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.
The proposed work aims to evaluate a new crosslinking treatment for post-traumatic osteoarthritis, a debilitating disease with few effective available treatments. The mechanical and biological responses to acute cartilage trauma serve to weaken the cartilage tissue such that it is less able to withstand even normal mechanical loading; photo-initiated collagen crosslinking has the potential to strengthen the tissue and protect the cartilag from further damage and degradation.
| Bonitsky, Craig M; McGann, Megan E; Selep, Michael J et al. (2017) Genipin crosslinking decreases the mechanical wear and biochemical degradation of impacted cartilage in vitro. J Orthop Res 35:558-565 |
