In Vitro Evaluation of Small Molecule Delivery into Articular Cartilage: Effect of Synovial Clearance and Compressive Load

Abstract

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.