3D rendering of a micro-network: endothelial capillaries in red, supporting cells in green. Courtesy of Andrea Banfi.

As stated in the name of the project (from Breast to Bone), B2B relies on the connection between two tissues. Indeed, the two chambers, one with the breast tumoroid and the other with the ossicle, are connected with a system that resembles the physiological blood circulation, a set of vessels that brings the blood with oxygen and nutrients to the organs. As in the cardiovascular system, the B2B connecting network is made of two parts: the micro-network for the exchange of material from the tissue to the circulatory system and the macro network for its fast transportation from one side to another.

“As part of the micro-network it was crucial to include the capillaries” – explains Andrea Banfi, head of the Cell and Gene Therapy group at Basel University Hospital and the B2B partner responsible for the micro-network – “Two key events happen only there: the intra- and extravasation of the metastatic cells, the process by which cancer cells move, respectively, from the main tumor to the blood circulation and from the circulation to the target tissue”.

The two processes happen only in the smallest vessels (10-20 micrometers of caliber) because here the blood flow is slow enough to allow metastatic cells to roll and adhere to the blood vessels’ surface, the endothelium, and leak out. Instead, in larger vessels, the higher velocity of the flow hinders cell movement through the vessel wall. Also, structurally the capillaries encourage the exchange of cells and substances: they are made of a thin layer of mainly endothelial cells – so, to exit, a metastatic cell just needs to squeeze through the gaps between them. However, the small dimensions of the capillaries make them non-engineerable: therefore, they need to self-assemble under the guidance of provided biological signals and molecules (read more here).

The branching of an artery-vein pair. Courtesy of Andrea Banfi.

The organoid chambers are connected by large macro-fluidic tubing, made of silicone, whose function is equivalent to that of large arteries and veins in the body, whose flux quickly transports substances from one side to the other. To bring flow from this tubing system to the self-assembled micro-vessels, an actual vascular network of decreasing size and increasing branching is required. This is the macro-vascular network, which is built by a set of engineered vessels bio-printed into and around the micro-vascularized organoids, whose diameters gradually range from large to small. This system follows the same laws that regulate the relationship between flow and dimension in the cardiovascular tree. But, unlike the self-assembled capillaries, at the moment the bio-printed vessels lack part of the structural features found in the physiological counterpart, like the smooth muscle surrounding arteries and responsible for their elasticity and contraction. This doesn’t impair the scope of the B2B device, as the global flow can be regulated by an external pump.

The integration between the macro- and micro-networks is one of the most innovative points in B2B. The full vascular network is realized in collaboration by two groups: the micro-network by Dr. Andrea Banfi’s lab at the Basel University Hospital and the macro-network by Lorenzo Moroni’s group at MERLN. Their joint efforts will result in an innovative vascular system with a smooth transition from the macro- to the micro-scale (read more here).

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