Promoting spinal cord repair using a polymer-based drug delivery system

Ohio State University, Columbus OH

Investigators

Abstract

ABSTRACT Traumatic spinal cord injury (SCI) causes devastating neurological deficits and long-term disability due to detrimental structural and functional alteration in neuronal circuits. Despite recent progress, no effective disease-modifying treatment is currently available for SCI. This may be because the cellular and molecular mechanisms that cause or contribute to pathophysiological changes in neuronal structure and function after SCI are poorly understood. Many studies, including ours, have demonstrated a remarkable convergence between the structural and functional organization of neuronal circuits and the expression of α2δ subunits of voltage-gated calcium channels (VGCC). Neuronal α2δ subunits positively regulate synaptic transmission by increasing plasma membrane expression of VGCC. However, these subunits may also play a pathological role following axonal injury. Expression of α2δ1/2 increases following axonal injury, resulting in aberrant neuron activities associated with chronic pain and axon regeneration failure. We recently showed that α2δ1/2 pharmacological blockade through systemic administration of gabapentinoids (e.g., gabapentin and pregabalin), drugs used clinically to treat various neurological disorders, promotes axon regeneration and functional recovery after SCI in adult mice. Whereas the beneficial action of gabapentinoids in promoting neurological recovery after SCI is gaining support, systemic administration of this class of drugs can cause adverse side effects. More recently, gabapentinoids' rise as drugs of abuse generates concern. Given that neuronal α2δ1/2 subunits accumulate at the growth cone and presynaptic nerve terminals, targeted interventions could prove to be more effective than systemic delivery strategies. Our preliminary data suggest that localized intraspinal delivery of gabapentinoids through biocompatible polymer-based injectable microspheres favors spinal cord repair while circumventing detrimental side effects and misuse associated with the systemic administration of this class of drugs. Accordingly, experiments in Aim 1 will implement electrospray techniques to optimize conditions for microsphere fabrication, consistent drug loading and homogeneous release profiles. We will further characterize physicochemical properties including porosity, swelling, drug entrapment efficiency and release profile at predetermined time intervals upon reconstitution. We will also test microsphere performance and behavior in vitro using time-lapse microscopy of primary neuronal and macrophage cultures. Aim 2 will test whether localized gabapentinoids delivery at the lesion site favors axon regeneration and SCI repair. Our multi-layered electrosprayed delivery system will facilitate the development of novel and more effective strategies creating favorable conditions for neurological recovery after injury to the mammalian spinal cord.