PLG Bridge Implantation in Chronic SCI Promotes Axonal Elongation and Myelination

Abstract

One million estimated cases of spinal cord injury (SCI) have been reported in the United States and repairing an injury has constituted a difficult clinical challenge. The complex, dynamic, inhibitory microenvironment post injury, which is characterized by pro-inflammatory signaling from invading leukocytes and lack of sufficient factors that promote axonal survival and elongation, limits regeneration. Herein, we investigated the delivery of polycistronic vectors, which have the potential to co-express factors that target distinct barriers to regeneration, from a multiple channel PLG bridge to enhance spinal cord regeneration. In the present study, we investigated polycistronic delivery of IL-10, that targets pro-inflammatory signaling, and NT-3 that targets axonal survival and elongation. A significant increase was observed in the density of regenerative macrophages for IL-10+NT-3 condition relative to conditions without IL-10. Furthermore, combined delivery of IL-10+NT-3 produced a significant increase of axonal density and notably myelinated axons compared to all other conditions. A significant increase in functional recovery was observed for IL-10+NT-3 delivery at 12 wpi that was positively correlated to oligodendrocyte myelinated axon density, suggesting oligodendrocyte-mediated myelination as an important target to improve functional recovery. These results further support the use of multiple channel PLG bridges as a growth supportive substrate and platform to deliver bioactive agents to modulate the SCI microenvironment and promote regeneration and functional recovery.

Neurotrophic Factors as Regenerative Therapy for Neurodegenerative Diseases: Current Status, Challenges and Future Perspectives

“…Poly-lactide-co-glycolide (PLG) is one of the most frequently used synthetic biomaterials for drug delivery, due to its controlled and sustained release properties, low toxicity, and biocompatibility with tissue and cells [ 46 , 47 ]. PLG has been widely used as a material for spinal cord repair or peripheral nerve conduits [ 47 ].…”

“…NTFs regulate the development and survival of neurons, and they appear to be involved in the endogenous neuroprotection of different neurons. Several studies have reported that NTFs, particularly glial cell-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5), act regeneratively in different animal models [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ] and patients [ 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ,…”

Engineering Tissues of the Central Nervous System: Interfacing Conductive Biomaterials with Neural Stem/Progenitor Cells

“…[ 177 ] Alternatively, single axons have been reported to align well with features on the order of 1 µm [ 178,179 ] and bundles of spinal cord axons regenerate robustly through guidance tubes on the order of 100's of µm. [ 180–182 ]…”

“…[ 365,367 ] Similar guidance conduits have been explored for their ability to facilitate axon regeneration across spinal cord lesions and as carriers for transplanted NS/PCs that direct their maturation. [ 180,181,366 ] Multilayered, tubular structures have been typically made by either stacking multiple films or nanofiber mats that are then rolled together [ 337 ] or electrospinning layers directly onto a cylinder. [ 365,366 ] Qian et al created layered, tubular scaffolds in which the innermost layer consisted of polydopamine and arginylglycylaspartic acid (RGD), followed by two layers of a PCL/graphene film, and an outermost layer of polydopamine and RGD.…”

“…[171,174] The size and geometry of the biomaterial and its features (e.g., pores, surface roughness, etc.) influence virtually all cell behaviors, including inflammatory cell activation [175] and NS/PC differentiation. [176] For example, biomaterial implants with an interconnected network of uniform pores on the order of tens of microns, which are large enough to permit host cell infiltration yet small enough to still provide some guidance via confinement, promote the formation of a seamless tissue interface with minimal scarring in the rodent spinal cord.…”