title: Merging pathology with biomechanics using CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration): a novel, surgery-free model of traumatic brain injury.
abstract: BACKGROUND
  Traumatic brain injury (TBI) is a major health care concern that currently lacks any effective treatment. Despite promising outcomes from many preclinical studies, clinical evaluations have failed to identify effective pharmacological therapies, suggesting that the translational potential of preclinical models may require improvement. Rodents continue to be the most widely used species for preclinical TBI research. As most human TBIs result from impact to an intact skull, closed head injury (CHI) models are highly relevant, however, traditional CHI models suffer from extensive experimental variability that may be due to poor control over biomechanical inputs. Here we describe a novel CHI model called CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration) that fully integrates biomechanical, behavioral, and neuropathological analyses. CHIMERA is distinct from existing neurotrauma model systems in that it uses a completely non-surgical procedure to precisely deliver impacts of prescribed dynamic characteristics to a closed skull while enabling kinematic analysis of unconstrained head movement. In this study, we characterized head kinematics as well as functional, neuropathological, and biochemical outcomes up to 14d following repeated TBI (rTBI) in adult C57BL/6 mice using CHIMERA.
  
  
  RESULTS
  Head kinematic analysis showed excellent repeatability over two closed head impacts separated at 24h. Injured mice showed significantly prolonged loss of righting reflex and displayed neurological, motor, and cognitive deficits along with anxiety-like behavior. Repeated TBI led to diffuse axonal injury with extensive microgliosis in white matter from 2-14d post-rTBI. Injured mouse brains also showed significantly increased levels of TNF-α and IL-1β and increased endogenous tau phosphorylation.
  
  
  CONCLUSIONS
  Repeated TBI using CHIMERA mimics many of the functional and pathological characteristics of human TBI with a reliable biomechanical response of the head. This makes CHIMERA well suited to investigate the pathophysiology of TBI and for drug development programs.
authors.forename: Dhananjay R
authors.initials: DR
authors.lastname: Namjoshi
authors.forename: Wai Hang
authors.initials: WH
authors.lastname: Cheng
authors.forename: Kurt A
authors.initials: KA
authors.lastname: McInnes
authors.forename: Kris M
authors.initials: KM
authors.lastname: Martens
authors.forename: Michael
authors.initials: M
authors.lastname: Carr
authors.forename: Anna
authors.initials: A
authors.lastname: Wilkinson
authors.forename: Jianjia
authors.initials: J
authors.lastname: Fan
authors.forename: Jerome
authors.initials: J
authors.lastname: Robert
authors.forename: Arooj
authors.initials: A
authors.lastname: Hayat
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cripton
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada. wcheryl@mail.ubc.ca.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Wellington
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001930:Brain Injuries / Q000378:metabolism* / Q000503:physiopathology*; D004195:Disease Models, Animal; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha