# An Engineered Hydrogel Platform to Improve Neural Organoid Reproducibility for a Multi-Organoid Disease Model of 22q11.2 Deletion Syndrome

> **NIH NIH F31** · STANFORD UNIVERSITY · 2023 · $45,648

## Abstract

Project Summary l
The complexity of the human brain and lack of adequate models severely hinders our ability to understand
mechanisms guiding neurodevelopment and neurodevelopmental disorders (NDDs), necessitating an innovative
bioengineered approach for improving in vitro organotypic models of the human brain. Recent advances in stem
cell-based neural organoids enable the formation of assembloids, which are fusions of organoids representing
different brain regions. However, current approaches remain limited in the ability to properly recapitulate native
brain cytoarchitecture and maturation within these organoids and also result in large heterogeneity due to the
lack of a well-defined matrix. The proposed research seeks to resolve these critical issues by creating a reliable
and reproducible in vitro environment for neural organoid culture to study aspects of neurodevelopment and
NDDs that have been difficult to achieve with current platforms. To do this, I will 1) assess the effect of matrix
biochemical cues for improving neural organoid architecture and maturation; 2) define the role of matrix stress
relaxation and confinement on organoid growth; and 3) leverage the engineered hydrogel platform to study
impaired interneuron migration in a disease model of 22q11.2 deletion syndrome (22q11DS). I hypothesize that
the experiments described in my proposal will show that matrix-derived biochemical and biophysical signaling
will allow for more robust neural organoid culture that better recapitulates the architecture and maturation of the
human brain compared to conventional neural organoid models. I also hypothesize that fusion of 22q11DS neural
organoids within engineered hydrogels will robustly demonstrate dysregulated interneuron migration mediated
by the deletion of DCGR8. Of note, interneuron migration is a phenomenon that does not occur in murine systems
and therefore cannot be studied using conventional murine models. To test this hypothesis, I will utilize a minimal
matrix (HELP) to culture brain region-specific neural organoids derived from induced pluripotent stem cells
(iPSCs) from healthy and 22q11DS patients. I will perform robust characterization of neural organoid architecture,
maturation, and growth rate in response to tuning matrix biochemical and biophysical properties. I will also
assess the ability of interneurons from 22q11DS patients to migrate into the dorsal forebrain by establishing a
dorsal–ventral forebrain assembloid disease model. Together, these results will be critical for engineering a
platform that is both permissive and instructive for robust and efficient neural organoid culture. In addition to
expanding my scientific technical skills, my training plan includes development of mentorship, scientific writing,
and presentation skills; training in research ethics; and enhancement of collaboration skills through a series of
on-campus courses, workshops, and seminars as well as off-campus conferences. Altogether, this res...

## Key facts

- **NIH application ID:** 10679749
- **Project number:** 1F31NS132505-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Michelle S Huang
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $45,648
- **Award type:** 1
- **Project period:** 2023-06-16 → 2025-12-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10679749

## Citation

> US National Institutes of Health, RePORTER application 10679749, An Engineered Hydrogel Platform to Improve Neural Organoid Reproducibility for a Multi-Organoid Disease Model of 22q11.2 Deletion Syndrome (1F31NS132505-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10679749. Licensed CC0.

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