Summary: Cardiovascular disease is the leading cause of death in the western and developing countries. Percutaneous transluminal coronary interventions have become the most prevalent treatment option for coronary artery disease; however, due to serious complications, such as stent thrombosis and in-stent restenosis (ISR), the efficacy and safety of the procedure remain important issues to address. Strategies to overcome these aspects are under extensive investigation. In this review, we summarise relevant milestones during the time to overcome these limitations of coronary stents, such as the development of polymer-free drug-eluting stents (DES) to avoid pro-inflammatory response due to the polymer coating or the developement of stents with cell-directing drugs to, simultaneously, improve re-endothelialisation and inhibit ISR amongst other techniques most recently developed, which have not fully entered the clinical stage. Also the novel concept of fully biodegradable DES featured by the lack of a permanent foreign body promises to be a beneficial and applicable tool to restore a natural vessel with maintained vasomotion and to enable optional subsequent surgical revascularisation.

Extracellular collagen remodeling is one of the central mechanisms responsible for the structural and compositional coherence of myocardium in patients undergoing myocardial infarction (MI). Activated primary cardiac fibroblasts following myocardial infarction are extensively investigated to establish anti-fibrotic therapies to improve left ventricular remodeling. To systematically assess vitamin C functions as a potential modulator involved in collagen fibrillogenesis in an in vitro model mimicking heart tissue healing after MI. Mouse primary cardiac fibroblasts were isolated from wild-type C57BL/6 mice and cultured under normal and profibrotic (hypoxic + transforming growth factor beta 1) conditions on freshly prepared coatings mimicking extracellular matrix (ECM) remodeling during healing after an MI. At 10 μg/mL, vitamin C reprogramed the respiratory mitochondrial metabolism, which is effectively associated with a more increased accumulation of intracellular reactive oxygen species (iROS) than the number of those generated by mitochondrial reactive oxygen species (mROS). The mRNA/protein expression of subtypes I, III collagen, and fibroblasts differentiations markers were upregulated over time, particularly in the presence of vitamin C. The collagen substrate potentiated the modulator role of vitamin C in reinforcing the structure of types I and III collagen synthesis by reducing collagen V expression in a timely manner, which is important in the initiation of fibrillogenesis. Altogether, our study evidenced the synergistic function of vitamin C at an optimum dose on maintaining the equilibrium functionality of radical scavenger and gene transcription, which are important in the initial phases after healing after an MI, while modulating the synthesis of de novo collagen fibrils, which is important in the final stage of tissue healing.

Endothelial progenitor cells (EPCs) are involved in vascular repair and modulate properties of smooth muscle cells (SMCs) relevant for their contribution to neointima formation following injury. Considering the relevant role of the CXCL12–CXCR4 axis in vascular homeostasis and the potential of EPCs and SMCs to release CXCL12 and express CXCR4, we analyzed the engagement of the CXCL12–CXCR4 axis in various modes of EPC–SMC interaction relevant for injury- and lipid-induced atherosclerosis. We now demonstrate that the expression and release of CXCL12 is synergistically increased in a CXCR4-dependent mechanism following EPC–SMC interaction during co-cultivation or in response to recombinant CXCL12, thus establishing an amplifying feedback loop Additionally, mechanical injury of SMCs induces increased release of CXCL12, resulting in enhanced CXCR4-dependent recruitment of EPCs to SMCs. The CXCL12–CXCR4 axis is crucially engaged in the EPC-triggered augmentation of SMC migration and the attenuation of SMC apoptosis but not in the EPC-mediated increase in SMC proliferation. Compared to EPCs alone, the alliance of EPC–SMC is superior in promoting the CXCR4-dependent proliferation and migration of endothelial cells. When direct cell–cell contact is established, EPCs protect the contractile phenotype of SMCs via CXCL12–CXCR4 and reverse cholesterol-induced transdifferentiation toward a synthetic, macrophage-like phenotype. In conclusion we show that the interaction of EPCs and SMCs unleashes a CXCL12–CXCR4-based autoregulatory feedback loop promoting regenerative processes and mediating SMC phenotype control to potentially guard vascular homeostasis.

Additive manufacturing (AM) is an emerging method for the fabrication of stents, which is cost-saving and capable of producing personalised stent designs. However, poor surface finish and dimension discrepancy in the manufactured stents can significantly affect not only their own mechanical behavior but also mechanical response of arteries. This study investigates the effects of surface irregularities and dimension discrepancy of a 316L stainless steel stent, manufactured using laser powder bed fusion (LPBF), on its biomechanical performance, in comparison with the original design and a commercial stent. In silico simulations of stent deployment in a patient-specific coronary artery, based on intravital optical coherency tomography imaging, are conducted to assess the stent deformation as well as arterial stress and damage. Severe plastic strain concentrations (with a maximum value of 1.93) occur in the LPBF stent after deployment due to surface irregularities, suggesting a high risk of stent fracture. The LPBF stent is harder to expand due to its thicker struts and closed-cell design (diameter of 4.14 mm at the peak inflating pressure during deployment, compared to 4.58 mm and 4.65 mm for the designed and MULTI-LINK RX ULTRA stents, respectively). Also, the LPBF stent induces a higher level of stress concentration (with a maximum value of 23.04 MPa) to the arterial layers, suggesting a higher risk of tissue damage and in-stent restenosis. This study demonstrates a clear need for further development of the AM process for manufacturing medical implants, especially the surface finish and dimension accuracy.