Description
- Abstract:
- Abstract of “Evaluating 3D In Vitro Models for Translational Relevance: From Spheroid Architecture to Clinically Relevant Potency” by Yiyin Chen, Sc.M in Biotechnology, Brown University, May 2026 Conventional two-dimensional cell culture systems remain central to preclinical research because they are standardized, scalable, and well suited for measuring molecular and early phenotypic responses. However, they often fail to preserve the three-dimensional architectural, diffusion-related, and microenvironmental constraints that shape functional behavior in human tissues. This thesis examines that problem from two complementary angles. First, an experimental study systematically compared five HepG2 spheroid-generation methods—35- and 96-microwell agarose gels, microwell and single-well ultra-low attachment plates, and hanging drop—across seeding density and culture duration. Morphological and functional analyses showed that culture platform substantially influenced spheroid geometry and hepatocyte-like output: 35-microwell agarose gels produced the most circular spheroids and, among the multi-spheroid formats functionally assessed, the strongest albumin and ATP readouts. Meanwhile, no single method simultaneously optimized throughput, reproducibility, and functional robustness. Second, a review of organoid-based potency assays for RNA therapeutics in solid tumors develops the concept of clinically relevant potency, defined as dose-response relationship between a therapeutic candidate and a mechanism-appropriate functional endpoint, measured under conditions that preserve the barriers and interactions that are rate-limiting for therapeutic performance. Under this framework, 3D models are valuable not simply because they are more complex than 2D culture, but because they can reveal failure modes related to delivery, extracellular matrix, spatial heterogeneity, and immune or stromal context that conventional monolayers under-represent. Together, these chapters argue that three-dimensional in vitro systems should be selected and interpreted according to the mechanistic question they are meant to answer. The central thesis is that model architecture is not a neutral technical detail, but an experimental variable that directly shapes biological readout and translational inference.
- Notes:
- Thesis (Sc. M.)--Brown University, 2026
Citation
Chen, Yiyin,
"Evaluating 3D In Vitro Models for Translational Relevance: From Spheroid Architecture to Clinically Relevant Potency"
(2026).
Biotechnology, Biology and Medicine Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://repository.library.brown.edu/studio/item/bdr:zvuj774w/
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