Drug-eluting Bioresorbable Vascular Scaffolds Research Articles

3D-printed, citrate-based bioresorbable vascular scaffolds for coronary artery angioplasty

Fully bioresorbable vascular scaffolds (BVSs) aim to overcome the limitations of metallic drug-eluting stents (DESs). However, polymer-based BVSs, such as Abbott's Absorb, the only US FDA-approved BVS, have had limited use due to increased strut thickness (157 μm for Absorb), exacerbated tissue inflammation, and increased risk of major cardiac events leading to inferior clinical performance when compared to metallic DESs. Herein we report the development of a drug-eluting BVS (DE-BVS) through the innovative use of a photopolymerizable, citrate-based biomaterial and a high-precision additive manufacturing process. BVS with a clinically relevant strut thickness of 62 μm can be produced in a high-throughput manner, i.e. one BVS per minute, and controlled release of the anti-restenosis drug everolimus can be achieved by engineering the structure of polymer coatings to fabricate drug-eluting BVS. We achieved the successful deployment of BVSs and DE-BVSs in swine coronary arteries using a custom-built balloon catheter and BVS delivery system and confirmed BVS safety and efficacy regarding maintenance of vessel patency for 28 days, observing an inflammation profile for BVS and DE-BVS that was comparable to the commercial XIENCE™ DES (Abbott Vascular).

InSilc Computational Tool for In Silico Optimization of Drug-Eluting Bioresorbable Vascular Scaffolds.

Stents made by different manufacturers must meet the requirements of standard in vitro mechanical tests performed under different physiological conditions in order to be validated. In addition to in vitro research, there is a need for in silico numerical simulations that can help during the stent prototyping phase. In silico simulations have the ability to give the same stent responses as well as the potential to reduce costs and time needed to carry out experimental tests. The goal of this paper is to show the achievements of the computational platform created as a result of the EU-funded project InSilc, used for numerical testing of most standard tests for validation of preproduction bioresorbable vascular scaffolds (BVSs). Within the platform, an ad hoc simulation protocol has been developed based on the finite element (FE) analysis program PAK and user interface software CAD Field and Solid. Two different designs of two different stents have been numerically simulated using this integrated tool, and the results have been demonstrated. The following standard tests have been performed: longitudinal tensile strength, local compression, kinking, and flex 1-3. Strut thickness and additional pocket holes (slots) in two different scaffolds have been used as representative parameters for comparing the mechanical characteristics of the stents (AB-BVS vs. AB-BVS-thinner and PLLA-prot vs. PLLA-plot-slot). The AB-BVS-thinner prototype shows better overall stress distribution than the AB-BVS, while the PLLA-prot shows better overall stress distribution in comparison to the PLLA-plot-slot. In all cases, the values of the maximum effective stresses are below 220 MPa—the value obtained by in vitro experiment. Despite the presented results, additional considerations should be included before the proposed software can be used as a validation tool for stent prototyping.

Modulated molecular markers of restenosis and thrombosis by in-vitro vascular cells exposed to bioresorbable scaffolds

Drug-eluting bioresorbable vascular scaffolds (BVSs) have emerged as a potential breakthrough for the treatment of coronary artery stenosis, providing mechanical support and drug delivery followed by complete resorption. Restenosis and thrombosis remain the primary limitations in clinical use. The study aimed to identify potential markers of restenosis and thrombosis analyzing the vascular wall cell transcriptomic profile modulation triggered by BVS at different values of shear stress (SS). Human coronary artery endothelial cells and smooth muscle cells were cultured under SS (1 and 20 dyne cm−2) for 6 h without and with application of BVS and everolimus 600 nM. Cell RNA-Seq and bioinformatics analysis identified modulated genes by direct comparison of SS conditions and Gene Ontology (GO). The results of different experimental conditions and GO analysis highlighted the modulation of specific genes as semaphorin 3E, mesenchyme homeobox 2, bone morphogenetic protein 4, (heme oxygenase 1) and selectin E, with different roles in pathological evolution of disease. Transcriptomic analysis of dynamic vascular cell cultures identifies candidate genes related to pro-restenotic and pro-thrombotic mechanisms in an in-vitro setting of BVS, which are not adequately contrasted by everolimus addition.

Vasculature-on-chip for Assessment of Bioresorbable Scaffolds and Endothelial Barrier Integrity.

Endothelial cells adhere to one another through junctional structures formed by intercellular adhesion molecules. These intercellular proteins regulate barrier function in response to the hemodynamic shear rate and enable the selective passage of solutes and fluids across the endothelium. After endovascular device implantation, the endothelial barrier is compromised and becomes discontinuous, which increases permeability, allowing transmigration of leukocytes and lipoproteins and leading to the accumulation of lipid-laden foamy macrophages in the subendothelial space. Drug-coated bioresorbable vascular scaffold implants have been associated with unexpected thrombotic complications, which were not predicted in animals because of dissimilarities in endothelial regeneration and realignment between animals and humans. The development of a microengineered, microfluidics-based system of patterned channels lined with human endothelial and smooth muscle cells perfused with blood allows for the evaluation of endothelial function and barrier integrity. This review highlights the translational potential of vasculature-on-chip, which recreates the microphysiological milieu to evaluate the impact of drug-eluting bioresorbable vascular scaffolds on endothelial barrier integrity and to characterize polymer biodegradation behavior and drug release kinetic profiles over time.

Effect of shear stress on vascular cell transcriptomics in an vitro setting of drug-eluting bioresorbable vascular scaffolds (BVS)

Effect of shear stress on vascular cell transcriptomics in an vitro setting of drug-eluting bioresorbable vascular scaffolds (BVS)

Design and implementation of in silico clinical trial for Bioresorbable Vascular Scaffolds.

In the recent years, Bioresorbable Vascular Scaffolds (BVS) for the treatment of atherosclerosis have been introduced. InSilc is a cloud based in silico clinical trial (ISCT) platform for drug-eluting BVS. The platform integrates multidisciplinary and multiscale models predicting the BVS performance. In this study, we present a use case scenario and demonstrate the functioning of the individual modules and of the whole pipeline and the ability to predict BVS short, medium, long-term outcomes.

Poly (l-lactic acid) bioresorbable scaffolds versus metallic drug-eluting stents for the treatment of coronary artery disease: A meta-analysis of 11 randomized trials.

Bioresorbable vascular scaffolds (BVS) have been proposed for overcoming the long-term limitations of permanent metallic stents, while theoretically warranting similar advantages in plaque stabilization and anti-restenotic drug delivery in the early postrevascularization phase. However, increased rates of malapposition, restenosis, or thrombosis have emerged from initial trials with BVS, that were nevertheless underpowered for the evaluation of the real outcome benefits of these coronary devices. The recent completion of newer randomized clinical trials paves the way to the present meta-analysis, aiming at the comparison of Poly (l-Lactic acid) BVS (PLLA-BVS) versus metallic drug-eluting stents (DES) in the treatment of coronary stenoses. Literature and main scientific session abstracts were searched for randomized clinical trials (RCTs) comparing drug-eluting BVS versus metallic DES for the treatment of coronary artery disease (CAD). The primary efficacy endpoint was mortality, secondary endpoints were cardiovascular death, myocardial infarction, target lesion revascularization (TLR), stent thrombosis and the composite of device-oriented target lesion failure (TLF). We included 11 randomized trials, for a total population of 10,707 patients, 54.5% treated with BVS. The major indication for PCI was stable CAD, whereas acute coronary syndrome represented 30% of the patients. At a mean follow-up of 2.64 years (1-5 years), mortality occurred in 2.71% of the patients, with no difference according to the type of implanted stent (OR[95%CI] = 0.94 [0.74, 1.20], p = .62). No interaction was observed according to patients' risk profile or the rate of diabetes and ACS. However, a significant increase in myocardial infarction, stent thrombosis, TLR and TLF was observed with BVS as compared to DES. The present meta-analysis provides the most updated data on the use of PLLA-BVS for the treatment of CAD. We documented a poorer performance of these new coronary devices, as compared to new generation metallic DES, being associated with an increased rate of recurrent cardiovascular events. However, such ischemic complications did not impact on mortality, with a comparable survival independently from the type of stent.

InSilc: 3D Reconstruction and plaque characterization tool.

Coronary artery disease (CAD) is the leading cause of mortality in Europe and worldwide. Atherosclerosis is the most common pathologic process that is highly related with CAD, while the implantation of drug-eluting Bioresorbable Vascular Scaffolds (BVS) is the most promising procedure for treating patients with CAD. InSilc is an textbfin silico clinical trial (ISCT) platform for the development and assessment of drugeluting BVS. The InSilc platform provides insight in the performance of drug-eluting BVS in their short term and medium/long term through the Mechanical Modelling Module, the Deployment Module, the Fluid Dynamics Module, the Myocardial Perfusion Module, the Drug-delivery Module and the Degradation Module. In order for the aforementioned modules to be developed, the utilization of the reconstructed patient specific arterial segment and the BVS design are required, which is achieved through the 3D reconstruction and plaque characterization tool.In this study, the overall architecture of the InSilc platform is presented with special emphasis on the 3D reconstruction and plaque characterization tool. The tool will be able to implement different medical image processing workflows. The workflows will require minimum user intervention in order to be used in large scale clinical trials.

Stent Thrombosis With Drug-Eluting Stents and Bioresorbable Scaffolds: Evidence From a Network Meta-Analysis of 147 Trials.

This study sought to perform a systematic review and network meta-analysis to compare the relative safety and efficacy of contemporary DES and BVS. To improve outcomes of patients undergoing percutaneous coronary revascularization, there have been advances in the design of drug-eluting stents (DES), including the development of drug-eluting bioresorbable vascular scaffolds (BVS). Prospective, randomized, controlled trials comparing bare-metal stents (BMS), paclitaxel-eluting stents (PES), sirolimus-eluting stents (SES), Endeavor zotarolimus-eluting stents (E-ZES), cobalt-chromium (CoCr) everolimus-eluting stents (EES), platinum-chromium (PtCr)-EES, biodegradable polymer (BP)-EES, Resolute zotarolimus-eluting stents (R-ZES), BP biolimus-eluting stents (BP-BES), hybrid sirolimus-eluting stents (H [Orsiro]-SES), polymer-free sirolimus- and probucol-eluting stents, or BVS were searched in online databases. The primary endpoint was definite or probable stent thrombosis at 1 year. A total of 147 trials including 126,526 patients were analyzed in this study. All contemporary DES were superior to BMS and PES in terms of definite or probable stent thrombosis at 1 year. CoCr-EES, PtCr-EES, and H-SES were associated with significantly lower risk than BVS. CoCr-EES and H-SES were superior to SES and BP-BES. The risk of myocardial infarction was significantly lower with H-SES than with BVS. There were no significant differences regarding all-cause or cardiac mortality. Contemporary devices including BVS showed comparably low risks of repeat revascularization. Contemporary DES, including biocompatible DP-DES, BP-DES, and polymer-free DES, showed a low risk of definite or probable stent thrombosis at 1 year. BVS had an increased risk of device thrombosis compared with CoCr-EES, PtCr-EES, and H-SES. Data from extended follow-up are warranted to confirm the long-term safety of contemporary coronary devices.

Degree of bioresorbable vascular scaffold expansion modulates loss of essential function

Drug-eluting bioresorbable vascular scaffolds (BVSs) have the potential to restore lumen patency, enable recovery of the native vascular environment, and circumvent late complications associated with permanent endovascular devices. To ensure therapeutic effects persist for sufficient times prior to scaffold resorption and resultant functional loss, many factors dictating BVS performance must be identified, characterized and optimized. While some factors relate to BVS design and manufacturing, others depend on device deployment and intrinsic vascular properties. Importantly, these factors interact and cannot be considered in isolation. The objective of this study is to quantify the extent to which degree of radial expansion modulates BVS performance, specifically in the context of modifying device erosion kinetics and evolution of structural mechanics and local drug elution. We systematically varied degree of radial expansion in model BVS constructs composed of poly dl-lactide-glycolide and generated in vitro metrics of device microstructure, degradation, erosion, mechanics and drug release. Experimental data permitted development of computational models that predicted transient concentrations of scaffold-derived soluble species and drug in the arterial wall, thus enabling speculation on the short- and long-term effects of differential expansion. We demonstrate that degree of expansion significantly affects scaffold properties critical to functionality, underscoring its relevance in BVS design and optimization. Statement of SignificanceBioresorbable vascular scaffold (BVS) therapy is beginning to transform the treatment of obstructive artery disease, owing to effective treatment of short term vessel closure while avoiding long term consequences such as in situ, late stent thrombosis – a fatal event associated with permanent implants such as drug-eluting stents. As device scaffolding and drug elution are temporary for BVS, the notion of using this therapy in lieu of existing, clinically approved devices seems attractive. However, there is still a limited understanding regarding the optimal lifetime and performance characteristics of erodible endovascular implants. Several engineering criteria must be met and clinical endpoints confirmed to ensure these devices are both safe and effective. In this manuscript, we sought to establish general principles for the design and deployment of erodible, drug-eluting endovascular scaffolds, with focus on how differential expansion can modulate device performance.

Clinical, Angiographic, Functional, and Imaging Outcomes 12 Months After Implantation of Drug-Eluting Bioresorbable Vascular Scaffolds in Acute Coronary Syndromes.

The purpose of this study was to describe the multimodal outcome 12 months after implantation of coronary bioresorbable scaffolds (BVS) for the treatment of patients with acute coronary syndromes (ACS). Functional and imaging data on the use of BVS are limited to simple, stable lesions; in the setting of ACS, only short-term clinical follow-up data are available, and no information from intracoronary imaging and vasomotion tests has been reported. A total of 133 patients (age 62 ± 12 years, 74% males, 15% diabetic) underwent BVS (n= 166) implantation for the treatment of thrombotic lesions in the setting of ACS (43% non-ST-segment elevation myocardial infarction, 38% ST-segment elevation myocardial infarction, 20% unstable angina). Clinical, angiographic, intracoronary imaging, and vasomotor endpoints were evaluated at 12 months. During the 374 days (interquartile range: 359 to 411 days) of follow-up, there were 4 deaths; 3 definite and 1 probable in-BVS thromboses (all in the first 6 months). At 12-month angiography (75 patients, 83 BVS), in-segment late lumen loss was 0.19 ± 0.45 mm, and 3 (4%) patients showed binary restenosis. Optical coherence tomography (80 BVS, n = 70) showed a mean lumen area of 6.3 ± 2.3 mm(2). Malapposition was evidenced in 21 (26%) BVS. Endothelium-dependent and -independent vasodilation were observed in 48% and 49% of the BVS. Twelve months after BVS implantation, clinical, intracoronary imaging, and vasomotion data appear to provide a rationale for the use of BVS in the setting of ACS and the basis for a randomized study.

In vivo assessment of the three-dimensional haemodynamic micro-environment following drug-eluting bioresorbable vascular scaffold implantation in a human coronary artery: fusion of frequency domain optical coherence tomography and angiography

In vivo assessment of the three-dimensional haemodynamic micro-environment following drug-eluting bioresorbable vascular scaffold implantation in a human coronary artery: fusion of frequency domain optical coherence tomography and angiography

TCT-564 Implications of the local hemodynamic forces on vessel wall responses following drug-eluting bioresorbable vascular scaffold implantation: an optical coherence tomography analysis

TCT-564 Implications of the local hemodynamic forces on vessel wall responses following drug-eluting bioresorbable vascular scaffold implantation: an optical coherence tomography analysis

Prospective, multi-center evaluation of the desolve NX novolimus-eluting bioresorbable coronary scaffold: principal clinical and imaging endpoints

Background and aims: Bioresorbable vascular scaffolds represent an exciting advance in percutaneous coronary intervention (PCI), providing an initial coronary scaffold which are eventually resorbed by the body. The DESolve Nx BCSS is a novel drug eluting bioresorbable vascular scaffold that combines a PLLA-based scaffold coated with a biodegradable polylactide-based polymer and the drug Novolimus, a macrocyclic lactone mTOR inhibitor which has demonstrated potent anti-proliferative properties in previous clinical trials using Elixir's metallic Novolimus-eluting coronary stents. The drug dose is 5 mcg per mm of scaffold length and is available in three diameters (3.0, 3.25 and 3.5) and two lengths (14 and 18 mm). The DESolve NX study is a prospective, multicenter evaluation of the safety and efficacy of the DESolve™ Nx Novolimus-Eluting Bioresorbable Coronary Scaffold (BCSS) in patients with single de novo native coronary artery lesions through clinical endpoints and multiple imaging modalities. Methods and results: 126 patients with single, de novo coronary artery lesions were enrolled in this prospective, multi-center, single-arm study. Those patients receiving the study device are being analysed for multiple clinical endpoints including: Device and Procedure Success; Major Adverse Cardiac Events (MACE), a composite endpoint of cardiac death, target vessel MI, or clinically-indicated target lesion revascularization (CI-TLR); Clinically-indicated Target Lesion and Target Vessel Revascularization, (CI-TVR) and Stent Thrombosis assessed at 1, 6 and 12 months and annually to 5 years. All patients underwent angiographic assessment at 6 months and a subset of patients underwent IVUS and OCT assessment at 6 months. Additional imaging analyses will be conducted in the subset of patients at 12 months using MSCT and at 24 months using Angiography, IVUS and OCT to assess the long-term scaffold, lesion and vessel characteristics. Device Success and Procedure Success were 95.2% and 100% respectively demonstrating the feasibility and initial safety of this novel device. Conclusion: The DESolve™ Nx Novolimus-Eluting BCSS demonstrated initial safety and efficacy in this study. A first report of the principal clinical and imaging outcomes through 6 months will be presented.

Industry Update: the Latest Developments in Therapeutic Delivery

This month’s update covers the timeframe 16 December 2010–15 January 2011, a period over which one might expect business activity to slow. However, despite the holiday break, a number of deals took place including the acquisition of CPEX Pharmaceuticals by FCB I Holdings and the creation of a number of strategic partnerships and collaborations between big pharmaceutical/biotechnology companies and companies offering novel technologies. These included agreements between Avila and sanofi-aventis, Novo Nordisk and Emisphere, Spirogen and Genentech, Seattle Genetics and Pfizer and last but not least, Sutro Biopharma and Pfizer. 2011 also got off to a good start for Abbott Laboratories and Alnylam Pharmaceuticals. On 10 January, Abbott announced that it had received CE Mark approval for the world’s first drug-eluting bioresorbable vascular scaffold; while on 4 January, Alnylam reported that pharmacologically relevant silencing RNA (siRNA) drug levels had been achieved in tissues following dosing of its ALN–VSP product in a Phase I liver cancer trial. As ever, the information in this article has been sourced from company websites, press releases and where appropriate, the scientific literature and patent databases.