For organ-on-a-chip to mimic the human body, there is no way around a “decent blood vessel” — vessels, renal tubules, and intestines are essentially tubes with an endothelial lining. The tube can be printed; the trouble is the surface: PCL, the material used to make the tube, is famously “bio-inert” — cells do not like to live on it. To make cells comfortable, vascular endothelial growth factor (VEGF) must be immobilized on the surface, but both traditional routes have pitfalls — physical adsorption does not hold well; wet chemical steps are complex and may leave toxic residues.

In 2025, teams from the University of Sydney and Eindhoven University of Technology published an elegant two-step combination in Materials Today Bio: melt electrowriting (MEW) first weaves a micron-precision porous tube, then plasma immersion ion implantation (PIII) buries “molecular hooks” directly into the surface — soak in growth factor solution and the protein is covalently welded in place; culture for 4 weeks without adding a single additional VEGF molecule, and the endothelial monolayer still forms.

01 What Organ-on-a-Chip Lacks Is a Real Vessel With Endothelium

The paper’s starting point is an old pain point in drug testing: many drugs pass animal experiments but fail in humans. Animal models are expensive, low-throughput, and carry ethical pressure — so organ-on-a-chip has been pushed to the fore: microfluidic devices culturing human cells, closer to the real physiological environment than 2D culture dishes, with bone marrow, kidney, and lung models already demonstrated.

The common building block of such devices is tubular structures: vessels, renal tubules, gastrointestinal tract — the same logic. Among them, blood vessels are the most critical — nutrient delivery, waste removal, homeostasis maintenance all depend on them. The difficulty is also here: the “vessels” in current chips are mostly perfusion channels + porous scaffolds, which cannot replicate the core function of a real vessel — that endothelial cell layer responsible for filtration and molecular transport.

To make endothelial cells form a complete monolayer on the tube wall, the approach is to immobilize pro-angiogenic vascular endothelial growth factor (VEGF) on the scaffold surface. But both traditional routes have weaknesses:

The University of Sydney team brought a third route — a technology they had been refining on 2D surfaces for years — plasma immersion ion implantation (PIII): combining the simplicity of physical adsorption with the robustness of wet chemistry, without inheriting the flaws of either. This time, they had to move it from “flat surfaces” to “3D porous tubes” — precisely the hardest transition.

Two requirements must be met simultaneously: uniform treatment — plasma bombardment is directional, and 3D porous tubes are hard to treat evenly; non-damaging treatment — PCL is heat-sensitive, and bombardment-generated heat could deform the microstructure.

02 Weave the Tube First: MEW Melt Electrowriting, a “Vascular Blank”

The tube-making process is melt electrowriting (MEW) — one of the highest-precision members of the bio 3D printing family. The principle can be imagined as “charged winding”: PCL pellets are heated and melted, and when extruded from a fine nozzle, are stretched by a high-voltage electric field into micron-scale filaments, stacked layer by layer following pre-defined paths.

The paper first optimized the process on flat substrates, then transferred the parameters to a cylindrical collector, ultimately producing two tubular scaffold specifications:

03 Bury the Hooks: PIII Welds “Molecular Hooks” into the Surface

With the tube woven, the next step is to turn the PCL surface from “bio-inert” into “cell-friendly.” The paper uses plasma immersion ion implantation (PIII) — placing the scaffold in a vacuum chamber, introducing nitrogen gas, applying high-voltage pulses, and letting nitrogen ions bombard the scaffold surface from all directions.

This bombardment process does three things at the nanoscale:

The key parameter is treatment duration. The paper systematically compared different durations:

04 No VEGF Supplementation: Endothelial Cells Line Up and Form a Layer

With VEGF-immobilized scaffolds ready, the next step is “culturing cells.” The paper uses human umbilical vein endothelial cells (HUVEC), seeded on the luminal side, statically cultured. The key experimental design is “no VEGF supplementation” — no additional VEGF is added to the medium throughout the culture; the question is whether cells can form a layer relying on scaffold-surface-immobilized VEGF alone.

The results are quite impressive:

• Within the 4-week culture period, endothelial cells spread, proliferated, and migrated on the luminal side, ultimately forming a continuous endothelial monolayer;
• Cells aligned along the luminal direction — the micron-scale alignment cues of MEW fibers guide endothelial cells to “line up on their own”;
• The barrier function of the endothelial monolayer (assessed by transendothelial electrical resistance TEER and fluorescein permeability assays) was comparable to conventional growth-factor-supplemented protocols (continuous VEGF supplementation in the medium);
• PIII treatment itself does not affect cell viability — on PIII scaffolds without immobilized VEGF, cells also adhered but did not form a complete monolayer.

05 Why 20 Minutes: The Balance Between Uniform Treatment and Non-Damaging Treatment

PIII treatment duration is the core variable of the entire process. The paper provides detailed screening logic:

Specifically: at 5 minutes treatment, free radical density is insufficient, VEGF grafting is low, and although endothelial cells can adhere, they do not spread fully; 20 minutes is the shortest duration at which free radical density reaches saturation, with maximum VEGF grafting, and the tensile mechanical properties of PCL show no statistically significant difference compared with the untreated group; 30 minutes begins to show surface microcracks, with decreased mechanical properties — “over-bombarded.”

The paper also validated the penetration depth of PIII treatment: XPS depth profiling shows nitrogen and free radicals are concentrated within a few tens of nanometers of the surface, with no effect on the mechanical properties of the PCL bulk. This is precisely PIII’s advantage — it modifies only the surface, not the bulk.

06 What This Technology Means for Organ-on-a-Chip

For researchers in organ-on-a-chip and vascular tissue engineering, this paper offers three reusable assets:

① A complete “MEW weave-tube + PIII bury-hooks” two-step process package

MEW printing parameters (fiber diameter 10–20 µm, tube diameter 2/4 mm) and PIII treatment parameters (nitrogen, 20 min) can be directly transferred to the construction of other tubular organ-on-a-chip systems, such as renal tubules and intestinal tubes.

② A “no growth factor supplementation” surface functionalization paradigm

Immobilizing VEGF covalently on the scaffold surface rather than adding it to the medium reduces growth factor consumption and avoids activity loss during long-term culture. This approach can be extended to the immobilization of other growth factors (such as BDNF, FGF).

③ A feasibility evidence chain for “PIII applied to 3D porous scaffolds”

XPS surface analysis, free radical quantification, mechanical testing, 4-week endothelial monolayer formation and functional evaluation — from surface chemistry to cell function, the evidence chain is complete, proving that PIII can achieve uniform surface activation without damaging 3D microstructures.

The paper also candidly lists its boundaries: the current endothelial monolayer was formed under static culture conditions, not yet validated under perfusion conditions; long-term stability of PIII treatment, VEGF release behavior in vivo, and other issues require further study. Cautiously viewed, this is an engineering study completing the full chain of “process development–surface characterization–in vitro cell validation,” still some distance from scaled application of organ-on-a-chip.

📄 Paper Information

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