Encapsulation-Free Local Delivery of BDNF Enhances Recovery in Stroke-Injured Rats

Until the early 1990s it was common belief that the adult brain did not possess the capacity to change or regenerate. We now know that the adult brain is not static and is able to repair itself to a small degree. Through examination of endogenous processes, brain-derived neurotrophic factor (BDNF) has emerged as a key modulator of plasticity in both the healthy and stroke-injured brains, and benefits to recovery have been demonstrated upon its administration; yet, current delivery strategies are highly invasive or inefficient. The work presented herein describes an effective, biomaterial-based strategy for minimally invasive local delivery of BDNF using a revolutionized approach to control protein release. BDNF incorporation into a composite consisting of poly(lactic-co-glycolic acid) (PLGA) nanoparticles and a hyaluronan and methyl cellulose (HAMC) hydrogel provided sustained release of the protein, using electrostatics to control release without encapsulation. When delivered epi-cortically to a rat endothelin-1 model of stroke injury, BDNF diffused from the HAMC/PLGA composite into the lesioned tissue and resulted in improved early forelimb recovery and delayed hindlimb performance enhancement. Tissue analysis revealed synaptic plasticity in the contralesional hemisphere at the time of sacrifice, suggesting that these behavioural effects were due to increased plasticity in the uninjured tissue. These studies validate the use of BDNF for plasticity-mediated stroke treatment and provide a minimally invasive strategy for effective, local delivery to the brain.Ph.D