Microfluidic Model for Evaluation of Immune Checkpoint Inhibitors in Human Tumors

Abstract

Presented is the first demonstration of real‐time monitoring of the response of resident lymphocyte populations in biopsied tumor tissue to immunotherapeutic agents in a perfused tumor microenvironment. This technology comprises a microfluidic tumor trapping device constructed from a novel 3D‐printed, transparent, noncytotoxic substrate. The 3D‐printed device sustains viability of biopsied tissue fragments under dynamic perfusion for at least 72 h while enabling simultaneous administration of various drug treatments, illustrating a useful tool for drug development and precision medicine for immunotherapy. Confocal microscopy of the tumor tissue and resident lymphocytes in the presence of fluorescent tracers provides real‐time monitoring of tumor response to various immunotherapies. Devices are additively manufactured in Pro3dure GR‐10 (i.e., a relatively new, high‐resolution stereolithographic resin with properties suitable for biomedical applications), allowing integration of a set of finely featured functional components into a monolithically constructed platform. The presented platform comprises a new methodology for modeling and analyzing tumor response for the improved prediction of patient‐specific immunotherapy efficacy. It is acknowledged that this is the first report of human tumor fragments cultured in a dynamic perfusion system capable of testing the effect of circulating immune checkpoint inhibitors on resident tumor‐infiltrating lymphocytes.

Engineering approaches for studying immune-tumor cell interactions and immunotherapy

“…These groups found that immunotherapy tended to increase the number of T cells in the organoid, as well as the fraction of T cells that were CD8+. A different model was designed to culture organoids from non-small cell lung cancer specimens under constant flow rather than embedded in gel ( Beckwith et al, 2019 ). After treatment with anti-PD-1 antibodies, fluorescent staining and confocal microscopy imaging revealed that regions of tumor cell death co-localized with tumor infiltrating lymphocytes.…”

Oncoimmunology Meets Organs-on-Chip

“…In this case they used the agarose as main biomaterial of the OOC. In addition, a microfluidic prototype has been developed by Borenstein and co-Workers to study the immune checkpoint inhibitors in human cancer (Beckwith et al, 2019). Specifically, this OOC system allows the trapping of a lung tumor biopsy and a real-time monitoring of the programmed cell death protein-1 (PD-1) expression.…”

Can 3D Printing Bring Droplet Microfluidics to Every Lab?—A Systematic Review

“…First of all, surveying the distribution of channel dimensions in papers ( Figure 3 ), it is clear that most chips have channels within the 100–500 µm range. This is the range which is comfortably printable on most SLA printers [ 40 , 52 , 53 , 60 , 65 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 ], but it is also achievable with material jetting and, after some fine-tuning, with FDM [ 42 , 101 , 102 , 103 , 104 , 105 , 106 , 107 ]. This size regime is still within the microfluidics domain, although larger than mainstream microfluidic channels.…”

“…We also compared the distribution for all 3DP microfluidics papers in general, as well as 3DP droplet microfluidics specifically. For 3DP microfluidics in general, by far the most popular application area is the entrapment of microparticles [ 39 , 41 , 50 , 55 , 56 , 57 , 61 , 70 , 75 , 89 , 91 , 96 , 99 , 100 , 104 , 113 , 119 , 120 ]. Chemical analysis and diagnostics are also highly popular [ 42 , 47 , 49 , 52 , 53 , 59 , 67 , 77 , 86 , 90 , 97 , 103 , 106 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 ].…”