Pass the salt : elucidating the chondroprotective properties of hyperosmolar saline irrigation solutions

[EMBARGOED UNTIL 12/1/2024] Arthroscopy is the most commonly performed orthopaedic surgery procedure. During arthroscopic surgery, a continuous flow of irrigation solution is necessary to distend the joint, remove debris, prevent tissue desiccation, and maintain visualization and access to intra-articular structures. The most commonly used irrigation solutions, such as normal saline or Ringer's lactate, disrupt joint physiology when hyperosmolar synovial fluid (400 mOsm/L) is diluted by these isotonic fluids (~270-300 mOsm/L). Disruptions include cell apoptosis and necrosis, altered gene expression, protein synthesis and calcium signaling, and extracellular matrix compositional changes with resultant material property perturbations, which persist until the imbalance is restored. As such, creating and validating formulations for arthroscopic irrigation solutions that maintain and protect the joint, rather than disrupt it, are vital to making this high-volume procedure safer for patients. The overall objective of the programmatic research presented in this dissertation was to further elucidate the chondroprotective properties of hyperosmolar saline irrigation solutions for application to clinical practice. The first section of this dissertation (Chapters 1 & 2) provides a compressive introduction and literature review of the synovial joint, and the history, advances, and limitations of arthroscopic surgery. Chapter 3 examines the differences in pro-inflammatory and degradative mediator production and extracellular matrix degradation from osteoarthritic knee articular cartilage and meniscus explants treated with either hyperosmolar saline or isotonic saline. Chapter 4 builds on these findings in a prospective randomized double-blind controlled clinical trial that assessed initial clinical outcomes associated with use of a hyperosmolar irrigation solution in patients undergoing arthroscopic knee surgery. Finally, Chapter 5 details the differences in pro- inflammatory and degradative mediator production from osteoarthritic knee articular cartilage explants treated with a hyperosmolar saline solution supplemented with anti-inflammatory components (L-glutamine, ascorbic acid, sodium pyruvate, epigallocatechin gallate (EGCG), and dexamethasone) or normal saline using an in vitro model for knee arthroscopy. Numerous significant findings are illustrated throughout this dissertation. The work described in Chapter 3 demonstrates that treatment of cartilage and meniscus explants with hyperosmolar saline effectively mitigated key pro-inflammatory mediator production as well as degradative mediator production and GAG loss from meniscus with no detrimental effects noted compared to isotonic saline. The randomized controlled trial described in Chapter 4 illustrates that a hyperosmolar irrigation solution is safe and relatively inexpensive for use in patients undergoing arthroscopic knee surgery and contributes to a reduction in initial postoperative narcotic pain medication consumption. Chapter 5 introduces a hyperosmolar saline solution supplemented with anti-inflammatory components; treatment of cartilage explants with a hyperosmolar saline arthroscopic irrigation solution supplemented with anti-inflammatory components was associated with significant decreases in inflammatory and degradative mediator production and mitigation of proteoglycan loss. As such, this novel solution may have further benefits for patients when it can be validated for clinical use. Taken together, this body of research supports the clinical application of hyperosmolar saline irrigation solutions for use in patients undergoing arthroscopic procedures.