Microfluidics-assisted synthesis of Dapagliflozin-loaded liposomes for heart fibrosis: Development of a 3D bioprinted multicellular in vitro model

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, with half of CVDs deaths being caused by coronary artery disease.

Myocardial infarction is the most common cause of cardiac insufficiency, leading to fibrosis and ultimately heart failure. Since current therapies for cardiac fibrosis have limitations, there is a need for more effective strategies.

Gliflozins (e.g., Dapagliflozin and Empagliflozin), hypoglycemic agents and SGLT2 inhibitors usually used for the treatment of type 2 diabetes, have been shown in recent clinical trials (i.e., DAPA-HF, DELIVER, EMPEROR-Reduced, EMPEROR-Preserved) to reduce the combined risk of cardiovascular death or hospitalization for heart failure in patients with reduced and preserved ejection fraction, regardless of diabetes status.

They have also been shown to ameliorate myocardial fibrosis post-ischemia.

Nevertheless, most of the underlying mechanisms of these benefits remain elusive and the potential adverse effects of the systemic administration of gliflozins must be recognised.

In this regard, the use of liposomes as in situ injectable drug delivery systems offers many potential advantages for the therapy of myocardial infarction.

Therefore, the SAVETHEHEART project aims to develop a new therapeutic approach for the efficient treatment of cardiac fibrosis by using liposomes, produced by microfluidics to encapsulate Dapagliflozin (DAPA).

Their effect will be studied in a 3D model of cardiac fibrosis, that will be obtained by bioprinting a biomimetic type I collagen hydrogel, bioengineered with human induced pluripotent stem cells-derived cardiomyocytes, myofibroblasts and endothelial cells, and cultured under perfusion and hypoxic conditions to better mimic a fibrotic response.

Understanding cell behaviour in the proposed setting, this work opens perspective to the optimization of injectable DAPA-liposome formulations, intended as an innovative therapeutic strategy for the treatment of cardiac fibrosis.