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Purpose <p>Overcoming the limitations of synthetic vascular grafts in the development of biocompatible and regenerative vessels remains a long-term objective in tissue engineering. In this study, we engineered large-diameter fibrin-based vascular grafts with a target inner diameter of 21&#xa0;mm replicating all three layers of the native human vessel wall in vitro.</p> Methods <p>The <i>Tunica media</i> was reconstructed using a compressed high-density (25&#xa0;mg/mL) fibrin matrix seeded with smooth muscle cells expressing α-SMA and calponin, differentiated from adipose-derived mesenchymal stem cells (ASCs). The <i>Adventitia</i>-equivalent was formed in a 5&#xa0;mg/mL fibrin gel containing ASCs, human umbilical vein endothelial cells (HUVECs), and normal human dermal fibroblasts (NHDFs) to enable the formation of a capillary-like network resembling the native adventitial <i>Vasa vasorum</i>. The luminal surface was endothelialized with HUVECs to replicate the <i>Tunica intima</i>. While controls were cultured statically for 7&#xa0;days, other grafts were evaluated under pulsatile perfusion at physiological pressures using the TransMedics<sup>®</sup> “Organ Care System Heart<sup>™</sup>”.</p> Results <p>The stepwise fabrication technique resulted in three-layered bioartificial vessel equivalents with a mean inner diameter of 21&#xa0;mm. All constructed vessels (<i>n</i> = 3) maintained sufficient biomechanical stability to withstand physiological pressure (120.9 ± 1.2 to 61.4 ± 12.5&#xa0;mmHg) at 60&#xa0;bpm throughout the perfusion period. The aortic grafts exhibited a cyclic stretch (8.95 ± 2.03%) within the physiological range of native vessels. Mechanical stimulation induced a layer-specific physiological cell morphology and alignment across all three layers of the vascular wall. Endothelial coverage was high on static grafts (81.39 ± 2.37%) and on one of three dynamic grafts. Shear stress during perfusion (0.38 ± 0.03 dyn cm<sup>−2</sup>) remained below physiological levels, and further evaluation under prolonged perfusion (&gt; 21&#xa0;days) is required to assess long-term biomechanical stability and vascular functionality.</p> Conclusion <p>This approach may be considered a proof of concept and constitutes a first step toward the development of biometric and functional large-diameter vessel replacements.</p>

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Generation of Fibrin-Based Aortic Vessels with Layer-Specific Cell Architecture Under Pulsatile Perfusion in a Clinical Organ Care System

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月27日

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  • Celina Delia Käding,
  • Clara-Sophie Glomb,
  • Patrick Stadler,
  • Imke Becker,
  • Melanie Klingenberg,
  • Hans-Klaus Höffler,
  • Michael Pflaum,
  • Arjang Ruhparwar,
  • Mathias Wilhelmi,
  • Florian Helms

摘要

Purpose

Overcoming the limitations of synthetic vascular grafts in the development of biocompatible and regenerative vessels remains a long-term objective in tissue engineering. In this study, we engineered large-diameter fibrin-based vascular grafts with a target inner diameter of 21 mm replicating all three layers of the native human vessel wall in vitro.

Methods

The Tunica media was reconstructed using a compressed high-density (25 mg/mL) fibrin matrix seeded with smooth muscle cells expressing α-SMA and calponin, differentiated from adipose-derived mesenchymal stem cells (ASCs). The Adventitia-equivalent was formed in a 5 mg/mL fibrin gel containing ASCs, human umbilical vein endothelial cells (HUVECs), and normal human dermal fibroblasts (NHDFs) to enable the formation of a capillary-like network resembling the native adventitial Vasa vasorum. The luminal surface was endothelialized with HUVECs to replicate the Tunica intima. While controls were cultured statically for 7 days, other grafts were evaluated under pulsatile perfusion at physiological pressures using the TransMedics® “Organ Care System Heart™”.

Results

The stepwise fabrication technique resulted in three-layered bioartificial vessel equivalents with a mean inner diameter of 21 mm. All constructed vessels (n = 3) maintained sufficient biomechanical stability to withstand physiological pressure (120.9 ± 1.2 to 61.4 ± 12.5 mmHg) at 60 bpm throughout the perfusion period. The aortic grafts exhibited a cyclic stretch (8.95 ± 2.03%) within the physiological range of native vessels. Mechanical stimulation induced a layer-specific physiological cell morphology and alignment across all three layers of the vascular wall. Endothelial coverage was high on static grafts (81.39 ± 2.37%) and on one of three dynamic grafts. Shear stress during perfusion (0.38 ± 0.03 dyn cm−2) remained below physiological levels, and further evaluation under prolonged perfusion (> 21 days) is required to assess long-term biomechanical stability and vascular functionality.

Conclusion

This approach may be considered a proof of concept and constitutes a first step toward the development of biometric and functional large-diameter vessel replacements.