ABSTRACT
Current treatment approaches toward spinal cord injuries (SCI) have mainly focused on overcoming the inhibitory microenvironment that surrounds lesion sites. Unfortunately, the mere modulation of the cell/tissue microenvironment is often insufficient to achieve desired functional recovery. Therefore, stimulating the intrinsic growth ability of injured neurons becomes crucial. MicroRNAs (miRs) play significant roles during axon regeneration by regulating local protein synthesis at growth cones. However, one challenge of using miRs to treat SCI is the lack of efficient delivery approaches. Here, a 3D fiber-hydrogel scaffold is introduced which can be directly implanted into a spinal cord transected rat. This 3D scaffold consists of aligned electrospun fibers which provide topographical cues to direct axon regeneration, and collagen matrix which enables a sustained delivery of miRs. Correspondingly, treatment with Axon miRs (i.e., a cocktail of miR-132/miR-222/miR-431) significantly enhances axon regeneration. Moreover, administration of Axon miRs along with anti-inflammatory drug, methylprednisolone, synergistically enhances functional recovery. Additionally, this combined treatment also decreases the expression of pro-inflammatory genes and enhance gene expressions related to extracellular matrix deposition. Finally, increased Axon miRs dosage with methylprednisolone, significantly promotes functional recovery and remyelination. Altogether, scaffold-mediated Axon miR treatment with methylprednisolone is a promising therapeutic approach for SCI.
Subject(s)
Axons/metabolism , Gene Transfer Techniques , Hydrogels/metabolism , MicroRNAs/metabolism , Spinal Cord Injuries/therapy , Spinal Cord Regeneration/physiology , Tissue Scaffolds/chemistry , Animals , Disease Models, Animal , Methylprednisolone/administration & dosage , Nanofibers/chemistry , Rats , Rats, Sprague-Dawley , Recovery of Function/physiology , Spinal Cord/metabolism , Spinal Cord Injuries/metabolismABSTRACT
Spinal cord injury (SCI) is a traumatic event which leads to the loss of sensory and motor functions of the body. Complete recovery of these functions are usually limited due to the inability of the damaged axons within the central nervous system (CNS) to regenerate autonomously. Here, a combinatorial regenerative and rehabilitative approach to regrow damaged axons was proposed. Sprague-Dawley rats were subjected to a severe T9-T10 full tranection injury with a 2mm gap. Neurotrophin-3 (NT-3) loaded fibrous scaffold was implanted within the gap to provide topographical guidance for the axons to cross the injured region. To study the effect of rehabilitation, the rats were separated into 2 groups; those that undergo rehabilitation (trained, N=4) and those that do not undergo rehabilitation (untrained, N=3). In order to rehabilitate the rats, a rehabilitation robotic system consisting of a body weight support, hindlimb manipulator, and treadmill was developed. Preliminary results showed that rats which underwent rehabilitation had more robust axonal regeneration within the scaffold after 1 month. However, the Basso, Beattie, and Bresnahan (BBB) score, which is an indicator of locomotor recovery, do not show much significance between trained and untrained rats.
