A Foreign Body Response-on-a-Chip Platform

Abstract

Understanding the foreign body response (FBR) and desiging strategies to modulate such a response represent a grand challenge for implant devices and biomaterials. Here, the development of a microfluidic platform is reported, i.e., the FBR-on-a-chip (FBROC) for modeling the cascade of events during immune cell response to implants. The platform models the native implant microenvironment where the implants are interfaced directly with surrounding tissues, as well as vasculature with circulating immune cells. The study demonstrates that the release of cytokines such as monocyte chemoattractant protein 1 (MCP-1) from the extracellular matrix (ECM)-like hydrogels in the bottom tissue chamber induces trans-endothelial migration of circulating monocytes in the vascular channel toward the hydrogels, thus mimicking implant-induced inflammation. Data using patient-derived peripheral blood mononuclear cells further reveal inter-patient differences in FBR, highlighting the potential of this platform for monitoring FBR in a personalized manner. The prototype FBROC platform provides an enabling strategy to interrogate FBR on various implants, including biomaterials and engineered tissue constructs, in a physiologically relevant and individual-specific manner.

Keywords: biomaterials; foreign body responses; immune responses; implants; organs-on-a-chip.

Figure 1.

Design of the FBROC device. a) Exploded schematic diagram showing the multilayer structure of the bioreactor, where an endothelialized porous membrane is sandwiched in between a vascular channel on top and a tissue chamber at the bottom, the latter of which implant of Ti microbeads was placed. b) Perspective- and side-view photographs showing the bioreactor in the multilayer configuration. c) Schematic diagram showing the operation of the FBROC device, where immune cells are circulated from the top vascular channel of the bioreactor to probe their interactions with the Ti microbeads in the bottom tissue chamber through the endothalial barrier.

Figure 2.

Characterization of monocyte distribution, vascular barrier, and monocyte-endothelium interactions. a,b) Simulated distributions of the circulating immune cells in the top vascular channel of the bioreactor. c–f) Immunostaining of VE-cadherin and ICAM for confluent HUVECs cultured under (c,d) static and (e,f) dynamic conditions on the porous PET membrane. g–n) THP-1 monocyte interactions with the confluent endothelium under static and dynamic conditions.

Figure 3.

FBR of THP-1 monocytes to the Ti microbeads. a) Photograph showing the GelMA hydrogel ring in the bottom tissue chamber for MCP-1 release. b) MCP-1 release over a 96-h period. c–f) THP-1 monocyte trans-endothelial migration towards the bottom Ti microbeads under (c,d) static and (e,f) dynamic conditions, in the (c,e) absence and (d,f) presence of MCP-1. The cells were pre-labeled with cell tracker (pink) and post-labeled for nuclei (blue). g) Quantifications of the number of THP-1 monocyte migration. h,i) CD80 (green)/CD206 (red) expressions of activated THP-1 monocytes on the Ti microbeads, in the h) absence and i) presence of MCP-1, under dynamic conditions. The nuclei were counterstained in blue. The white dotted circles indicate the Ti microbeads. *p< 0.05.

Figure 4.

Donor-specific FBR of patient PBMC-derived monocytes to the Ti microbeads. a) Monocyte/PET membrane interactions in the absence or presence of HUVECs under static or dynamic conditions. b) Trans-enothelial migration of monocytes onto Ti microbeads in the bottom tissue chamber in the absence or presence of MCP-1 under dynamic conditions. c) Quantification of trans-enothelial migration of monocytes onto Ti microbeads in the bottom tissue chamber in the absence or presence of MCP-1. d) CD206/CD80 expressions of activated monocytes from three different human donors on Ti microbeads in the presence of MCP-1 under dynamic conditions. e) Quantifications of CD206 and CD80 expressions of activated monocytes on the Ti microbeads in the presence of MCP-1 under dynamic conditions for monocytes derived from three different human donors. f) Quantifications of CD206/CD80 expression ratios of activated monocytes on the Ti microbeads in the presence of MCP-1 under dynamic conditions for monocytes derived from three different human donors. *p < 0.05 and **p < 0.01.