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

项目摘要/摘要： 意义：脊髓损伤(SCI)是一种毁灭性的创伤，大约会留下10,000到20,000个 在美国，每年都有人瘫痪，每年给医疗保健系统造成405亿美元的损失。尽管它已经 研究表明，脊髓损伤后的炎症反应有利于清除碎片和释放神经营养物质。 因素，炎症反应的过度反应导致进一步的神经破坏和 炎性巨噬细胞持续时间较长。炎性细胞因子强烈上调 在脊髓损伤后的24小时内，在14小时左右出现第二波炎性细胞因子的表达 几天。虽然，使用抗炎细胞因子来减轻脊髓损伤后的炎症反应已经显示出一些 令人鼓舞的结果是，使用抗炎细胞因子需要克服几个限制 作为脊髓损伤的一种治疗方法，包括半衰期短，无法越过血脊髓屏障，清除快 当使用大剂量全身剂量时，感染风险更高。因此，这将是有益的 进行局部持续的抗炎细胞因子输送，恰逢随后的关键阶段 炎症反应，直接在损伤部位给予至少14天。 创新：新兴的细胞因子递送方法往往受到次优释放特性和 体内给药时细胞因子的生物活性较差。我们假设矿物包裹的微粒 (MCMS)将结合、稳定和释放生物活性抗炎细胞因子，当注射到 临床相关时间通过优化的剂量和释放曲线，它们将减少炎症，导致更小的 脊髓损伤后损伤和较高水平的功能保留。 目标：拟议的计划是：1)开发一种使用MCMS的细胞因子递送系统，并表征 IL-4、IL-10和IL-13的掺入、释放和生物活性；2)优化细胞因子的剂量和治疗 在大鼠挫伤模型中的时间线；以及3)探索细胞因子组合的协同作用以减少 炎症和改善脊髓损伤后保留在损伤水平以下的功能量。 影响：成功完成拟议的研究计划将产生三个直接结果。首先，它 将建立一种方法来减轻脊髓损伤后的炎症，使用局部输送的生物活性抗炎药物 具有最佳剂量和时机的炎性细胞因子。第二，它将探索两国之间的根本协同效应 影响炎症特定阶段的细胞因子。第三，它将开发可控的药物输送系统 用于脊髓损伤后的生物活性分子。鉴于可溶性细胞因子在人类免疫系统中的重要性 脊髓损伤后的炎症反应，以及促进轴突信号和指导线索的生长因子 随着时间的推移，拟议的MCMS有望成为神经组织工程中的一项独特的使能技术。 每一项成果都意义重大，并将比本文探讨的那些成果具有更广泛的应用。

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.