Abstract

The synovium is a thin, multi-layered tissue that envelops the diarthrodial joint and regulates molecular transport between the intra-articular (IA) joint space and systemic circulation; it also drives inflammation during joint pathology. Local drug delivery to the IA space is appealing for its efficacy in targeting disease of localized joints such as osteoarthritis. However, benefits of IA drug delivery are hindered by rapid clearance through the synovium, warranting investigations of solute--matrix interactions in trans-synovial solute diffusion as well as pathological changes to the synovial matrix to enhance models of IA drug transport. This dissertation first explores the effect of molecular weight (MW) on solute diffusion through porcine and human synovial explants as a model of IA drug clearance. Here, a previously established multiphasic finite element model (FEM) of synovium was combined with an unsteady diffusion experiment in vitro that mimicked a bolus drug delivery to the joint space. Concentration profiles of neutral solutes measured experimentally over time were numerically matched to those predicted by the FEM and fitted to a first-order exponential decay, yielding an effective diffusivity and a time constant that correlated well with each other after controlling for sample thickness. Experimental data also agreed with MW-dependent IA clearances previously reported in the literature. These are the first reports of intrinsic solute diffusivities through synovium, which form the foundation for understanding trans-synovial solute transport. The second aim of the dissertation builds upon the first by adapting the FEM of synovium to accommodate charged solutes, allowing for measurement of the effective diffusivity of anionic, cationic, and neutral dextrans of two MWs (4 kDa and 20 kDa) through human explants. Another prerequisite was the inclusion of the fixed charge density of synovium, which was reported here for the first time and found to be negligible, orders of magnitude lower than that of other soft tissues. Based on FEM predictions and exponential fitting of experimental clearance data, both charge and MW contributed to solute diffusivity. Cationic charge accelerated solute diffusion, one of the first findings related to charged solute--matrix interactions in synovium. In the third aim of the dissertation, collagen-induced arthritis (CIA) was established in rats as a platform for characterizing the collagen morphology and mechanical properties of diseased synovium. Optical tissue clearing, second harmonic generation microscopy, and the gray-level co-occurrence matrix (GLCM) were combined, promoting image texture analysis of full-thickness z-stacks of healthy and CIA rat synovium. GLCM-derived texture parameters suggested the presence of thicker and less organized collagen fibers in CIA synovium. Additionally, nanoindentation data showed that CIA synovial explants are softer than non-degenerate ones, particularly in the intimal layer. This work included the first quantitative assessment of collagen fibers in synovium that bolster our understanding of synovial architecture during pathology; it also presented moduli that can be used to further refine models of drug transport through diseased synovium. The work presented in this dissertation further elucidates the role of the synovial matrix in both drug transport and disease. These findings will enhance not only future complex models of drug transport to better guide the rational design of IA therapeutics for treating arthritis, but also our fundamental understanding of the pathology of synovium.

Committee Chair

Lori Setton

Committee Members

Jessica Wagenseil; Matthew Bersi; Simon Tang; Spencer Lake

Degree

Doctor of Philosophy (PhD)

Author's Department

Biomedical Engineering

Author's School

McKelvey School of Engineering

Document Type

Dissertation

Date of Award

12-19-2025

Language

English (en)

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Available for download on Friday, December 18, 2026

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