Cardioprotection of PLGA/gelatine cardiac patches functionalised with adenosine in a large animal model of ischaemia and reperfusion injury: A feasibility study

Abstract

The protection from ischaemia‐reperfusion‐associated myocardial infarction worsening remains a big challenge. We produced a bioartificial 3D cardiac patch with cardioinductive properties on stem cells. Its multilayer structure was functionalised with clinically relevant doses of adenosine. We report here the first study on the potential of these cardiac patches in the controlled delivery of adenosine into the in vivo ischaemic‐reperfused pig heart. A Fourier transform infrared chemical imaging approach allowed us to perform a characterisation, complementary to the histological and biochemical analyses on myocardial samples after in vivo patch implantation, increasing the number of investigations and results on the restricted number of pigs (n = 4) employed in this feasibility step. In vitro tests suggested that adenosine was completely released by a functionalised patch, a data that was confirmed in vivo after 24 hr from patch implantation. Moreover, the adenosine‐loaded patch enabled a targeted delivery of the drug to the ischaemic‐reperfused area of the heart, as highlighted by the activation of the pro‐survival signalling reperfusion injury salvage kinases pathway. At 3 months, though limited to one animal, the used methods provided a picture of a tissue in dynamic conditions, associated to the biosynthesis of new collagen and to a non‐fibrotic outcome of the healing process underway. The synergistic effect between the functionalised 3D cardiac patch and adenosine cardioprotection might represent a promising innovation in the treatment of reperfusion injury. As this is a feasibility study, the clinical implications of our findings will require further in vivo investigation on larger numbers of ischaemic‐reperfused pig hearts.

Current advances in biodegradable synthetic polymer based cardiac patches

“…Electrospinning is a common way to fabricate nano or sub‐micro fibrous scaffolds (Figure 2h; He et al, ), while phase separation can also achieve nano‐fibrous morphology (Figure 2i; Liu et al, ). Additionally, patches with pattern surface were fabricated using film casting (Figure 2j; Cristallini et al, ). The reported polymeric cardiac patches that were placed on the heart infarction animal models are summarized in Table .…”

“…Copyright 2015, published by Elsevier Ltd. (j) PLGA film cast scaffold on patterned surface. Reproduced with permission (Cristallini et al, ). Copyright 2019, published by Wiley…”

“…Additionally, cardiac function and ventricular remodeling were improved in response to the patch. To improve PLGA bioactivity, Cristallini et al produced PLGA/gelatin cardiac patches functionalized with adenosine and examined their efficacy for heart healing of ischemic‐reperfused hearts in a pig model ( n = 4; Cristallini et al, ). To create the patch, blends were evenly distributed onto a mold, produced by soft lithography, to produce a microstructure like that of myocardium.…”

Nanoengineering in Cardiac Regeneration: Looking Back and Going Forward

“…An effective and multifunctional approach to treat myocardial ischaemia-reperfusion was developed by introducing relevant doses of a cardioprotective drug (adenosine) into multi-layered scaffolds having cardio-inductive properties on stem cells [66]. The further encapsulation of adenosine-core shell polymeric NPs into polymeric scaffold was implemented for a targeted controlled release of cardioprotective drug to improve the reperfusion injury treatment [67].…”

Cardiac tissue engineering, biomaterial scaffolds, and their fabrication techniques

“…With the use of PLGA, significant improved wall thickness and an increase in blood vessels and an increase in cell density and local production of VEGF were indicated in Fleischer et al and Zhou et al studies, respectively 154,155. Also, PLGA/gelatin resulted in a rise in cell presence showed through using porcine for in vivo experiments 156. In addition, a decrease in fibrotic response due the use of polylactic acid (PLLA) has been reported by several researchers, one of which is Liu et al149 who studied the PLLA as a standalone polymer.…”