Intra-articular injection of drug depots is considered as a therapeutic strategy for the treatment of osteoarthritis. In this study, we designed an in vitro assay in a previously described bioreactor system to evaluate the uptake of a small molecule drug mimic as a function of drug clearance by the synovium and compressive load. Bromophenol blue (BPB) loaded hydrogels were placed on top of bovine articular cartilage explants and were compressed in a dual flow bioreactor. As a control, BPB was directly injected in the bioreactor compartment mimicking the synovial fluid. Subsequently, diffusion coefficients of the dye were estimated based on Fick's law. Mimicking synovial clearance revealed that dye penetration of BPB when released from a drug delivery system placed on top of a cartilage explant was enhanced compared to direct injection of BPB into a simulated synovial fluid. Furthermore, we show the synergistic effect of the amount of load and the frequency on drug uptake by the cartilage. In the described model, we have shown that, under compressive load, drug delivery from a depot was beneficial over conventional intra-articular drug administration. The assay mimics the complexity of the knee joint in several key aspects, which results in a more close representation of the expected drug outcome. In this study, we have evaluated the penetration of a model small molecule drug into articular cartilage under compressive conditions, and future development will focus on incorporating synovial(-like) fluid, synovium, and bone to increase the predictive potential of the assay further.

中文翻译：

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小分子进入关节软骨的体外评估：滑膜间隙和压缩负荷的影响。

关节腔内注射药物仓库被认为是治疗骨关节炎的治疗策略。在这项研究中，我们在先前描述的生物反应器系统中设计了一种体外测定法，以评估小分子药物模拟物的摄取与滑膜和压缩负荷对药物清除的影响。将负载溴酚蓝（BPB）的水凝胶放在牛关节软骨外植体上，并在双流生物反应器中压缩。作为对照，将BPB直接注射到模仿滑液的生物反应器隔室中。随后，基于菲克定律估计染料的扩散系数。模拟滑膜清除显示，与将BPB直接注射到模拟滑液中相比，从放置在软骨外植体顶部的药物输送系统释放时，BPB的染料渗透性得到增强。此外，我们显示了负荷量和频率对软骨药物吸收的协同作用。在描述的模型中，我们已经表明，在压缩负荷下，从储库中递送药物比常规关节内给药更为有益。该测定法在几个关键方面模拟了膝关节的复杂性，从而可以更接近地表示预期的药物结果。在这项研究中，我们评估了在压缩条件下小分子模型药物对关节软骨的渗透性，