Treating Spinal Cord Injury with Mineral Coated Microparticles Releasing Anti-Inflammatory Cytokines - Project Summary / Abstract: Significance: Spinal Cord Injury (SCI) is a devastating trauma that leaves approximately 10,000 to 20,000 people paralyzed every year in the U.S., costing the health care system $40.5 billion annually. Although it has been shown that the inflammatory response after SCI is beneficial in removing debris and releasing neurotrophic factors, there is an overreaction of the inflammatory response causing further neural destruction and inflammatory macrophages remain for a prolonged time period. Using anti-inflammatory cytokines to attenuate inflammation after SCI has shown some encouraging results. However, there are several limitations that need to be overcome to use anti-inflammatory cytokines as a treatment for SCI including, a short half-life, inability to cross the blood spinal cord barrier, rapid clearancefrom the injury site, and higher risk of infection when using large systemic doses. Therefore, it would be beneficial to have a local sustained delivery of anti-inflammatory cytokines, coinciding with critical stages of the ensuing inflammatory response. Innovation: Emerging cytokine delivery approaches are often limited by sub-optimal release characteristics and poor biological activity of the cytokine when delivered in vivo. We hypothesize that: mineral coated microparticles (MCMs) releasing anti-inflammatory cytokines can be injected at clinically relevant treatment times after SCI, which will reduce inflammation coinciding with critical stages of the ensuing secondary damage resulting in smaller lesions and a higher level of function retained after SCI. We have preliminary data showing that IL-4, IL-10, and IL-13 retain their bioactivity when bound to MCMs and are capable of reducing inflammation after SCI. Our preliminary results also show a clear synergistic effect at reducing inflammation when using the combination of IL-4, IL-10, and IL-13. Aims: The proposed plan is to 1) optimize IL-4, IL-10, and IL-13 dosage in a rat contusionmodel; 2) test the influence MCMs delivering IL-4, IL-10, and IL-13 have on immune cells during important stages of inflammation and glial scar development; and 3) explore the influence a sustained release of IL-4, IL-10, and IL-13 has on reducing inflammation and improving the amount of function retained below the level of injury after SCI. Impact: Successful completion of the proposed research will produce three direct outcomes. First, it will establish a method to attenuate inflammation after SCI using locally delivered biologically active anti- inflammatory cytokines with optimized dosage. Second, it will explore fundamental synergies between cytokines that influence specific stages of inflammation. Third, it will develop a controllable drug delivery system for biologically active molecules after SCI. In view of the importance of soluble cytokines involved in the inflammatory response after SCI, as well as growth factors for signaling and guidance cues for axonal growth, the proposed MCMs are expected to be a uniquely enabling technology in neural tissue engineering.
