Intelligent bioprinting of biomimetic hemostatic constructs: From bioink design and programmable fabrication to preclinical validation for non-compressible hemorrhage

Achoimre

Non-compressible hemorrhage (NCH) remains a leading cause of preventable trauma mortality because conventional gauze and oxidized cellulose act as passive barriers, whereas fibrin sealants depend on patient-derived fibrinogen; neither is reliable in coagulopathic patients. Recent convergence of bioink engineering, 3D/4D bioprinting, and artificial intelligence (AI)-assisted material design enables the fabrication of biomimetic hemostatic constructs with programmable composition, multiscale architecture, and dynamic responsiveness. This review critically examines how intelligent bioprinting—integrating stimuli-responsive bioinks, multi-axis extrusion/digital light processing printing, and AI-guided bioink optimization—fundamentally differs from conventional biomaterial fabrication in recapitulating the structural mechanics of natural thrombi. We first analyze the structure–function relationships of native fibrin/platelet/red blood cell networks that should be mimicked by bioprinted constructs. We then systematically compare bioink formulations (natural biopolymers, synthetic peptides, cell-membrane-coated nano-vectors, and inorganic–organic composites) across four bioprinting-relevant dimensions: printability, post-printing bioactivity, wet-tissue adhesion strength, and burst pressure. We further evaluate cross-tier preclinical validation, including microfluidic thrombosis-on-chip, small-animal models, and lethal large-animal NCH models (porcine liver/spleen/junctional injury), with explicit differentiation from rodent wound-healing studies. Finally, we identify translational bottlenecks (rheological paradox, Good Manufacturing Practice scale-up, regulatory pathways) and articulate future directions: AI-guided bioink discovery, organ-on-chip patient-specific screening, and deployable 4D-printed hemostats. By bridging biomimetic design, programmable fabrication, and quantitative translational evaluation, intelligent bioprinting offers a manufacturable and clinically translatable route to next-generation NCH therapeutics.