High-Throughput Bioprinting of Geometrically-Controlled Pre-Vascularized Injectable Microgels for Accelerated Tissue Regeneration.

Successful integration of cell-laden tissue constructs with the host depends on the presence of functional capillaries to provide oxygen and nutrients to the embedded cells. However, the diffusion limitations of cell-laden biomaterials create a challenge for regeneration of large tissue defects that require bulk-delivery of hydrogels and cells. In this paper, w e introduce a strategy to bioprint geometrically-controlled, endothelial and stem-cell laden microgels in high-throughput, allowing these cells to form mature and functional pericyte-supported vascular capillaries in-vitro, and then injecting these pre-vascularized constructs minimally invasively in-vivo. W e demonstrate that this approach offers both desired scalability for translational applications as well as unprecedented levels of control over multiple microgel parameters to design spatially-tailored microenvironments for better scaffold functionality and vasculature formation. As a proof-of-concept, w e compared the regenerative capacity of o ur bioprinted pre-vascularized microgels versus that of cell-laden monolithic hydrogels of the same cellular and matrix composition in hard-to-heal defects in vivo. O ur results demonstrate that the bioprinted microgels h ad faster and higher connective tissue formation, more vessels per area, and widespread presence of functional chimeric (human and murine) vascular capillaries across the regenerated sites. The proposed strategy, therefore, addresses a significant issue in regenerative medicine, demonstrating a superior potential to facilitate translational regenerative efforts. This article is protected by copyright. All rights reserved.