Addressing the pathological mechanisms of osteoarthritis using rationally designed biomaterials
Embargo Date
2027-05-22
OA Version
Citation
Abstract
The ends of bones meet in the synovial joint, a highly organized structure that protects the bones from the high loads and high frictions that are inherent with locomotion. Within the synovial joint, the two main components that impart load bearing capacity and lubricity are the synovial fluid (SF) and articular cartilage. SF is a dialysate of blood plasma containing high concentrations of the lubricating biomacromolecules hyaluronic acid, surface active phospholipids, and lubricin which interact at the cartilage surface to form a hydration layer that provides a nearly frictionless surface for articulation to occur. Cartilage consists mainly of collagen, proteoglycans, and water; the collagen fibers form a dense network throughout which the proteoglycans are entrapped, leading to an influx of water and swelling of the tissue. Proteoglycans contain a protein core that is decorated with glycosaminoglycans (GAGs) and aggregate by attaching to hyaluronic acid chains, via the link protein, to form a network. The GAGs are highly sulfated carbohydrates, which impart the cartilage extracellular matrix (ECM) with an anionic charge and coordinate water such that when a load is applied, the fluid entrapped within the ECM pressurizes and supports a majority of the load. Osteoarthritis (OA), a degenerative disease in which synovial joint function is impaired due to degradation of the synovial fluid and cartilage, affects hundreds of millions of people worldwide by causing pain, stiffness, and decreased mobility. In OA, the concentration of lubricin, and the molecular weight and concentration of hyaluronic acid decrease in the SF, reducing the lubricity that is provided to the joint. Simultaneously, the cartilage is depleted of GAGs which reduces the ability of the tissue to coordinate water and support loads through fluid pressurization, causing the solid ECM to bear the load. The degradation of the SF and cartilage is exacerbated by the inflammatory environment of the osteoarthritic synovial joint, in which an increase of deleterious cytokines upregulates the expression of enzymes that catabolize the biomacromolecules that are imperative to proper functioning.In this work, I rationally design biomaterials to address key pathological traits of OA: 1) the degradation of lubricating macromolecules that decrease in SF lubricity; 2) the depletion of GAGs that reduces the load bearing ability of the cartilage; and 3) the inflammatory environment of the joint that increases the concentration of catabolic enzymes. First, I show that adjusting the architecture and concentration of a zwitterionic polymer, poly (2-methacryloyloxyethyl phosphorylcholine), tunes the viscoelastic character of aqueous solutions of the polymer and that a network architecture at a concentration of 5 w/v% effectively lubricates and protects cartilage during articulation. Second, I form a cartilage interpenetrating network (IPN) using a sulfonated monomer, 3-sulfopropylmethacrylate, to understand the effect of a negatively charged synthetic network on the material properties of GAG-depleted cartilage. Third, I develop a sulfated carbohydrate analog, methacrylated-6-sulfated poly-amido-saccharide, to form a GAG-mimetic IPN to restore the mechanical and solute infiltration properties of GAG-depleted cartilage. Finally, I use a positively charged carbohydrate mimetic, amino-poly-amido-saccharide, to encapsulate microRNA and deliver it to mitigate the effect of inflammatory cytokines on articular chondrocytes. Together, this work highlights the ability to target specific pathological mechanisms in OA that are detrimental to the function of the synovial joint through the rational design of biomaterials.
Description
2025