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ECM fibril bundles on the surface of engineered vascular graft

Vascular Graft Tissue Engineering in the RCCS


Key Points:
  • RCCS used to enhance mechanical conditioning of cells to form more functional and biomimetic extracellular matrix (ECM).
  • Cell-derived ECM offers advantages over tissue-derived ECM.
  • Cell-derived ECM contains complex ECM molecules: Collagen, elastin and proteoglycans, closer to that found in native vessels.
  • Customizable since different cell sources, types and culture methods can be used to create specific models.
Dr. Xing and Zhao et al. of Michigan Tech University have published a paper entitled: "Aligned Nanofibrous Cell-Derived Extracellular Matrix for Anisotropic Vascular Graft Construction"

The research group was successful in generating a vascular graft with biomimetic circumferential tensile strength and expression of smooth muscle cell specific genes over static culture.

In previous studies, fibroblast cells were used to create vascular grafts by wrapping a decellularized fibroblast seeded matrix sheet around a temporary mandrel into tubes. This acellular tube was then seeded with autologous endothelial cells, inside the lumen. The graft remained functional 8 weeks after implantation. The graft showed anisotropy which mimicked arteries in vivo, with circumferential alignment of cells. However, the manufacturing time of 5 weeks was a major pit fall.

The authors of this study sought to decrease manufacturing time as well as reduce proinflammatory cytokines. As an alternative to fibroblasts, they cultured human mesenchymal stem cells (hMSCs) in the lumen, since they can be differentiated into vascular cells, in addition to offering antithrombogenic and immunoregulatory properties. Further, the study utilized Synthecon’s RCCS to culture and mature the grafts.  This bioreactor culture simplified manipulation of the tissue constructs as well as reduced the culture period to 1-2 weeks. The RCCS cultured graft showed greatly increased structural and mechanical ansiotropy over static culture, as well as more uniform cell distribution and smooth muscle cell phenotype expression.

Typically, when researchers use the RCCS, they are seeking dynamic conditions which promote nutrient accessibility and waste removal. Researchers also value the low-shear conditions within the bioreactor vessel.  For this study, the authors at Michigan Tech University used the fluid dynamics within the vessel differently. Fibroblasts were seeded onto a polymer nano-grated silicon substrate and the cells were allowed to proliferate. The scaffolds were decellularized to obtain an ECM (extra cellular matrix) with a parallel aligned orientation. The hMSCs were seeded onto this scaffold and a steel mandrel was used to roll the tissue into tubes. This entire construct, including the mandrel, was placed in Synthecon’s STLV (slow turning lateral vessel) and allowed to mature for two weeks. Because of the weight of the construct and mandrel, the circumferential stress induced tissue contraction and large ECM fibril bundles. The authors speculate that the cells cultured in these conditions could induce rapid regeneration of tunica media when implanted in vivo.

Conclusions:
 
  • Myogenic Genes were significant enhanced in the RCCS bioreactor over static culture
  • The ECM can be produced and stored in advance, reducing graft culture time to 1-2 weeks
  • hMSCs used in place of fibroblasts reduce inflammatory response and provide antithrombogenic properties
  • The RCCS provided optimal dynamic conditions for the health of the construct, as well as circumferential stress.
  • Allowed for proper arrangement and directionally dependent mechanical strength which was comparable to native muscles as well as comparative values for the anisotropy index in native vessels.
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