The Application of Nanoscience for the Treatment of Spinal Cord Injuries

Research output: Book/anthology/dissertation/reportPh.D. thesisResearch

  • Andrew Louw, Denmark
Spinal cord injuries (SCI) are progressive neurodegenerative conditions, that have extremely limited medical recourse. Upon insult to the spinal cord, axons are severed, the blood brain barrier is compromised, and effector cells are activated to seal the lesion and clean up the debris. The astroglial scar and the secondary inflammatory response are primary causes preventing the natural restoration of the spinal cord. The lack of guidance to exploratory and potential regenerative axons towards their targets also presents challenging obstacle. As the acute presence of the astroglial scar is absolutely required to prevent excessive tissue disruption from prolonged inflammation, I chose to focus my studies on reducing secondary neuroinflammation and promoting axon regeneration and guidance.
Chitosan nanoparticles have been extensively used for the delivery of small interfering RNA molecules to affect protein translation in a variety of tissues and cell types - most specifically to macrophages, the primary mediators of the inflammatory response. As microglia are functionally indistinguishable from activated macrophages in SCI, the chitosan nanoparticle system was selected to deliver a micro RNA (miRNA-124) species that has been shown to induce quiescence in macrophages. Our results after administering miRNA-124/chitosan nanoparticles in ex vivo rat microglia show uptake and a marked reduction of inflammatory markers (TNF-α, ROS, and MHC-II). In vivo spinal microinjection of nanoparticles showed macrophage-specific uptake by OX-42/ED-1 positive cells. To explore a less invasive delivery method, nanoparticles injected in the peritoneum were shown to be transported by macrophages to the SCI site, as seen by Cy-3 fluorescence co-localized with ED-1 expression at the lesion 72 h later. Microinjections of chitosan/miR-124 nanoparticles significantly reduced the activation of ED-1 positive macrophages in the injured spinal cord.
Taken together these data present a potential minimally invasive treatment technique to reduce inflammation for a multitude of neurodegenerative conditions in the CNS
After injury, neurons have the capacity to seal severed axons and reorganize their cytoskeleton remarkably quickly to produce new, exploratory growth cones that could benefit from directional guidance. Applying electrospinning techniques to nerve regeneration has been a central goal for the field, as the fabricated nanofibers have been shown in numerous examples to be highly conducive to neurite outgrowth in 2-dimensional in vitro studies. Here we apply heparan sulfate proteoglycan (HSPG) coatings to regenerated, aligned, silk fibroin nanofibers and show rapid neurite outgrowth of dorsal root ganglia. The HSPG coating is also capable of rendering the neurites insensitive to neurocan, a growth inhibitory chondroitin sulfate proteoglycan, in vitro. Prior attempts to implant nanofibers have been limited by their lack of biomimicry in the form of their tightly woven superstructures preventing cellular ingrowth. We manage to insert our nanofibers inside a synthetic tube, prompting an application to patent our novel nanofiber nerve regeneration conduit. The efficacy of this implantable, 3-dimensional nanofiber device is currently being evaluated in the rat hemisection SCI model.
Assuming the success of our conduit, the combination of our studies should provide the basis of a multifaceted approach for treating SCI.
Original languageEnglish
Number of pages195
Publication statusPublished - 2015

    Research areas

  • Spinal Cord injuries, Microglia, Inflammation, Nerve Regeneration, neurite guidance, Nanoparticles

See relations at Aarhus University Citationformats

ID: 85986855