An experimental-computational approach for measuring charged solute diffusivity through human synovium.

Intra-articular drug delivery has shown promise in targeting arthritic joints, but its therapeutic efficacy is hindered by the synovium, a multilayered connective tissue that rapidly clears locally delivered drugs from the joint space. To better understand the mechanisms behind synovial drug clearance, we previously developed a finite element model of synovium as a multiphasic tissue and used an inverse method to determine the effective diffusivity (Deff) of neutral solutes through synovium, which was found to decrease with increasing molecular weight. Here, we adapted this experimental-computational approach to measure Deff of charged dextrans through human synovium. The fixed charge density of synovium was found to be negligible and orders of magnitude lower than that of other soft tissues, and Deff was significantly affected by not only molecular weight but also charge, particularly among higher-molecular-weight solutes. According to FEM predictions and single exponential fitting of experimental data, Deff and t1/2 of cationic dextrans were higher and lower, respectively, than their anionic and neutral counterparts. Apart from cationic dextrans, 4 kDa dextrans diffused through synovium faster than 20 kDa dextrans as expected. These data are among the first to explore charged solute-matrix interactions in synovium and will guide future experimental and computational studies on charged drug transport.