Biofidelic Three-Dimensional Brain Surrogate Models of mTBI-Induced Alzheimer s Disease Pathology
Abstract
Mild traumatic brain injury and Alzheimer s neurodegenerative disease in Soldiers exposed to explosives: New body armor introduced in 2003 has led to a marked change of injury patterns in Soldiers caused by explosives in conflict zones. Deaths from pulmonary damage have been greatly reduced; however, Soldiers that then survive combat-related blasts have a likelihood of permanent brain damage called mild traumatic brain injury (mTBI), in which patients suffer from altered consciousness, a confused or disoriented mental state, and memory loss. mTBI may give rise to Alzheimer s-related neurodegenerative disease (AD) (mTBI/AD). Approximately 313,000 Service members and 10%-20% of Veterans have suffered from TBI, the overwhelming majority caused by blasts from improvised explosive devises. The personal suffering of Soldiers and the care they need have created a great burden on patients, individuals, families, and society. Understanding the mechanism(s) that cause blast-induced mTBI and AD pathology may prevent brain trauma with improved equipment or aid in the diagnosis, monitoring, or treatment of the resulting brain damage. Studies of blast impact on the brain and the consequences to mTBI/AD development are for the vast majority performed in living rodents, which limits the freedom of manipulation and throughput of experiments. Experiments sometimes have exhibited heterogeneous outcomes, contradictory findings, or problems with reproducibility due to significant differences in rodent and human anatomy and physiological response mechanisms to injury. This has created a strong medical need for realistic and well-validated cellular laboratory models to elucidate, diagnose, and monitor the pathophysiology of mTBI and AD. Bioengineering new, three-dimensional brain laboratory models to identify the mechanisms causing mTBI/AD: The organization in networks of neurons and supporting cells lies at the heart of the human brain s myriad of functions, endowing us with a unique higher consciousness. Proper brain function requires coordination of neural circuit activity, just like how organs harmonize their activities for our body to execute its tasks. Damage to neurons and their circuitry induced by explosives, consequently, may manifest itself in many forms of brain illness, including mTBI/AD pathology of Soldiers exposed to explosive device. To understand, treat, and prevent blast-induced mTBI/AD, experimental strategies are needed designed on the growing and examining of neurons and supporting cells under laboratory conditions that accurately represent human brain function before and after blast exposure. Objective of our proposal: We address the unmet medical need of in vitro laboratory models to study and test novel treatment options for mTBI/AD by creating bioengineering (or bioprinting) technology to mimic actual brain circuits in composition, architecture, and function. The crucial aspect of this technology is the ability to grow actual neurons in three dimensions (3D), mimicking the actual 3D nature of our brain, in contrast to conventional flat, two-dimensional petri dishes (our brains are not flat, after all). Our proposal is built on the shock wave model, which postulates that mTBI is caused by the primary shock wave from a blast generated by detonating a high-energy explosive and striking a living body. As a consequence, several physical events take place: a fraction of the shock wave is reflected, whereas another fraction of the shock wave energy is absorbed and propagates through the body/brain as a tissue-transmitted shock wave. The resulting ultrastructural (nanometer) damage and molecular, cellular, and brain circuit level injuries may lead to mTBI/AD pathology. In militarily relevant conditions generated in open-field blast environment, we will monitor these effects of blasts on bioengineered 3D brains as a way to predict the effect of explosives on the human brain. These 3D models present h
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510576
Entities
People
- Utkan Demirci
Organizations
- Stanford University
- United States Army