Assembling Cells and Scaffolds into a Suitable Trachea Replacement

Researchers here report on their efforts to build a suitable structure to replace a trachea, starting with patient cells and artificial scaffolds. Since the trachea is a thin-walled pipe, engineered tissue can be constructed in this way without the need for complex blood vessel networks, as at no point is the tissue so thick as to prevent direct perfusion of nutrients and oxygen to the inner cells. Unfortunately, it remains the case that decellularized donor tissue is the only reliable solution for the production of capillaries to support thicker tissues, scores of such vessels passing through every square millimeter. This is why most of the more ambitious work, closer to clinical application, involves thin tissues and tubular structures - larger blood vessels, skin, and so forth - while everyone else is working with the tiny sections of engineered tissue known as organoids.

Biomedical engineers are growing tracheas by coaxing cells to form three distinct tissue types after assembling them into a tube structure - without relying on scaffolding strategies currently being investigated by other groups. "The unique approach we are taking to this problem of trachea damage or loss is forming tissue modules using a patient's cells and assembling them into a more complex tissue." Recent tissue engineering approaches using synthetic or natural materials as scaffolding for cells have met with challenges. Difficulties have included uniformly seeding cells on the scaffolding, recreating the multiple different tissue types found in the native trachea, tailoring the scaffolding degradation rate to equal the rate of new tissue formation, and recreating important contacts between cells because of the intervening scaffold.

The trachea engineering strategy now being pursued, however, wouldn't have those problems because it doesn't rely on a separate scaffold structure. A new trachea replacement must do three critical things to function properly: (1) maintain rigidity to prevent airway collapse when the patient breathes; (2) contain immunoprotective respiratory epithelium, the tissue lining the respiratory tract, which moistens and protects the airway and functions as a barrier to potential pathogens and foreign particles; and (3) integrate with the host vasculature, or system of blood vessels, to support epithelium viability.

The self-assembling rings developed by researchers meet all three of those requirements because they can fuse together to form tubes of both cartilage and "prevascular" tissue types. Prevascular refers to tissues potentially ready to participate in the formation of blood vessels, though not yet functional in that way. The cartilage rings are formed by aggregating marrow-derived-stem cells in ring-shaped wells. Polymer microspheres containing a protein that induces the stem cells to become "chondrocytes," or cells that form cartilage, are also incorporated into the cell aggregates. These prevascular rings are comprised of both these marrow-derived stem cells and endothelial cells, the thin layer of cells that line the interior of blood vessels.

The researchers then coat the tubes with epithelial cells to form multi-tissue constructs that satisfy all of those requirements: cartilage provides rigidity, epithelium serves the role of immunoprotection and the vascular network would ultimately permit blood flow to feed and integrate the new trachea tissue. Using this method, the team has been able to engineer highly elastic "neo-tracheas" of various sizes, including tissues similar to human trachea. When these tracheas were implanted under the skin in mice, there was evidence the prevascular structures could join up with the host vascular supply.



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