Self-healing hydrogels

Cell

Organic chemistry

Biology

Gene

Induced pluripotent stem cell

Regenerative medicine

Embryonic stem cell

Biomedical engineering

Regeneration (biology)

Spheroid

Chemistry

In vitro

Stem cell

3D bioprinting

Tissue engineering

Cell biology

Genetics

Biochemistry

Medicine

Cell fusion

Nature Communications

Cellular models are needed to study human development and disease in vitro, and to screen drugs for toxicity and efficacy. Current approaches are limited in the engineering of functional tissue models with requisite cell densities and heterogeneity to appropriately model cell and tissue behaviors. Here, we develop a bioprinting approach to transfer spheroids into self-healing support hydrogels at high resolution, which enables their patterning and fusion into high-cell density microtissues of prescribed spatial organization. As an example application, we bioprint induced pluripotent stem cell-derived cardiac microtissue models with spatially controlled cardiomyocyte and fibroblast cell ratios to replicate the structural and functional features of scarred cardiac tissue that arise following myocardial infarction, including reduced contractility and irregular electrical activity. The bioprinted in vitro model is combined with functional readouts to probe how various pro-regenerative microRNA treatment regimes influence tissue regeneration and recovery of function as a result of cardiomyocyte proliferation. This method is useful for a range of biomedical applications, including the development of precision models to mimic diseases and the screening of drugs, particularly where high cell densities and heterogeneity are important.

3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels