟议的工作将在台式研究中进一步研究光引发的胶原与受损软骨的交联性，然后在PTOA的动物模型中进行测试。光化学疗法将是一种非常有吸引力的临床干预措施，因为光激活将交联物定位于感兴趣的组织。此外，可以在关节镜下引入光化学引发剂和光，以实现微创治疗。第一个需要检验的假设是，光引发的关节软骨交联是一种有效的治疗方法，可以提高组织在体外对生化降解和机械磨损的抵抗力。撞击的软骨标本和生化降解的软骨移植块将用交联剂或对照条件处理；压痕反应、摩擦、磨损和通过组织深度的胶原酶消化量将被量化。第二个假设是，如果在兔膝关节损伤后立即应用，光引发的交联会延缓在体兔膝关节撞击模型中PTOA的发展。在开放关节中钝性撞击兔股骨内侧髁后，将应用光引发的交联剂。损伤和交联治疗的效果将在损伤后0个月和6个月通过量化软骨降解的生物标志物，通过压痕测量软骨硬度，用组织学分级标准和软骨细胞代谢和胶原损伤的免疫组织化学方法来评估。最后，我们将在活体兔膝关节撞击模型中测试光引发的交联会延缓PTOA发展的假说，即使治疗延迟两周。在治疗时和损伤后6个月对损伤和交联治疗的效果进行评估。PTOA是一种使人衰弱的疾病，几乎没有有效的治疗方法。该项目为一种新的PTOA治疗方法奠定了基础。

 DESCRIPTION (provided by applicant): The overall objective of the proposed work is to evaluate a photo-initiated crosslinking treatment that protects acutely injured articular cartilage from progressing to post-traumatic osteoarthritis (PTOA). PTOA develops because the mechanical and biological effects of acute trauma weaken the cartilage tissue. The weakened tissue is less able to withstand mechanical loading such that even normal activities produce abnormal wear. In contrast, we and others have previously shown that collagen crosslinking increases the stiffness, strength, and resistance to mechanical wear and biochemical degradation of healthy cartilage. We further show that collagen crosslinking increases the wear resistance of cartilage that has been damaged by impact, and that photo-initiated crosslinking techniques also enhance the wear resistance of cartilage without compromising cell viability. The proposed work will further investigate photo-initiated collagen crosslinking with damaged cartilage in benchtop studies before testing it in an animal model of PTOA. A photochemical therapy would be a very attractive clinical intervention, because light activation localizes the crosslinking to the tissue of interest. Additionally, both the photochemical initiator and light ma be introduced arthroscopically for a minimally invasive treatment. The first hypothesis to be tested is that photo-initiated crosslinking of damaged articular cartilage is an effective treatmen that improves the resistance of the tissue to biochemical degradation and mechanical wear in vitro. Impacted cartilage specimens and biochemically degraded cartilage explants will be treated with crosslinking or control conditions; the indentation response, friction, wear and amount of collagenase digestion through the depth of the tissue will be quantified. The second hypothesis is that photo-initiated crosslinking will retard the development of PTOA in an in vivo rabbit knee impact model if applied immediately after injury. After a blunt impact to the rabbit medial femoral condyle in an open joint, photo-initiated crosslinking will be applied. The effect o the injury and crosslinking treatment will be evaluated at 0 and 6 months post-injury by quantifying biomarkers of cartilage degradation, measuring cartilage stiffness via indentation, with a histological grading scale and with immunohistochemistry for chondrocyte metabolism and collagen damage. Finally, we will test the hypothesis that photo-initiated crosslinking will retard the development of PTOA in an in vivo rabbit knee impact model even when treatment is delayed by two weeks. The effect of injury and crosslinking treatment will be evaluated at the time of treatment and at 6 months post-injury. PTOA is a debilitating disease with few effective available treatments. This project lays the foundation for a novel treatment modality for PTOA.