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

项目概要/摘要： 脊髓损伤（SCI）是一种毁灭性的创伤，大约有10，000到20，000人 美国每年都有瘫痪的人，每年花费医疗保健系统405亿美元。虽然 研究表明，SCI后的炎症反应有利于清除碎片和释放神经营养物质， 在这些因素中，炎症反应过度，导致进一步的神经破坏， 炎性巨噬细胞保持延长的时间段。炎症细胞因子被强烈上调 在SCI后的前24小时内，在14小时左右有第二波炎性细胞因子表达， 天虽然，使用抗炎细胞因子减轻SCI后的炎症已经显示出一些 令人鼓舞的结果，有几个限制，需要克服使用抗炎细胞因子 作为SCI的治疗，包括半衰期短，不能穿过血液脊髓屏障，快速清除 当使用大的全身剂量时，因此， 有一个局部持续交付的抗炎细胞因子，符合关键阶段，随后 炎症反应，直接在损伤部位给药至少14天。 创新：新兴的细胞因子递送方法通常受到次优释放特性的限制， 当在体内递送时，细胞因子的生物活性差。我们假设矿物涂层微粒 （MCMs）将结合，稳定和释放生物活性抗炎细胞因子，并且当以 具有优化的剂量和释放曲线的临床相关时间，它们将减少炎症，导致更小的 损伤和更高水平的功能保留后SCI。 目的：提出的计划是1）使用MCMs开发细胞因子递送系统，并表征 IL-4、IL-10和IL-13掺入、释放和生物活性; 2）优化细胞因子剂量和治疗 大鼠挫伤模型中的时间轴;和3）探索细胞因子组合的协同作用，以减少大鼠挫伤模型中的损伤。 炎症和改善SCI后损伤水平以下保留的功能量。 影响：成功完成拟议的研究计划将产生三个直接成果。一是 将建立一种方法，以减轻炎症后SCI使用局部交付的生物活性抗- 炎症细胞因子与优化的剂量和时机。第二，它将探索以下方面的根本协同作用： 影响炎症特定阶段的细胞因子。第三，它将开发一个可控的药物输送系统 对SCI后的生物活性分子的影响鉴于可溶性细胞因子参与细胞凋亡的重要性， SCI后的炎症反应，以及促进轴突生长的信号传导和引导线索的生长因子， 生长，提出的MCMs有望成为神经组织工程中独特的使能技术。 每项成果都意义重大，并且将具有比本文所探讨的更广泛的应用。

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.