Drug-induced cardiotoxicity manifests either acutely as a functional disturbance or progressively as a structural effect. Approaches for evaluating drug-induced structural cardiotoxicity and perturbations to the complex multicellular human myocardium are limited. Most in vitro models are two-dimensional cultures of cardiomyocytes, which don’t reflect the complex nature of cardiac tissue. Development of complex multicellular human cardiac models is therefore a major requirement to improve drug development.

We have successfully created a three-dimensional cellular model of the human ventricular “chamber” using state-of the-art reactive jet impingement (ReJI) bioprinting. The in vitro model comprises a cell-hydrogel-fibre structure containing co-cultures of human cardiomyocytes and cardiac fibroblasts, integrated into a perfusion culture system. These models comprise a functional multicellular ‘cardiac’ structure which can be evaluated with respect to changes to structure and morphology, but also which incorporate fluid flow representative of the ‘pumping’ nature of the heart. This offers many novel opportunities for drug-induced cardiotoxicity evaluation, which are not currently available in other models, and therefore new paradigms to improve drug development.

Project aims: To assess clinical-relatability of our bioprinted ventricular “chamber” model and qualify it for evaluation of “clinically-relevant” drug-induced structural cardiotoxicity.

Approach: Introduction of human endothelial cells to the inner surface of the “chamber” will be developed to better recapitulate the endocardial fluid-barrier of the heart and improve the current biomimetic model. The improved model, incorporating cardiomyocytes, fibroblasts and endothelial cells will then be exposed to physiological stresses, such as hypertension (increased fluid pressure) and cardiac hypertrophy (angiotensin-hormone-induced) to gain a better picture of the capabilities and to qualify the scope of this model for incorporation into the drug development pathway. Once achieved, the model will then be characterised using a panel of known clinically-applicable drugs and chemicals to identify the limits and utility of the model for identification of structural cardiotoxicities. This will also interrogate the cellular interplay and temporal/ spatial presentation of the mechanistic basis of drug-induced structural cardiotoxicity.

Drug-induced cardiotoxicity manifests either acutely as a functional disturbance or progressively as a structural effect. Approaches for evaluating drug-induced structural cardiotoxicity and perturbations to the complex multicellular human myocardium are limited. Most in vitro models are two-dimensional cultures of cardiomyocytes, which don’t reflect the complex nature of cardiac tissue. Development of complex multicellular human cardiac models is therefore a major requirement to improve drug development.

We have successfully created a three-dimensional cellular model of the human ventricular “chamber” using state-of the-art reactive jet impingement (ReJI) bioprinting. The in vitro model comprises a cell-hydrogel-fibre structure containing co-cultures of human cardiomyocytes and cardiac fibroblasts, integrated into a perfusion culture system. These models comprise a functional multicellular ‘cardiac’ structure which can be evaluated with respect to changes to structure and morphology, but also which incorporate fluid flow representative of the ‘pumping’ nature of the heart. This offers many novel opportunities for drug-induced cardiotoxicity evaluation, which are not currently available in other models, and therefore new paradigms to improve drug development.

Project aims: To assess clinical-relatability of our bioprinted ventricular “chamber” model and qualify it for evaluation of “clinically-relevant” drug-induced structural cardiotoxicity.

Approach: Introduction of human endothelial cells to the inner surface of the “chamber” will be developed to better recapitulate the endocardial fluid-barrier of the heart and improve the current biomimetic model. The improved model, incorporating cardiomyocytes, fibroblasts and endothelial cells will then be exposed to physiological stresses, such as hypertension (increased fluid pressure) and cardiac hypertrophy (angiotensin-hormone-induced) to gain a better picture of the capabilities and to qualify the scope of this model for incorporation into the drug development pathway. Once achieved, the model will then be characterised using a panel of known clinically-applicable drugs and chemicals to identify the limits and utility of the model for identification of structural cardiotoxicities. This will also interrogate the cellular interplay and temporal/ spatial presentation of the mechanistic basis of drug-induced structural cardiotoxicity.