Abstract

Cardiovascular diseases are responsible for the greatest proportion of deaths in the Western countries. A major cause of heart dysfunction following heart attack is the extensive remodelling of the extracellular matrix, which leads to the formation of fibrotic scar and death of heart muscle cells (cardiomyocytes, CMs) – a collective process known as myocardial remodelling. Diagnosis and treatment of this progressive pathological remodelling process are a top priority in the modern healthcare.

The current research aims to engineer a novel 3-dimensional (3D) human patterned cardiac construct based on a unique nano-technological approach of human CMs manipulation by magnetic force.

Novel magnetic nanoparticles (MNPs) were first developed to target human CMs. Prussian blue assay, electron microscopy, confocal microscopy as well as cell viability assays confirmed that these MNPs can efficiently and selectivity bind to the human heart cells and preserve their phenotype and viability.

Next, a simple, cost-effective, one-step approach for fabrication of a patterned and magnetic heart tissue was demonstrated by manipulating the magnetically labelled heart cells to the desired orientation in a 3D hydrogel under the influence of magnetic field. The biochemical, morphological, and electrical properties of the patterned 3D heart tissue were fully characterised by histological, gene expression, and advanced electrophysiological methods (multi-electrode array and optical mapping). The current data indicate that the 3D construct preserves characteristics similar to the native heart tissue, including cell-cell and cell-matrix interactions. Finally, in-vivo studies using pre-clinical cardiac MRI and two-dimensional echocardiography demonstrated patch location within the healthy rat heart and showed increase in cell retention with no alteration to normal cardiac function.

Taken together, this state-of-the-art approach enables geometrically controlled microarchitecture of human heart tissues that are uniform and reproducible in size and shape without any supporting structures (such as micro-posts or thin films). This platform can be translated to treat the remodelled area in the heart by restoring structure and function to the damaged heart tissue; and marks a major breakthrough in magnetic targeting therapy for lesions localised deeper in the body. The outcome of this novel research has the potential to become a vital component in therapeutic approaches to cardiovascular diseases.