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

Consistent with the idea that 3D structural motives in the extracellular matrix possess immunomodulatory capacity as part of the natural healing process, we found that human monocyte-derived macrophages show a strong M2a like pro-healing polarization when cultured on type I rat-tail collagen fibers (hereafter termed "collagen I") but not on collagen I films.

Therefore, we hypothesized that highly aligned nanofibrils also of synthetic polymers, if packed into larger bundles in 3D topographical similarity to native collagen I, would induce a localized macrophage polarization.

For the automated fabrication of such bundles in a 3D printing manner, we pioneered the strategy of "Melt Electrofibrillation" by the integration of flow directed polymer phase separation into Melt Electrowriting and subsequent selective dissolution of the matrix polymer. This process yields nano-fiber bundles with a remarkable structural similarity to native collagen I fibers, particularly for medical grade polycaprolactone (PCL).

These biomimetic fibrillar structures indeed induced a pronounced elongation of human monocyte-derived macrophages and unprecedentedly triggered their M2-like polarization as efficiently as IL-4 cytokine treatment.

Our data evidence the biological importance of human macrophage-elongation on collagen fibers and pioneers a strategy to fabricate scaffolds that exploit this effect to drive macrophage polarization through precise and biomimetic material design.