An Integrated Microfluidic Biomimetic Tumor-on-a-Chip for Wide-Range Screening of Chemotherapy and Photodynamic Therapy.

Abstract

Microengineered cancer model is exceedingly practical in preclinical screening, while establishing a highly tumor-biomimetic pathophysiological microsystem with multi-function integration remains challenging. Here, an integrated microfluidic biomimetic tumor-on-a-chip (IMBTC) platform is established to reinforce at once the spatiotemporal control of fluid/cell samples and wide-range gradient (WRG), as well as the in vitro multi-feature reconstruction of native tumors for supporting diverse preclinical therapy evaluations. The active pneumatic manipulators enable precise cell capture and array-like organization with high positioning efficiency. The WRG generator can unprecedentedly create a wide range of chemical gradients with up to 8 orders of magnitude, affording efficient therapy screening evaluation in a single chip capable of producing hundreds of tumors with size-uniformity via coculturing under a physiological flow condition. Multiple high-biomimetic characteristics in the engineered tumors, including complex multilayer organization, various phenotypic/biochemical gradients involving proliferation, viability, metabolism, hypoxia, and molecular penetration, and heterogeneous cell and stroma compositions, are validated. The IMBTC system is applied to successively evaluate individual drug chemotherapy, combinatorial chemotherapy, and photosensitive drug-dominant photodynamic therapy, thereby identifying the effective lethal doses from wide-range antitumor concentration screenings. The verified IMBTC system offers considerable benefits for advancing the development of next-generation tumor-on-a-chip and an innovative preclinical screening paradigm.