Morphological characteristics of lesions with thin cap fibroatheroma-a substudy from the COMBINE (OCT-FFR) trial.

AIMS: To study if any qualitative or quantitative optical coherence tomography (OCT) variables in combination with thin cap fibroatheroma (TCFA) patients could improve the identification of lesions at risk for future major adverse cardiac events (MACEs). METHODS AND RESULTS: From the combined optical coherence tomography morphologic and fractional flow reserve hemodynamic assessment of non- culprit lesions to better predict adverse event outcomes in diabetes mellitus patients: COMBINE (OCT-FFR) trial database (NCT02989740), we performed a detailed assessment OCT qualitative and quantitative variables in TCFA carrying diabetes mellitus (DM) patients with vs. without MACE during follow-up. MACEs were defined as a composite of cardiac death, target vessel myocardial infarction, clinically driven target lesion revascularization, and hospitalization for unstable angina. From the 390 fractional flow reserve (FFR)-negative DM patients, 98 (25.2%) had ≥1 OCT-detected TCFA, of which 13 (13.3%) had MACE and 85 (86.7%) were event-free (non-MACE). The baseline characteristics were similar between both groups; however, a smaller minimal lumen area (MLA) and lower mean FFR value were observed in MACE group (1.80 vs. 2.50 mm2, P = 0.01, and 0.85 vs. 0.89, P = 0.02, respectively). Prevalence of healed plaque (HP) was higher in the MACE group (53.85 vs. 21.18%, P = 0.01). TCFA were predominantly located proximal to the MLA. TCFA area was smaller in the MACE group, while no difference was observed regarding the lesion area. CONCLUSION: Within TCFA carrying patients, a smaller MLA, lower FFR values, and TCFA location adjacent to a HP were associated with future MACE. Carpet-like measured lesion area surface was similar, while the TCFA area was smaller in the MACE arm, and predominantly located proximal to the MLA.

Polymer Coating Integrity, Thrombogenicity and Computational Fluid Dynamics Analysis of Provisional Stenting Technique in the Left Main Bifurcation Setting: Insights from an In-Vitro Model.

Currently, the provisional stenting technique is the gold standard in revascularization of lesions located in the left main (LM) bifurcation. The benefit of the routine kissing balloon technique (KBI) in bifurcation lesions is still debated, particularly following the single stent treatment. We compared the latest-generation drug-eluting stent (DES) with no side branch (SB) dilatation "keep it open" technique (KIO) vs. KBI technique vs. bifurcation dedicated drug-eluting stent (BD-DES) implantation. In vitro testing was performed under a static condition in bifurcation silicone vessel models. All the devices were implanted in accordance with the manufacturers' recommendations. As a result, computational fluid dynamics (CFD) analysis demonstrated a statistically higher area of high shear rate in the KIO group when compared to KBI. Likewise, the maximal shear rate was higher in number in the KIO group. Floating strut count based on the OCT imaging was significantly higher in KIO than in KBI and BD-DES. Furthermore, according to OTC analysis, the thrombus area was numerically higher in both KIO and KBI than in the BD-DES. Scanning electron microscopy (SEM) analysis shows the highest degree of strut coating damage in the KBI group. This model demonstrated significant differences in CFD analysis at SB ostia with and without KBI optimization in the LM setting. The adoption of KBI was related to a meaningful reduction of flow disturbances in conventional DES and achieved results similar to BD-DES.

How does the Nature of an Excipient and an Atheroma Influence Drug-Coated Balloon Therapy?

The advent of drug-eluting stents and drug-coated balloons have significantly improved the clinical outcome of patients with vascular occlusions. However, ischemic vascular disease remains the most common cause of death worldwide. Improving the current treatment modalities demands a better understanding of the processes which govern drug uptake and retention in blood vessels. In this study, we evaluated the influence of urea and butyryl-trihexyl citrate, as excipients, on the efficacy of drug-coated balloon therapy. An integrated approach, utilizing both in-vitro and in-silico methods, was used to quantify the tracking loss, vessel adhesion, drug release, uptake, and distribution associated with the treatment. Moreover, a parametric study was used to evaluate the potential influence of different types of lesions on drug-coated balloon therapy. Despite the significantly higher tracking loss (urea: 35.5% vs. butyryl-trihexyl citrate: 8.13%) observed in the urea-based balloons, the drug uptake was almost two times greater than with its hydrophobic counterpart. Non-calcified lesions were found to delay the transmural propagation of sirolimus while calcification was shown to limit the retentive potential of lesions. Ultimately this study helps to elucidate how different excipients and types of lesions may influence the efficacy of drug-coated balloon therapy.

Stent malapposition generates stent thrombosis: Insights from a thrombosis model.

BACKGROUND: Currently, there exists differing conclusions on the role of acute stent malapposition and its role in stent thrombosis (ST). The European Association of Percutaneous Cardiovascular Interventions (EAPCI) consensus recommends that acute malapposition <0.4 mm with longitudinal extension <1 mm need not be corrected since there is no clear correlation of malapposition with adverse clinical outcomes. However, malapposition was identified as the main mechanism of ST in the Bern and PESTO registries, and one of the three leading mechanism in the PRESTIGE study. METHODS: In this study, a validated perfused benchtop thrombosis model was deployed to evaluate the role of both stent under-expansion (UE) and acute stent malapposition (MA) on thrombus formation in vitro in a controlled reproducible environment. RESULTS: The results showed that UE alone did not result in acute thrombus formation, but UE together with MA did. The data suggested that a MA distance of 0.25 mm led to significant thrombus formation; and a positive correlation exists between the longitudinal extension of the MA and the thrombus volume formed. CONCLUSION: Experiments in this in vitro model demonstrated that platelets and a thrombosis cascade were activated and developed around large segments of malapposed stent. This was significantly more thrombus formation than in the under-expanded stent region.

Progress in drug-delivery systems in cardiovascular applications: stents, balloons and nanoencapsulation.

Drug-delivery systems in cardiovascular applications regularly include the use of drug-eluting stents and drug-coated balloons to ensure sufficient drug transfer and efficacy in the treatment of cardiovascular diseases. In addition to the delivery of antiproliferative drugs, the use of growth factors, genetic materials, hormones and signaling molecules has led to the development of different nanoencapsulation techniques for targeted drug delivery. The review will cover drug delivery and coating mechanisms in current drug-eluting stents and drug-coated balloons, novel innovations in drug-eluting stent technologies and drug encapsulation in nanocarriers for delivery in vascular diseases. Newer technologies and advances in nanoencapsulation techniques, such as the use of liposomes, nanogels and layer-by-layer coating to deliver therapeutics in the cardiovascular space, will be highlighted.

Nanoparticles-reinforced poly-l-lactic acid composite materials as bioresorbable scaffold candidates for coronary stents: Insights from mechanical and finite element analysis.

Current generation of bioresorbable coronary scaffolds (BRS) posed thrombogenicity and deployment issues owing to its thick struts and overall profile. To this end, we hypothesize that the use of nanocomposite materials is able to provide improved material properties and sufficient radial strength for the intended application even at reduced strut thickness. The nanocomposite formulations of tantalum dioxide (Ta2O5), L-lactide functionalized (LA)-Ta2O5, hydroxyapatite (HA) and LA-HA with poly-l-lactic acid (PLLA) were evaluated in this study. Results showed that tensile modulus and strength were enhanced with non-functionalized nanofillers up until 15 wt% loading, whereas ductility was compromised. On the other hand, functionalized nanofillers/PLLA exhibited improved nanofiller dispersion which resulted higher tensile modulus, strength, and ductility. Selected nanocomposite formulations were evaluated using finite element analysis (FEA) of a stent with varying strut thickness (80, 100 and 150 µm). FEA data has shown that nanocomposite BRS with thinner struts (80-100 µm) made with 15 wt% LA-Ta2O5/PLLA and 10 wt% LA-HA/PLLA have increased radial strength, stiffness and reduced recoil compared to PLLA BRS at 150 µm. The reduced strut thickness can potentially mitigate issues such as scaffold thrombosis and promote re-endothelialisation of the vessel.

Provisional Stenting for the Treatment of Bifurcation Lesions: In Vitro Insights.

Provisional stenting is considered the gold standard approach for most bifurcation lesions, but the benefit of routine side branch (SB) strut dilatation has not been fully elucidated. A benchtop model was used to determine the benefits of routine side branch (SB) dilatation techniques on strut apposition, acute thrombogenicity, and flow disruption. Three different provisional bifurcation techniques were compared: no SB dilatation "keep it open" method (KIO), sequential balloon dilatation (SBD), and kissing balloon inflation (KBI). Stents were deployed in a silicon bifurcation model and perfused with blood at a flow rate of 200 ml/min for 60 min. Optical coherence tomography (OCT) pullbacks were obtained before and after flow perfusion to conduct strut analysis and acute thrombus measurement respectively. Computational fluid dynamics (CFD) models were created using OCT pullbacks and simulated based on experimental conditions to analyze flow disruption. The strut analysis showed that KBI had the lowest percentage of floating (10.6 ± 2.3%) (p = 0.0004) and malapposed (41.2 ± 8.5%) struts (p = 0.59), followed by SBD and then KIO. This correlated to KBI having the lowest amount of thrombus formed at the SB, followed by SBD, with KIO being the most thrombogenic (KBI: 0.84 ± 0.22mm2, SBD: 1.17 ± 0.25mm2, KIO: 1.31 ± 0.36mm2, p = 0.18). CFD models also predicted a similar trend, with KBI having the lowest amount of area of high shear rate as well as flow recirculation. Based on this benchtop model, SB intervention strategies demonstrated a reduction in number of struts and resulting thrombogenicity at the bifurcation ostia. Graphical abstract.

Assessing the influence of atherosclerosis on drug coated balloon therapy using computational modelling.

Interventional therapies such as drug-eluting stents (DES) and drug-coated balloons (DCB) have significantly improved the clinical outcomes of patients with coronary occlusions in recent years. Despite this marked improvement, ischemic cardiovascular disease remains the most common cause of death worldwide. To address this, research efforts are focused on improving the safety and efficacy of the next generation of these devices. However, current experimental methods are unable to account for the influence of atherosclerotic lesions on drug uptake and retention. Therefore, in this study, we used an integrated approach utilizing both in vitro and in silico methods to assess the performance of DCB therapy. This approach was validated against existing in vivo results before being used to numerically estimate the effect of the atheroma. A bolus release of sirolimus was observed with our coating matrix. This, coupled with the rapid saturation of specific and non-specific binding sites observed in our study, indicated that increasing the therapeutic dose coated onto the balloons might not necessarily result in greater uptake and/or retention. Additionally, our findings alluded to an optimal exposure time, dependent on the coating matrix, for the DCBs to be expanded against the vessel. Moreover, our findings suggest that a biphasic drug release profile might be beneficial for establishing and maintaining the saturation of bindings sites within severely occluded vessels. Ultimately, we have demonstrated that computational methods may be capable of assessing the efficacy of DCB therapy as well as predict the influence of atherosclerotic lesions on said efficacy.

Comparison of overexpansion capabilities and thrombogenicity at the side branch ostia after implantation of four different drug eluting stents.

Interventions in bifurcation lesions often requires aggressive overexpansion of stent diameter in the setting of long tapering vessel segment. Overhanging struts in front of the side branch (SB) ostium are thought to act as a focal point for thrombi formation and consequently possible stent thrombosis. This study aimed to evaluate the overexpansion capabilities and thrombogenicity at the SB ostia after implantation of four latest generation drug-eluting stents (DES) in an in-vitro bifurcation model. Four clinically available modern DES were utilized: one bifurcation dedicated DES (Bioss LIM C) and three conventional DES (Ultimaster, Xience Sierra, Biomime). All devices were implanted in bifurcation models with proximal optimization ensuring expansion before perfusing with porcine blood. Optical coherence tomography (OCT), immunofluorescence (IF) and scanning electron microscope analysis were done to determine thrombogenicity and polymer coating integrity at the over-expanded part of the stents. Computational fluid dynamics (CFD) was performed to study the flow disruption. OCT (p = 0.113) and IF analysis (p = 0.007) demonstrated lowest thrombus area at SB ostia in bifurcation dedicated DES with favorable biomechanical properties compared to conventional DES. The bifurcated DES also resulted in reduced area of high shear rate and maximum shear rate in the CFD analysis. This study demonstrated numerical differences in terms of mechanical properties and acute thrombogenicity at SB ostia between tested devices.

Bioresorbable Polymeric Scaffold in Cardiovascular Applications.

Advances in material science and innovative medical technologies have allowed the development of less invasive interventional procedures for deploying implant devices, including scaffolds for cardiac tissue engineering. Biodegradable materials (e.g., resorbable polymers) are employed in devices that are only needed for a transient period. In the case of coronary stents, the device is only required for 6-8 months before positive remodelling takes place. Hence, biodegradable polymeric stents have been considered to promote this positive remodelling and eliminate the issue of permanent caging of the vessel. In tissue engineering, the role of the scaffold is to support favourable cell-scaffold interaction to stimulate formation of functional tissue. The ideal outcome is for the cells to produce their own extracellular matrix over time and eventually replace the implanted scaffold or tissue engineered construct. Synthetic biodegradable polymers are the favoured candidates as scaffolds, because their degradation rates can be manipulated over a broad time scale, and they may be functionalised easily. This review presents an overview of coronary heart disease, the limitations of current interventions and how biomaterials can be used to potentially circumvent these shortcomings in bioresorbable stents, vascular grafts and cardiac patches. The material specifications, type of polymers used, current progress and future challenges for each application will be discussed in this manuscript.

Double-kissing culotte technique for coronary bifurcation stenting.

AIMS: The aim of this study was to assess whether the culotte technique could be improved by an additional kissing dilation prior to main branch (MB) stenting. METHODS AND RESULTS: Double-kissing (DK) culotte was compared to the culotte and DK-crush techniques in a bench model (n=24). Results were evaluated for stent apposition, luminal opening and flow dynamics. The total procedure duration of DK-culotte was 18.3±3.4 minutes, significantly lower than for DK-crush (24.3±5.7 min; p=0.015), but similar to culotte (21.6±5.9 min, p=0.104). In DK-culotte the overall rate of moderate (200-500 µm) and significant (>500 µm) malapposition was 2.1±1.9% and 0.4±0.2%, similar as compared to culotte (3.7±3.8%, p=0.459 and 1.0±1.0%, p=0.517, respectively), and lower as compared to DK-crush (8.1±2.5%, p<0.001 and 3.7±5.3%, p=0.002, respectively). The lower malapposition rate of DK-culotte as compared to DK-crush was due to less moderate and significant malapposition in the proximal MB (0.0±0.0% vs 14.0±7.6%, p<0.001 and 0.0±0.0% vs 4.2±9.1%, p=0.026, respectively). Micro-computed tomography did not show a difference in luminal opening at the proximal MB, distal MB or SB. There was no difference either in the maximum shear rate or in areas of high shear or recirculation. CONCLUSIONS: Bench test data suggest that the DK approach facilitates the culotte technique. The clinical validity and relevance remain to be confirmed in a larger in vivo population.

Adventitial injection delivery of nano-encapsulated sirolimus (Nanolimus) to injury-induced porcine femoral vessels to reduce luminal restenosis.

Endovascular therapy in peripheral intervention has grown exponentially in the past decade, but the issue of high restenosis rates in lower extremity arteries still persist. While drug-coated balloons (DCB) have been the device of choice, recent controversary regarding the long-term safety of paclitaxel have raised concern over current DCBs. In our study, we proposed that the direct injection of a sirolimus nanoliposomal formulation (Nanolimus) using a infusion catheter can attenuate inflammation response in injured vessels. In vitro characterization showed retention of the nanoliposomes size and detectable drug amount up to 336 days in storage. For in vivo study, four female, mixed breed swines were subjected to balloon injury of the femoral arteries before treatment with either injection of saline (n = 4) or Nanolimus (n = 12) using the Bullfrog catheter. Pharmacokinetic analysis demonstrated sustained sirolimus release in the arteries and undetectable systemic drug level at 28 days. Arteries treated with Nanolimus showed significant reduction in neointima area (0.2 ± 0.3 mm2 vs 2.0 ± 1.2 mm2, p < 0.01) and luminal stenosis (14.2 ± 7.2% vs. 67.7 ± 24.8%, p < 0.01) compared to controls. In summary, adventitial delivery of sirolimus using an infusion catheter is a feasible and safe method to reduce vascular restenosis.

Radiopaque Fully Degradable Nanocomposites for Coronary Stents.

Bioresorbable scaffolds (BRS) were introduced to overcome limitations of current metallic drug-eluting stents and poly-L-lactide (PLLA) has been used in the fabrication of BRS due to its biodegradability and biocompatibility. However, such polymers have weaker mechanical properties as compared to metals, limiting their use in BRS. We hypothesized that nanofillers can be used to enhance the mechanical properties considerably in PLLA. To this end, polymer-matrix composites consisting of PLLA reinforced with 5-20 wt% barium sulfate (BaSO4) nanofillers as a potential BRS material was evaluated. Stearic-acid (SA) modified BaSO4 nanofillers were used to examine the effect of functionalization. Rigid nanofillers improved the tensile modulus and strength of PLLA (60% and 110% respectively), while the use of SA-BaSO4 caused a significant increase (~110%) in the elongation at break. Enhancement in mechanical properties is attributed to functionalization which decreased the agglomeration of the nanofillers and improved dispersion. The nanocomposites were also radiopaque. Finite element analysis (FEA) showed that scaffold fabricated from the novel nanocomposite material has improved scaffolding ability, specifically that the strut thickness could be decreased compared to the conventional PLLA scaffold. In conclusion, BaSO4/PLLA-based nanocomposites could potentially be used as materials for BRS with improved mechanical and radiopaque properties.

Tailoring the mechanical and biodegradable properties of binary blends of biomedical thermoplastic elastomer.

Blending polymers with complementary properties capitalizes on the inherent advantages of both components, making it possible to tailor the behaviour of the resultant material. A polymer blend consisting of an elastomer and thermoplastic can help to improve the mechanical integrity of the system without compromising on its processibility. A series of blends of biodegradable Poly(L-lactide-co-ɛ-caprolactone) (PLC) and Poly-(l,l-lactide-co-glycolic acid) (PLLGA), and PLC with Poly-(d,l-lactide-co-glycolic acid) (PDLLGA) were evaluated as a potential material for a biodegradable vesicourethral connector device. Based on the Tg of the blends, PLC/PLLGA formed an immiscible mixture while PLC/PDLLGA resulted in a compatible blend. The results showed that with the blending of PLC, the failure mode of PLLGA and PDLLGA changed from brittle to ductile fracture, with an significant decreas in tensile modulus and strength. SEM images demonstrated the different blend morphologies of different compositions during degradation. Gel Permeation Chromatography (GPC) and mechanical characterization revealed the degradation behaviour of the blends in this order (fastest to slowest): PDLLGA and PLC/PDLLGA blends > PLLGA and PLC/PLLGA blends > PLC. The PLC/PLLGA (70:30) blend was recommended as a suitable for the vesicourethral connector device application, highlighting the tailoring of blends to achieve a desired mechanical performance.

Local Hemodynamic Forces After Stenting: Implications on Restenosis and Thrombosis.

Local hemodynamic forces are well-known to modulate atherosclerotic evolution, which remains one of the largest cause of death worldwide. Percutaneous coronary interventions with stent implantation restores blood flow to the downstream myocardium and is only limited by stent failure caused by restenosis, stent thrombosis, or neoatherosclerosis. Cumulative evidence has shown that local hemodynamic forces affect restenosis and the platelet activation process, modulating the pathophysiological mechanisms that lead to stent failure. This article first covers the pathophysiological mechanisms through which wall shear stress regulates arterial disease formation/neointima proliferation and the role of shear rate on stent thrombosis. Subsequently, the article reviews the current evidence on (1) the implications of stent design on the local hemodynamic forces, and (2) how stent/scaffold expansion can influence local flow, thereby affecting the risk of adverse events.

Mechanical behavior of polymer-based vs. metallic-based bioresorbable stents.

Bioresorbable scaffolds (BRS) were developed to overcome the drawbacks of current metallic drug-eluting stents (DES), such as late in-stent restenosis and caging of the vessel permanently. The concept of the BRS is to provide transient support to the vessel during healing before being degraded and resorbed by the body, freeing the vessel and restoring vasomotion. The mechanical properties of the BRS are influenced by the choice of the material and processing methods. Due to insufficient radial strength of the bioresorbable material, BRS often required large strut profile as compared to conventional metallic DES. Having thick struts will in turn affect the deliverability of the device and may cause flow disturbance, thereby increasing the incidence of acute thrombotic events. Currently, the bioresorbable poly-l-lactic acid (PLLA) polymer and magnesium (Mg) alloys are being investigated as materials in BRS technologies. The bioresorption process, mechanical properties, in vitro observations and clinical outcomes of PLLA-based and Mg-based BRS will be examined in this review.

Bioresorbable stents: Current and upcoming bioresorbable technologies.

Bioresorbable scaffolds (BRS) represent a novel horizon in interventional cardiology for the treatment of coronary artery disease. The technology was introduced to overcome limitations of current metallic drug-eluting stents such as late in-stent restenosis and permanently caging the vessel. The concept of the BRS is to provide temporal support to the vessel during healing before being degraded and resorbed by the body, promoting restoration of the vessel vasomotion. Currently, there are several BRS that are under development or already commercially available. Although several reviews have elegantly covered progress of current clinical programs and newer scaffold technologies, little is available currently to describe the mechanistic differences between biomaterials used in current and newer bioresorbable technologies. This aim of this review is to discuss the status of the different BRS technologies and materials currently under investigation, explore the newer strategies being adopted to improve material mechanical properties and optimize BRS degradation and summarize the performance of BRS in the clinical setting so far.

Over-expansion capacity and stent design model: An update with contemporary DES platforms.

BACKGROUND: Previously, we examined the difference in stent designs across different sizes for six widely used Drug Eluting Stents (DESs). Although stent post-dilatation to larger diameter is commonly done, typically in the setting of long tapering segment or left-main PCI, there is an increasing recognition that information with regard to the different stent model designs has a critical impact on overexpansion results. This study aims to provide an update on stent model designs for contemporary DES platforms as well as test overexpansion results under with oversized post-dilatation. METHODS AND RESULTS: We studied 6 different contemporary commercially available DES platforms: Synergy, Xience Xpedition, Ultimaster, Orsiro, Resolute Onyx and Biomatrix Alpha. We investigated for each platform the difference in stent designs across different sizes and results obtained after post-expansion with larger balloon sizes. The stents were deployed at nominal diameter and subsequently over expanded using increasingly large post dilatation balloon sizes (4.0, 5.0 and 6.0mm at 14ATM). Light microscopy was used to measure the changes in stent geometry and lumen diameter after over-expansion. For each respective DES platform, the MLD observed after overexpansion of the largest stent size available with a 6.0mm balloon was 5.7mm for Synergy, 5.6mm for Xience, 5.2mm for Orsiro, 5.8mm for Ultimaster, 5.5mm for 4mm Onyx (5.9mm for the 5mm XL size) and 5.8mm for BioMatrix Chroma. CONCLUSION: This update presents valuable novel insights that may be helpful for careful selection of stent size for contemporary DES based on model designs. Such information is especially critical in left main bifurcation stenosis treatment where overexpansion to larger oversized diameter may be required to ensure full stent apposition.