About Me.
I am Dr. Brian O'Grady, currently a postdoctoral fellow at Vanderbilt University. My academic journey began at the University of Texas at San Antonio, where I earned both my B.S. and M.S. in Neurobiology. I then moved to Vanderbilt University, obtaining a Ph.D. in Materials Science.
During my predoctoral training, I was involved in developing pump perfusion systems and bioreactors. These innovative systems were designed to control the spatiotemporal differentiation of stem cells in 3D hydrogels, a project I am particularly proud of. In my current role as a postdoctoral fellow in Dr. Ethan Lippmann’s Lab, I have developed several applications for a biomimetic hydrogel. These applications include the 3D culture of single-cell suspensions of iPSC-derived neurons, which transform into mature and synaptically connected networks. Additionally, I've used this technology to support human ex vivo capillary maturation and arteriogenesis.
My ongoing work is focused on accurately replicating the anatomical architecture of the neurovascular unit. This research is pivotal in studying the mechanisms of pathologies affecting diseases of the brain. Moreover, it plays a significant role in screening novel therapies for various diseases affecting this delicate system. I have been fortunate to have my research supported by an NIH T32 postdoctoral fellowship. Even more gratifying, I was recently awarded an NIH K99/R00 grant. This grant supports my endeavors to develop a platform dedicated to studying the mechanisms of the neurovascular unit, blood-brain barrier pathologies and screening promising therapeutics.
Looking ahead, I am eager to establish an independent research group. My vision is to develop innovative platforms for disease modeling and drug discovery in the field of tissue engineering.
Education
Bachelor of Science -Neurobiology
University of Texas at San Antonio
As an undergraduate, I contributed to research in the pathophysiology of Sudden Infant Death Syndrome (SIDS) in a specialized lab. My primary role involved devising a method to induce intracellular acidification in chemosensitive neurons of a tadpole brainstem in vitro. I identified the efficacy of nitrobenzaldehyde (NBA), a compound that releases hydrogen under ultraviolet light, to induce intracellular acidosis and stimulate increased respiration.
Our team demonstrated that the introduction of amiloride, a sodium hydrogen exchanger (NHE) blocker, prior to inducing intracellular acidosis, simulated a hypercapnia-like event, akin to the pathophysiology observed in SIDS. This research was pivotal, leading to both first- and co-authored poster presentations and a co-authored manuscript.
These accomplishments were instrumental in my acceptance into the Graduate Program in Neurobiology at the University of Texas at San Antonio. My undergraduate research experience laid a foundation for my advanced studies and future contributions to the field of neurobiology.
Masters of Science - Biology
University of Texas at San Antonio
Upon joining the Master’s program at the University of Texas at San Antonio, my academic journey led me to a pivotal class in cancer biology. There, I delved into the complex nature of cancerous cells, particularly their propensity to foster an acidic intracellular environment due to increased metabolic production and the upregulation of NHE.
Drawing on my prior research experience, I hypothesized that the acidification of cancer cells using NBA could induce cell death while minimizing damage to healthy tissue. My extensive experiments across various cancer cell types validated this theory. I uncovered that the persistent activation of NHE in response to increased intracellular acidification resulted in osmotic swelling and subsequent cell death in over 98% of cancerous cells, with less than 4% of healthy cells affected.
This revelation propelled the development of a targeted NBA delivery method utilizing upconversion nanoparticles (UNP). In collaboration with the physics department, we engineered a specialized UNP conjugated to NBA, enhancing the focal activation of NBA and intracellular acidification. Tested in a mouse tumor model, this innovation resulted in an over 80% reduction in tumor size.
This research journey not only honed my skills in animal care, nanoparticle synthesis, and longitudinal statistical analysis but also led to my contribution as an inventor on a patent (US Patent 10,946,096, 2021) for the innovative use of Nitrobenzaldehyde in manipulating cellular acidosis.
Doctor of Philosophy - Materials Science and Engineering
Vanderbilt University
Following the attainment of my M.S. in Neurobiology, I joined the Interdisciplinary Materials Science Program at Vanderbilt for my Ph.D. under the guidance of Dr. Leon Bellan.
In this new academic chapter, my focus shifted to developing an advanced model system for patterning stem cell differentiation within 3D hydrogels. I identified three critical components to master this process: morphogen concentration, its spatiotemporal presentation, and the specific types of stem cells involved. To adeptly manage these variables, I engineered a programmable pump perfusion system that was both highly customizable and cost-effective, proving instrumental in validating experimental mathematical models of morphogen diffusion.
This work enabled the creation and manipulation of morphogen gradients via embedded perfusion channels within 3D hydrogels on a large scale. I further employed Raman spectroscopy to measure the diffusion gradients of multiple morphogens, culminating in a comprehensive computational model of their spatiotemporal presentation.
This intensive research honed my skills in various domains, including bioreactor machining, 3D printing, programming perfusion systems, Multiphysics software utilization, and advanced stem cell culturing and embedding techniques. My contributions were documented in four first-author manuscripts and showcased in two oral presentations.
Postdoctoral Research -
Vanderbilt University
In 2019, I initiated my postdoctoral research under the guidance of Dr. Ethan Lippmann at Vanderbilt University, marking the beginning of an intensive exploration into tissue engineering. My inaugural project involved the development of a biomimetic hydrogel to optimize the survival and maturation of single-cell neuron suspensions in 3D tissue constructs. The process entailed grafting an N-cadherin peptide to gelatin methacrylate, resulting in a hydrogel with enhanced mechanical properties and increased neuron survival and neurite process extension. This research is documented in a first-author publication and is the subject of a filed patent application.
My subsequent project addressed a prevailing challenge in creating microfluidic devices. I identified a solution to the cytotoxicity of high-resolution 3D prints using resin by applying a vapor coating of parylene, rendering them cytocompatible. This discovery has led to a manuscript currently under review and fostered collaborations with other laboratories utilizing our refined microfluidic devices.
In my latest research, I have focused on the vascularization of N-cadherin containing hydrogels using ex vivo human brain tissue. Early observations noted vascular proliferation within 24 hours of embedding the tissue, without the introduction of exogenous growth factors. A provisional patent application has been filed in light of these findings, and a first-author manuscript is in preparation. This work underscores the potential of this material in promoting arterial and capillary growth and inducing neovascularization in a 3D setting.
These research endeavors, facilitated by the collaborative and innovative environment at Vanderbilt University, have significantly contributed to my academic and professional development. My ongoing commitment is anchored in advancing technologies that accurately replicate brain anatomy and physiology. The objective is to foster an in-depth understanding of the intricate interactions within the neurovascular unit and their adaptive responses to therapeutics, contributing to the broader knowledge and intervention strategies in this essential field.