Drug delivery via passive and active mechanisms

Delivery of protein therapeutics has been a target for neural regeneration in a host of CNS diseases and injuries including Parkinson’s, Alzheimer’s, spinal cord injury, and stroke. These therapies are limited by the short half-life of proteins and the off-target effects that occur when the whole brain is exposed to high concentrations of growth factors. Neurotrophic factors including brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and nerve growth factor (NGF), are commonly used in vitro to induce survival and axon extension, but their targeted, local, sustained delivery is a challenge to translational medicine due to fast clearance from the target site or degradation within a couple hours of delivery. Delivery of such molecules with spatial and temporal control would greatly enhance their effectiveness.

To meet the clinical needs of the CNS, a source of drug should be localized at a target site via a minimally invasive implantation, i.e. injection through a narrow gauge needle. Both diffusion-based (passive) and on-demand (active) delivery can create complex release profiles of different drugs important at hyperlocal regions, for example, at the tips of extending axon growth cones. We aim to accomplish CNS drug delivery via injectable materials that can easily pass through a small diameter needle and be retained at the site of injection until full biodegradation. As cells invade or proliferate within the hydrogel, the secreted enzymes that naturally remodel the extracellular matrix can also regulate the release of the tethered protein or peptide drugs.