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Abstract
We report the development of an entirely 3D-printed, monolithic microfluidic platform that provides a dynamic microenvironment for perfusing and sustaining tumor fragments from a biopsy sample. The finely featured, noncytotoxic, and transparent tumor trap is integrated with threaded connectors for rapid, leak-proof fluid interfacing, an in-line trap for removal of bubbles arising from oxygenated media flow or tumor loading procedures, and a network of microchannels for supplying media (and potentially immune cells) to the trapped tumor fragment. The devices were additively manufactured in Pro3dure GR-10 -a relatively new, high-resolution stereolithographic resin with properties suitable for biomedical applications requiring interrogation via fluorescence microscopy. Overlaid bright-field and fluorescence microscopy images demonstrate trapping of human tumor fragments by the printed microfluidic device, as well as visualization of individual cells within the fragment. A multi-day trapping experiment evidences the ability to sustain a live tumor fragment under dynamic perfusion within the device-a configuration capable of modeling of interactions between tumors and various drug treatments in the presence of circulating immune cells, e.g., for assessment of the efficacy of chemotherapy and immunotherapy treatments.
Highlights
M ICROFLUIDICS enable precise manipulation of small volumes of fluid for the investigation and analysis of microscopic physical, chemical, and biological phenomena
The external in-plane dimensions of the Tumor Analysis Platform (TAP) device are governed by the capabilities of the Digital Light Projection Stereolithography (DLP-SLA) printer used in this study, while the out-of-plane dimension of the microfluidic chip reflects the separation between the objective and condenser of the confocal microscope Zeiss LSM 880 (Carl Zeiss AG, Oberkochen, Germany) utilized to conduct fluorescence imaging
We reported the TAP device, i.e., a fully 3DP, monolithic microfluidic that provides a platform for retaining and sustaining tumor tissues ex vivo for an extended period under continuous perfusion of media
Summary
M ICROFLUIDICS enable precise manipulation of small volumes of fluid for the investigation and analysis of microscopic physical, chemical, and biological phenomena. The requirements of the printable material include (1) water tightness, (2) non-cytotoxicity over an extended period of time, (3) optical transparency, (4) little to no auto-fluorescence to enable data capture of the device operation via fluorescence images, and (5) high-resolution fabrication to be able to reproduce small features. A printing process could be inherently too coarse to produce optically clear surfaces (e.g., fused filament fabrication [34]) or use as feedstock powders that create non-leak-tight parts with surfaces that adsorb/absorb species (e.g., selective laser sintering [35]) From this survey, four materials were down-selected for experimental investigation–all of them are liquid resins with an associated printing process that harnesses photopolymerization to create solid objects. To the best of our knowledge, the resin Pro3dure GR-10 has not been thoroughly characterized in the open literature, in the context of microfluidic development
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