Shape Evolution of Multicellular Systems; Application to Tissue Engineering

Organs are in high demand. Tissue engineering and regenerative medicine might be the answer to this challenge of the 21st century. Towards this goal our objective is to optimize the conditions for cells to self assemble into functional structures, such as tissues and eventually organoids. To facilitate self-assembly we employ the technology of bioprinting. To maintain the extended cellular assemblies, they need to be vascularized. Thus we first concentrate on the fabrication of blood vessels. We prepare convenient bioink particles, multicellular units composed of the relevant cell types and we deposit them into a geometry, consistent with the shape of the vessels. Self-assembly and the maturation of the construct takes place post-printing in special-purpose bioreactors by the fusion of the bioink units and the rearrangement of the cells within them. The time to achieve near physiological biomechanical properties has so far been found by trial and error. We have developed an experimental-theoretical-computational framework to optimize the postprinting maturation process, in particular the fusion of the bioink units. This paper focuses on the experimental component of this formalism, in particular on the fusion of spherical and cylindrical bioink units. The connection between experiments and computer simulations are guided by theory. Here we report the results of extended fusion experiments and on their comparison with predictions of the theory. The excellent agreement we find, on one hand, provides a verification of the theoretical component of the formalism, and, on the other hand, the input for the computational component of the formalism. Specifically, our experiments, together with the theory, allow the calibration of the basic simulation parameters, which in turn allows to fully implement the computational component of the formalism to optimize the fabrication of blood vessels through the bioprinting process.