Abstract
The functional and structural resemblance of organoids to mammalian organs suggests that they might follow the same allometric scaling rules. However, despite their remarkable likeness to downscaled organs, non-luminal organoids are often reported to possess necrotic cores due to oxygen diffusion limits. To assess their potential as physiologically relevant in vitro models, we determined the range of organoid masses in which quarter power scaling as well as a minimum threshold oxygen concentration is maintained. Using data on brain organoids as a reference, computational models were developed to estimate oxygen consumption and diffusion at different stages of growth. The results show that mature brain (or other non-luminal) organoids generated using current protocols must lie within a narrow range of masses to maintain both quarter power scaling and viable cores. However, micro-fluidic oxygen delivery methods could be designed to widen this range, ensuring a minimum viable oxygen threshold throughout the constructs and mass dependent metabolic scaling. The results provide new insights into the significance of the allometric exponent in systems without a resource-supplying network and may be used to guide the design of more predictive and physiologically relevant in vitro models, providing an effective alternative to animals in research.
Highlights
The functional and structural resemblance of organoids to mammalian organs suggests that they might follow the same allometric scaling rules
By combining computational models with images of mature brain organoid slices stained with a nuclear dye, Berger et al.[17] recently identified a minimum threshold oxygen concentration for viability, Ccrit, of 0.04 mol/m3, which is the critical value needed for mitochondrial ATP production[18]
Referring to published data on brain organoids derived from human induced pluripotent stem cells[13,17], we modelled both stem cell proliferation and organoid volume expansion to identify a range of experimental organoid masses and corresponding cell densities
Summary
The functional and structural resemblance of organoids to mammalian organs suggests that they might follow the same allometric scaling rules. Despite their remarkable likeness to downscaled organs, non-luminal organoids are often reported to possess necrotic cores due to oxygen diffusion limits To assess their potential as physiologically relevant in vitro models, we determined the range of organoid masses in which quarter power scaling as well as a minimum threshold oxygen concentration is maintained. Recent advances in in vitro technology have led to the development of organoids, i.e. cell aggregates grown from a small number of stem cells able to self-assemble, recapitulating the three-dimensional architecture of an organ at the micro-scale[1,2] They are currently considered as one of the most promising ways to study cell behaviour and may have significant potential as a tool for investigating developmental biology, disease pathology, regenerative medicine and drug toxicity. By combining computational models with images of mature brain organoid slices stained with a nuclear dye, Berger et al.[17] recently identified a minimum threshold oxygen concentration for viability, Ccrit, of 0.04 mol/m3, which is the critical value needed for mitochondrial ATP production[18]
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