Dynamically reconfigurable materials for 4D bioprinting of a human gut-brain axis - Project Summary Significance: Disorders of gut-brain interaction (DGBIs) impact tens of millions of Americans yet remain poorly understood due to their complex etiology across multiple tissues. Our growing understanding of the importance of the gut-brain axis, nicknamed the “second brain,” is also hindered by a lack of suitable animal and cell culture models. However, there is consensus on the importance of the enteric nervous system (ENS) in DGBIs and growing evidence of their genetic and molecular profiles. Therefore, bottom-up tissue engineering platforms could improve our basic understanding of gut-brain axis development and associated diseases through mechanistic insight into its self-organization and morphogenesis. This Pathway to Independence Award proposes to develop 4D bioprinting, a method that provides spatial and temporal cues to guide tissue development in time, toward construction of a human gut-brain axis using stem cell-derived assembloids. Innovation: This proposal hypothesizes that reconfigurable bioprinting materials will enable guided tissue self- organization and morphogenesis in a process mimicking development. This will be tested by developing composite materials comprised of (1) granular microgels that permit reconfiguration and (2) interstitial materials that provide key biochemical and viscoelastic signals (Aim 1). These matrices will enable construction of stem cell-derived assembloids of human intestine and ganglia at different developmental timepoints (Aim 2). Finally, microfluidic perfusion will facilitate better models DBGI-relevant processes, such as impaired peristalsis, and resulting changes to ENS gene expression (Aim 3). Broadly, the proposed work will establish new design rules for tissue engineering and new living materials for bioprinting and 3D cell culture applications. Candidate and Environment: Dr. Austin Graham is committed to leading an independent research group that addresses unmet biomedical challenges through the design of living materials and engineered tissues. He has a strong research and mentorship track record, including a recent publication on the development of living materials for organoid bioprinting and morphogenesis as well as research, teaching, and mentorship awards from the Materials Research Society and National Science Foundation. Through his postdoctoral fellowship, he has established an interdisciplinary advisory team that leverages the top research quality and unique collaboration between UCSF and the Chan Zuckerberg Biohub. These facilities provide him with the expertise, equipment, and resources required to successfully achieve the proposed Aims. Career Development: During the mentored period, the candidate will gain additional training in pluripotent stem cell culture, transcriptomics, and mouse genetics, in which his advisory team are hands-on experts. The proposed work will provide the candidate with a unique expertise in developing living materials for 4D bioprinting. This will position the candidate to start his own research program with interdisciplinary focuses on bioengineering (e.g. living materials for human organoids) and mechanobiology (e.g. peristaltic dysregulation in DGBI).
