Innate immune cell instruction using micron-scale 3D objects of varied architecture and polymer chemistry: the ChemArchiChip

To design effective immunomodulatory implants, innate immune cell interactions at the surface of biomaterials need to be controlled and understood. The architectural design freedom of two-photon polymerization is used to produce arrays of surface-mounted, geometrically diverse 3D polymer objects. This reveals the importance of the interplay between architecture and materials chemistry in determining human macrophage fate in vitro. The ChemoArchiChip identifies key structure-function relationships and design rules from machine learning models to build a mechanistic understanding of cell attachment and polarization. Object shape, vertex/cone angle, and size are key drivers of attachment. Particular shapes are found to heavily modulate pro- or anti-inflammatory cell polarization, while triangular pyramids drastically reduce or even eliminate attachment. Caveola-dependent endocytosis is a principal mechanism by which cells respond to objects with sharp points; i.e., low vertex/cone angles. The discovery of these putative design rules points to surfaces decorated with architectures to augment implant performance.