Melt electrowriting of synclastically curved patches compensating the mechanical anisotropy of the infarcted myocardium

Cardiovascular diseases (CVDs) are the leading cause of global mortality and morbidity, representing a socioeconomic burden worldwide. Myocardial infarction (MI) is a severe health condition considered as one of the largest contributors to CVDs; following MI, millions of cardiomyocytes die and, owing to cardiac fibroblast recruiting, a scar formation occurs, resulting in impaired cardiac functionality. Cardiac patches have emerged as a potential solution to treat the infarcted myocardium and, recently, focus has increased on the role of cardiac macrophages and extracellular matrix remodelling in response to MI. It is now clear that inflammation driven by immune cells is a crucial step in the progression of post-MI tissue remodelling and scarring which, in turn, limits cardiac function causing a reduction in heart contractility and blood pumping capacity. Currently, the combination of immunomodulation and structural support has not been investigated for MI treatment. Itaconate (ITA) is an immunoregulator and anti-inflammatory compound naturally present in the body and able to modulate macrophage behaviour; despite, ITA promising therapeutic potential is hindered by a limited bioactive timeline and a rapid clearance from the body. Therefore, the development of alternative presentation and delivery strategies is needed. In this work melt electrowritten PCL:polymer itaconate (PITA) cardiac patches, able to restore cardiac physiological functioning, by combining ITA immunomodulatory effect with PCL beneficial mechanical support, are presented. PITA was provided by Prof. Radisic research group from University of Toronto and the project was carried out in Prof. Monaghan lab in Trinity College Dublin. PCL:PITA novel blend was characterized in terms of physiochemical and mechanical properties. Biocompatibility and ability to support cell attachment, growth and proliferation was assessed prior with murine fibroblasts and next with human blood monocytes derived macrophages (MDMs). PCL:PITA immunomodulatory effect was tested on LPS+IFN-γ activated human blood MDMs. Preliminary cell studies results demonstrated PCL:PITA blend patches potential to foster cell attachment, growth, and proliferation and to buffer post-MI inflammatory response severity by alleviating pro-inflammatory defence pathways and by promoting anti-inflammatory factors up-regulation. Despite the need for further characterization, this preliminary study presents PCL:PITA MEW cardiac patches as potential novel strategy for MI treatment with the prospective of ameliorating post-MI inflammatory response by breaking the sustained activation of pro-inflammatory macrophages that can occur post-MI and that results in cardiac function impairment and, eventually, heart failure. Future in vivo study on MI murine models could demonstrate that, after being placed over the infarcted heart region in the aftermath of MI, PCL:PITA patch acts as support material owing to PCL mechanical properties and modulation of post-MI inflammatory response is achieved through controlled delivery of ITA.