Assessment of osteoarthritis functional outcomes and intra-articular injection volume in the rat anterior cruciate ligament transection model.

The rat surgical anterior cruciate ligament transection (ACLT) model is commonly used to investigate intra-articular osteoarthritis (OA) therapies, and histological assessment is often the primary outcome measure. However, histological changes do not always correlate well with clinical outcomes. Therefore, this study evaluated functional outcomes in the rat surgical ACLT model and compared intra-articular injection volumes ranging from 20 to 50 µl. Unilateral ACLT was surgically induced and static weight-bearing, mechanical allodynia, motor function, and gait were assessed in four groups of male, Sprague-Dawley rats (n = 6 per group). Intra-articular injections of 20 µl Dulbecco's phosphate-buffered saline (DPBS), 50 µl DPBS, or 50 µl of synthetic biomimetic boundary lubricant were administered once weekly for 3 weeks postoperatively. Structural changes were evaluated histologically at 20 weeks. Rat cadaver knees were injected with 20, 30, 40, or 50 µl of gadolinium solutions and were imaged using magnetic resonance imaging (MRI). Static weight-bearing, mechanical allodynia, and gait parameters in ACLT groups revealed differences from baseline and naïve controls for 4 weeks post-ACLT; however, these differences did not persist beyond 6 weeks. Different intra-articular DPBS injection volumes did not result in functional or histological changes; however, peri-articular leakage was documented via MRI following 50, 40, and 30 µl but not 20 µl gadolinium injections. Statement of clinical significance: Differences in functional parameters were predominantly restricted to early, postoperative changes in the rat surgical ACLT model despite evidence of moderate histologic OA at 20 weeks. Injection volumes of 20-30 µl are more appropriate for investigating intra-articular therapies in the rat knee.

Binding and lubrication of biomimetic boundary lubricants on articular cartilage.

The glycoprotein, lubricin, is the primary boundary lubricant of articular cartilage and has been shown to prevent cartilage damage after joint injury. In this study, a library of eight bottle-brush copolymers were synthesized to mimic the structure and function of lubricin. Polyethylene glycol (PEG) grafted onto a polyacrylic acid (pAA) core mimicked the hydrophilic mucin-like domain of lubricin, and a thiol terminus anchored the polymers to cartilage surfaces much like lubricin's C-terminus. These copolymers, abbreviated as pAA-g-PEG, rapidly bound to cartilage surfaces with binding time constants ranging from 20 to 39 min, and affected lubrication under boundary mode conditions with coefficients of friction ranging from 0.140 ± 0.024 to 0.248 ± 0.030. Binding and lubrication were highly correlated (r2 = 0.89-0.99), showing that boundary lubrication in this case strongly depends on the binding of the lubricant to the surface. Along with time-dependent and dose-dependent behavior, lubrication and binding of the lubricin-mimetics also depended on copolymer structural parameters including pAA backbone length, PEG side chain length, and PEG:AA brush density. Polymers with larger backbone sizes, brush sizes, or brush densities took longer to bind (p < 0.05). Six of the eight polymers reduced friction relative to denuded cartilage plugs (p < 0.05), suggesting their potential to lubricate and protect cartilage in vivo. In copolymers with shorter pAA backbones, increasing hydrodynamic size inhibited lubrication (p < 0.08), while the opposite was observed in copolymers with longer backbones (p < 0.05). These polymers show similar in vitro lubricating efficacy as recombinant lubricins and as such have potential for in vivo treatment of post-traumatic osteoarthritis. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:548-557, 2017.