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

 描述（由申请人提供）：拟议工作的总体目标是评价保护急性损伤关节软骨的光引发交联治疗 创伤后骨关节炎（PTOA）。PTOA的发展是因为急性创伤的机械和生物效应削弱了软骨组织。弱化的组织较不能够承受机械载荷，使得即使正常活动也会产生异常磨损。相比之下，我们和其他人先前已经表明，胶原交联增加了健康软骨的刚度，强度和对机械磨损和生化降解的抵抗力。我们进一步表明，胶原交联增加了已被损坏的冲击软骨的耐磨性，光引发的交联技术也提高了软骨的耐磨性，而不损害细胞活力。拟议的工作将进一步研究光引发的胶原交联与受损软骨在实验室研究之前，在PTOA的动物模型中进行测试。光化学疗法将是非常有吸引力的临床干预，因为光活化将交联定位到感兴趣的组织。此外，光化学引发剂和光都可以在关节镜下引入以进行微创治疗。待检验的第一个假设是，受损关节软骨的光引发交联是一种有效的治疗方法，可提高组织对体外生化降解和机械磨损的抵抗力。将在交联或对照条件下处理受影响的软骨标本和生化降解的软骨外植体;将量化压痕反应、摩擦、磨损和组织深度的胶原酶消化量。第二个假设是，如果在损伤后立即应用，则光引发的交联将延缓体内兔膝关节撞击模型中PTOA的发展。在开放关节中对家兔内侧股骨髁进行钝性撞击后，将应用光引发交联。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、使用组织学分级量表和使用软骨细胞代谢和胶原蛋白损伤的免疫组织化学来评价损伤和交联处理的效果。最后，我们将检验以下假设：即使治疗延迟两周，光引发的交联也会延缓体内兔膝关节撞击模型中PTOA的发展。将在治疗时和损伤后6个月评价损伤和交联治疗的效果。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PTOA的新型治疗模式奠定了基础。

 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.