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Researchers from Politecnico di Torino and Maastricht University have developed a biomimetic scaffold design method using a custom Voronoi path generator for extrusion-based 3D printing. Published in the journal Biomaterials Science, the study introduces a Python-based software tool capable of fabricating irregular, biomimetic structures using melt electrowriting (MEW) and fused deposition modeling (FDM). The goal is to build more physiologically relevant in vitro lung tissue models.

The system can generate continuous toolpaths for complex Voronoi geometries, which are difficult to manufacture using standard slicing software. These geometries were used to fabricate scaffolds capable of replicating alveolar tissue structures. The printed scaffolds were combined with electrospun nanofiber membranes to form a multiscale composite structure designed to mimic the alveolar-capillary barrier.

Voronoi-based scaffold design on the left, and structures printed using fused deposition modeling (FDM) and melt electrowriting (MEW). Image source: Farina.

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ustom Toolpath Generation for Irregular Biomimetic Structures

The study highlights that conventional slicing software is optimized for regular or parameterized geometries and cannot generate continuous extrusion paths for non-repetitive structures such as Voronoi patterns. To overcome this limitation, the team developed a customized Python software tool called the Voronoi Path Generator, or PyVoroGen, which converts Voronoi layouts into G-code optimized for extrusion-based additive manufacturing.

The software allows users to define parameters through a graphical user interface, including the number of seed points, pattern diameter, and fiber thickness. It uses graph theory algorithms to generate continuous toolpaths, ensuring compatibility with the MEW process, which requires uninterrupted extrusion.

For FDM printing, additional processing steps were implemented to prevent material overlap. When the printhead needs to pass over areas where material has already been deposited, the nozzle is lifted to avoid collision. In addition to generating toolpaths, the software also provides predictive analysis of scaffold properties, including porosity and pore area, establishing a direct link between design parameters and expected printing outcomes.

Workflow for generating continuous toolpaths from Voronoi geometries, including seed distribution, graph conversion, and path optimization. Image source: Farina.

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Fabrication Using MEW and FDM Processes

Voronoi-based scaffolds were fabricated using both melt electrowriting and fused deposition modeling. Confocal imaging confirmed the accurate reproduction of the designed geometries, demonstrating the feasibility of manufacturing non-repetitive biomimetic structures through extrusion-based 3D printing.

Differences were observed between the two fabrication methods. MEW produced finer fibers, with an average diameter of approximately 92 micrometers. FDM, by contrast, produced thicker fibers and showed higher geometric fidelity in node definition, although occasional connection defects caused adjacent cells to merge.

In comparison, MEW structures showed reduced fidelity on shorter segments due to rapid changes in direction. Porosity measurements closely matched the software predictions. The normalized measured values deviated from the theoretical values by approximately 2.2% for FDM scaffolds and about 1.7% for MEW scaffolds.

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Hybrid Scaffold Design Integrating Electrospinning

After fabrication, the 3D-printed Voronoi framework was combined with an electrospun membrane made of polycaprolactone (PCL) and gelatin. This thin membrane, with an average thickness of approximately 3 micrometers, was deposited directly onto the printed structure to form a composite scaffold.

Scanning electron microscopy showed that the nanofiber layer conformed to the underlying Voronoi structure and partially bridged the pores, creating a three-dimensional membrane architecture that integrates microscale printed fibers with nanoscale electrospun fibers.

Scanning electron microscopy (SEM) images show the integration of electrospun nanofibers with the 3D-printed Voronoi scaffold. Image source: Farina.

In Vitro Co-Culture Demonstrates Compartmentalized Barrier Formation

To evaluate biological performance, the researchers cultured A549 human alveolar epithelial cells and HUVEC human umbilical vein endothelial cells on opposite sides of the membrane. The constructs were maintained under air-liquid interface conditions for a total culture period of ten days.

The results showed that cells successfully adhered and proliferated on both sides. Epithelial cells formed a continuous layer on the apical side, while endothelial cells colonized the basal side. Immunofluorescence imaging confirmed the formation of a compartmentalized cellular structure resembling the alveolar-capillary barrier.

The thin electrospun membrane allowed both cell layers to be observed simultaneously and supported cellular interactions across the scaffold. The Voronoi structure also influenced spatial organization, with the printed microfibers altering cell morphology.

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Toward More Biomimetic In Vitro Tissue Models

The study demonstrates that this platform can fabricate scaffolds with greater structural complexity than conventional scaffold geometries. By combining customized computational design, extrusion-based 3D printing, and electrospinning, the method offers a pathway for producing more physiologically relevant in vitro models.

Although the current scaffolds have not yet reached the scale of natural alveolar structures, the study presents a framework for integrating biomimetic geometries into additive manufacturing workflows for tissue engineering.

Immunofluorescence and bright-field images show epithelial and endothelial cells growing on opposite sides of the Voronoi scaffold, forming a separated barrier structure. Image source: Farina.

Pursuing More Realistic Scaffold Architectures in Tissue Engineering

To improve 3D-printed scaffolds for biomedical applications, researchers are increasingly focused on replicating natural tissue architectures. For example, researchers at the University of New South Wales Canberra developed 3D-printed bone scaffolds designed to more closely match natural bone structures, with the aim of improving tissue regeneration.

Similarly, recent research on spinal cord repair has shown that scaffold architecture plays a key role in supporting functional recovery, with 3D-printed constructs capable of guiding cell growth and tissue integration.

While these approaches all emphasize the importance of geometry in determining biological performance, most rely on relatively regular or controlled structures to maintain compatibility with existing manufacturing workflows. Translating more irregular and heterogeneous designs into printable structures remains a challenge.

The method proposed in this study addresses this limitation by generating continuous toolpaths for non-repetitive geometries, thereby supporting the fabrication of scaffold architectures that more closely reflect natural tissue structures.

The study, titled “Biomimetic Scaffold Design via Extrusion-Based 3D Printing Using a Custom Voronoi Path Generator,” was conducted by Federico Farina, Michela Licciardello, Lorenzo Moroni, Joanna Babilotte, Gianluca Ciardelli, and Chiara Tonda-Turo.

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Voronoi-Bassed 3D Printing Toel for Biomimretic Lung Tissue Scaffolds

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