Towards the development of human immune-system-on-a-chip platforms

Abstract

Organ-on-a-chip (OoCs) platforms could revolutionize drug discovery and might ultimately become essential tools for precision therapy. Although many single-organ and interconnected systems have been described, the immune system has been comparatively neglected, despite its pervasive role in the body and the trend towards newer therapeutic products (i.e., complex biologics, nanoparticles, immune checkpoint inhibitors, and engineered T cells) that often cause, or are based on, immune reactions. In this review, we recapitulate some distinctive features of the immune system before reviewing microfluidic devices that mimic lymphoid organs or other organs and/or tissues with an integrated immune system component.

FIGURE 1

Examples of microfluidic devices for studying cell-cell Interactions. (a) Illustration of the microfluidic model Ex Vivo Immuno-oncology Dynamic ENvironment for Tumor biopsies (EVIDENT) and its control system. (b) Map of tumor death through one plane of a z-stack confocal image. (c) Perimeter of tumor-infiltrating lymphocyte (TIL) infiltration versus time, showing the advancing front of TIL penetration into the tumor. (d) Conceptual diagram of the human-microbial crosstalk (HuMiX) device comprising three co-laminar microchannels: a medium perfusion microchamber; a human epithelial cell culture microchamber; and a microbial culture microchamber. Flow cytometry analysis of the viability of CD4⁺ T cells cultured alone (e), or co-cultured for 24 h with LGG (Lactobacillus rhamnosus GG) (f). Reproduced, with permission, from Ref. [28] (a–c). Adapted, with permission, from Ref. [38] (d–f). Abbreviation: PCB, XXXX.

FIGURE 2

Bone marrow (BM) structure and an example of a BM-on-a-chip platform. (a) Schematic cross-section of the BM highlighting the different hematopoietic areas (where platelets, erythrocytes, lymphocytes, monocytes, and granulocytes are continuously created and released into the blood), the immunological niches (where memory T and B cells locate), and the large vasculature, necessary for the massive cell movement in the BM. (b) An engineered BM (eBM) was produced by implanting a polydimethylsiloxane (PDMS) device in vivo and later transferring it into a microfluidic platform. (c) A bone-inducing material is placed in a PDMS structure (left), implanted for 8 weeks to form a visible pink marrow (center) and then integrated in a microfluidic system (right). Scale bars: 2 mm. Adapted, with permission, from Ref. [75] (a) and Ref. [44] (b,c).

FIGURE 3

Lymph node structure and an example of an ex vivo engineered B cell follicle organoid. (a) Schematic of a lymph node showing the vessels that allow the in-and- out movement of lymphocytes, antigen-presenting cells, pathogens, and biomolecules. Specialized antigen-sampling, T cell, and B cell zones are indicated. (b) Schematic of the in vivo follicular interaction between mature naïve B cells, follicular T helper (T_FH) cells and follicular dendritic cells (FDCs), supporting the maturation of naive B cells through the B cell activation factor (BAFF). (c) The cells were encapsulated in a silica nanoparticle-gelatin composite, which crosslinks at 37 °C and allows a proper B cell viability as shown in (d) and (e) (green calcein marking active B cells. Scale bar: 10 mm. Adapted, with permission, from Ref. [78] (a) and Ref. [50] (b-e). Abbreviations: FRC, fibroblastic reticular cells; HEV, high endothelial venules.