Researchers at the University of Notre Dame and collaborators at Harvard Medical School and Brigham and Women’s Hospital have developed a hybrid bioprinting strategy capable of producing vascular networks with capillaries less than 10 micrometers in diameter. These structures are narrower than the width of a human hair and approach the scale of the smallest blood vessels found in the body. The work, led by Yanliang Zhang, Advanced Materials and Manufacturing Collegiate Professor in Notre Dame’s Department of Aerospace and Mechanical Engineering, represents a significant step toward fabricating tissues that can exchange oxygen and nutrients throughout their internal volume. The study, published in Nature Chemical Engineering, describes a system that combines two printing methods with machine-learning-assisted process control.

The central difficulty in building functional organs outside the body is not simply creating the correct shape. Living cells require a continuous supply of oxygen, glucose and other nutrients, as well as a route for removing carbon dioxide and metabolic waste. In natural organs, this exchange is handled by a hierarchical vascular network that begins with large arteries and branches repeatedly into smaller arterioles, capillaries and venules. Capillaries are particularly important because they bring blood close enough to individual cells for diffusion to occur. Without a comparable microvascular network, cells in the interior of a thick engineered tissue rapidly become starved of oxygen and die, limiting the size and usefulness of most lab-grown organs.

Zhang’s team addressed this problem by integrating extrusion bioprinting with aerosol jet printing. In the first stage, extrusion printing deposits a soft, gel-like biomaterial in successive layers to form the main tissue matrix. This matrix acts as a supportive, hydrated scaffold designed to resemble some of the mechanical and biological characteristics of living tissue. Within the printed matrix, the researchers use aerosol jet printing to place extremely fine gelatin filaments. The gelatin functions as a temporary sacrificial material. Once the surrounding matrix has stabilized, the gelatin can be removed, leaving behind hollow channels that form the internal architecture of the artificial vascular system.

Aerosol jet printing gives the process a level of control that conventional extrusion systems cannot easily achieve. The technique uses a carrier gas and a surrounding sheath flow to aerodynamically focus an aerosolized stream of material. By changing the flow conditions, researchers can adjust the diameter of the deposited filament while maintaining a finely controlled trajectory. In the Notre Dame system, the approach allows channel dimensions to be varied from hundreds of micrometers down to only a few micrometers. That range is essential because biological vascular systems are not composed of tubes with a single uniform diameter; they contain large vessels that gradually divide into dense networks of microscopic branches.

The researchers also incorporated machine learning to reduce the trial-and-error traditionally required to tune the printing process. Small changes in the gelatin ink’s flow rate or in the sheath gas can significantly alter the final channel diameter, continuity and structural quality. Instead of testing every combination manually, the computational framework analyzes the relationship between printing parameters and the resulting structures. It then identifies promising operating conditions for a desired channel size and configuration. This automated optimization is particularly valuable when a single vascular design contains vessels of many different dimensions. By rapidly adjusting the parameters, the system can produce complex architectures with greater efficiency and consistency than conventional manual calibration.

Using the combined platform, the team fabricated hierarchical vascular structures in one, two and three dimensions. These included networks designed to reproduce the branching organization found in biological tissues rather than isolated, straight channels. After the temporary gelatin was removed, selected channels were seeded with endothelial cells, the specialized cells that line blood and lymphatic vessels in the human body. The cells attached to the inner surfaces of the printed channels and spread to form continuous single-cell layers. This lining is crucial because endothelial cells regulate the exchange of materials between blood and tissue, control vessel permeability and contribute to the barrier function that prevents uncontrolled leakage.

The successful formation of endothelial layers suggests that the channels were not merely geometric features but could support a basic biological function. According to the researchers, the cells rapidly adhered to the channel walls and developed a barrier resembling the lining of natural capillaries. Demonstrating this behavior is an important milestone because artificial vessels must do more than transport fluid: they must interact with living tissue and maintain an environment in which other cell types can survive. The study’s results indicate that the hybrid-printed networks may provide a platform for constructing more sophisticated tissue models, although additional work will be required to test long-term stability, blood compatibility, flow behavior and integration with larger tissue systems.

The technology could also accelerate drug development through improved organ-on-a-chip models. Many existing laboratory models lack the three-dimensional structure and microvascular complexity of human organs, making it difficult to predict how a drug will behave in patients. A printed vascular network populated with living cells could help researchers study drug transport, toxicity and therapeutic response under more realistic conditions. If patient-derived cells are incorporated, the same system might eventually be used to compare how a particular individual’s tissue responds to different treatments before a therapy is administered. Such personalized models could be especially useful for diseases involving the heart, liver, kidneys and blood vessels, where vascular behavior strongly influences treatment outcomes.

Zhang’s longer-term goal is to develop an autonomous bioprinting system capable of manufacturing fully functional tissues and, ultimately, organs such as hearts, kidneys and livers. The current work does not represent a complete printed organ, and significant scientific and engineering barriers remain, including the development of multiple interacting cell types, mature blood-flow systems, immune compatibility and reliable connections to a patient’s circulation. Nevertheless, the ability to print capillary-scale channels within larger, hierarchical networks addresses one of the most persistent obstacles in regenerative medicine. Supported by new National Institutes of Health funding, the Notre Dame and Harvard collaborators plan to build a more advanced version of the hybrid printer. If the approach can be scaled and shown to function over long periods, it could help transform bioprinting from the fabrication of tissue-shaped structures into the production of living, physiologically active replacements.

Subject of Research: Hybrid bioprinting of hierarchical vascular networks containing capillary-scale channels.

Article Title: Hybrid bioprinting of hierarchical vascular networks at capillary-scale resolution

News Publication Date: 28-May-2026

Web References: University of Notre Dame Department of Aerospace and Mechanical Engineering: https://ame.nd.edu/ ; Yanliang Zhang: https://engineering.nd.edu/faculty/yanliang-zhang/ ; Nature Chemical Engineering: https://www.nature.com/natchemeng/volumes/3/issues/6

References: Nature Chemical Engineering, DOI: 10.1038/s44286-026-00396-x

Image Credits: Photo by Wes Evard / University of Notre Dame’s College of Engineering

Keywords: Bioprinting, 3D printing, vascular networks, capillaries, tissue engineering, organ engineering, regenerative medicine, aerosol jet printing, machine learning, endothelial cells, organ-on-a-chip, personalized medicine, transplantation

Traditional methods of fabricating vascular networks have been constrained by the limitations of resolution and scalability. While extrusion bioprinting excels in rapid deposition of cellular matrices, it falls short on the sub-10-micron precision necessary to emulate capillaries, which are pivotal for nutrient exchange and waste removal in tissues. Conversely, high-resolution techniques often suffer from slow throughput and lack real-time adaptability. Addressing these challenges, the new study introduces a dual-modality bioprinting strategy that melds aerosol jet printing of sacrificial materials with conventional extrusion printing, unlocking unprecedented control over microvascular architecture.

The crux of this innovation lies in utilizing aerosol jet printing to deposit sacrificial inks with remarkable spatial fidelity. These inks form the blueprint for complex vascular channels once they are removed, creating void spaces that mimic capillary networks. Aerosol jet printing achieves channel dimensions below 10 microns, a resolution hitherto unattained in tissue engineering. Complementing this, the robust extrusion printing deposits cellular and extracellular matrix components around these sacrificial templates, providing structural integrity and biological functionality.

Yet, such technical prowess alone cannot guarantee replicability. Recognizing this, the researchers integrated constrained Bayesian optimization, an intelligent algorithmic approach, to dynamically fine-tune critical printing parameters. This machine learning-driven process expedites the identification of optimal print settings to achieve precise channel diameters without exhaustive trial and error. Real-time feedback loops empower the system to adjust on the fly, enabling bespoke modulation of vessel dimensions tuned to specific biological or regenerative requirements.

The result is a versatile printing platform capable of synthesizing vascular conduits that scale from one-dimensional channels to three-dimensional, multibranched hierarchical networks mirroring native tissue complexity. This architectural fidelity is not merely aesthetic but functional. The engineered vessels are subsequently seeded with endothelial cells—the natural lining of blood vessels—which form continuous, confluent monolayers integral to vascular health and selective permeability.

Crucially, the endothelialization process within these microchannels yields a dramatic reduction in permeability compared to non-optimized vasculature models. This hallmark indicates the formation of a stable, quasi-native barrier that modulates molecular transport, an essential property for sustaining tissue homeostasis and preventing leakage. Additionally, the cells exhibit robust viability and proliferation, underscoring the biocompatibility and physiological relevance of the hybrid-printed constructs.

Transcending conventional bioprinting limits, this methodology pioneers a new pathway for fabricating intricately branched vasculature capable of supporting living tissues in vitro and, potentially, in vivo. The implications are expansive: beyond regenerating complex organs for transplantation, these engineered vascular networks serve as vital platforms for drug testing and disease modeling, where microvascular behavior profoundly influences therapeutic outcomes.

The integration of adaptive machine learning algorithms within the bioprinting workflow heralds a paradigm shift, transforming a traditionally static process into a dynamic, precision-engineered practice. By harnessing rapid optimization and real-time modulation, researchers can now customize vascular geometries and dimensions tailored to specific research or clinical applications, fostering personalized medicine approaches.

Moreover, the scalable nature of this approach addresses the pressing need for manufacturing complexity without sacrificing throughput. The capacity to generate hierarchically organized vascular networks—spanning from major conduits to capillary beds—enables the fabrication of tissue constructs with native-like perfusion capabilities, critical for maintaining cell viability in thicker tissues.

The research aligns with the broader vision of biomimetic tissue engineering: constructing living structures that not only mirror the form but also the function of natural organs. By capturing the vascular intricacies down to the capillary scale, this technology closes a crucial gap in organ fabrication, facilitating enhanced nutrient delivery, waste removal, and cell signaling pathways necessary for organ development and function.

Equally notable is the demonstration that this hybrid printing method supports endothelial cell cultures over an extended period, maintaining monolayer integrity and proliferative capacity. This stability suggests potential for long-term studies and implantation scenarios, where vascular integrity and adaptability are paramount.

Looking forward, the synergy of aerosol jet printing and extrusion-based bioprinting augmented by artificial intelligence offers limitless possibilities. The strategy can potentially be extended to incorporate multiple cell types, extracellular matrix components, and growth factors, crafting fully vascularized tissue models tailored to specific organ systems.

In the context of regenerative medicine, these advances could revolutionize approaches to repairing or replacing damaged tissues, offering patient-specific grafts engineered to exact specifications. Similarly, the platform’s utility in pharmacological research provides a nuanced environment for assessing drug delivery and vascular responses at a granular level, accelerating drug discovery pipelines.

In summation, this hybrid bioprinting technique marks a pivotal milestone in vascular tissue engineering, deftly merging high-resolution fabrication with computational intelligence to overcome previous scalability and precision roadblocks. By ushering in capillary-scale vascular networks with hierarchical complexity, it not only elevates the state-of-the-art but also lays a foundational framework for the next generation of organ fabrication technologies.

As this technology matures and integrates with other biofabrication innovations, it portends an era where the fabrication of intricate, functional human tissues transitions from aspiration to routine practice. The seamless blending of adaptive machine learning with advanced printing heralds a future where the minute architecture of life itself can be recreated with fidelity, ushering transformative impacts on healthcare and biomedical research.

Subject of Research: Fabrication of hierarchical vascular networks using hybrid bioprinting methods enhanced by machine learning algorithms.

Article Title: Hybrid bioprinting of hierarchical vascular networks at capillary-scale resolution.

Article References:
Liao, Y., Gallegos-Martínez, S., Kuang, X. et al. Hybrid bioprinting of hierarchical vascular networks at capillary-scale resolution. Nat Chem Eng (2026). https://doi.org/10.1038/s44286-026-00396-x

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s44286-026-00396-x