Controlled Sequential Delivery of Two Growth Factors for the Stimulation of Endogenous Brain Repair after Stroke.

摘要

Stroke is a leading cause of disability in the world, for which there currently is no effective treatment. One potential method for treating stroke is to stimulate the endogenous neural stem/progenitor cells (NSPCs) in the subventricular zone (SVZ) of adult brain to replace the tissue lost during stroke. Two growth factors that have shown promise in eliciting functional repair in rodent models of stroke are epidermal growth factor (EGF) and erythropoietin (EPO). However, there is a significant challenge in delivering protein drugs in a minimally invasive yet effective manner. In this thesis, a minimally invasive polymer-based system is developed to control the sequential release of EGF followed by EPO. This system comprises of a hyaluronan-methylcellulose (HAMC) hydrogel and two types of polymeric particles, and is applied epicortically to deliver EGF and EPO to stroke-injured mouse brains in a minimally invasive manner. In this thesis, the following are demonstrated:;1) The ability of therapeutics delivered locally to reach the target site after delivery is crucial for the success of local delivery strategies. PEG-modification leads to enhanced penetration distance of EGF. 2) When delivered epicortically to the stroke-injured mouse brain using HAMC, PEG-EGF penetrates further into the brain compared to unmodified EGF. Both EGF and PEG-EGF stimulated NSPC proliferation in the SVZ, but the extent of stimulation is greater when PEG-EGF is delivered compared to unmodified EGF. 3) The transport of EPO is similar in the uninjured and the stroke-injured brain following epicortical delivery from HAMC. EPO delivered epicortically from HAMC is able to reach the SVZ and can enhance neurogenesis in the stroke-injured brain. 4) A composite delivery system is engineered where PEG-EGF and EPO are individually encapsulated in different polymeric particles, and the particles are embedded in the HAMC hydrogel matrix. Stroke-injured animals that receive composite-mediated growth factor treatments ultimately achieve repair comparable to that achieved using a conventional catheter/osmotic minipump infusion system, without causing tissue damage associated with insertion of the infusion system into the brain.