Advances in viscosupplementation and tribosupplementation for early-stage osteoarthritis therapy

Abstract

Joint kinematic instability, arising from congenital or acquired musculoskeletal pathoanatomy or from imbalances in anabolism and catabolism induced by pathophysiological factors, leads to deterioration of the composition, structure and function of cartilage and, ultimately, progression to osteoarthritis (OA). Alongside articular cartilage degeneration, synovial fluid lubricity decreases in OA owing to a reduction in the concentration and molecular weight of hyaluronic acid and surface-active mucinous glycoproteins that form a lubricating film over the articulating joint surfaces. Minimizing friction between articulating joint surfaces by lubrication is fundamental for decreasing hyaline cartilage wear and for maintaining the function of synovial joints. Augmentation with highly viscous supplements (that is, viscosupplementation) offers one approach to re-establishing the rheological and tribological properties of synovial fluid in OA. However, this approach has varied clinical outcomes owing to limited intra-articular residence time and ineffective mechanisms of chondroprotection. This Review discusses normal hyaline cartilage function and lubrication and examines the advantages and disadvantages of various strategies for restoring normal joint lubrication. These strategies include contemporary viscosupplements that contain antioxidants, anti-inflammatory drugs or platelet-rich plasma and new synthetic synovial fluid additives and cartilage matrix enhancers. Advanced biomimetic tribosupplements offer promise for mitigating cartilage wear, restoring joint function and, ultimately, improving patient care.

Fig. 1 |. Types of viscosupplementation and tribosupplementation.

This figure depicts the various categories of clinical, hyaluronic acid-based viscosupplements and tribosupplements that are discussed in this Review. The term viscosupplement describes an exogenous hyaluronic acid-based solution. Viscosupplements can be further subdivided on the basis of structure (linear versus cross-linked) and composition (administered alone versus in combination with additional components that enhance the drugs’ therapeutic effects). Tribosupplements are alternative non-hyaluronic acid-based lubricants that can be further divided by structure (linear polymer, hydrogel or particle) and matrix-binding capacity (that is, whether the tribosupplement remains suspended in the synovial fluid or contains a matrix binder that localizes it to the cartilage surface).

Fig. 2 |. The composition, morphology and biomechanics of cartilage and synovial fluid in the healthy and osteoarthritic states.

a, Hyaline cartilage consists of three layers: the superficial zone, transition zone and deep zone, each with a different morphology, composition and structure. Chondrocytes are embedded within the extracellular matrix (ECM) of cartilage and synthesize and maintain the ECM constituents. The superficial zone interfaces with the synovial fluid, which contains hyaluronic acid and proteoglycan 4 (PRG4). Hyaluronic acid is an anionic, non-sulphated, high-molecular-weight biopolymer that endows synovial fluid with its viscosity. PRG4, a surface-active glycoprotein, attaches to the lamina splendens, binds to hyaluronic acid present in the synovial fluid to localize it to the articular surface and thereby provides a discontinuous, sacrificial layer that enhances superficial zone pressurization and boundary lubrication. b, During osteoarthritis (OA), the composition, morphology and biomechanics of cartilage and synovial fluid change. Compositionally, osteoarthritic cartilage contains decreased amounts of hyaluronic acid, PRG4, and type II collagen compared with healthy tissue because of wear and an aberrant balance between anabolism and catabolism. Similarly, in the synovial fluid, the concentration and molecular weight of sodium hyaluronate decreases and the concentration of PRG4 decreases during OA. OA also results in morphological changes to cartilage as the structure of the collagen matrix transitions from the characteristic arching fibrils, producing a matrix that is perpendicular to the subchondral bone in the middle and deep zones and parallel to the articular surface, to a disorganized distribution of fibrils. Ultimately, the compositional and morphological changes in OA reduce cartilage stiffness, such that the same applied force (F_N) produces a larger strain (ε) in osteoarthritic cartilage than in healthy cartilage.

Fig. 3 |. Clinical results for several clinically approved viscosupplements.

a,b, Results from clinical trials of linear viscosupplements (a) and crosslinked viscosupplements (b). On the x-axis, the viscosupplements are grouped by molecular weight of sodium hyaluronate. The left y-axis, corresponding to the bars, represents the relative decrease in average pain at the study end point compared with the average pain reported at baseline. The dark blue bars represent Western Ontario and McMaster Universities Osteoarthritis pain scores whereas the light blue bars represent visual analogue scale pain. The right y-axis, corresponding to the symbols, represents the total amount of sodium hyaluronate injected. The shape reflects the size of the clinical trial (key). c,d, The clinical outcomes for pain (c) and function (d) for those trials that included a placebo control, and a summary estimate of 24 placebo-controlled trials for pain and 19 placebo-controlled trials for function (Overall), are compared using standardized mean differences. A standardized mean difference of less than 0 indicates that the viscosupplementation is favoured over placebo. The shaded region demonstrates the values for which clinical outcomes between viscosupplementation and placebo are equivalent, on the basis of a minimal clinically significant difference of 0.37. Data are represented as mean with 95% confidence intervals. All of the viscosupplements are FDA approved, except for Suplasyn, which is approved for clinical use in Canda. NR, not reported.

Fig. 4 |. Structures of various linear tribosupplements.

a–d, Various linear polymers are under investigation as tribosupplements, including fluid additives and matrix enhancers. These include fluid additives that mimic the bottlebrush polymers present in synovial fluid, such as HA/PA (a) and HA/PM (b) and linear polymers that mimic proteoglycan 4 (PRG4, also known as lubricin), such as full-length PRG4 (c) and LUB:1 (d). HA/PA and HA/PM consist of synthetic polymers poly(acryloylamino-2-methyl-1-propanesulfone) (PA), and poly(2-methacryloyloxyethyl phosphorylcholine) (PM) covalently bound to an hyaluronic acid (HA) backbone, respectively. Full-length PRG4 is derived from natural sources or produced via recombinant protein synthesis. The yield of recombinant PRG4 is maximized by truncating the mucin-like domain to form LUB:1. e–g, Matrix additives are also under investigation that contain a cartilage-binding domain, as well as a lubricity domain, including PRG4-CHO (e), PGA-PMOXA-HBA (f) and HABPep-PEG-COLBPep (g). PRG4-CHO contains succinimidyl-4-formylbenzamide, which enables PRG4 to covalently attach to the articular surface and improve lubricity. For PGA-PMOXA-HBA, the HBA domains covalently bond to cartilage and the PMOXA blocks create a lubricious film between articulating surfaces. HABPep-PEG-COLBPep consists of PEG flanked by a collagen-binding peptide (COLBpep) and a HA-binding peptide (HABpep). The COLBpep allows the construct to specifically bind collagen at the cartilage surface, whereas the HABpep interacts with HA suspended in synovial fluid to promote lubrication.