Towards In Silico Bioprinting

Abstract

Bioprinting is a computer-controlled procedure for building three-dimensional tissue constructs via layer-by-layer delivery of cells and supportive hydrogels. To describe the post-printing self-assembly of multicellular structures, we performed computer simulations that incorporate a basic principle of developmental biology, the differential adhesion hypothesis (DAH). DAH states that cell motility combined with differences in the adhesive properties of different cell types yields tissue conformations with the largest number of strong bonds between cells. Metropolis Monte Carlo (MMC) simulations based on DAH predicted the emergence of long-lived structures (cell sheets, toroidal and tubular constructs) in accord with experiments. The MMC method, however, does not describe time evolution. We propose a kinetic Monte Carlo (KMC) approach, where transition rates are associated with possible rearrangements of cells. The system is represented on a lattice, with sites occupied either by cells or by volume elements of cell culture medium. We associate rates to swapping cells with nearest neighbors of different types (cells or medium). The new approach was tested against experiments on cell sorting within an aggregate composed of two cell types. In quantitative studies, we determined the time evolution of the interfacial area between two fusing spherical cell aggregates experimentally, analytically and by KMC simulations. In the analytic approach, we used continuum hydrodynamics to describe the coalescence of two identical, highly viscous liquid droplets, and obtained good agreement with experiments on smooth muscle cell aggregates. Apart from the early stages of fusion, the KMC method predicted a fusion pattern similar to the experimental one. Comparison with measurements allowed relating KMC transition rates to experimental time scales. Our results indicate that the KMC method can give an accurate account of the time evolution of complex cellular structures, thus it may be a useful tool for tissue engineering applications. Work supported by NSF-056854.