A Sacrificial 3D Printed Vessel-on-Chip Demonstrates a Versatile Approach to Model Granulation Tissue

For in vitro organ models, perfused vasculature is crucial to overcome nutrient diffusion limits and to generate immunocompetent models by allowing trans-endothelial migration of immune cells in and out of the tissue. However, vasculature is often disregarded due to its complexity to generate and the necessity to integrate flow. The aim here is to overcome these limitations by combining 3D printing and multi-organ-chip technology to generate a vascularized, fibroblast-populated connective tissue matrix on-chip. A 3D printed, sacrificial, water-dissolvable structure is incorporated into a multi-organ-chip to generate hollow channels within a collagen/fibrin hydrogel. Subsequently, the channels are populated with endothelial cells. Different hydrogel concentrations of fibrin are used to mimic healthy and early granulation tissue. The vessels are perfused, and stable metabolic/viability conditions (lactate dehydrogenase, glucose, lactate) acquired after 3 days for 7 days total. In high fibrin gels, angiogenic sprouting and increased secretion of angiogenic cytokines is observed. Perfusion with monocytes revealed differentiation into macrophages and migration across the endothelium into the tissue. In conclusion, the versatile, easy method to pattern hydrogels in multi-organ-chips can serve as the basis to build the next generation of vascularized, immunocompetent human organ models, and opens new possibilities to study health and disease.