Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide, contributing to 235,000 hospitalizations and 50,000 deaths each year in the US alone. The lack of effective treatment strategies motivates research into not only new treatments but also into the mechanics of the injury to better prevent, diagnosis, and understand the mechanical events that lead to TBI. The aims of this thesis are:​ (1) to advance the understanding of brain injury biomechanics by quantifying the influence of age, anatomic region, and species on the mechanical properties of brain tissue, (2) to determine the relationship between tissue deformation and subsequent cell death for living brain tissue, and (3) to develop new theories and potential treatments for edema, one of the most detrimental clinical consequences of TBI.

Brain is a morphologically and mechanically heterogeneous organ. Rat models of TBI are common, however little is known about the mechanical properties of rat brain. An atomic force microscope (AFM) was used to measure region-dependent mechanical properties of the rat brain at different ages. The nonlinear apparent elastic modulus was significantly different across anatomic regions and increased significantly with age. The distribution of mechanical properties in the adult rat hippocampus was consistent with histological distributions of damage following experimental injury reported in the literature, suggesting that mechanical heterogeneity influences injury causation. Since brain is a viscoelastic material, the relaxation behavior of anatomic regions was determined with a custom-designed microindentation device. The time-dependent shear modulus ranged from approximately 1 kPa for short term moduli (G_100ms) to approximately 0.4 kPa for long term moduli. White matter and regions of the cerebellum were much more compliant than those of the hippocampus, cortex, and thalamus in the rat brain. Viscoelastic properties were also determined for porcine brain, a commonly used surrogate for human brain. The time-dependent shear modulus ranged from approximately 0.8 kPa for short term moduli (G/oms) to approximately 0.2 kPa for long term moduli. The statistical similarity of reduced relaxation functions for 10, 20, and 30% indentation strains suggested that quasilinear viscoelastic models are appropriate to describe large deformation behavior of porcine brain. In the frequency domain, oscillatory tests were performed with the AFM at frequencies ranging from 5-400 Hz from which frequency and depth-dependent storage and loss shear modulus was calculated. These data will be useful for understanding the biomechanics of TBI at a finer spatial resolution than previously possible.

Knowledge of brain tissue mechanical properties can help predict brain deformations during injury;​ however, predicting the biological consequences of induced brain deformation requires tolerance criteria. Using a well characterized in vitro model of stretch injury, a tolerance criterion for the cortex was developed. Compared to the hippocampus, the cortex was less vulnerable to stretch-induced injury, with strains below 20% inducing little cell death. Strain rate was also a significant factor affecting cortical cell death but not hippocampal cell death. We conclude that different regions of the brain respond differently to identical mechanical stimuli, and this difference must be taken into account when interpreting the region-specific outcomes in response to TBI-induced deformation.

Following injury, cerebral edema or brain tissue swelling is a significant complication which can increase intracranial pressure (ICP) and cause cerebral ischemia. We have identified the fixed charge density (FCD) within cells as a potential driver of edema. When these negatively charged molecules, which are fixed within cells, were exposed, the brain tissue swelled according to the Donnan effect. Swelling behavior was well-described by triphasic mixture theory, predicting a reference-state FCD very similar to that measured experimentally. Reducing this FCD experimentally by approximately 20% reduced swelling by approximately 50%. Chondroitinase ABC was most effective at reducing brain tissue swelling suggesting that it may be a novel treatment for reducing brain edema and controlling ICP following injury.