Sex as a Biological Variable in Preclinical Modeling of Blast-Related Traumatic Brain Injury

Abstract

Approaches to furthering our understanding of the bioeffects, behavioral changes, and treatment options following exposure to blast are a worldwide priority. Of particular need is a more concerted effort to employ animal models to determine possible sex differences, which have been reported in the clinical literature. In this review, clinical and preclinical reports concerning blast injury effects are summarized in relation to sex as a biological variable (SABV). The review outlines approaches that explore the pertinent role of sex chromosomes and gonadal steroids for delineating sex as a biological independent variable. Next, underlying biological factors that need exploration for blast effects in light of SABV are outlined, including pituitary, autonomic, vascular, and inflammation factors that all have evidence as having important SABV relevance. A major second consideration for the study of SABV and preclinical blast effects is the notable lack of consistent model design-a wide range of devices have been employed with questionable relevance to real-life scenarios-as well as poor standardization for reporting of blast parameters. Hence, the review also provides current views regarding optimal design of shock tubes for approaching the problem of primary blast effects and sex differences and outlines a plan for the regularization of reporting. Standardization and clear description of blast parameters will provide greater comparability across models, as well as unify consensus for important sex difference bioeffects.

Keywords: animal models; blast; brain injury; common data elements; sex differences; standardization.

Figure 1

Illustrations for implementation of shock tubes. (A) An example of a Friedlander-type shock wave initiated in an ABS. The tube has been previously described (205), and in this setting, a Valmex (7270, Low & Bonar, Martinsville, VA) membrane was employed to generate a shock wave of ~22 psi “peak pressure” (green arrow). The time-pressure trace shows the almost instantaneous change (yellow arrow) in ambient pressure from the shock wavefront, as well as the positive phase (red horizontal bar) and negative phase (blue horizontal bar) that follows as “blast wind.” (B) An example of the complex end-jet waveform. The shock wave [A in upper left of photo in (B)] emerges from the end of the shock tube and quickly diffracts into a curved front. Following [B in (B)] is a “ring vortex” and [C in (B)] a venting jet which has a different waveform than the static pressure phase of a Friedlander waveform [from (198)]. (C) Illustration of the flow field of a shock wave as it diffracts around a test object. Larger test objects in a confined shock tube can alter the flow of the shock wave, distorting free-field conditions [From (198). (D) Photograph of the ABS at the Uniformed Services University of the Health Sciences [cf., (205)]. The illustration depicts several aspects of optimal design of a shock tube. The driver section (I) is distal to the position of the test section (II), where, e.g., an animal would be secured for study. Likewise, the position of the animal is distal to the end of the tube, obviating end-jet effects (including reflected waves) resulting from the emergence of the shock wave from the tube.