Overlooked? Underestimated? Effects of Substrate Curvature on Cell Behavior

In biological systems, form and function are inherently correlated. Despite this strong interdependence, the biological effect of curvature has been largely overlooked or underestimated, and consequently it has rarely been considered in the design of new cell–material interfaces. This review summarizes current understanding of the interplay between the curvature of a cell substrate and the related morphological and functional cellular response. In this context, we also discuss what is currently known about how, in the process of such a response, cells recognize curvature and accordingly reshape their membrane. Beyond this, we highlight state-of-the-art microtechnologies for engineering curved biomaterials at cell-scale, and describe aspects that impair or improve readouts of the pure effect of curvature on cells. There is increasing evidence that substrate curvature on a (near‐)cell scale affects cell fate. High-resolution rapid prototyping/additive manufacturing technologies – including stereolithography, two-photon polymerization (2PP) laser lithography, and digital mirror device-based digital light processing – can create structures with defined, complex (out-of-plane) curvature. 2PP technology can create smooth structures or structures with defined superimposed surface roughness, texture, or topography. Curvature chip technologies are about to drastically ease systematic studies on cell–curvature interactions, and to enable the (re)creation of microanatomically shaped cellular microenvironments in tissues/organs on chips. These new techniques are expected to change how cell–biomaterial interfaces in vitro and in vivo will be engineered in the future.