Combination therapies in the CNS: engineering the environment

Abstract

The inhibitory extracellular environment that develops in response to traumatic brain injury and spinal cord injury hinders axon growth thereby limiting restoration of function. Several strategies have been developed to engineer a more permissive central nervous system (CNS) environment to promote regeneration and functional recovery. The multi-faced inhibitory nature of the CNS lesion suggests that therapies used in combination may be more effective. In this mini-review we summarize the most recent attempts to engineer the CNS extracellular environment after injury using combinatorial strategies. The advantages and limits of various combination therapies utilizing neurotrophin delivery, cell transplantation, and biomaterial scaffolds are discussed. Treatments that reduce the inhibition by chondroitin sulfate proteoglycans, myelin-associated inhibitors, and other barriers to axon regeneration are also reviewed. Based on the current state of the field, future directions are suggested for research on combination therapies in the CNS.

Figure 1

Neurofilament labeling demonstrates penetration and remarkably linear growth of axons within channels of freeze-dried agarose scaffolds. (A) Scaffold lacking growth factor. (B) Scaffold loaded with 2 µg recombinant human BDNF into walls and matrix-filled lumen of individual channels. Magnitude of linear axonal growth is significantly increased. (C) Best example of linear axonal growth through complete length of channel. Scale bars = 100 µm. Reprinted with permission from [62]