An official website of the United States government
Abstract Articular joints facilitate motion and transfer loads to underlying bone through a combination of cartilage tissue and synovial fluid, which together generate a low‐friction contact surface. Traumatic injury delivered to cartilage and the surrounding joint capsule causes secretion of proinflammatory cytokines by chondrocytes and the synovium, triggering cartilage matrix breakdown and impairing the ability of synovial fluid to lubricate the joint. Once these inflammatory processes become chronic, posttraumatic osteoarthritis (PTOA) development begins. However, the exact mechanism by which negative alterations to synovial fluid leads to PTOA pathogenesis is not fully understood. We hypothesize that removing the lubricating macromolecules from synovial fluid alters the relationship between mechanical loads and subsequent chondrocyte behavior in injured cartilage. To test this hypothesis, we utilized an ex vivo model of PTOA that involves subjecting cartilage explants to a single rapid impact followed by continuous articulation within a lubricating bath of either healthy synovial fluid, phosphate‐buffered saline (PBS), synovial fluid treated with hyaluronidase, or synovial fluid treated with trypsin. These treatments degrade the main macromolecules attributed with providing synovial fluid with its lubricating properties; hyaluronic acid and lubricin. Explants were then bisected and fluorescently stained to assess global and depth‐dependent cell death, caspase activity, and mitochondrial depolarization. Explants were tested via confocal elastography to determine the local shear strain profile generated in each lubricant. These results show that degrading hyaluronic acid or lubricin in synovial fluid significantly increases middle zone chondrocyte damage and shear strain loading magnitudes, while also altering chondrocyte sensitivity to loading.
more »
« less
Intra-Articular Administration of a Synthetic Lubricin in Canine Stifles
Abstract Objective The aim of this study was to evaluate the functional, systemic, synovial and articular changes after intra-articular administration of a synthetic lubricin within healthy canine stifles. Study Design A prospective randomized blinded placebo-controlled study composed of 10 dogs equally divided into either a treatment group (intra-articular synthetic lubricin injection, n = 5) or control group (saline, n = 5). Clinical (orthopaedic examination, gait observation, gait analysis), biochemical (complete blood count and biochemistry profile) and local tissue outcomes (joint fluid analysis, joint capsule and articular cartilage histopathology) were evaluated over a time period of 3 months. Results No significant differences between the treatment group and control group were identified with regard to baseline patient parameters. No clinically significant orthopaedic examination abnormalities, gait abnormalities, biochemical alterations, joint fluid alterations or histopathological alterations were identified over the course of the study. Conclusion The synthetic lubricin studied herein is both biocompatible and safe for a single administration within the canine stifle joint. Further research is necessary to evaluate the clinical efficacy of the synthetic lubricin in canine osteoarthritic joints.
more »
« less
- Award ID(s):
- 1719875
- PAR ID:
- 10325586
- Date Published:
- Journal Name:
- Veterinary and Comparative Orthopaedics and Traumatology
- Volume:
- 35
- Issue:
- 02
- ISSN:
- 0932-0814
- Page Range / eLocation ID:
- 090 to 095
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract The low friction nature of articular cartilage has been attributed to the synergistic interaction between lubricin and hyaluronic acid in the synovial fluid (SF). Lubricin is a mucinous glycoprotein that lowers the boundary mode coefficient of friction of articular cartilage in a dose‐dependent manner. While there have been multiple attempts to produce recombinant lubricin and lubricin mimetic cartilage lubricants over the last two decades, these materials have not found clinical use due to challenges associated with large scale production, manufacturing, and purification. Recently, a novel method using codon scrambling was developed to produce a stable, full‐length bioengineered equine lubricin (eLub) in large reproducible quantities. While preliminary frictional analysis of eLub and other recombinantly produced forms revealed they can lubricate cartilage, a complete tribological characterization is lacking, with previous studies evaluating the friction coefficient only at a single dose or a single speed. The objective of this study was to analyze the dose‐dependent tribological properties of eLub using the Stribeck framework of tribological analysis. Recombinantly produced eLub at doses greater than 1.5 mg/mL exhibits friction coefficients on par with healthy bovine SF, and a maximal 5 mg/mL dose exhibits a nearly 50% lower friction coefficient than healthy SF. eLub also modulates the shift in lubrication mode of the cartilage from the high friction boundary mode to the low friction minimum mode at high concentrations.more » « less
-
Abstract Inflammation of the synovium, known as synovitis, plays an important role in the pathogenesis of osteoarthritis (OA). Synovitis involves the release of a wide variety of pro‐inflammatory mediators in synovial fluid (SF) that damage the articular cartilage extracellular matrix and induce death and apoptosis in chondrocytes. The composition of synovial fluid is dramatically altered by inflammation in OA, with changes to both hyaluronic acid and lubricin, the primary lubricating molecules in SF. However, the relationship between key biochemical markers of joint inflammation and mechanical function of SF is not well understood. Here, we demonstrate the application of a novel analytical framework to measure the effective viscosity for SF lubrication of cartilage, which is distinct from conventional rheological viscosity. Notably, in a well‐established equine model of synovitis, this effective lubricating viscosity decreased by up to 10,000‐fold for synovitis SF compared to a ~4 fold change in conventional viscosity measurements. Further, the effective lubricating viscosity was strongly inversely correlated (r = −0.6 to −0.8) to multiple established biochemical markers of SF inflammation, including white blood cell count, prostaglandin E2(PGE2), and chemokine ligand (CCLs) concentrations, while conventional measurements of viscosity were poorly correlated to these markers. These findings demonstrate the importance of experimental and analytical approaches to characterize functional lubricating properties of synovial fluid and their relationships to soluble biomarkers to better understand the progression of OA.more » « less
-
We report the design of a diblock copolymer with architecture and function inspired by the lubricating glycoprotein lubricin. This diblock copolymer, synthesized by sequential reversible addition–fragmentation chain-transfer polymerization, consists of a cationic cartilage-binding domain and a brush-lubricating domain. It reduces the coefficient of friction of articular cartilage under boundary mode conditions (0.088 ± 0.039) to a level equivalent to that provided by lubricin (0.093 ± 0.011). Additionally, both the EC 50 (0.404 mg/mL) and cartilage-binding time constant (7.19 min) of the polymer are comparable to purified human and recombinant lubricin. Like lubricin, the tribological properties of this polymer are dependent on molecular architecture. When the same monomer composition was evaluated either as an AB diblock copolymer or as a random copolymer, the diblock effectively lubricated cartilage under boundary mode conditions whereas the random copolymer did not. Additionally, the individual polymer blocks did not lubricate independently, and lubrication could be competitively inhibited with an excess of binding domain. This diblock copolymer is an example of a synthetic polymer with lubrication properties equal to lubricin under boundary mode conditions, suggesting its potential utility as a therapy for joint pathologies like osteoarthritis.more » « less
-
Abstract Intra‐articular injections of hyaluronic acid (HA) are the cornerstone of osteoarthritis (OA) treatments. However, the mechanism of action and efficacy of HA viscosupplementation are debated. As such, there has been recent interest in developing synthetic viscosupplements. Recently, a synthetic 4 wt% polyacrylamide (pAAm) hydrogel was shown to effectively lubricate and bind to the surface of cartilage in vitro. However, its ability to localize to cartilage and alter the tribological properties of the tissue in a live articulating large animal joint is not known. The goal of this study was to quantify the distribution and extent of localization of pAAm in the equine metacarpophalangeal or metatarsophalangeal joint (fetlock joint), and determine whether preferential localization of pAAm influences the tribological properties of the tissue. An established planar fluorescence imaging technique was used to visualize and quantify the distribution of fluorescently labeled pAAm within the joint. While the pAAm hydrogel was present on all surfaces, it was not uniformly distributed, with more material present near the site of the injection. The lubricating ability of the cartilage in the joint was then assessed using a custom tribometer across two orders of magnitude of sliding speed in healthy synovial fluid. Cartilage regions with a greater coverage of pAAm, that is, higher fluorescent intensities, exhibited friction coefficients nearly 2‐fold lower than regions with lesser pAAm (Rrm = −0.59,p < 0.001). Collectively, the findings from this study indicate that intra‐articular viscosupplement injections are not evenly distributed inside a joint, and the tribological outcomes of these materials is strongly determined by the ability of the material to localize to the articulating surfaces in the joint.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1055/s-0041-1736189
