Tissue engineering: A hearty chip

The rapid formation of blood vessels when creating or implanting new tissue is crucial to ensure the successful integration of an engineered tissue into a host. This is particularly important for heart and liver tissues, which are highly dependent on an immediate and constant oxygen supply. Although larger-diameter vessels, such as arteries, can be created by suturing polymeric tubes to existing vasculature, the formation of branched networks of smaller vessels is a greater engineering challenge.

Credit: Milica Radisic, University of Toronto

Now, Milica Radisic and co-workers at the University of Toronto have devised a multipurpose microchip technology — called the AngioChip — that can be used to make functional heart and liver tissues containing a 3D vascular network. Millimetre-thick heart tissue grown using the AngioChip can be implanted in vivo and connected with the vasculature of the host, resulting in the immediate flow of blood through the vessels. In addition, the heart and liver AngioChip tissues could be used for laboratory screening of potential drug candidates before in vivo testing.

The AngioChip is formed from a biodegradable polymer and contains a network of microchannels formed by a 3D stamping technique. The microchannels are lined with endothelial cells and parenchymal cells are located in the external space. The walls of the microchannels have microscale holes and nanopores, enabling the exchange of molecules between the channels and parenchymal space, which is important for mimicking physiological conditions in drug screening experiments. In addition, this permeability permits the extravasation of endothelial cells into the matrix of parenchymal cells in response to certain biomolecular triggers, allowing intracellular crosstalk.

“For the first time, we have a fully branched vascular bed with a single inlet and single outlet that is made of polymer and isolated cells,” says Radisic. “The AngioChip does not require harvesting of donor vascular beds, and it enables direct connection with the host vasculature in a rat model. The smallest vessel in the AngioChip is as thin as a human hair, but blood is still able to flow through it with ease.”

“The smallest vessel in the AngioChip is as thin as a human hair, but blood is still able to flow through it with ease”

Several AngioChips comprising different tissues can be integrated in series to provide a platform of more complex functionality with the aim of answering some specific pharmacological questions. For example, linking AngioChips containing tumour and heart tissues could enable a laboratory-based test to identify new compounds that kill tumour cells but leave heart tissue unaffected. In a similar manner, the connection of AngioChips containing tumour and liver tissues could be used to determine whether certain compounds may prevent metastasis of tumour cells to the liver.

In the future, Radisic and co-workers aim to carry out longer-term studies — of around 1 month — to determine the patency of the AngioChip vasculature over this time and whether this patency is necessary. “Perhaps there will be enough angiogenesis from the host, such that perfusion through the AngioChip in the long term won't be necessary,” says Radisic. “Most cell death in vivo occurs over the first week or so, and that may be the minimum time AngioChip vessels need to remain perfusable to achieve successful integration and tissue survival.” The degradation of the polymer scaffold in vivo also requires further investigation: in particular, how the degradation rate affects the role of native cells and extracellular matrix in the process, and whether the vessels created by the microchannels remain after the complete degradation of the scaffold.

References

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    Zhang, B. et al. Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis. Nat. Mater.http://dx.doi.org/10.1038/nmat4570 (2016)

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Stoddart, A. Tissue engineering: A hearty chip. Nat Rev Mater 1, 16026 (2016). https://doi.org/10.1038/natrevmats.2016.26

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