Understanding a Role for Synovium in Intra-Articular Drug Clearance: A Computational and Experimental Approach
Date of Award
Doctor of Philosophy (PhD)
The synovium is a membranous tissue that governs molecular transport between the intra-articular (IA) joint space and the systemic circulatory system. Drug delivery to the IA space is an attractive option to treat localized joint diseases such as osteoarthritis. However, short residence times due to rapid clearance from the joint diminishes efficacy of IA injected drugs. While many studies exist on the clearance of drugs from the IA space, these studies lack the ability to isolate and characterize trans-synovial transport.The first aim of this dissertation establishes a computational finite element (FE) model of trans-synovial transport using multiphasic mixture theory. The model simulates a bolus injection of drug into a bath representing the joint space, with unsteady drug concentrations over time as the drug clears from the bath through the tissue. Using parametric studies of the different tissue material properties, we identified key determinants of transport in the model. Effective diffusivity (Deff) of the model solute was determined to be the predominant property in governing transport, and is a property intrinsic to the solute and tissue. Hydraulic permeability and modulus of the tissue were also identified as relevant to solute transport under conditions with sufficient fluid movement through the tissue. Given the lack of knowledge of material properties of the synovium, the parametric studies were used to inform selection of material properties to be used in the model. In the second aim of this dissertation, an experimental model using devitalized porcine and human synovial explant tissue was combined with the model developed in the first aim to study the effect of molecular weight on Deff. Different molecular weight molecules, ranging from 60 Da – 70 kDa, were sampled from the upstream bath in an unsteady model of transport. The bath concentration profile was described with the using the computational model and with a single exponent curve-fit. This yielded parameters of Deff from the computational model and a time-constant from the exponential curve-fit. The two parameters correlated well with one another when sample thickness was controlled for, indicating the importance of geometry when evaluating intra-articular transport. This aim represents the first reports of solute diffusivity as dependent on molecular weight through the synovium, a key measurement towards understanding trans-synovial transport. In the final aim of this dissertation, the synovium underwent mechanical testing to determine previously unmeasured properties of the tissue relevant to transport. Synovial tissue underwent a confined compression stress-relaxation experiment to measure the modulus and hydraulic permeability of synovial tissue. Synovium modulus was found to be much softer than moduli of other joint tissues. Values of hydraulic permeability were estimated to be much lower than in any other connective tissue. The evaluation of modulus and permeability allows for refinement of the model used to estimate solute diffusivity in the previous aims. The work presented in this dissertation improves our understanding of the role molecular weight and synovium tissue properties have in governing trans-synovial transport. This work forms the basis for more complex models of transport incorporating charge, active transport, and intra-articular pressure, towards the goal of predicting factors that regulate solute clearance in healthy and pathological synovium.
Lori A. Setton
James A. Fitzpartick, Farshid Guilak, Spencer Lake, Christine T. Pham,