Women are two to ten times more likely to develop a fatigue-induced fracture whether from osteoporosis, military combat training, or sports. This increased risk has long been thought to be a consequence of intrinsic factors such as smaller bones, lower bone mineral density (BMD), lower cortical thickness, hormonal imbalance, etc. However, a robust fracture-risk assessment has yet to be developed using these predictors, and stress fractures remain a tremendous economic burden and cause of morbidity.

Traumatic brain injury (TBI) and many other brain diseases/injuries exhibit sex differences in prevalence. onset. and outcomes. Some of these differences are attributed to the fact that the human brain is sexually dimorphic and there are certain regional and structural differences that exist between male and female brains. However. the effect of these sex variations in biomechanical responses of brain have not been elucidated. The paucity of sex-specific knowledge in brain biomechanics and TBI fields is mainly due to the fact that. these fields have predominantly focused on males.

Traditional lab-based biomechanical analysis of baseball pitchers is used as the standard to identify pitchers with mechanics that predispose them to shoulder and elbow injury. While informative, these traditional analyses have two key limitations that narrow their utility in reducing pitching injuries.

Traumatic brain injury (TBI) is the most common cause of cognitive and behavioral deficits in the U.S and worldwide. Most TBIs are classified as mild-TBI and concussion (C) that are associated with minor symptoms and microscopic damage with no observable pathology on imaging scans, and thus are challenging to be diagnosed. Equally important are asymptomatic sub-concussive (SC) head exposures that when left undiagnosed put the subjects at higher risk of repeated exposures, resulting in cognitive declines and initiation of chronic neurodegenerative disease.

In light of the currently extant Covid pandemic. the impact of understanding upper airway health and being prepared for the rapid development of novel therapeutics has been reinforced. While preclinical animal models have long been the gold standard for the testing and development of novel therapeutics. they are expensive and time consuming. The availability of validated. reproducible and scalable in vitro diagnostics that reproduce relevant physiology and function as test-benches for the rapid testing and development of personalized medicine therapeutics is thus invaluable.

In the U.S. alone, 2.8 million people sustain a traumatic brain injury (TBI) each year and seek medical care.1,2 However, there are no FDA approved therapies for effective treatment of TBI (or concussion) patients. Current medications are limited to only reducing secondary damage to the brain following TBI, such as using diuretics to reduce the pressure inside the brain by increasing urine output.

Major Goal: The goal of this grant application is to produce clinical grade human neural stem cells from embryonic stem cells and to demonstrate their long-term safety and efficacy in a rodent and a nonhuman primate model (marmoset) of acute focal traumatic brain injury (TBI).