Development of Biomaterials that Release Therapeutic Agents to Modulate Inflammat

开发释放治疗剂来调节炎症的生物材料

• 批准号: 7826975
• 负责人: Ryan J. Gilbert
• 金额: $ 0.35万
• 依托单位: MICHIGAN TECHNOLOGICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2010-06-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7826975
• 关键词: Acute; Affect; Astrocytes; Biocompatible Materials; Bolus Infusion; Buffers; Cell Death; Cells; Chemicals; Chills; Chronic; Cicatrix; Contusions; Coupling; Data; Environment; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Free Radicals; Glutathione; Goals; Hydrogels; Implant; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Injectable; Injection of therapeutic agent; Injury; Interleukin-10; Intervention; Intravenous; Laboratories; Lesion; Liquid substance; Locomotor Recovery; Mass Spectrum Analysis; Methylcellulose; Modeling; Natural regeneration; Nerve Regeneration; Neuraxis; Neuroglia; Neurons; Ohio; Patients; Physiological; Pilot Projects; Process; Pump; Rattus; Reaction; Reducing Agents; Research; Rhodamine; Rhodamines; Sepharose; Site; Spinal Cord; Spinal cord injury; Syringes; Techniques; Technology; Temperature; Testing; Therapeutic; Therapeutic Agents; Time; Work; aqueous; biomaterial development; controlled release; cytokine; experience; improved; in vivo; injured; model development; new technology; novel; public health relevance

DESCRIPTION (provided by applicant): The goal of this study is to develop new technology to reduce secondary injury following spinal cord injury. Currently, there are no viable treatments for patients who have sustained spinal cord injury. Clinically, interventions involve injection of agent intravenously. Experimentally, most interventions involve injection of agent intravenously or intraperiotoneally. Although these treatments have improved functionality, technology has not yet been developed to supply continuous delivery of agents to the damaged site without the need of pumps or through the administration of several injections. Here, we present a novel biomaterial blend composed of agarose and methylcellulose. Prior preliminary data has shown that these blends exist as a liquid at room temperature and quickly solidify at physiological temperatures. They are injectable through a syringe for ease of application to an injured site. Within this revised application, we present data showing that glutathione and interleukin-10 can be released for five and six days in vitro respectively. The hydrogel is fabricated in a chilled environment using just aqueous buffers. Thus, loaded agents are not subjected to harsh processing conditions and should be functional after release. Data shows that released glutathione is able to protect dissociated chick DRG neurons from free radicals produced by the Fenton reaction. Also, interleukin-10 released from the hydrogel was detected by an interleukin-10 ELISA. A pilot study was conducted where hydrogel loaded with interleukin-10 and glutathione were injected into a rat spinal cord injury model. Preliminary data show that hydrogel loaded with therapeutics had higher BBB scores 42 days post-injury compared to those injected with just plain hydrogel. In aim one of this proposal; techniques are described to couple the fluorescent chemical rhodomine to both glutathione and interleukin-10. Fluorescent conjugation will also be confirmed in aim 1. In aim two; the proposal overviews a collaborative research experience with Dr. Phillip Popovich at Ohio State. Hydrogels developed will then be applied to a rat spinal cord injury model developed at Ohio State. Work there will determine the acute in vivo release of therapeutic, acute and chronic mitigation of the inflammatory response, chronic assessment of lesion volume and neuronal sparing, and chronic assessment of locomotor recovery. PUBLIC HEALTH RELEVANCE: Current techniques to administer agents to reduce secondary injury following spinal cord trauma involve intravenous or intraperiotoneally injection. Using biomaterials, hydrogels made from agarose and methylcellulose can be loaded with agents that reduce secondary injury for a sustained period of time. The research described in this proposal will determine if hydrogels loaded with glutathione or interleukin-10 are more effective at reducing secondary injury than injection of these agents in a rat spinal cord injury model.

描述（由申请人提供）：本研究的目标是开发新技术以减少脊髓损伤后的继发性损伤。目前，对于脊髓损伤的患者没有可行的治疗方法。临床上，干预措施包括静脉注射药剂。实验上，大多数干预措施涉及静脉内或腹膜内注射药剂。尽管这些治疗方法改善了功能，但尚未开发出无需泵或通过多次注射即可将药剂连续输送到受损部位的技术。在这里，我们提出了一种由琼脂糖和甲基纤维素组成的新型生物材料混合物。先前的初步数据表明，这些混合物在室温下以液体形式存在，并在生理温度下快速固化。它们可以通过注射器注射，以便于应用于受伤部位。在这个修订后的申请中，我们提供的数据显示谷胱甘肽和白细胞介素 10 可以分别在体外释放五天和六天。该水凝胶是在冷冻环境中仅使用水性缓冲液制造的。因此，负载的试剂不会受到恶劣的加工条件的影响，并且在释放后应该能够发挥作用。数据显示，释放的谷胱甘肽能够保护解离的鸡 DRG 神经元免受芬顿反应产生的自由基的影响。此外，通过白细胞介素10 ELISA检测从水凝胶中释放的白细胞介素10。进行了一项初步研究，将负载有白细胞介素 10 和谷胱甘肽的水凝胶注射到大鼠脊髓损伤模型中。初步数据显示，与仅注射普通水凝胶的水凝胶相比，加载治疗剂的水凝胶在受伤后 42 天的 BBB 评分更高。该提案的目标之一是；描述了将荧光化学罗多明与谷胱甘肽和白细胞介素 10 偶联的技术。荧光缀合也将在目标 1 中得到证实。在目标 2 中；该提案概述了与俄亥俄州立大学菲利普·波波维奇博士的合作研究经历。开发的水凝胶随后将应用于俄亥俄州立大学开发的大鼠脊髓损伤模型。那里的工作将确定治疗药物的急性体内释放、炎症反应的急性和慢性缓解、病变体积和神经元保留的长期评估，以及运动恢复的长期评估。公共卫生相关性：目前施用药物以减少脊髓损伤后继发性损伤的技术包括静脉内或腹膜内注射。使用生物材料，由琼脂糖和甲基纤维素制成的水凝胶可以负载能够持续减少继发性损伤的药物。该提案中描述的研究将确定在大鼠脊髓损伤模型中，负载谷胱甘肽或白细胞介素 10 的水凝胶是否比注射这些药物更能有效减少继发性损伤。