Pre-clinical models in pediatric traumatic brain injury—challenges and lessons learned

Abstract

PURPOSE Despite the enormity of the problem and the lack of new therapies, research in the pre-clinical arena specifically using pediatric traumatic brain injury (TBI) models is limited. In this review, some of the key models addressing both the age spectrum of pediatric TBI and its unique injury mechanisms will be highlighted. Four topics will be addressed, namely, 1) unique facets of the developing brain important to TBI model development, 2) a description of some of the most commonly used pre-clinical models of severe pediatric TBI including work in both rodents and large animals, 3) a description of the pediatric models of mild TBI and repetitive mild TBI that are relatively new, and finally 4) a discussion of challenges, gaps and potential future directions to further advance work in pediatric TBI models. METHODS This narrative review on the topic of pediatric TBI models was based on review of PUBMED/Medline along with a synthesis of information on key factors in pre-clinical and clinical developmental brain injury that influence TBI modeling. RESULTS In the contemporary literature, six types of models have been used in rats including weight drop, fluid percussion injury (FPI), impact acceleration, controlled cortical impact (CCI), mechanical shaking, and closed head modifications of CCI. In mice, studies are largely restricted to CCI. In large animals, FPI and rotational injury have been used in piglets and shake injury has also been used in lambs. Most of the studies have been in severe injury models, although more recently studies have begun to explore mild and repetitive mild injuries to study concussion. CONCLUSIONS Given the emerging importance of TBI in infants and children, the morbidity and mortality that is produced, along with its purported link to the development of chronic neurodegenerative diseases, studies in these models merit greater systematic investigations along with consortium type approaches and long-term follow-up to translate new therapies to the bedside.

Toward development of clinically translatable diagnostic and prognostic metrics of traumatic brain injury using animal models: A review and a look forward

“…The selection of an appropriately aged animal model to reflect the desired human population under study is based on the stages of development of the animal that closely resembles the human stage of maturation and is not simply based on age after birth ( Finnie, 2012 ). Researchers have proposed that rodent models at 7 days old, 7–11 days, 17–21 days, and adult can be used to represent human birth, infants, and toddlers, and adults respectively ( Hagberg et al, 2002 ; Kochanek et al, 2017 ). While rodents tends to be the most commonly used species in research with a large number of published studies available regarding pathophysiology, functional and behavior outcomes, these animals have smaller, lissencephalic brains, composed of less white matter tissue than grey matter than those typically seen in the human brain ( Cernak, 2005 ; Finnie, 2001 ; Vink, 2018 ).…”

Animal Models of Post-Traumatic Epilepsy

“…The investigation regarding the management of pediatric post-traumatic epilepsy remains limited, and the pathogenesis remains poorly understood. Until recently, clinically relevant models for post-traumatic epilepsy in the pediatric population were lacking; however, previous studies have worked to develop pre-clinical models of pediatric PTE with some success [50].…”

Neuro-Inflammation in Pediatric Traumatic Brain Injury—from Mechanisms to Inflammatory Networks

“…In pre-clinical studies, pediatric TBI has been modeled using a variety of animals, type of TBI, age at time of injury, post-injury analysis time points, behavioural tests, and molecular markers, in an effort to more clearly define how the developing brain responds to injury. As described in a detailed review of pediatric TBI models by Kochanek et al, rodents aged P7-P21 are typically used to model pediatric TBI up to the age of a human toddler [28]. This age range encompasses the perinatal and weanling stages of the rodent life cycle.…”