Applicability of corticosteroid releasing microspheres in degenerative joint diseases

Abstract

Osteoarthritis (OA) and intervertebral disc (IVD) degeneration are two musculoskeletal conditions that can seriously affect the quality of life of individual patients, strain health and social care systems and thereby the economy worldwide. The prevalence of both conditions is expected to grow due to increasing life expectancy and/or incidence of risk factors. The predominant burden of musculoskeletal conditions in patients is pain, often in combination with a limitation of movement and as such affecting the quality of life. Local corticosteroid (CS) injection is a commonly applied treatment targeting inflammation and pain, especially in the osteoarthritic joint. However, locally administered CSs only provide a temporal reduction in pain, while the multiple injections that are needed for sustained effects are accompanied by several risks. Promising approaches to prolong the anti-inflammatory and analgesic effects of CS are to extend local drug exposure by a drug delivery system (DDS), while avoiding harmful peak concentrations or the side-effects that come with multiple injections. Therefore, this thesis investigated the applicability of local controlled release of corticosteroids for prolonged inhibition of inflammation, pain and degeneration in degenerative joint diseases. The controlled release of the CS triamcinolone acetonide (TAA) can be applied for the inhibition of inflammation and pain in various knee joint diseases. Chapter 2 demonstrated the characteristics of the polyesteramides (PEAs) drug delivery platform. TAA release from PEA microspheres was extended, while the potentially harmful TAA peak exposure was diminished, compared to bolus TAA. Also, local joint inflammation was successfully inhibited 7 weeks post-injection. It was seen in chapter 3 that extended CS release is not applicable in every subtype of knee joint diseases as the extended local presence worsened the tissue damage and lead to calcifications in unstable joints with ligament trauma. Chapter 4 and 5 revealed that in (stable) arthritic joints, the release of TAA by our PEA platform was extended and more superior in the reduction of inflammatory-associated pain over the conventional poly lactic-co-glycolic acid (PLGA) platform. This thesis also reported the findings regarding the applicability of controlled release of TAA in degenerated IVDs, in terms of safety and efficacy. It was found in chapter 6 that local controlled release of TAA in degenerated IVDs does not affect the tissues in and surrounding the IVD and has the potential to provide long-term analgesia. The research question of what the relation is between the retention of small molecules released by PEA microspheres and the location and disease status of the injected site was addressed in chapter 7. It was found that in tissues with a relatively low fluid exchange, such as the IVD, retention of the injected molecules was higher compared to tissues with a rapid clearance (such as the skin and knee joint). Moreover, in the IVD were the retention was delayed, it was also observed that in degenerated tissues retention was further prolonged.