Intra-articular drug delivery can be effective in targeting a diseased joint but is hampered by rapid clearance times from the diarthrodial joint. The synovium is a multi-layered tissue that surrounds the diarthrodial joint and governs molecular transport into and out of the joint. No models of drug clearance through synovium exist to quantify diffusivity across solutes, tissue type and disease pathology. We previously have developed a finite element model of synovium as a porous, permeable, fluid-filled tissue and used an inverse method to determine urea’s effective diffusivity (Deff) in de-vitalized synovium explants.22 Here we apply this method to determine Deff from unsteady diffusive transport of model solutes and confirm the role of molecular weight in solute transport. As molecular weight increased, Deff decreased in both human and porcine tissues, with similar behavior across the two species. Unsteady transport was well-described by a single exponential transient decay in concentration, yielding solute half-lives (t1/2) that compared favorably with the Deff determined from the finite element model fit. Determined values for Deff parallel prior observations of size-dependent in vivo drug clearance and provide an intrinsic parameter with greater ability to resolve size-dependence in vitro. Thus, this work forms the basis for understanding the influence of size on drug transport in synovium and can guide future studies to elucidate the role of charge and tissue pathology on the transport of therapeutics in healthy and pathological human synovium.
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We thank Dr. Michael Talcott, DVM, in the Division of Comparative Medicine, Washington University School of Medicine in St. Louis, for providing porcine samples. We additionally thank the Mid-America Transplant Center for providing human samples. Work was performed with support from The National Institutes of Health (R01 AR070975, R61AR076820), Washington University Center for Cellular Imaging (WUCCI) funded by Washington University School of Medicine, the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813), The Foundation for Barnes-Jewish Hospital (3770 and 4642), the Washington University Rheumatic Diseases Resource-based Research Center (RDRRC) (NIH P30AR073752), and the Washington University Musculoskeletal Research Center (NIH P30 AR074992). Use of the open-source software FEBio is supported in part by a grant from the NIH.
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Guang, Y., Davis, A.L., McGrath, T.M. et al. Size-Dependent Effective Diffusivity in Healthy Human and Porcine Joint Synovium. Ann Biomed Eng (2021). https://doi.org/10.1007/s10439-020-02717-4
- Finite element modeling
- Drug delivery
- Mass transport
- In vitro