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Please use this identifier to cite or link to this item: http://hdl.handle.net/1807/24777

Title: Neuroprotective Drug Delivery to the Injured Spinal Cord with Hyaluronan and Methylcellulose
Authors: Kang, Catherine
Advisor: Shoichet, Molly
Department: Chemical Engineering and Applied Chemistry
Keywords: Drug Delivery
Spinal Cord Injury
Spinal Cord Blood Flow
CT Imaging
Tissue Diffusion
Fibroblast Growth Factor 2
Erythropoietin
Injectable
Intrathecal
Poly(ethylene glycol)
PEGylation
Dynamic Contrast Enhancement
Issue Date: 13-Aug-2010
Abstract: Traumatic spinal cord injury (SCI) is a devastating condition for which there is no effective clinical treatment. Neuroprotective molecules that minimize tissue loss have shown promising results; however systemic delivery may limit in vivo benefits due to short systemic half-life and minimal passage across the blood-spinal cord barrier. To overcome these limitations, an injectable intrathecal delivery vehicle comprised of hyaluronan and methylcellulose (HAMC) was developed, and previously demonstrated to be safe and biocompatible intrathecally. Here, HAMC was determined to persist in the intrathecal space for between 4-7 d in vivo, indicating it as an optimal delivery system for neuroprotective agents to reduce tissue degeneration after SCI. HAMC was then investigated as an in vivo delivery system for two neuroprotective proteins: erythropoietin (EPO) and fibroblast growth factor 2 (FGF2). Both proteins demonstrated a diffusive release profile in vitro and maintained significant bioactivity during release. When EPO was delivered intrathecally with HAMC to the injured spinal cord, reduced cavitation in the tissue and significantly improved neuron counts were observed relative to the conventional delivery strategies of intraperitoneal and intrathecal bolus. When FGF2 was delivered intrathecally from HAMC, therapeutic concentrations penetrated into the injured spinal cord tissue for up to 6 h. Poly(ethylene glycol) modification of FGF2 significantly increased the amount of protein that diffused into the tissue when delivered similarly. Because FGF2 is a known angiogenic agent, dynamic computed tomography was developed for small animal serial assessment of spinal cord hemodynamics. Following SCI and treatment with FGF2 from HAMC, moderate improvement of spinal cord blood flow and a reduction in permeability were observed up to 7 d post-injury, suggesting that early delivery of neuroprotective agents can have lasting effects on tissue recovery. Importantly, the entirety of this work demonstrates that HAMC is an effective short-term delivery system for neuroprotective agents by improving tissue outcomes following traumatic SCI.
URI: http://hdl.handle.net/1807/24777
Appears in Collections:Doctoral
Department of Chemical Engineering and Applied Chemistry - Doctoral theses

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