Polyacrylamide for Joint Therapy - Critical Things Unknown

Grants and Contracts Details

Description

Polyacrylamide for joint therapy–critical things unknown Our long-term goal is to assess the safety of using polyacrylamide hydrogel (PAAG) to treat equine osteoarthritis (OA). The purpose of this study is to characterize the inflammatory response following joint injection with PAAG, and how synovial incorporation of PAAG affects inflammatory signaling and nociception. We hypothesize that joint injection with PAAG will induce macrophage recruitment, inflammation resolution and synovial remodeling, and that remodeling of synovial architecture due to PAAG incorporation will not impair inflammatory signaling or nociception. Rationale: OA is the leading cause of lameness in horses. Synovial inflammation is a key feature of OA, yet most therapies fail to resolve inflammation long-term, producing short-lasting effects. Over the last decade, PAAG has been investigated as a treatment for OA identifying lasting improvements (up to 24 months). Despite very positive effects, the mechanisms of action and, most importantly, the safety of PAAG as a joint therapy are still unknown and debated. While PAAG is known to incorporate into the synovial architecture and increase joint lubrication, research into how PAAG affects joint inflammation has not been reported. Importantly, remodeling of the synovium due to PAAG incorporation have raised concerns amongst equestrian authorities that PAAG could have neurolytic effects, precluding detection of impending catastrophic injuries. Hence, for Thoroughbred racehorses, HISA rule 4224 states “Intra- articular injections of polyacrylamide hydrogels are prohibited within 180 days prior to Post-Time.” Despite clinical perceptions and concerns related with the use of PAAG, there are critical knowledge gaps about 1) how PAAG changes the inflammatory response of joints, and 2) whether PAAG-induced remodeling of the synovium affects inflammatory nociception. The following specific aims are high priority questions in addressing HISA concerns and the safe use of this promising joint therapy. First Hypothesis (H1)1: PAAG injection into OA joints will induce a transient pro-inflammatory response, followed by inflammation resolution and synovial architecture remodeling. Specific Aim 1 (SA1): Characterize the longitudinal changes in the inflammatory response in OA metacarpophalangeal joints following injection with PAAG. Synovial inflammation resolution is a primary goal of joint therapies. To date, the inflammatory response of joints to PAAG injection has only been assessed histologically (H&E), identifying increased cellular infiltrate and synovial remodeling. Collective interpretation of available data suggest PAAG induces macrophage recruitment and a response that resolves inflammation as PAAG is incorporated into the synovium. However, the identity and phenotype of recruited cells has not been characterized. The objective of this aim is to characterize the innate immune response (proinflammatory / pro- resolving) and expression of nociceptive mediators in the synovial membrane and fluid from OA metacarpophalangeal (MCP) joints following PAAG injection (at 8, 30, and 90 days; n=6 horses/time point). Synovial fluid and membrane samples from contralateral vehicle-treated joints will serve as controls. Second Hypothesis (H2): PAAG-induced remodeling of the synovium will not impair inflammatory signaling or nociception. Specific Aim 2 (SA2): Characterize the inflammatory and nociceptive response of PAAG-injected joints to lipopolysaccharide (LPS)-induced synovitis. This aim is designed to determine whether PAAG-induced remodeling of the synovium impairs inflammatory signaling and nociception. One middle-carpal joint from the same horses in SA 1 will be injected with PAAG and the contralateral joint with vehicle. 24 hours prior to the harvest of tissues for both SA1 and SA2 (Days 8, 30 and 90), both middle-carpal joint joints will be challenged with LPS (n=6 horses/time point). During the 24 hour period between LPS challenge and tissue harvesting, horses will be evaluated for the equality of load bearing and weight shifting between forelimbs (previously injected with PAAG or with vehicle) using a custom made and tested load cell boots to assess whether PAAG treatment alters nociception in this commonly used model of synovitis. At each time point (n=6 horses/time point), synovial fluid and synovial membrane samples will be harvested.
StatusActive
Effective start/end date7/1/246/30/25

Funding

  • Grayson Jockey Club Research Foundation Inc: $126,369.00

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.