The Vascularization Crisis in 3D Bioprinting: Channel Engineering, Anastomosis, and the Missing Bridge to In Vivo Perfusion

Abstract

Fabricating living tissues thick enough to sustain organ-level function requires a functional vascular supply, as cells beyond approximately 200 µm from a nutrient source cannot maintain aerobic metabolism regardless of architectural refinement. This review examines the vascularization challenge in 3D bioprinting through the lens of engineering failure analysis, identifying the specific barriers preventing in vitro success from translating to in vivo function. Three interlocking challenges are systematically addressed: fabricating hierarchically organized channels spanning the full vascular tree from millimetre-scale trunks to sub-100 µm capillary beds; the range of anastomotic strategies researchers are pursuing to connect printed channels with host circulation; and the persistent, poorly explained failure of constructs that perform well in bioreactors to maintain perfusion after implantation. Drawing on mechanistic evidence from materials science, vascular biology, and surgical literature, four root causes of in vivo failure are identified: stiffness mismatch between printed and native vessel walls; temporal mismatch between hydrogel degradation and angiogenic invasion; the near-universal omission of pericyte support from bioprinted endothelial networks; and immunological assault on allogeneic endothelial linings inadequately shielded by current bioinks. None of these failure modes is inevitable, yet none will be resolved through printing technology alone. Progress requires simultaneous advances in bioink mechanobiology, co-culture vascular biology, bioreactor conditioning, and shared performance benchmarks that the field currently lacks. A structured three-phase translational roadmap organized around objectively measurable milestones is proposed to focus research effort on the specific barriers that current evidence identifies as rate-limiting.