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

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.

Cre8™ coronary stent: preclinical in vivo assessment of a new generation polymer-free DES with Amphilimus™ formulation.

AIMS: This new generation of DES has attempted to improve clinical safety by avoiding the presence of polymers. The present preclinical in vivo study was designed to investigate the safety profile of Cre8™ stent. This is a new coronary stent based on Amphilimus™, a sirolimus formulated with a polymer-free amphiphilic carrier released from reservoirs machined onto the abluminal stent surface. METHODS AND RESULTS: Cre8™ stents were compared with two controls: R3 (the same platform only loaded with an amphiphilic carrier) and the Cypher Select Plus® stent (Cordis, Johnson & Johnson, Warren, NJ, USA). All devices (48 stents) were implanted in porcine coronary arteries with subsequent histological and morphometric evaluations at seven, 30 and 90 days. Early endothelisation at seven days was almost complete in all stents. Vessel wall histology at 30 days demonstrated a mild inflammation score in all groups (an inflammation score lower than 1 was observed in 100% of Cre8 stent, 71.5% for R3 and 66.7% for Cypher; p=n.s.) while morphometry showed a significantly smaller neointimal area in Cre8™ (Cre8 0.93±0.43 mm2; R3 1.49±0.67 mm2; Cypher 1.81±0.94 mm2; Cre8 vs. Cypher p<0.05); this difference was maintained after 90 days (inflammation score lower than 1 in 100% of Cre8 stent, 100% for R3 and 66.7% for Cypher; p=n.s. Neointimal area was 1.27±0.56 mm2 for Cre8, 1.74±0.60 mm2 for R3 and 2.79±1.14 mm2 for Cypher; Cre8 and R3 vs. Cypher p<0.05 while neointimal thickness was 0.15±0.07 mm for Cre8, 0.21±0.12 mm for R3 and 0.31±0.15 mm for Cypher; Cre8 vs. Cypher p<0.05). CONCLUSIONS: The most significant experimental evidence appears to be the absence of chronic inflammatory response in Cre8™ stent. This is expressed by a reduced neointimal thickness and inflammatory score at all follow-ups. Such an outcome positively compares with the other DES where a trend to neointimal growth and increased cell infiltration was observed.