Biomimetic proteoglycans diffuse throughout articular cartilage and localize within the pericellular matrix

Abstract

Biomimetic proteoglycan (BPG) diffusion into articular cartilage has the potential to restore the lost proteoglycan content in osteoarthritic cartilage given these molecules mimic the structure and properties of natural proteoglycans. We examined the diffusion characteristics of BPGs through cartilage with the use of a custom‐made in vitro cartilage diffusion model in both normal bovine and human osteoarthritic cartilage explants. BPGs were introduced into the cartilage through essentially one‐dimensional diffusion using osteochondral plugs. The molecular diffusion was shown to be size and concentration dependent. Diffusion profiles were found over different diffusion time intervals and the profiles were fit to a nonlinear Fickian diffusion model. Steady state 011012‐7diffusion coefficients for BPGs were found to be 4.01 and 3.53 μm2/s for 180 and 1600 kDa BPGs, respectfully, and these values are similar to other large molecule diffusion in cartilage. In both bovine and osteoarthritic human cartilage, BPGs were found localized around the chondrocytes. BPG localization was examined by labeling collagen type VI and soaking 5 μm thick sections of cartilage with BPG solutions demonstrating that the BPGs diffused into the cartilage and preferentially localized alongside collagen type VI in the pericellular matrix.

Hyaluronic Acid-Binding, Anionic, Nanoparticles Inhibit ECM Degradation and Restore Compressive Stiffness in Aggrecan-Depleted Articular Cartilage Explants

“…Unconjugated hNPsRBITC and 20 GAH-hNPsRBITC permeated into aggrecan-depleted explants while they remained at the surface of the healthy explants. These data agreed with previous studies where anionic bottle-brush polymers and pNIAPm-based nanoparticles diffused into damaged cartilage [ 21 , 23 ], while pNIPAm-based nanoparticles remained on the surface of healthy cartilage [ 23 ]. The 20 GAH-hNPsRBITC diffused slower than the hNPsRBITC, potentially due to differences in HA binding within the explant, though both particle types significantly permeated into AD cartilage after 4 h.…”

“…Moreover, roughly 4 h was required for unconjugated hNPsRBITC and 20 GAH-hNPsRBITC to significantly diffuse into the AD explant ( Supplemental Figure S3 ). The diffusion coefficient of the 20 GAH-hNP into the AD explant was 6.5 µm 2 /s [ 21 ].…”

Dynamic cell–cell adhesion mediated by pericellular matrix interaction – a hypothesis

“…In chondrocytes, for example, the outer PCM can be peeled from the cell-attached inner part (Cohen et al, 2003). Pores in the PCM that permit the diffusion of large proteoglycans (Chang et al, 2016;Phillips et al, 2019) also argue against a dense, impenetrable polymer brush, and the experimental finding that PCMs easily reconfigure around penetrating probe particles (McLane et al, 2013) contradicts simulation results based on brush models (Kabedev and Lobaskin, 2018). Thus, although the supramolecular architecture of PCMs is not well understood, available evidence suggests that PCMs are best described as complex hydrogels (Fig.…”

Proteoglycans in Biomedicine: Resurgence of an Underexploited Class of ECM Molecules

“…and integrate into rabbit tissue before and after static loading, demonstrating the ability to engineer ECM on a molecular level (Sarkar et al, 2012;Prudnikova et al, 2017;Prudnikova et al, 2018;Phillips et al, 2019).…”

“…This work is supported in part by the National Heart, Lung, and Blood Institute and the National Institute on Drug Abuse through grant 1U54HL119893. (Han et al, 2016) Syndecan 1-4 Heparan sulfate Diabetic wound healing (Das et al, 2016a;Das et al, 2016b;Das et al, 2016c) Aggrecan Chondroitin sulfate, keratan sulfate Osteoarthritis (Bernhard and Panitch, 2012;Place et al, 2014a;Phillips et al, 2019;Place et al, 2014b;Sarkar et al, 2012;Sharma et al, 2013;Sharma et al, 2016;Prudnikova et al, 2017;Prudnikova et al, 2018)…”