Effect of Mechanical Convection on the Partitioning of an Anionic Iodinated Contrast Agent in Intact Patellar Cartilage Vahid Entezari, 1 Prashant N. Bansal, 1,2 Rachel C. Stewart, 1,2 Benjamin A. Lakin, 1,2 Mark W. Grinstaff, 2,3 Brian D. Snyder 1,4 1 Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, 2 Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, 3 Department of Chemistry, Boston University, Boston, Massachusetts 02215, 4 Department of Orthopedic Surgery, Boston Children’s Hospital, Boston, Massachusetts 02215 Received 4 January 2014; accepted 14 May 2014 Published online 24 June 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jor.22662 ABSTRACT: To determine if mechanical convection accelerates partitioning of an anionic contrast agent into cartilage while maintaining its ability to reflect the glycosaminoglycan (GAG) content in contrast-enhanced computed tomography (CECT) of cartilage. Bovine patellae (N ¼ 4) were immersed in iothalamate and serially imaged over 24 h of passive diffusion at 34˚C. Following saline washing for 14 h, each patella was serially imaged over 2.5 h of mechanical convection by cyclic compressive loading (120N, 1 Hz) while immersed in iothalamate at 34˚C. After similar saline washing, each patella was sectioned into 15 blocks (n ¼ 60) and contrast concentration per time point as well as GAG content were determined for each cartilage block. Mechanical convection produced 70.6%, 34.4%, and 16.4% higher contrast concentration at 30, 60, and 90 min, respectively, compared to passive diffusion (p < 0.001) and boosted initial contrast flux 330%. The correlation between contrast concentration and GAG content was significant at all time points and correlation coefficients improved with time, reaching R 2 ¼ 0.60 after 180 min of passive diffusion and 22.5 min of mechanical convection. Mechanical convection significantly accelerated partitioning of a contrast agent into healthy cartilage while maintaining strong correlations with GAG content, providing an evidence-based rationale for adopting walking regimens in CECT imaging protocols. ß 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1333–1340, 2014. Keywords: articular cartilage; contrast agent; contrast enhanced computed tomography; diffusion; mechanical convection Hyaline cartilage is the load bearing tissue that supports and distributes applied forces across articular joints while providing a smooth, low friction, gliding surface that minimizes wear during joint motion. Glycosaminoglycans (GAGs) are negatively charged polysaccharides bound to proteoglycan backbones in the cartilage extracellular matrix (ECM) that influ- ence the unique mechanical properties of hyaline cartilage. 1,2 Loss of GAGs from the cartilage ECM is an early hallmark of cartilage degeneration associated with osteoarthritis (OA). 3 Currently, OA is diagnosed based on clinical findings of pain, abnormal joint appearance, and radiographic changes in joint struc- ture, all of which appear relatively late in the disease process. Consequently, imaging methods capable of measuring changes in the biochemical content, struc- ture, and mechanical properties of articular cartilage may provide physicians an opportunity to diagnose and treat OA early. Thus, contrast enhanced magnetic resonance (MR) 4 and computed tomography (CT) 5–10 imaging techniques are being developed to quantify changes in the structural, biochemical, and mechanical properties of cartilage. In order to estimate cartilage GAG content, delayed gadolinium enhanced MRI of cartilage (dGEMRIC) uses changes in the T1 relaxation time after intravas- cular injection of gadopentetate, an anionic contrast agent, while contrast enhanced CT (CECT) utilizes iodinated anionic or cationic contrast agents after intra-articular injection into a single joint to be imaged. 7 Both techniques, however, are hindered by the time required for contrast agents to reach equilib- rium partitioning (an amount of contrast accumulated in the tissue at steady-state, often normalized to the contrast solution concentration) in the cartilage. Although MRI-based methods are more commonly employed for evaluating joint pathologies, widespread clinical use of dGEMRIC is deterred by its high cost, long acquisition time, and the time delay between contrast injection and imaging necessitated by the slow acquisition of sufficient contrast by cartilage tissue. CECT of cartilage, on the other hand, acquires images much more quickly while simultaneously imag- ing the subchondral bone with high fidelity. 11 CECT is also subject to slow contrast agent diffusion, as is MRI, and is subject to other complications such as beam hardening from highly attenuating contrast agent injections and patient exposure to ionizing radiation. However, new cone-beam scanners are beginning to have a presence in clinic. These offer higher resolution imaging (with isotropic voxel size) and greatly reduced radiation dose, and promise new opportunities for cartilage imaging in the extremities. CECT of cartilage accurately predicts GAG content, equilibrium compressive modulus, and coefficients of friction of hyaline cartilage in isolated cartilage plugs. 5,9,12–14 Despite these promising results using an osteochondral plug model, multiple studies report slow rates of passive diffusion with average times to reach Conflicts of interest: None. Vahid Entezari and Prashant N. Bansal contributed equally to this work. Grant sponsor: Coulter Foundation; Grant sponsor: Boston University; Grant number: R01GM098361; Grant sponsor: NIH; Grant number: R01GM098361; Grant sponsor: Harvard Catalyst Program; Grant sponsor: Children’s Orthopaedic Surgery Foundation; Grant sponsor: Henry Luce Foundation. Correspondence to: Mark W. Grinstaff (T: þ1-617-358-3429; F: þ1-617-358-3186; E-mail: mgrin@bu.edu) Correspondence to: Brian D. Snyder (T: þ1-617-355-7409; F: þ1- 617-730-0622; E-mail: brian.snyder@childrens.harvard.edu) # 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. JOURNAL OF ORTHOPAEDIC RESEARCH OCTOBER 2014 1333