Combined Experimental Approach and Finite Element Modeling of Small Molecule Transport Through Joint Synovium to Measure Effective Diffusivity

Abstract

Trans-synovial solute transport plays a critical role in the clearance of intra-articularly (IA) delivered drugs. In this study, we present a computational finite element model (FEM) of solute transport through the synovium validated by experiments on synovial explants. Unsteady diffusion of urea, a small uncharged molecule, was measured through devitalized porcine and human synovium using custom-built diffusion chambers. A multiphasic computational model was constructed and optimized with the experimental data to extract effective diffusivity for urea within the synovium. A monotonic decrease in urea concentration was observed in the donor bath over time, with an effective diffusivity found to be an order of magnitude lower in synovium versus that measured in free solution. Parametric studies incorporating an intimal cell layer with varying thickness and varying effective diffusivities were performed, revealing a dependence of drug clearance kinetics on both parameters. The findings of this study indicate that the synovial matrix impedes urea solute transport out of the joint with little retention of the solute in the matrix.

Hydraulic permeability and compressive properties of porcine and human synovium

“…The E s measured here is approximately two orders of magnitude lower than average values used to estimate solute diffusivity in prior work; however, k measured here is approximately the same order of magnitude of that assumed. This indicates that the tissue deforms more easily than initially assumed, while fluid flows as readily through the mixture as our previous solute diffusivity studies assumed (6,7). Preliminary studies using these new values indicate minimal changes in diffusivity values (data not shown), suggesting that the assumption of little bulk fluid movement through the synovium under experimental conditions was valid.…”

“…Porcine ( n = 23) and human ( n = 22) synovial tissue samples were harvested as previously described from three distinct anatomic regions of the knee joint ( 6 , 7 ). Samples were immediately placed in sucrose solutions and frozen to de-vitalize the tissue.…”

“…S1 ). Each phase was assumed to be intrinsically incompressible, and the solid volume fraction ( ) was chosen as 0.19 based on prior measurements of water content ( 6 ). The mean value for the estimated Poisson's ratio ( ) for synovium was used in the model prediction ( 11 , 12 ) together with a specimen-specific value for the Young's modulus E s , where E s was determined from the specimen-specific, aggregate compressive modulus ( H A ), …”

“…Intrinsic diffusivity of uncharged solutes, or effective diffusivity (D eff ) independent of sample geometries, has been previously reported from unsteady diffusion experiments across porcine and human synovial explants using a combined experimental and modeling approach (6,7). Briefly, explants were modeled as porous and permeable tissues using a multiphasic mixture, assuming that the tissue consists of a porous solid phase, a solute phase capable of gradient-induced solute flow, and an aqueous fluid phase capable of pressure-induced fluid movement (6,7). These studies showed that uncharged solute diffusivity in synovium is less than that in free solution and decreases with increasing molecular weight as observed in vivo.…”

“…Although IA drug delivery has many advantages over systemic delivery in treating arthritis, compounds delivered via IA injection are rapidly cleared from the joint space into the surrounding blood and lymphatic vessels ( 4 , 5 ). Previous studies have characterized drug clearance after IA injections in vivo, but there remains a need to understand the physical structures and mechanisms that regulate molecular clearance through synovium and its multiple constituents including the synovial intima, subintima, vasculature, and draining lymphatics ( 4 , 6 , 7 ).…”