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

Abstract

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 (D_eff) of neutral solutes through synovium, which was found to decrease with increasing molecular weight. Here, we adapted this experimental-computational approach to measure D_eff 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 D_eff 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, D_eff and t_1/2 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.