The incorporation of growth factor and chondroitinase ABC into an electrospun scaffold to promote axon regrowth following spinal cord injury

Abstract

Spinal cord injury results in tissue necrosis in and around the lesion site, commonly leading to the formation of a fluid-filled cyst. This pathological end point represents a physical gap that impedes axonal regeneration. To overcome the obstacle of the cavity, we have explored the extent to which axonal substrates can be bioengineered through electrospinning, a process that uses an electrical field to produce fine fibres of synthetic or biological molecules. Recently, we demonstrated the potential of electrospinning to generate an aligned matrix that can influence the directionality and growth of axons. Here, we show that this matrix can be supplemented with nerve growth factor and chondroitinase ABC to provide trophic support and neutralize glial-derived inhibitory proteins. Moreover, we show how air-gap electrospinning can be used to generate a cylindrical matrix that matches the shape of the cord. Upon implantation in a completely transected rat spinal cord, matrices supplemented with NGF and chondroitinase ABC promote significant functional recovery. An examination of these matrices post-implantation shows that electrospun aligned monofilaments induce a more robust cellular infiltration than unaligned monofilaments. Further, a vascular network is generated in these matrices, with some endothelial cells using the electrospun fibres as a growth substrate. The presence of axons within these implanted matrices demonstrates that they facilitate axon regeneration following spinal cord injury. Collectively, these results demonstrate the potential of electrospinning to generate an aligned substrate that can provide trophic support, directional guidance cues and regeneration-inhibitory neutralizing compounds to regenerating axons following spinal cord injury. Copyright © 2016 John Wiley & Sons, Ltd.

Therapeutic repair for spinal cord injury: combinatory approaches to address a multifaceted problem

“…Impressively, the combination of ChABC with neurotrophin delivery has also reported to be therapeutic in complete transection models in which ChABC typically has a very limited therapeutic benefit. ChABC and NGF delivery from an electrospun scaffold following thoracic complete transection in rats displayed a significant improvement in BBB functional recovery and that the electrospun matrix is an important factor in this observation (Colello et al, ). Likewise, antagonism of Nogo, EphrinB3 and sema4D receptor combined with the growth factors BDNF, NT‐3 and cAMP administration after complete transection reduced the volume of cavitation, facilitated axonal regeneration and promoted neuronal generation leading to enhanced locomotion recovery (Table ; Li et al, ).…”

Local Release of Paclitaxel from Aligned, Electrospun Microfibers Promotes Axonal Extension

“…Poly (l ‐lactic acid) (PLA) aligned, electrospun microfibers have been shown to provide a directional guidance that enhances axonal extension in vitro and decreases the cystic cavity volume in vivo after an SCI . While this system does not directly overcome the inhibitory environment that prevents axonal regeneration and extension after an SCI, paclitaxel has been previously incorporated in poly(lactic‐co‐glycolic acid) electrospun microfibers as a targeted anticancer therapy, which could address this issue.…”

Combinatorial Therapies After Spinal Cord Injury: How Can Biomaterials Help?

“…This became especially apparent with electrospun nanofibers, which clearly promoted oriented outgrowth and migration of axons, Schwann cells and astrocytes in vitro . However, although some 3D nanofiber scaffolds have been developed, their application after SCI remains sparse . Nonetheless, several different oriented 3D scaffolds have been developed and tested after SCI, and have been shown to promote oriented repair.…”

“… The combination treatment resulted in improved axonal sprouting and motor recovery. Similarly, ChABC‐ and NGF–loaded alginate microspheres, which were incorporated into polydioxane electrospun fibres, led to improved locomotor function after implantation into a complete T9/T10 transection injury . The implantation of a poly(ε‐caprolactone) scaffold loaded with NT‐3 overexpressing NSCs in combination with ChABC (via an osmotic pump) into T‐7/8 hemisection models of SCI resulted in rostro‐caudal migration of transplanted cells, axonal growth into the scaffold, and locomotor functionality in both the ipsilateral and contralateral hindlimbs .…”