Evaluation of Drug Combinations for Aging-Related Multimorbidity Management Using a 3D Printed Human Multi-Organ Microphysiological System

Engineering ›› DOI: 10.1016/j.eng.2025.08.026

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Abstract

Polypharmacy presents a critical challenge in the management of age-related multimorbidity, in which empirical combination therapies may inadvertently exacerbate drug toxicity through complex pharmacokinetic interactions. To address this issue, a three-dimensional (3D) printed human multi-organ microphysiological system (HMOMPS) was developed featuring induced pluripotent stem cell (iPSC) differentiation, 3D cell spheroids, and a multi-drug scoring system. This engineered platform simulated co-occurring cancer and cardiomyopathy and systematically evaluated single-agent and combination therapies through dynamic toxicity monitoring. The system provided quantitative comparisons of mechanistically distinct drug combinations to support the clinical demand of multi-target interventions. Recognizing the interplay between polypharmacy and aging, we induced cellular senescence to establish a geriatric 3D HMOMPS model, which revealed significant age-dependent variations in pharmacodynamics across identical drug regimens. Experimental validation demonstrated the capacity of the 3D HMOMPS to maintain preserved cellular viability and functionality while recapitulating inter-organ communication. These findings advance the use of microphysiological systems in personalized anti-aging pharmacotherapy for multimorbid conditions.

Keywords

Microphysiological system / Human-on-a-chip / Organ-on-a-chip / Multimorbidity / Aging-related polypharmacy

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Jing Wang, Yuxiu Wang, Yakun Wang, Yueyang Qu, Bingcheng Lin, Xiuli Zhang, Yong Luo. Evaluation of Drug Combinations for Aging-Related Multimorbidity Management Using a 3D Printed Human Multi-Organ Microphysiological System. Engineering DOI:10.1016/j.eng.2025.08.026

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