A collaboration between researchers at the University of Notre Dame and Harvard Medical School has produced a method for 3D printing vascular networks at resolutions approaching the size of the body’s smallest blood vessels. The work, published in Nature Chemical Engineering, addresses one of the central unsolved problems in tissue engineering: how to build vascular networks fine enough to keep cells alive throughout a larger construct — and in doing so, move bioprinted tissue closer to clinical relevance.
A Custom Printer Combining Two Technologies
The researchers designed a custom-built system that merges extrusion bioprinting with aerosol jet printing, rather than adapting a commercial bioprinter. Extrusion handles larger tissue structures, while aerosol jet printing produces fine sacrificial channels that are later converted into vessel-like passages.
The result is a system capable of producing channels under 10 microns in diameter — and in some cases between 5 and 6 microns — comparable to the capillaries found in human tissue. Channel size and geometry can be adjusted during printing, allowing for branching, hierarchical networks that more closely approximate the architecture of natural vasculature. The technology is not limited to a single vessel size: the team demonstrated networks ranging from larger vessel-like channels down to capillary-scale structures.
Machine Learning Reduces Parameter Guesswork
The system incorporates Bayesian optimization to identify the printing settings needed to produce channels of a given size. According to the study, the optimization process typically converged on suitable parameters within approximately eight rounds of testing, reducing the trial-and-error work that would otherwise be required to calibrate the system for different channel specifications.
In laboratory experiments, endothelial cells, the type that line blood vessels in the body, attached to the channel walls, spread through the structures, and formed continuous linings with functional characteristics similar to natural vessel walls. The team also demonstrated that fluids could flow through the printed networks and that cells remained viable as they grew.
Potential Applications and Longer-Term Goals
The research is part of a broader National Institutes of Health (NIH)-funded project announced earlier this year — a four-year, $2.6 million effort aimed at developing vascularized tissues that can function beyond the small sample scale typical of current laboratory work. The near-term applications the team identifies include drug testing and disease modeling, where vascularized tissue constructs could provide more physiologically relevant conditions for studying human disease or evaluating therapies prior to animal or clinical studies. The longer-term objective is to advance toward larger engineered tissues and, eventually, organ fabrication.
Keeping Tissue Alive: The Vascularization Problem in Bioprinting
The work by Yanliang Zhang and Yu Shrike Zhang fits into a well-documented gap in regenerative medicine: bioprinted tissues, once they surpass a few hundred microns in thickness, cannot sustain cell viability without an internal supply network. Oxygen and nutrients cannot diffuse far enough to reach cells in the interior of larger constructs, and without channels to remove metabolic waste, tissue degrades. The Notre Dame-Harvard collaboration addresses this directly, building a hybrid printing system capable of producing hierarchical vessel networks — from larger passages down to capillary-scale channels — within soft tissue-like materials, with the longer-term goal of producing constructs large and stable enough to be clinically relevant.
Other academic groups have pursued similar objectives through different technical routes. Harvard’s Wyss Institute developed co-SWIFT, embedding interconnected vascular networks within cardiac tissue, while Stanford’s Mark Skylar-Scott group has worked on platforms to accelerate vascular network design and on stimulating growth of vessels too fine to 3D print directly.
The recurring challenge across all of these efforts is resolution: most existing methods can produce larger vessel-like channels but struggle at the capillary scale, where natural vasculature becomes too fine to replicate with conventional extrusion alone. The Notre Dame-Harvard hybrid approach — pairing aerosol jet printing with extrusion and using machine learning to calibrate parameters — represents one of the more direct attempts to close that gap.
Titled “Hybrid bioprinting of hierarchical vascular networks at capillary-scale resolution,” the study was conducted by Yuxuan Liao, Salvador Gallegos-Martínez, Xiao Kuang, Yipu Du, Yu Shrike Zhang, and Yanliang Zhang.
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Featured image shows Hybrid bioprinting of hierarchical vascular networks at capillary-scale resolution. Image via Yanliang Zhang, et al., Nature Chemical Engineering.
