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Theranostics, 2025-9-8; 16(1):220-238. doi:10.7150/thno.114415
A convective transport–enhanced multi–organoid device for therapeutic modeling of the liver–pancreas axis in obesity
Jisu Kim1*, Jungho Bae2*, Baofang Cui2, Seung-Woo Cho2,3,4, Kisuk Yang1,5,6
1Department of Bioengineering and Nano-Bioengineering, College of Life Sciences and Bioengineering, Incheon National University, Incheon, 22012, Republic of Korea.
2Department of Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
3Center for Nanomedicine, Institute for Basic Science (IBS), Seoul, 03722, Republic of Korea.
4Cellartgen Inc., Seoul, 03722, Republic of Korea.
5Division of Bioengineering, College of Life Sciences and Bioengineering, Incheon National University, Incheon, 22012, Republic of Korea.
6Research Center for Bio Materials & Process Development, Incheon National University, Incheon, 22012, Republic of Korea.
*J. K. and J. B. contributed equally to this work.
Corresponding authors: Prof. Seung-Woo Cho, Prof. Kisuk Yang
1Department of Bioengineering and Nano-Bioengineering, College of Life Sciences and Bioengineering, Incheon National University, Incheon, 22012, Republic of Korea.
2Department of Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
3Center for Nanomedicine, Institute for Basic Science (IBS), Seoul, 03722, Republic of Korea.
4Cellartgen Inc., Seoul, 03722, Republic of Korea.
5Division of Bioengineering, College of Life Sciences and Bioengineering, Incheon National University, Incheon, 22012, Republic of Korea.
6Research Center for Bio Materials & Process Development, Incheon National University, Incheon, 22012, Republic of Korea.
*J. K. and J. B. contributed equally to this work.
Corresponding authors: Prof. Seung-Woo Cho, Prof. Kisuk Yang
Abstract
Rationale: Obesity-associated metabolic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus (T2DM) are increasing rapidly, necessitating physiologically relevant in vitro models of the liver-pancreas axis. While recent multi-organoid systems have advanced inter-organ modeling, many systems still fall short of replicating the complex and directional metabolic interactions required to accurately reflect disease progression. This is partly due to inherent limitations such as reliance on passive diffusion for metabolic exchange and the use of shared or non-compartmentalized media, which restrict tissue-specific functions and fail to mimic in vivo-like physiological gradients.
Methods: To overcome these limitations, we developed a multi-organoid device (MOD) that incorporates convective flow and physically separates liver and pancreatic organoids in distinct media environments. To evaluate the effectiveness of this co-culture system, we assessed metabolic transport using FITC-dextran and examined pancreatic and liver organoid function by measuring insulin and albumin secretion respectively. The effectiveness of the MOD in modeling MASLD-induced T2DM was further validated through functional assays and transcriptomic analysis.
Results: The MOD successfully recapitulated key pathological features of MASLD-induced T2DM. Convective flow significantly enhanced directional transport of glucose and other metabolic molecules compared to passive diffusion, as validated by simulation and diffusion assays. Media separation preserved organoid function, increasing insulin and albumin secretion by 1.8- and 1.6-fold, respectively, compared with the non-separated group. Importantly, the device achieved rapid glucose regulation following glucose stimulation, with normoglycemia restored within 2 hours closely mimicking physiological glucose regulation not previously attainable in existing systems. Under MASLD conditions, the platform further revealed that liver-derived Fetuin-A was associated with β-cell apoptosis in pancreatic organoids.
Conclusion: This MOD effectively models the pathophysiological cascade linking MASLD and T2DM by integrating organ-specific environments, convective flow, and multi-organ crosstalk. It offers a robust and biologically relevant tool for mechanistic studies of metabolic diseases and provides a promising platform for preclinical drug screening and therapeutic development.
Methods: To overcome these limitations, we developed a multi-organoid device (MOD) that incorporates convective flow and physically separates liver and pancreatic organoids in distinct media environments. To evaluate the effectiveness of this co-culture system, we assessed metabolic transport using FITC-dextran and examined pancreatic and liver organoid function by measuring insulin and albumin secretion respectively. The effectiveness of the MOD in modeling MASLD-induced T2DM was further validated through functional assays and transcriptomic analysis.
Results: The MOD successfully recapitulated key pathological features of MASLD-induced T2DM. Convective flow significantly enhanced directional transport of glucose and other metabolic molecules compared to passive diffusion, as validated by simulation and diffusion assays. Media separation preserved organoid function, increasing insulin and albumin secretion by 1.8- and 1.6-fold, respectively, compared with the non-separated group. Importantly, the device achieved rapid glucose regulation following glucose stimulation, with normoglycemia restored within 2 hours closely mimicking physiological glucose regulation not previously attainable in existing systems. Under MASLD conditions, the platform further revealed that liver-derived Fetuin-A was associated with β-cell apoptosis in pancreatic organoids.
Conclusion: This MOD effectively models the pathophysiological cascade linking MASLD and T2DM by integrating organ-specific environments, convective flow, and multi-organ crosstalk. It offers a robust and biologically relevant tool for mechanistic studies of metabolic diseases and provides a promising platform for preclinical drug screening and therapeutic development.
논문정보
- Research article
- 2025년 10월 (BRIC 등록일 2025-10-21)
- 국내(교신)+국외 연구진
- 바이오·의료융합 > 바이오소재
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