Biofabrication Strategies for Engineering Heterogeneous Artificial Tissues

Abstract The persistent shortage of donor-organs for transplantation and accurate tissue models for disease study has resulted in a high demand for artificial tissues and organs. The field of biofabrication steers efforts into building 3D-tissue scaffolds by applying a combination of cells, biomaterials and engineering methods. Although researchers have successfully fabricated various tissue-like constructs in the past, these models often only comprise of a single cell type and are vastly oversimplified. In comparison, native tissues in the human body consist of a wide variety of cells that perform diverse functions and are housed in complex cell-specific microenvironments. Therefore, employing biofabrication techniques for systematically mimicking the complexity and heterogeneity of native tissues is a substantial challenge. This review introduces novel advanced biofabrication techniques that are classified as either top-down or bottom-up processes and reports comprehensive strategies for generating artificial heterogeneous tissues in vitro. Analogous to nanofabrication in practice, in biofabrication, top-down strategies seek to first develop 3D porous scaffolds via techniques such as multi-nozzle extrusion and hybrid bioprinting, followed by the seeding of cells for tissue growth. Conversely, bottom-up strategies involve the assembly of different building block units that include; droplets, microtubes and cell sheets, via molding, weaving, tunneling, stacking and rolling into complex 3D tissue structures. The review outlines the strengths and shortcomings of each of these approaches and provides the reader with an in-depth prospectus and overview of future opportunities in this rapidly progressing field.