Interactions of primary insult biomechanics and secondary cascades in spinal cord injury: implications for therapy

Interactions of primary insult biomechanics and secondary cascades in spinal cord injury: implications for therapy

SCI can occur abruptly due to motor vehicle accidents, falls,and sport injuries, or it can occur gradually as a result of spinal stenosis, osteoarthritis, abscess, and tumors. Acute traumatic SCI encompasses a variety of biomechanical injuries (e.g.,contusion, compression, laceration) and a wide range of injury severities. Despite heterogeneity, the primary mechanical insult creates acute damage at the injury epicenter and triggers a cascade of secondary injury events including inflammation, apoptosis, oxidative stress/lipid peroxidation, and demyelination.ese primary and secondary injury events lead to progressive tissue loss and dysfunction.

It is well documented that primary insult biomechanics influence the overall pathophysiology of SCI. For example, the impact severity of contusive injury to the spinal cord correlates with anatomical and functional recovery. Graded increases in contusion impact force, or contusion-induced tissue displacement, result in graded decreases in tissue sparing and functional recovery (Basso et al., 1996; Ghasemlou et al., 2005).e degree of spinal cord compression at the time of injury similarly determines outcomes, but compression depth causes unique stepwise decreases in tissue sparing and function (Gruner et al.,1996).us, the severity of contusion and compression injuries plays a key role in determining overall anatomical and functional outcomes in SCI.

We consider the primary insult unavoidable due to its silent or accidental development. However, each aspect of the secondary injury provides a potential therapeutic target either as a lynchpin in damage progression or as a tool to promote regeneration. While it is necessary to understand the cause and effect relationship between the primary insult and the secondary cascades to fully realize the benefit of translational therapies, we are only beginning to understand these relationships. Here we consider one example, residual compression following a contusion injury, to provide insight into the extent to which primary insult biomechanics influence secondary cascades and the final SCI outcomes.

Residual compression alters the acute SCI microenvironment. For example, compression increases hemorrhage, thus,altering the fluid dynamics of the contused spinal cord (Sjovold et al., 2013). Additionally, residual compression alters acute hypoxia and cellular bioenergetics with significantly higher lactate:pyruvate ratios compared to contusion alone, likely due to hemorrhage-induced ischemia (Okon et al., 2013). We observed that residual compression drives a potentially destructive inflammatory response. As late as two weeks aer the initial insult, acute residual compression (for 20 seconds) at the time of contusion SCI increased the relative ratio of pathological/pro-inflammatory vs. purportedly reparative microglia and macrophages compared to contusion alone (Orr et al.,2017). Together, these findings indicate that the addition of compression to the contusion SCI results in different microenvironments and downstream secondary cascades including,but not limited to, fluid dynamics, cellular bioenergetics, and inflammation (Figure 1). Further, we observed that acute residual compression increases anatomical and functional deficits and causes premature cessation of functional recovery (Orr et al., 2017). Collectively, these findings support the notion that primary SCI biomechanics have distinct effects on downstream,secondary events that significantly impact SCI recovery (Figure 1). Interestingly, similar injury mode-specific effects have been observed aer contusion, dislocation, and distraction primary spinal cord injuries (Choo et al., 2008).erefore, the primary mode of SCI may determine the efficacy of treatments targeting fluid dynamics, cellular bioenergetics, inflammation, or other secondary cascades.

Figure 1 Primary spinal cord injury (SCI) biomechanics influence anatomical and functional recovery coincident with altered secondary injury cascades that serve as therapeutic targets.

Several lines of evidence support an intimate link between the primary insult biomechanics and secondary cascades that impact overall outcomes of SCI.e implications of these relationships should be considered both in the lab and in the clinic.Strengthening our understanding of how injury biomechanics affect secondary cascades will enable researchers to draw more accurate conclusions between studies that utilize different injury modalities and will improve future research designs by properly pairing injuries to research questions. Clinicians will likewise benefit by improving their ability to assess and predict SCI progression, potentially enabling personalized treatment based on the type of SCI suffered. Ultimately, understanding how primary insult biomechanics affect secondary cascades and overall outcomes of SCI is achievable by probing past literature and consciously designing future studies. Such pursuits may surmount the challenge of SCI heterogeneity thereby improving the efficacy of translational research and future therapies for the SCI community.

Michael B. Orr, John C. Gensel＊

Spinal Cord and Brain Injury Research Center and the Department of Physiology, the University of Kentucky, Lexington, KY, USA(Orr MB, Gensel JC)

Integrated Biomedical Sciences Graduate Program, the University of Kentucky, Lexington, KY, USA (Orr MB)

＊Correspondence to:John C. Gensel, Ph.D., or Michael B. Orr,gensel.1@uky.edu, or mbor222@uky.edu.

orcid:0000-0001-8980-108X (John C. Gensel)

Accepted:2017-09-28

How to cite this article: Orr MB, Gensel JC (2017) Interactions of primary insult biomechanics and secondary cascades in spinal cord injury:implications for therapy. Neural Regen Res 12(10):1618-1619.

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Peer review:Externally peer reviewed.

Open access statement:is is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under identical terms.

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10.4103/1673-5374.217332