Cell-death tolerance criteria
A significant accomplishment of our efforts has been to quantitatively predict the temporal and spatial development of cell death in response to precisely controlled brain tissue deformation. The products of this research are mathematical functions to predict region-specific cell death in response to injurious tissue deformation (Cater et al., 2006, Morrison III et al., 2006, Elkin and Morrison III, 2007). We have shown quantitatively, and for the first time, that hippocampal cell death is dependent on tissue strain, cortical cell death is dependent on both tissue strain and strain rate, and that the cortex is much less vulnerable to mechanical injury than the hippocampus. These tolerance criteria are significant findings because no previous study has directly determined tolerance criteria for living brain tissue. One consequence of a lack of experimentally verified tissue tolerance criteria is that automobile safety systems (seat belts, air bags, crumple zones) are being designed to specifications which may or may not be safe. Our more accurate criteria will be instrumental in future engineering of improved safety systems to reduce TBI incidence.
Functional tolerance criteria
Determination of tolerance criteria depends on the definition of failure. For brain, the definition is an open question. Given complexities of neuronal networks including redundancy and the presence of both excitatory and inhibitory neurons, cell death may not correlate with dysfunction. We have therefore embarked on the challenging task of incorporating quantitative measures of electrophysiological function with our in vitro model of TBI (Yu et al., 2009, Yu and Morrison III, 2010). We have shown that functional changes occur at levels of tissue deformation that induce minimal cell death. These findings have significant implications for the design of safety systems (Yu and Morrison III, 2010). This work is ongoing as we develop mathematical functions to predict neuronal activity changes given tissue-level biomechanical inputs. Ultimately, the criteria will provide finite element models the novel ability to predict loss of neuronal function. The significance is that safety systems will be designed to tolerances for clinically relevant, functional measures of injury.
High-resolution, heterogeneous mechanical properties
Brain is a structurally heterogeneous organ at many length scales, and the pattern of damage mirrors its anatomical complexity. A significant knowledge gap in the biomechanics of TBI that is preventing the design of better safety systems is mechanical-property data for individual anatomical structures. We have shown that brain is mechanically heterogeneous on a much finer anatomical scale than previously appreciated. For example, even within an anatomical structure, the hippocampus is mechanically heterogeneous (Elkin et al., 2007, Elkin et al., 2010a). The CA3 subregion of the adult hippocampus is one of the most vulnerable regions of the brain. For the first time, our studies have shown that CA3 is significantly more compliant than other regions of the hippocampus and that the CA1 region is one of the stiffest regions of the entire brain. This heterogeneity is a significant finding because it may explain why the CA3 and not the CA1 is particularly vulnerable to TBI, which has been a long-standing question. Interestingly, the cerebellum is the second most compliant structure of the brain; our data predict a concentration of cell loss in this under-studied region, which remains to be tested experimentally (Elkin et al., 2011a). Furthermore, we have shown that the distribution of mechanical properties is age-dependent (Elkin et al., 2010a, 2011a). The younger brain is more compliant and more homogeneous. These region- and age-dependent properties (up to a four-fold difference) are significant because they suggest that the biomechanics of adult and pediatric TBI are fundamentally different, which will have major implications for the design of age-appropriate safety systems.