Year: 2016
Type: dissertation
Abstract: Spinal cord injury (SCI) results in severe disability and currently lacks effective clinical treatments. Pre-clinical and clinical research have demonstrated the potential for both cell and protein therapeutic strategies; however, a critical challenge is the lack of localized, sustained delivery of bioactive therapeutics. A composite drug delivery system (DDS) consisting of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (np) dispersed in a hyaluronan/methyl cellulose (HAMC) hydrogel was previously found to provide sustained protein release in vitro and compatibility in vivo. This np/hydrogel DDS was further developed for the localized, sustained, and bioactive delivery of platelet-derived growth factor-AA (PDGF-AA), neurotrophin-3 (NT-3), and anti-NogoA. The release of PDGF-AA was sustained over 21 d and the PDGF-AA DDS induced the oligodendrocyte differentiation of neural stem/progenitor cells in vitro. The release of PDGF-AA was affected by the excipient poly(ethylene glycol) (PEG400), which had variable effects on protein stability. The delivery of NT-3 was sustained for up to 49 d in vitro and at least 28 d in vivo, and the NT-3 DDS induced axon growth and modest recovery of function in a model of compressive SCI. Surprisingly, electrostatic interactions occurred between soluble NT-3 and the DDS that delayed release. This discovery led to the development of an encapsulation-free np/hydrogel DDS that provides sustained, tunable release of NT-3 as well as stromal cell-derived factor (SDF) and brain-derived neurotrophic factor (BDNF) and is applicable to many other proteins. Finally, the np/hydrogel DDS was adapted for the combined, bioactive delivery of NT-3 and anti-NogoA. Combined delivery of NT-3 and anti-NogoA increased axon density, reduced the inhibitory environment, and promoted functional recovery after delivery to the injured spinal cord. This work demonstrates that the np/hydrogel DDS is effective for the delivery of growth/differentiation factors as well as therapeutic proteins for the treatment of spinal cord injury.
Source: TSpace (University of Toronto)
Author: Irja Elliott Donaghue
Language: English
Topic: Spinal Cord Injury Research
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2567178783