With AMA: Healthcare on June 4th putting 3D printing for healthcare under the spotlight, voices from across the industry are weighing in on where the technology is heading.
Tissue models have long been constrained by the same three problems: they take too long to build, they cannot scale meaningfully, and their structure falls short of biological reality. Oksana Dudaryeva, formerly a Postdoctoral Researcher at the University Medical Center Utrecht, is working on all three at once.
Presenting her latest findings on volumetric generation of complex tissue-engineered liver systems, research conducted in the group of Riccardo Levato, Dudaryeva made the case that volumetric printing is not an incremental improvement on existing bioprinting methods, but a structural departure from them.
Unlike conventional bioprinting approaches that build structures layer by layer, volumetric printing works by projecting multiple light angles simultaneously onto a rotating vial filled with a photo-responsive solution. The light projections converge to form a three-dimensional hologram of the target object, which then solidifies within seconds to minutes.
“Volumetric printing is not an iteration on what came before, it collapses the time and structural limitations that have defined bioprinting from the start,” said Dudaryeva. The speed advantage over DLP or extrusion-based methods, she notes, is substantial.
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From Bone to Pancreas: What the Technology Can Already Build
The Levato lab has used volumetric printing to produce a range of tissue constructs that would be difficult or time-prohibitive to generate through other means. A trabecular bone model, one centimeter in diameter, incorporating human mesenchymal stem cells, endothelial cells, and small internal vessels, was generated in 12.5 seconds. A liver-on-a-chip organoid embedded within a perfusable hydrogel demonstrated functional ammonia elimination when tested.
More recently, the group has been developing a pancreas model using beta cell-like spheroids capable of producing insulin, with ongoing work toward Langerhans islets derived from pluripotent stem cells that express PDX1, a key marker of endocrine cells to make a bioprinted pancreas model that can be used for drug testing.
“Each of these models demonstrates what the technology can do. What many other models still lack is the vascular architecture that makes tissue actually function,” said Dudaryeva. Each model targets a different organ system, but they share that same structural gap: none yet includes the dense, hierarchical vascular networks that real tissue depends on for oxygen delivery, nutrient exchange, and cellular signaling.
The Vascularization Problem
Vascularization is not a peripheral concern in tissue engineering, it is central to whether a model behaves like living tissue at all. “The hydrogels we use are simply not porous enough by default. Without porosity, cells cannot infiltrate, vessels cannot form, and the construct hits a hard size limit, and that is the problem we set out to solve,” said Dudaryeva.
Standard synthetic hydrogels, including those based on PEG-diacrylate, PEG-methacrylamide, and gelatin-methacrylamide, all crosslinked with light and a photoinitiator, are stable and printable, but nanoporous by default. Unless void spaces are physically printed into the structure, cells cannot move through them and vessels cannot form within them. The result is a hard ceiling on construct size at around 100 to 200 microns, beyond which oxygen diffusion fails.
Her solution draws from her research focus on macroporous materials created by liquid-liquid phase separation. Developed in collaboration with researchers at ETH Zurich, the approach introduces phase-separating agents, polysaccharides such as dextran that do not participate in crosslinking, into the hydrogel formulation.
Their presence triggers phase separation during crosslinking, causing the polymer to precipitate and reorganize into an interconnected porous network. Depending on the mechanism, spinodal or binodal, the resulting architecture produces either fully interconnected porosity or isolated pores within the matrix.
What makes this particularly useful in volumetric printing is that the scale of porosity can be tuned directly through light intensity. By manipulating light intensity gradients across the volumetric printer’s three-dimensional light field, it becomes possible to produce a single construct with gradient porosity, different pore scales in different regions of the same object, ranging from below one micron to several hundred microns.
Breaking the Diffusion Barrier
The practical outcome of this approach was tested directly. Macroporous constructs were seeded with mixtures of stromal cells and endothelial cells at varying concentrations and ratios onto the hydrogels. Within the porous space, endothelial structures formed that matched the dimensions of microcapillaries, an outcome that is particularly difficult to achieve in synthetic hydrogel systems due to their typical nanoporosity.
These vascular structures remained stable beyond 14 days. Compared to nanoporous controls, macroporous constructs showed higher junction density, greater capillary length, and a larger area occupied by endothelial structures across the construct volume. In nanoporous constructs, outgrowth was largely confined to stromal cells, with endothelial cells growing only in regions where printing artifacts had created small low-density channels, a structural coincidence rather than a reproducible result.
To further support vascular outgrowth, perfusible chips with a single channel were integrated into both nanoporous and macroporous constructs and connected to micropumps generating flow rates comparable to biological blood vessels. Cells seeded within the channel served as a reservoir for outgrowth into the bulk material.
Within one week, confocal microscopy showed stromal cells invading the pore space first, followed by endothelial cells that progressively endothelialized the protrusions, evidence of functional vessel formation within the perfusable construct. Vascular outgrowth extended beyond 800 microns in some cases, well past the 200-micron threshold that oxygen diffusion limits had previously imposed on bioprinted materials.
“As a takeaway message, we can now generate materials with the desired porosity only from a single formulation, only by tuning the light intensity, generate porosity gradients and objects with multi-scale porosity. And this porosity allows the infiltration of cell and vascular structures, vascularization of large constructs, endothelialization, and breaking the diffusion barrier,” Dudaryeva concluded.
Where Vascularization Becomes the Defining Problem
The work Dudaryeva presented sits within a broader research effort to solve what has become bioprinting’s most persistent bottleneck: building tissue that can actually sustain itself. Her approach addresses the same fundamental constraint that research groups worldwide are targeting through different means.
At Stanford, researchers published a platform that accelerates the design of vascular networks and translates them into 3D printable models, with the explicit goal of scaling bioprinted tissue beyond the size limits imposed by inadequate blood supply. Working from a different angle, Penn State is combining 3D bioprinted biomaterial templates with micropuncture, creating tiny holes in existing vessels to trigger rapid sprouting along printed vascular pathways, supported by a $3 million NIH grant.
On the materials side, researchers in Spain and the Netherlands have developed hybrid bioinks that enable bioprinting of artery models closely mimicking the layered structure and partial function of human blood vessels.
Vascularization is a shared target across the field. What sets Dudaryeva’s work apart is the method: porosity embedded directly into the material formulation, with light intensity as the only variable needed to control scale. No pre-designed channels, no surgical intervention, the vasculature grows from within. The clinical translation of any of these approaches, however, remains the field’s most unanswered challenge.
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