Date of Award
Doctor of Philosophy in Biomedical Engineering - (Ph.D.)
Bryan J. Pfister
Vivek A. Kumar
Joshua R. Berlin
Traumatic brain injury (TBI) is a major health problem for over 3.17 million people in the US. There is no FDA-approved drug for the treatment because the injury mechanisms have not been clearly identified. The knowledge gap is addressed here by the lateral fluid percussion injury (FPI) rat model, through the understanding of layer-structured mechanisms from physical vascular rupture to acute necrosis, as well as biochemical changes in perivascular space as secondary events.
Firstly, the cerebrovascular hemorrhage and related infarct volume are investigated as the primary events in moderate FPI, which is found to be increased with injury severity in FPI. The extent of coagulation is validated by the bio-distribution of fluorescent tracer in the cerebrospinal fluid (CSF) pathway after the injury. Bio-distribution of the tracer is specifically diminished at the site of coagulation, which blocks the CSF movement in subarachnoid and interstitial spaces. The pattern of coagulation is associated with the CSF blockage and correlates to necrotic cell death in and around the impact site. Different biomarkers for immune cells, neuronal death and tight junction proteins show that physical disruption of vasculature plays an important role for the acute induction of neuroinflammation and neurodegeneration in blunt TBI.
Additionally, free radicals generation is found to be significantly increased in the injured hemisphere immediately post FPI and decreases over time. Upregulation of radical-generating enzymes, NADPH oxidase 1 as well as inducible nitric oxide synthase, initiates biochemical damage of the injured brain. As a result, the signatures of oxidative/nitrosative damage markers 4-HNE and 3-NT are observed in the blood brain barrier (BBB) post-TBI, with temporal changes in the injury site. Oxidative/nitrosative damage and immune cells infiltration correlate with gliosis at 4 hours and 7 days post moderate FPI. Examination of apoptosis, tau phosphorylation, and neuronal survivability at day 7 post FPI further validate neurodegeneration. Thus, it is confirmed that the acute and long-term neuroinflammation and neurodegeneration are correlated with cerebral vascular disruption.
Finally, novel regenerative medicines are explored for in-situ repair with angiogenesis and neuroprotection mechanisms in the injured brain post-TBI. An injectable self-assembling peptide-based hydrogel (SAPH) appended with vascular endothelial growth factor (VEGF) mimic is used to create a regenerative microenvironment for neovascularization at the injury site. VEGF is an angiogenic and neuroprotective growth factor that is involved in the process of brain repair. Supramolecular assembly allows for thixotropy; the injectable drug delivery system provides sustained in vivo efficacy. Application of the angiogenic SAPH directly in the injury site promotes disrupted vasculature repair in and around the hydrogel implant at day 7 post-TBI. Upregulation of VEGF-receptor 2 is observed, demonstrating an angiogenic response in the presence of angiogenic SAPH. Moreover, vascular markers von-Willebrand factor (vWF) and a-smooth muscle actin (a-SMA) show a concomitant increase with blood vessels in response to the angiogenic SAPH. The neuronal rescue examination by NeuN and myelin basic protein shows that the SAPH has the potential to provide neuroprotective benefits in the long-term recovery.
Ma, Xiaotang, "Cerebro-vascular disruption mediated initiation and propagation of traumatic brain injury in a fluid percussion injury model" (2019). Dissertations. 1632.