Development of Biomaterials that Release Therapeutic Agents to Modulate Inflammat

Michigan Technological University, Houghton MI

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Abstract

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.