Endogenous repair signaling after brain injury and complementary bioengineering approaches to enhance neural regeneration - PubMed (original) (raw)

Review

. 2015 May 12;10(Suppl 1):43-60.

doi: 10.4137/BMI.S20062. eCollection 2015.

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Review

Endogenous repair signaling after brain injury and complementary bioengineering approaches to enhance neural regeneration

Caroline P Addington et al. Biomark Insights. 2015.

Abstract

Traumatic brain injury (TBI) affects 5.3 million Americans annually. Despite the many long-term deficits associated with TBI, there currently are no clinically available therapies that directly address the underlying pathologies contributing to these deficits. Preclinical studies have investigated various therapeutic approaches for TBI: two such approaches are stem cell transplantation and delivery of bioactive factors to mitigate the biochemical insult affiliated with TBI. However, success with either of these approaches has been limited largely due to the complexity of the injury microenvironment. As such, this review outlines the many factors of the injury microenvironment that mediate endogenous neural regeneration after TBI and the corresponding bioengineering approaches that harness these inherent signaling mechanisms to further amplify regenerative efforts.

Keywords: controlled release; stem cells; transplantation; traumatic brain injury.

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Figures

Figure 1

Figure 1

Schematic depicting the active cell types and their role in the pathophysiology of TBI.

Figure 2

Figure 2

Temporal and spatial pro-regenerative signaling patterns following TBI. (A) Within the injury penumbra, expression increases for SDF-1α, VEGF, EGF, FGF, and BDNF in unique temporal patterns. (B) Expression of EGF and BDNF has also been observed to increase in the hippocampus after injury.

Figure 3

Figure 3

Temporal and spatial inflammatory cytokine signaling patterns following TBI. (A) TNF expression increases for 1 week after injury in the injury penumbra, while (B, C) IL-6 expression has been shown to increase in the hippocampus and blood for 1 week after injury. (A–C) A more acute increase in expression has been observed for IL-1β in the injury penumbra, hippocampus, and blood.

Figure 4

Figure 4

The route of delivery to the central nervous system plays a critical role in determining the spatial and temporal distribution of infused agents. (A) Demonstrates conventional means of bypassing the blood–brain barrier, which includes the intracortical, intracerebroventricular, and intrathecal routes. Each route of delivery has its own strengths and weaknesses, and thus outcome of therapy depends heavily on proper selection of the means of administering the therapeutic agent/construct. Intrathecal injections are made directly in the subarachnoid space of the spinal cord, whereas intracerebroventricular and intracortical injections refer to infusion of drugs directly into the ventricles or into the cortical interstitium, respectively. Efficiency of drug accumulation in the CNS is very low, even in the cases where the blood–brain barrier is bypassed. This is especially a challenge for applications where high drug concentrations are required in a specific portion of the brain. (B) Bolus injections of a therapeutic have rather transient effects with minimal time in the therapeutic threshold window; however, (idealized) controlled release of bioactive molecules may achieve sustained biochemical effects throughout the therapeutic time window.

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