Redesigning the Viscosupplement to Enhance the Mechanical and Biological Actions of Hyaluronic Acid

摘要

Abstract Knee osteoarthritis (OA) is an immobilizing chronic disease that drastically decreases quality of life. Intra-articular injections of viscous, high molecular weight hyaluronic acid (HA) solutions are commonly administered to restore viscoelastic properties of synovial fluid and reduce OA related joint pain. In addition to its mechanical effects, cellular receptor binding to HA has been shown to reduce inflammatory signaling, cartilage degrading enzyme activity, and stimulate endogenous production of HA. Despite the tremendous potential of HA in treating OA based on its critical roles in joint function, sustaining high concentrations of exogenous HA in the synovial fluid has been challenging and therefore its clinical efficacy limited. Traditional viscosupplements rely on the same formulation approach of creating a viscous solution of HA, then introducing crosslinks to stabilize and retain HA after injection. This approach and considerations of material viscosity and acceptable injection forces has limited HA doses to less than 100 mg and half-lives to less than one week. In order to increase the dose and enhance duration of HA treatment, Prohibix LLC has redesigned the HA viscosupplement into dense hydrogel microparticles that slowly release high molecular weight HA into the synovial fluid over time. Our promising preliminary results demonstrate the ability to deliver over 200 mg of HA in a single injection that releases HA for over 4 weeks. This innovative HYALEASE hydrogel microparticle technology has tremendous potential to improve the therapeutic efficacy of HA in treating OA, and also has great potential as a platform to encapsulate and sustain the release of other promising but hard to formulate therapeutics. The objective of this Phase I SBIR proposal is to continue the development of the HYALEASE microparticle technology including (i) demonstrate biological activity of released HA, (ii) quantify synovial half-life in rats, and (iii) compare therapeutic efficacy to a traditional viscosupplement using an industry adopted rat OA model. Completion of these Aims will further motivate product development in a large animal model of OA (Phase II studies) towards first-in-man studies.