PRP in ACLR to Prevent PTOA

Description

Anterior cruciate ligament (ACL) injury is one of the most common clinical problems among active individuals, with over 250,000 ACL reconstructions (ACLR) per year in the United States. Surgical reconstruction of the ACL is typically required in individuals who wish to return to an active lifestyle due to the presence of knee instability. The results of ACLR are predictably good as far as the ability to re-establish knee stability and to allow return to cutting and pivoting activities. However, there is a lack of effective interventions that can successfully delay or prevent the progressive degenerative changes that are known to occur following injury and that will ultimately lead to post-traumatic osteoarthritis (PTOA). PTOA accounts for nearly 12% of all cases of symptomatic OA, or approximately 5.6 million cases of lower extremity OA in the United States, carrying a cost of over $11.8 billion annually. As injury rates rise and PTOA becomes more prevalent, the associated socioeconomic burden is a significant concern since these injuries have a particularly high incidence in young adults. Many different factors likely contribute to the development of PTOA following ACLR, including the inflammatory response that occurs following injury, altered knee kinematics that can persist despite "successful" ACLR, and persistent deficits in strength of the muscles around the knee. It is well-accepted that the accumulation of inflammatory mediators and matrix degrading proteases that occurs following joint injury likely plays an important role in the initiation of the pathological process leading to PTOA. Work in animal models shows that synovial inflammation plays a central role in the development of PTOA, and studies in patients undergoing ACLR uncovered synovial fluid biomarkers with prognostic value and showed that treatment with anti-inflammatory agents modulated biomarkers of cartilage degeneration. Our preliminary RNA-seq in synovial biopsies from patients undergoing arthroscopic ACLR revealed time-dependent changes in the inflammatory gene expression profile of these tissues, further suggesting that preventative therapies that dampen inflammation early after injury and before surgery may contribute to prevent the onset of PTOA. Abnormalities in the infrapatellar fat pad (IFP) are also associated with higher inflammatory synovial fluid cytokine profile following ACL tear, highlighting the contribution of the IFP-synovial compartment to the inflammatory burden of the knee. In addition to the inflammatory response that occurs following injury, inflammation also occurs following surgery. This "double hit" may play an important role in the development of PTOA, suggesting that methods to ameliorate the inflammatory process following joint injury could represent an effective therapeutic strategy.

The current standard methods available to clinicians to treat joint inflammation include oral non-steroidal anti-inflammatory (NSAID) medications and corticosteroid injection. However, clinicians have begun to use "orthobiologics" more frequently due to their potential to diminish inflammatory and catabolic mediators while also promoting repair, and because its autologous and minimally manipulated nature is not subjected to pre-market regulatory clearance from the Food and Drug Administration. Platelet rich plasma (PRP) is a non-surgical therapy increasingly used as an alternative to NSAIDs. PRP contains and releases a wide array of bioactive molecules it has been used to treat bone, tendon, and ligament injuries, and has emerged as a potential treatment for knee osteoarthritis (OA). The currently available studies comparing intra-articular PRP injections to other means of non-surgical intervention for knee OA report promising results with the use of PRP. These data suggest that positive clinical results in OA patients are mainly related to the immune modulatory effects of PRP, dampening the intra-articular inflammatory responses.

However, the role of PRP in the treatment of knee OA remains inconclusive, largely due to inconsistencies and high variability in PRP preparations, and the limited information about the relevant components in PRP that impact clinical responses. Factors including age, sex, medical comorbidities, and genetic profile may affect the composition and biologic activity of PRP samples derived from different individuals. In addition to inter-individual variations, there is currently very little data to define how the composition and biologic activity of PRP relates to the clinical outcomes. Our recent pilot data suggests that, indeed, there are changes in composition and PRP bioactivity that may be associated with variable clinical outcomes in patients with established knee OA receiving intra-articular PRP injections. However, larger clinical trials are still required to better define these changes and to establish truly mechanistic and functional correlations. Thus, a large knowledge gap remains in our understanding of the biologically active components of PRP. Furthermore, the limited data available related to PRP and knee OA addresses treatment of established OA. There is no information available about the potential of PRP for prevention of the pathological cascade leading to PTOA.

Details