Human Tendon-on-Chip: Unveiling the Effect of Core Compartment-T Cell Spatiotemporal Crosstalk at the Onset of Tendon Inflammation

The lack of representative in vitro models recapitulating human tendon(patho)physiology is among the major factors hindering consistent progressin the knowledge-based development of adequate therapies fortendinopathy.Here, an organotypic 3D tendon-on-chip model is designed thatallows studying the spatiotemporal dynamics of its cellular and molecularmechanisms.Combining the synergistic effects of a bioactive hydrogel matrixwith the biophysical cues of magnetic microfibers directly aligned on themicrofluidic chip, it is possible to recreate the anisotropic architecture, cellpatterns, and phenotype of tendon intrinsic (core) compartment. Whenincorporated with vascular-like vessels emulating the interface between itsintrinsic-extrinsic compartments, crosstalk with endothelial cells are found todrive stromal tenocytes toward a reparative profile. This platform is furtherused to study adaptive immune cell responses at the onset of tissueinflammation, focusing on interactions between tendon compartmenttenocytes and circulating T cells.The proinflammatory signature resultingfrom this intra/inter-cellular communication induces the recruitment of T cellsinto the inflamed core compartment and confirms the involvement of thiscellular crosstalk in positive feedback loops leading to the amplification oftendon inflammation.Overall, the developed 3D tendon-on-chip provides apowerful new tool enabling mechanistic studies on the pathogenesis oftendinopathy as well as for assessing new therapies.