RESUMO
Intra-articular delivery of disease-modifying osteoarthritis drugs (DMOADs) is likely to be most effective in early post-traumatic osteoarthritis (PTOA) when symptoms are minimal and patients are physically active. DMOAD delivery systems therefore must withstand repeated mechanical loading without affecting the drug release kinetics. Although soft materials are preferred for DMOAD delivery, mechanical loading can compromise their structural integrity and disrupt drug release. Here, we report a mechanically resilient soft hydrogel that rapidly self-heals under conditions resembling human running while maintaining sustained release of the cathepsin-K inhibitor L-006235 used as a proof-of-concept DMOAD. Notably, this hydrogel outperformed a previously reported hydrogel designed for intra-articular drug delivery, used as a control in our study, which neither recovered nor maintained drug release under mechanical loading. Upon injection into mouse knee joints, the hydrogel showed consistent release kinetics of the encapsulated agent in both treadmill-running and non-running mice. In a mouse model of aggressive PTOA exacerbated by treadmill running, L-006235 hydrogel markedly reduced cartilage degeneration. To our knowledge, this is the first hydrogel proven to withstand human running conditions and enable sustained DMOAD delivery in physically active joints, and the first study demonstrating reduced disease progression in a severe PTOA model under rigorous physical activity, highlighting the hydrogel's potential for PTOA treatment in active patients.
RESUMO
BACKGROUND: Studies have previously shown greater arterial and venous extracranial vascular changes in persons with multiple sclerosis (PwMS) when compared to healthy controls (HCs). OBJECTIVES: To determine the change in the number and size of secondary neck vessels in PwMS and HCs over a 5-year follow-up period. METHODS: Both at baseline and follow-up, 83 PwMS and 25 HCs underwent magnetic resonance angiography (MRA) imaging and analysis. The number and cross-sectional area (CSA) of all secondary neck vessels (excluding the common/internal carotid, vertebral artery, and internal jugular vein) measured at levels from C2-T1 were determined by semi-automated edge detection/ contouring software. The longitudinal change in the number and CSA of the secondary neck vessels from the PwMS and HCs were analyzed by non-parametric Wilcoxon repeated measure. Benjamini-Hochberg procedure adjusted for false discovery rate (FDR). RESULTS: For over 5 years, PwMS demonstrated a consistent longitudinal decrease in both the number of secondary neck vessels (Z-change between -3.3 and -5.4, q=0.001) and their CSA (Zchange between -2.9 and -5.2, q=0.004). On the contrary, the HCs did not demonstrate a significant longitudinal change in secondary neck vessels over the follow-up period. Due to the longitudinal decrease, the PwMS showed a lower number of secondary neck vessels when compared to HCs measured at follow-up (p<0.029, except for C4 with trending p=0.071). The PwMS changes were also corroborated within each MS phenotype. CONCLUSION: PwMS demonstrate a significant mid-term decrease in the number and the size of the secondary neck vessels. The clinical relevance of these findings and the effect on intracranial blood flow are currently unknown.