Reducing Inflammation After Spinal Cord Injury Via Mineral Coated Microparticles Releasing Anti-Inflammatory Cytokines

项目摘要/摘要：

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. Inflammatory cytokines are strongly upregulated during the first 24 hours after SCI, and there is a second wave of inflammatory cytokine expression around 14 days. Although, using anti-inflammatory cytokines to attenuate inflammation after SCI has shown some encouraging results, 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 clearance from 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, given directly in the injury site for at least 14 days. 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) will bind, stabilize and release biologically active anti-inflammatory cytokines, and when injected at clinically relevant times with optimized dose and release profile, they will reduce inflammation resulting in smaller lesions and a higher level of function retained after SCI. Aims: The proposed plan is to 1) develop a cytokine delivery system using MCMs, and characterize incorporation, release, and biological activity of IL-4, IL-10, and IL-13; 2) optimize cytokine dosage and treatment timeline in a rat contusion model; and 3) explore the synergistic effects of combinations of cytokines to reduce inflammation and improve the amount of function retained below the level of injury after SCI. Impact: Successful completion of the proposed research program 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 and timing. 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 that promote signaling and guidance cues for axonal growth, the proposed MCMs are expected to be a uniquely enabling technology in neural tissue engineering. Each outcome is significant, and will have far broader applications than those explored herein.