CAREER: Bioengineering of a Human Blood-Spinal Cord Barrier-on-a-Chip

The human body has a protective shield between the bloodstream and the central nervous system (CNS). This shield includes the blood-spinal cord barrier (BSCB). The BSCB strictly controls which molecules enter the spinal cord. A damaged or compromised BSCB can contribute to neurological disorders, including spinal cord injuries and Amyotrophic Lateral Sclerosis (ALS). Studying these diseases or testing new treatments is challenging, because researchers do not have laboratory models that accurately mimic the BSCB. This CAREER project will bioengineer a "BSCB-on-a-chip." The project will use advanced stem cell technology and micro-engineering tools to create a three-dimensional (3D) model that replicates complex interactions between human spinal cord tissue and blood vessels. The BSCB-on-a-chip will help researchers understand how the spinal cord barrier develops and screen new drugs without extensive animal testing. The project will also provide interdisciplinary training for college students and early-career researchers in bioengineering and neuroscience. Additionally, the project team will lead outreach programs to spark interest in STEM fields among elementary and middle school students, as well as pediatric patients and their families. The blood-spinal cord barrier (BSCB) is distinct from the blood-brain barrier (BBB) in its molecular composition, permeability, and susceptibility to pathological insults. Despite its critical role in the progression of neurodegenerative disorders, physiologically relevant in vitro models that capture the regional diversity of the BSCB remain undeveloped. This project will integrate microfluidic engineering with stem cell-based tissue assembly to develop a human BSCB assembloid-on-a-chip. The project will: (1) leverage microfluidics to generate a 3D spinal cord model with physiological rostral-caudal and dorsal-ventral organization and engineer a functional BSCB assembloid-on-a-chip that integrates vascular and neural tissues to faithfully recapitulate molecular, cellular, and transcriptomic signatures; and (2) elucidate the signaling mechanisms by which spinal cord tissues instruct endothelial cells to acquire BSCB identity. Additionally, the project will establish a bio-inspired, chemically defined approach for generating scalable BSCB organoids to facilitate high-throughput drug screening. This research will provide the first biomimetic platform to study the distinct regulatory mechanisms of the spinal cord barrier, offering transformative tools for neurovascular research, precision medicine, and the development of therapeutics for CNS disorders. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.