A perfused multi-well bioreactor platform to assess tumor organoid response to a chemotherapeutic gradient

Frontiers in Bioengineering and Biotechnology

Bioengineering and Biotechnology

Matthew A. Coleman¹  Aubree Hinckley¹  Wei He¹  Delaney Ruth Gray-Sherr²  Caleb Fisher Friedman³  Eveliina Karelehto⁴  Robert Warren⁴  Jesse Ahlquist⁵  Monica Lizet Moya⁵  Maxim Shusteff⁵  Elizabeth K. Wheeler⁵  Elisa Marie Wasson⁵  Michael Gregory Triplett⁵  William Fredrick Hynes⁵  Claire Robertson⁶ 

[1] Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA, United States;Department of Biomedical Engineering, Boston University, Boston, MA, United States;Department of Computational Media, University of California Santa Cruz, Santa Cruz, CA, United States;Department of Surgery, University of California, San Francisco, San Francisco, CA, United States;Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, United States;Materials Engineering Division, Lawrence Livermore National Laboratory, Livermore, CA, United States;Materials Engineering Division, Lawrence Livermore National Laboratory, Livermore, CA, United States;UC Davis Comprehensive Cancer Center, Davis, CA, United States;

关键词: tumor model;    drug transport;    flow transport;    colorectal (colon) cancer;    bioreactor 3D cell culture;   

DOI  :  10.3389/fbioe.2023.1193430

 received in 2023-03-24, accepted in 2023-05-17,  发布年份 2023

来源: Frontiers

【 摘 要 】

There is an urgent need to develop new therapies for colorectal cancer that has metastasized to the liver and, more fundamentally, to develop improved preclinical platforms of colorectal cancer liver metastases (CRCLM) to screen therapies for efficacy. To this end, we developed a multi-well perfusable bioreactor capable of monitoring CRCLM patient-derived organoid response to a chemotherapeutic gradient. CRCLM patient-derived organoids were cultured in the multi-well bioreactor for 7 days and the subsequently established gradient in 5-fluorouracil (5-FU) concentration resulted in a lower IC50 in the region near the perfusion channel versus the region far from the channel. We compared behaviour of organoids in this platform to two commonly used PDO culture models: organoids in media and organoids in a static (no perfusion) hydrogel. The bioreactor IC50 values were significantly higher than IC50 values for organoids cultured in media whereas only the IC50 for organoids far from the channel were significantly different than organoids cultured in the static hydrogel condition. Using finite element simulations, we showed that the total dose delivered, calculated using area under the curve (AUC) was similar between platforms, however normalized viability was lower for the organoid in media condition than in the static gel and bioreactor. Our results highlight the utility of our multi-well bioreactor for studying organoid response to chemical gradients and demonstrate that comparing drug response across these different platforms is nontrivial.

【 授权许可】

Unknown   
Copyright © 2023 Wasson, He, Ahlquist, Hynes, Triplett, Hinckley, Karelehto, Gray-Sherr, Friedman, Robertson, Shusteff, Warren, Coleman, Moya and Wheeler.