About Our Lab

A critical part of mitigating potential injury, attending to sustained injuries, and treating sequelae is understanding how mechanical factors damage the body. It is known that exposure to blast waves can injure tissues. Due to the variability in blast exposures, it is critical that we understand the biomechanical and material response of tissues using an integrated biomechanical approach, from macroscopic to microscopic levels.  

Our multidisciplinary team of engineers and scientists explore this transformation of energy into injury. Using state-of-the art facilities, our team investigates the challenging questions of the insult turns to injury.  Projects use established in vitro, preclinical, and surrogate models for clinically relevant applications. Our blast simulators allow us to investigate the interactions between blast waves and biological tissue.

We collaborate with sponsors to develop a wide array of technologies, including computational models, clinical therapies, personal protective equipment, sensors, and biofidelic surrogates, that advance the field’s ability to protect from blast-related injuries.

To decipher cell injury and repair mechanisms, neurotrauma studies have traditionally focused on neurons. However, mechanical insults, such as traumatic brain injury (TBI), lead to perturbations in cellular communication and neural networks involving glial cells and their precursors. Thus, emphasis has shifted to the significance of glial cells (astrocytes, microglia oligodendrocytes) and their role in the progression of and recovery from TBI.  Our approach is a combination of computational and experimental tools that provide unique but complementary data to help better understand the fundamental biological mechanisms. 

Current works are diving into how astrocytes play a distinct role in TBI progression, and thus studying their fundamental capacity and response to injury are important targets in the way of developing effective treatments. The projects incorporate aspects of cell biology and mechanics with signaling networks and computational biology algorithms to understand how force transduction via cell-matrix interactions may contribute to complex sequelae that occur after high-rate insult associated with injury across multiple species. This work will create a platform by which we can analyze relevant molecular relationships and potential therapeutic targets in relevant preclinical brain injury models.

Additional focus has been on oligodendrocyte precursor cells (OPCs) following mechanical insults.  A fundamental mechanism of OPC-specific responses after mechanical insult is still understudied. Current works are investigating how rates in proliferation, migration, and differentiation change following mechanical insults and can result in changing the functional outcomes of neurons, thus affecting brain recovery. The goal of these studies is to identify a potential therapeutic molecular OPC target that promotes tissue recovery after brain injury.

Osteopathy in the cranial field is the study of the anatomic and physiologic mechanisms in the cranium and their interrelationship with the body as a whole, including a system of diagnostic and therapeutic modalities with application to prevent and treat disease. Osteopathic manipulative medicine (OMM) has been used clinically to improve the quality of life for several pathological conditions and injuries including TBI; however, limited data is available on the brain’s response to this innovative treatment. Cranial OMM (cOMM) involves the gentle application of manual force to the head and the axial spine, subsequently affecting the patient by releasing soft tissue restrictions. It is theorized that this technique enhances motion of the tissues and fluid flow through the brain through natural channels and helps to regulate tissue fluid flows in the body as well as balancing the autonomic nervous system. Hence, we expect that cOMM will help to clear inflammatory molecules from the brain in clinical challenges.

We use preclinical models of TBI to elucidate the mechanistic effects of this integrative health approach, cOMM, on multiple systems. TBI is responsible for an estimated $60 billion in direct and indirect medical costs, such as loss of productivity. Not only is the incidence and economic cost of TBI high, no neuroprotective/restorative drug trials have extended past Phase III clinical trials. Thus, novel treatment strategies are needed to improve the outcome of those affected by TBI. Following TBI +/- cOMM, we examine markers of neuroinflammation, and neuropathology within the brain and correlate these to behavioral changes. We use a novel DCE-MRI imaging technique to examine and measure blood and Interstitial fluid flow (IFF) within the brain parenchyma following TBI +/- cOMM. Our preliminary data is the first to show that bTBI does indeed alter IFF with a lower velocity seen in the bTBI animals. The innovative analysis method allows for the selection of specific brain regions for mapping interstitial fluid velocities. Our broad, long-term objective is to determine the physiological response of the injured brain to cranial OMM as a treatment strategy.

The TNT Lab also hosts projects that explore the application of cOMM on Alzheimer's disease, which is the most common form of dementia and affects about 6.7 million individuals in the United States. Individuals with Alzheimer’s disease experience abnormal water channel expression and a decrease in cerebral vascular pulsation, which reduces interstitial and cerebral spinal fluid exchange. In this state, an increase in harmful proteins such as amyloid Beta can lead to neuroinflammation and Alzheimer’s Disease. There is a lack of physiological and pharmacological methods to increase fluid circulation, however, the demonstration of peripheral nervous system circulation improvement in animal studies via lymphatic pump treatment shows promise for cOMM. By implementing PET imaging, animal behavior assays, and molecular analyses, the project aims to further our understanding the mechanisms of cOMM and the benefits that may come from the treatment.

Complex traumatic brain injury (CTBI) induces distinct pathologic influences on the amygdala that can lead to acute and persistent anxiety. The neurobehavioral sequelae of CTBI may be partly linked to neuroplastic changes that occur in response to mechanical injury and associated stress. Our goal is to expand basic mechanistic insight into CTBI-induced epigenetic and molecular signaling effects on amygdala neuroplasticity and anxiety neural circuitry, with a long-term goal of identifying new molecular targets for future drug development.

This multidisciplinary approach combines epigenetic, histologic, and behavioral assessment techniques to divest and better understand the mechanistic underpinnings that govern amygdala neuroplasticity and aberrant neural circuitry of CTBI-induced anxiety. Linking broad neuromolecular alterations to distinct neurobehavioral phenotypes will help transcend interspecies differences and improve the translatability of acute neurotrauma findings to the clinical setting. Most importantly, this work will establish new pathologic molecular profiles that will guide future mechanistic investigations and identify novel molecular targets that will facilitate potential diagnostic and pharmacotherapeutic development.

Traumatic brain injury continues to be a serious problem in society with 1.7 million occurrences annually in the United States. Currently there have been no neuroprotective drug trials to survive past Phase III clinical trials. Previous in vivo testing involves injury models that are not clinically-relevant, do not include biological variability, and are typically small animal models. There is a need to study TBI in gyrencephalic models using novel injury devices that simulate human injury conditions.

Complex MR imaging techniques and cognitive/behavioral tests are used to measure changes compared to pre-injury assessments and longitudinally to evaluate possible recovery caused by impact/blast. Histology defines the underlying neuropathology. This data can ultimately be used to develop injury thresholds for human conditions. Cognitive impairments and MR imaging modalities can relate underlying damage to make a link between noninvasive and invasive measurements. These measures can also help ease translation to clinical tools to improve diagnosis and intervention.

Further, addressing biological variability and sex differences will help address some of the limitations in current preclinical models. Ultimately, developing a standardized preclinical model that produces clinically-relevant impact/blast TBI in a gyrencephalic model will better measure drug safety and efficacy. In addition, a well-characterized model can give insight into new drug targets that were missed by previously used in vivo models with non-realistic injury conditions.