Example of micro-network (capillaries) with endothelial cells in green. The cell nuclei (5 microns on average) are visible in blue or pink (if proliferating). Courtesy of Andrea Banfi.

In B2B, both the breast tumoroid and the ossicle have their self-assembled networks of capillaries.

In the first case, the tumoroid and its vascular network are generated in parallel. “We include cancer cells together with endothelial cells in a matrix of fibrin that contains growth factors for both tissues.” explains Andrea Banfi. Thanks to the biological signals, the system evolves by creating two ordered networks of cells of the same type: endothelial with endothelial and cancer with cancer. However, the two systems are in close contact, meaning that the tumoroid is fully vascularized.

Thanks to the large dimensions of the tumoroid, B2B reproduces well the stochastic growth of the cancer tissue. In some cases, it might exceed the flow capacity of the system, thus leading to the formation of necrotic and hypoxic areas. It is the presence of these areas that increases the metastatic predisposition of cells, as demonstrated by B2B partner Nicola Aceto, as if the lack of resources would trigger the need to migrate to new, richer areas. Only thanks to the peculiarities of the B2B system, based on spontaneous processes, it is possible to recreate such heterogeneity so vital for the selection of cells capable to metastasize (read more here).

Different is the approach for the ossicle, which is generated in vivo – by placing chondrogenic cells subcutaneously in a mouse. The resulting ossicle is then vascularized directly by the mouse system. “When we remove the ossicle, the major blood vessels are cut and we need to re-establish a connection, this time with the macro system“.  This is quite hard as the vessels are placed randomly around the tissue, therefore it would be impossible to engineer something ad hoc.

The solution proposed by the team of Andrea Banfi is to generate a pervasive micro-network (of human origin) that extends over the whole surface around the tissue, touching and connecting, on one side, with the ossicle capillaries and, on the other side, with the macro network. When the connection happens, then the flow, and the physical laws governing it, remodel the dimensions of the used vessels and dismiss the unused ones.

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