Translation of Collagen Ultrastructure to Biomaterial Fabrication for Material Independent but Highly Efficient Topographic Immunomodulation

Abstract

Supplement-free induction of cellular differentiation and polarization\nsolely through the topography of materials is an auspicious strategy but has so\nfar significantly lacked behind the efficiency and intensity of media-supplementation\nbased protocols. For immune cells, low intensity effects were achieved on\nrhodent cells using standard technologically driven surface patterns and\nscaffold geometries, but no effects could be achieved for human immune cells. \n\nConsistent with the idea that 3D structural motives in the extracellular\nmatrix possess immunomodulatory capacity as part of the natural healing\nprocess, we found that human monocyte-derived macrophages show a strong M2a\nlike pro-healing polarization when cultured on type I rat-tail collagen fibers\n(hereafter termed collagen I ) but not on collagen I films. Therefore, we hypothesized that highly aligned nanofibrils also of synthetic\npolymers, if packed into larger bundles in 3D topographical similarity to\nnative collagen I, would induce a localized macrophage polarization. \n\n \n\nFor the automated fabrication of such bundles in a 3D printing manner, we\npioneered the strategy of Melt Electrofibrillation by the\nintegration of flow directed polymer phase separation into Melt Electrowriting\nand subsequent selective dissolution of the matrix polymer. This process yields\nnano-fiber bundles with a remarkable structural similarity to native collagen I\nfibers, particularly for medical grade polycaprolactone (PCL). \n\n \n\nThese biomimetic fibrillar structures indeed induced a pronounced\nelongation of human monocyte-derived macrophages and unprecedentedly triggered\ntheir M2-like polarization as efficiently as IL-4 cytokine treatment.\n\n \n\nOur data evidence the\nbiological importance of human macrophage-elongation on collagen fibers and\npioneers a strategy to fabricate scaffolds that exploit this effect to drive\nmacrophage polarization through precise and biomimetic material design.