Bioinspired 3D microprinted cell scaffolds: Integration of graph theory to recapitulate complex network wiring in lymph nodes.

Physical networks are ubiquitous in nature, but many of them possess a complex organizational structure that is difficult to recapitulate in artificial systems. This is especially the case in biomedical and tissue engineering, where the microstructural details of 3D cell scaffolds are important. Studies of biological networks-such as fibroblastic reticular cell (FRC) networks-have revealed the crucial role of network topology in a range of biological functions. However, cell scaffolds are rarely analyzed, or designed, using graph theory. To understand how networks affect adhered cells, 3D culture platforms capturing the complex topological properties of biologically relevant networks would be needed. In this work, we took inspiration from the small-world organization (high clustering and low path length) of FRC networks to design cell scaffolds. An algorithmic toolset was created to generate the networks and process them to improve their 3D printability. We employed tools from graph theory to show that the networks were small-world (omega factor, ω = -0.10 ± 0.02; small-world propensity, SWP = 0.74 ± 0.01). 3D microprinting was employed to physicalize networks as scaffolds, which supported the survival of FRCs. This work, therefore, represents a bioinspired, graph theory-driven approach to control the networks of microscale cell niches.