Differential Monocyte Actuation in a Three‐Organ Functional Innate Immune System‐on‐a‐Chip

Abstract

A functional, human, multiorgan, pumpless, immune system‐on‐a‐chip featuring recirculating THP‐1 immune cells with cardiomyocytes, skeletal muscle, and liver in separate compartments in a serum‐free medium is developed. This in vitro platform can emulate both a targeted immune response to tissue‐specific damage, and holistic proinflammatory immune response to proinflammatory compound exposure. The targeted response features fluorescently labeled THP‐1 monocytes selectively infiltrating into an amiodarone‐damaged cardiac module and changes in contractile force measurements without immune‐activated damage to the other organ modules. In contrast to the targeted immune response, general proinflammatory treatment of immune human‐on‐a‐chip systems with lipopolysaccharide (LPS) and interferon‐ γ (IFN‐ γ ) causes nonselective damage to cells in all three‐organ compartments. Biomarker analysis indicates upregulation of the proinflammation cytokines TNF‐ α , IL‐6, IL‐10, MIP‐1, MCP‐1, and RANTES in response to LPS + IFN‐ γ treatment indicative of the M1 macrophage phenotype, whereas amiodarone treatment only leads to an increase in the restorative cytokine IL‐6 which is a marker for the M2 phenotype. This system can be used as an alternative to humanized animal models to determine direct immunological effects of biological therapeutics including monoclonal antibodies, vaccines, and gene therapies, and the indirect effects caused by cytokine release from target tissues in response to a drug's pharmacokinetics (PK)/pharmacodynamics (PD) profile.

Critical Considerations for the Design of Multi-Organ Microphysiological Systems (MPS)

“…Although immune components such as macrophages have been included in a variety of single organ systems ( Huh et al, 2010 ; Jones et al, 2012 ; Hamza and Irimia, 2015 ), their integration in a recirculating multiorgan MPS device is not advancing as rapidly. A recent article by Sasserath et al (2020) presented the integration of a monocyte-derived cell line, THP-1, as a recirculating immune component in a multiorgan human model. The monocytes were added as part of the recirculating medium (blood surrogate) and allowed to flow through the three-organ system.…”

Prenatal Development and Function of Human Mononuclear Phagocytes

“…Mononuclear phagocyte migration and its role in development and disease have been studied using OoC models (Biselli et al, 2017;Sasserath et al, 2020). Monocytes and macrophages embedded in OoCs respond to hypoxia and injury-associated signals, such as MCP-1 and IL-6, by migrating down chemokine gradients (Liu et al, 2018;Shanti et al, 2018).…”

“…These MPs express gene-expression programs similar to those observed to be crucial in development, such as programs involved in angiogenesis (VEGF, COX2, Wnt5a, FGF2), tissue remodeling (MMP9), glucose transport (e.g., solute carrier family 2 member 1), and glycolytic metabolism (enolase 2) (Chou et al, 2018;Shanti et al, 2018;Jang et al, 2019;Sriram et al, 2019). Other OoC models incorporating MPs have been developed for the spleen (Rigat-Brugarolas et al, 2014), skin (Sriram et al, 2019), bone marrow (Chou et al, 2018), liver (Jang et al, 2019), the feto-maternal interface (Richardson et al, 2020), and an inter-connected multi-organ platform (Sasserath et al, 2020). Sieber et al (2018) developed a BM-on-a-chip model consisting of two media perfused micro-channels filled with BM progenitor, stromal, and endothelial cells.…”

“…To achieve crosstalk of organs, long-term multi-OoC cultures have been developed to better mimic these multi-tissue interactions (Zhao et al, 2019). A multi-OoC model comprising cardiomyocytes, skeletal muscle, and the liver was successfully used to study the THP-1 macrophage response to drug and inflammatory stimuli (Sasserath et al, 2020). The multi-OoC model incorporated biological microelectromechanical systems (BioMEMS) to non-invasively measure cardiomyocyte electrical (microelectrode array) and muscle mechanical function (cantilever).…”

Immune Organs and Immune Cells on a Chip: An Overview of Biomedical Applications

“…Sasserath et al [ 76 ] developed a three-OoC device consisting of the liver, cardiomyocytes and skeletal muscle, including the innate immune system, represented by circulating THP-1 monocytes. Its functionality was maintained for up to 28 days.…”