Development of poly-L-lactic acid microfibers and nanoparticles for central nervous system repair

Abstract

To improve functional outcomes following CNS injury, electrospun fibers that alter astrocyte EAAT-2 expression, and magnetic nanoparticles that direct neurite extension by releasing nerve growth factor (NGF) have been fabricated. Fibronectin-coated poly-L-lactic acid microfibers were shown to increase EAAT-2 expression of astrocytes, leading to a functional increase in glutamate uptake. NGF-releasing magnetic nanoparticles were shown to direct neuronal extension of chick dorsal root ganglia both in tissue culture polystyrene controls and on aligned PLLA fibers. This is especially important, because a combinatorial therapy of PLLA fibers and growth factor-releasing particles may be used to both reduce glutamate induced secondary injury while also guiding axon extension to desired locations. This combinatorial therapy may have the potential to improve functional outcomes after CNS injury, improving the lives of millions while reducing the healthcare costs caused by losses in cognitive and motor function.

Spinal cord injuries affect more than 12,000 people each year in the U.S. alone, and can cost up to $4.5 million over the lifetime of a patient. Injuries to the central nervous system (CNS) are debilitating due to the lack of guided axonal regeneration following injury, leading to losses in motor and/or cognitive function. Astrocytes (a type of glial cell) play a vital role in the CNS following injury: they become reactive and form a glial scar that restricts entry into the nervous system by macrophages, fibroblasts, and bacteria, but also inhibits axon regeneration. Reactive astrocytes play a role in the development of glutamate induced secondary injury to neurons by altering their expression of glutamate transporters, specifically by down-regulation of the excitatory amino acid transporter 2 (EAAT-2) which uptakes glutamate. This results in an increased concentration of glutamate in the extracellular space, leading to neuronal death.