UMass Engineers Develop Spatially Patterned Brain Organoids

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Engineers in the UMass Amherst Riccio College of Engineering have developed a new method for modeling how the human brain organizes itself during early development, an advance that could improve the study of neurodevelopmental disorders and expand the biomedical use of brain organoids.

In a paper published by Cell Stem Cell, Yubing Sun, associate professor of mechanical and industrial engineering, and collaborators describe a strategy for spatially patterning human neural organoids using controlled gradients of signaling molecules known as morphogens. The study, “Spatial Patterning and Transcriptomic Landscapes of Human Neural Organoids by Localized Delivery of Morphogens,” introduces a Matrigel-free platform that enables stable, well-confined spatial signaling, thereby addressing an ongoing challenge in the field.

Sun leads the Laboratory for Multiscale Bioengineering and Mechanobiology, where researchers apply engineering principles such as biomechanics, materials science, and micro/nanoengineering to understand and harness stem-cell biology. A core mission of the lab is to develop engineered organoids and organ-chips as human-based new approach methodologies (NAMs) for modeling development and disease.

Sun’s research has attracted considerable support for advancing organoid engineering, including a three-year National Science Foundation award to create ultraflexible bioelectronics integrated brain organoids and a National Institutes of Health grant to improve their reproducibility and structural accuracy.

Organoids—three-dimensional, stem-cell–derived models that mimic aspects of human organs—have transformed brain development research. However, reliably directing their spatial organization has remained difficult. In the developing brain, regional identity emerges through precisely regulated morphogen gradients. Recreating those gradients in vitro within individual organoids has proven technically challenging.

Sun’s team addressed this challenge by developing a passive diffusion–based morphogen gradient generator (PdMG), a system that creates stable, reproducible signaling gradients across neural organoids without relying on animal-derived matrices. By delivering morphogens locally and continuously, the platform more closely mimics how spatial cues guide early brain development in the body.

Using this approach, the researchers generated distinct dorsal–ventral and rostral–caudal patterns within individual organoids—effectively guiding different brain regions to form in defined locations. Gene-expression mapping confirmed clear regional organization in early stages and, later, signs of active neurogenesis, including the emergence and migration of specialized neurons.

Because the system can be used with patient-derived or genetically engineered stem cells, it offers a promising foundation for next-generation in vitro models of neuropsychiatric disease and toxin screening. Sun’s team is working closely with the IALS Venture Development team to translate this technology to accelerate preclinical drug discovery in the neurodegenerative disease space. The team, Above Nerves, received strong support from IALS including a  Translational Seed Award and a translational graduate student assistantship, as well as support from the National Science Foundation National I-Corps program.

The study was led by first author Feiyu Yang, who earned her PhD from the Riccio College of Engineering in 2023, where she was a graduate researcher in Sun’s lab. Additional contributors from UMass include Narciso Pavon, Rebecca Sebastian, Beatriz Martinez-Martin, and ChangHui Pak.