Endothelial Progenitor Cell Capture Research Articles

A quick and effective modification method to improve the patency and endothelialization of cryopreserved allogenic blood vessels

Cryopreserved allogeneic blood vessels have received considerable attention for vascular reconstruction owing to their easy availability and excellent anti-infective property. However, current cryopreservation methods cause significant endothelium loss alongside directly exposing smooth muscle cells and extracellular matrix components to the circulating blood, which can induce thrombosis and/or restenosis. We covalently coupled PEGylated phospholipids (DMPE-PEG) with anti-coagulant bivalirudin (abbreviated as DPB) and endothelial progenitor cell (EPC)-capturing TPSLEQRTVYAK (TPS) (abbreviated as DPT), respectively. Both DPT and DPB were co-modified onto the lumen surface of cryopreserved allogeneic vessels through hydrophobic interaction between DMPE-PEG and the phospholipid bilayer of surviving cells. Cy7-labled DMPE-PEG was used to investigate the saturation concentration and incubation time on the lumen surface of cryopreserved vessels. DPB and DPT co-modified cryopreserved vessels were characterized through different assays, including tissue viability and gene expression, hemocompatibility, and EPC capture in vitro and an artery implantation model in vivo. Co-modification of DPB and DPT attained luminal saturation as earlier as 10 min while preserving the viability of the residual cells on the cryopreserved vessels. The optimally co-modified cryopreserved allogeneic vessels showed that the DPB can improve the hemocompatibility by reducing fibrinogen adsorption and platelets adhesion alongside protecting the EPCs-capturing function of the DPT via inhibiting the masking by blood components, which altogether promoted the patency and endothelialization. This work provided a quick, biocompatible and an effective approach to functionalize tissue-engineered constructs containing alive cells.

Effects of Cyclic Peptide LXW7 Coating on Short-term Vascular Graft Patency Using a Porcine (Sus scrofa) Model

We previously identified LXW7, a specific integrin αvβ3 targeting ligand capable of selectively capturing endothelial progenitor cells and endothelial cells, and developed a parylene-based conformal coating technology to covalently present LXW7 to prosthetic materials. In previous in vitro and in vivo studies, LXW7-coated grafts have demonstrated successful capture of endothelial progenitor cells and endothelial cells, which then promotes re-endothelialization of these prosthetic materials. This study aims to assess the function of LXW7 coating on interposition expanded polytetrafluoroethylene (ePTFE) graft thrombus formation and patency in a large animal model. Eight female Yorkshire pigs underwent transperitoneal implantation of bilateral iliac artery interposition bypasses using control plain ePTFE grafts (inner diameter 6 mm) and LXW7-coated ePTFE grafts. Each animal served as its own control and the implanting surgeon and experimental team were blinded to treatment and evaluations. The animals underwent computed tomography angiography (CTA) immediately postoperatively and at 3 and 6 weeks postimplantation. After final CTA imaging, animals were sacrificed and interposition grafts were harvested for histological evaluation. The project proceeded following the approval of United States Air Force, David Grant Medical Center Institutional Animal Care and Use Committee. Six animals were included in final analysis, with two excluded due to complications during their surgical and postoperative course requiring euthanasia. Average native artery diameter was 4.08 mm for the control grafts and 4.17 mm for LXW7-coated grafts (P = .296). Average clamp time was similar between groups (60 minutes for the control grafts vs 52 minutes on the LXW7-coated grafts; P = .291). The immediate postprocedure CTA demonstrated procedural success for all six pigs with no evidence of thrombus or stenosis. At the 3-week imaging, all grafts remained patent. At the 6-week imaging, all six LXW7-coated grafts were patent without evidence of thrombus or stenosis while four of the six control grafts were either fully or partially thrombosed. Repeated measures mixed effects analysis demonstrated significantly improved patency over time with LXW7 coated grafts (P < .001) (Figure). This is the first study using CTA to investigate the impact of LXW7 coating on prosthetic vascular graft patency in a clinically relevant large animal model. The findings demonstrate significantly improved graft patency over time with use of LXW7 coating, suggesting promise as a potential adjunct to clinical outcomes with prosthetic grafts in vascular bypass applications.Fig 2View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Abstract 601: Effects Of Cyclic Peptide Lxw7 Coating On Short Term Vascular Graft Patency Using A Porcine ( Sus Scrofa) Model

Introduction: We previously identified LXW7, a specific integrin αvβ3 targeting ligand capable of selectively capturing endothelial progenitor cells (EPCs) and endothelial cells (ECs), and developed a parylene-based conformal coating technology to covalently bind LXW7 to prosthetic materials. LXW7-coated grafts have demonstrated successful capture of EPCs and ECs, which then promotes endothelialization of prosthetic materials. This study aims to assess the function of LXW7 coating on interposition polytetrafluoroethylene (ePTFE) graft thrombus formation and patency in a large animal model. Methods: 8 Yorkshire pigs underwent implantation of bilateral iliac artery interposition bypasses using control ePTFE grafts and LXW7-coated ePTFE grafts. Each animal served as its own control and the implanting surgeon and experimental team were blinded to treatment and evaluations. Computed Tomography Angiogram (CTA) immediately post-operatively, 3 weeks, and 6 weeks post-implantation. After final CTA, animals were sacrificed and grafts were harvested. The project proceeded following the approval of United States Air Force, David Grant Medical Center Institutional Animal Care &amp; Use Committee. Results: 6 animals were included in final analysis, with 2 excluded due to complications during their surgical and post-operative course requiring euthanasia. Native artery diameter was 4.08mm for the control grafts and 4.17mm for LXW7-coated grafts (p=0.296). Post-procedure CTA demonstrated procedural success for all 6 pigs with no evidence of thrombus or stenosis. At 3 week imaging, all grafts remained patent. 6 week imaging, all LXW7-coated grafts were patent without evidence of thrombus or stenosis while 4 of the 6 control grafts were either fully or partially thrombosed. Repeated measures mixed effects analysis demonstrated significantly improved patency over time with LXW7 coated grafts (p&lt;0.001). Conclusion: This is the first study investigating LXW7-coating on prosthetic vascular graft patency in a large animal model. We demonstrate significantly improved graft patency use of LXW7-coating, suggesting promise as an adjunct for prosthetic grafts in vascular bypass applications.

Bioaffinity-based surface immobilization of antibodies to capture endothelial colony-forming cells.

Maximizing the re-endothelialization of vascular implants such as prostheses or stents has the potential to significantly improve their long-term performance. Endothelial progenitor cell capture stents with surface-immobilized antibodies show significantly improved endothelialization in the clinic. However, most current antibody-based stent surface modification strategies rely on antibody adsorption or direct conjugation via amino or carboxyl groups which leads to poor control over antibody surface concentration and/or molecular orientation, and ultimately bioavailability for cell capture. Here, we assess the utility of a bioaffinity-based surface modification strategy to immobilize antibodies targeting endothelial cell surface antigens. A cysteine-tagged truncated protein G polypeptide containing three Fc-binding domains was conjugated onto aminated polystyrene substrates via a bi-functional linking arm, followed by antibody immobilization. Different IgG antibodies were successfully immobilized on the protein G-modified surfaces. Covalent grafting of the protein G polypeptide was more effective than surface adsorption in immobilizing antibodies at high density based on fluorophore-labeled secondary antibody detection, as well as endothelial colony-forming cell capture through anti-CD144 antibodies. This work presents a potential avenue for enhancing the performance of cell capture strategies by using covalent grafting of protein G polypeptides to immobilize IgG antibodies.

Función endotelial y microvascular distal a stents farmacoactivos sin polímero y captadores de células endoteliales. Estudio aleatorizado FUNCOMBO

Introduction and objectivesThe vasomotor function of new-generation drug-eluting stents designed to enhance stent healing and reendothelialization is unknown. This study aimed to compare the endothelial function of the infarct-related artery (IRA) treated with bioactive circulating endothelial progenitor cell-capturing sirolimus-eluting stents (COMBO) vs polymer-free biolimus-eluting stents (BioFreedom) in ST-segment elevation myocardial infarction patients at 6 months. Secondary objectives were to compare the microcirculatory function of the IRA and stent healing at 6 months. MethodsSixty patients were randomized to bioactive sirolimus-eluting stent vs polymer-free biolimus-eluting stents implantation. At 6 months, patients underwent coronary angiography with vasomotor, microcirculatory and optical coherence tomography examinations. Endothelial dysfunction of the distal coronary segment was defined as ≥ 4% vasoconstriction to intracoronary acetylcholine infusion. ResultsEndothelial dysfunction was similarly observed between groups (64.0% vs 62.5%, respectively; P=.913). Mean lumen diameter decreased by 16.0 ±20.2% vs 16.1 ±21.6% during acetylcholine infusion (P=.983). Microcirculatory function was similar in the 2 groups: coronary flow reserve was 3.23 ±1.77 vs 3.23±1.62 (P=.992) and the index of microcirculatory resistance was 24.8±16.8 vs 21.3±12.0 (P=.440). Optical coherence tomography findings were similar: uncovered struts (2.3% vs 3.2%; P=.466), malapposed struts (0.1% vs 0.3%; P=.519) and major evaginations (7.1% vs 5.6%; P=.708) were observed in few cases. ConclusionsEndothelial dysfunction of the IRA was frequent and was similarly observed with new-generation drug-eluting stents designed to enhance stent reendothelialization at 6 months. Endothelial dysfunction was observed despite almost preserved microcirculatory function and complete stent coverage. Larger and clinically powered studies are needed to assess the role of residual endothelial dysfunction in ST-segment elevation myocardial infarction patients.Registered in ClinicalTrials.gov: NCT04202172Full English text available from:www.revespcardiol.org/en

Coronary endothelial and microvascular function distal to polymer-free and endothelial cell-capturing drug-eluting stents. The randomized FUNCOMBO trial

Introduction and objectivesThe vasomotor function of new-generation drug-eluting stents designed to enhance stent healing and reendothelialization is unknown. This study aimed to compare the endothelial function of the infarct-related artery (IRA) treated with bioactive circulating endothelial progenitor cell-capturing sirolimus-eluting stents (COMBO) vs polymer-free biolimus-eluting stents (BioFreedom) in ST-segment elevation myocardial infarction patients at 6 months. Secondary objectives were to compare the microcirculatory function of the IRA and stent healing at 6 months. MethodsSixty patients were randomized to bioactive sirolimus-eluting stent vs polymer-free biolimus-eluting stents implantation. At 6 months, patients underwent coronary angiography with vasomotor, microcirculatory and optical coherence tomography examinations. Endothelial dysfunction of the distal coronary segment was defined as ≥ 4% vasoconstriction to intracoronary acetylcholine infusion. ResultsEndothelial dysfunction was similarly observed between groups (64.0% vs 62.5%, respectively; P=.913). Mean lumen diameter decreased by 16.0 ±20.2% vs 16.1 ±21.6% during acetylcholine infusion (P=.983). Microcirculatory function was similar in the 2 groups: coronary flow reserve was 3.23 ±1.77 vs 3.23±1.62 (P=.992) and the index of microcirculatory resistance was 24.8±16.8 vs 21.3±12.0 (P=.440). Optical coherence tomography findings were similar: uncovered struts (2.3% vs 3.2%; P=.466), malapposed struts (0.1% vs 0.3%; P=.519) and major evaginations (7.1% vs 5.6%; P=.708) were observed in few cases. ConclusionsEndothelial dysfunction of the IRA was frequent and was similarly observed with new-generation drug-eluting stents designed to enhance stent reendothelialization at 6 months. Endothelial dysfunction was observed despite almost preserved microcirculatory function and complete stent coverage. Larger and clinically powered studies are needed to assess the role of residual endothelial dysfunction in ST-segment elevation myocardial infarction patients.Registered in ClinicalTrials.gov: NCT04202172

Nine-month angiographic and 2-year clinical outcomes of the RECOVERY trial: A randomized study of the biodegradable polymer sirolimus-eluting COMBO dual-therapy stent versus a polymer-free sirolimus-eluting stent in Chinese patients.

We evaluated the safety and efficacy of the novel dual-therapy sirolimus-eluting and endothelial progenitor cell (EPC) capture COMBO stent. (Very) late stent thrombosis (ST) and neo-atherosclerosis limit the performance of drug-eluting stents. The capture of EPCs accelerates stent re-endothelialization, thereby potentially decreasing the risk of restenosis and ST. In total, 440 patients with de novo lesions in native coronary arteries were randomized (1:1) to either receive the COMBO stent (n = 220) or Nano polymer-free sirolimus-eluting stent (n = 220). The primary endpoint was the 9-month angiographic in-segment late lumen loss (LLL). Secondary endpoints included target lesion failure (TLF), a patient-oriented composite endpoint (PoCE), and ST. At 9 months, the COMBO in-segment LLL (0.29 ± 0.46 mm) was non-inferior to that of the Nano comparator stent (0.31 ± 0.44 mm; pnon-inferiority < .0001). Clinical outcomes were also similar between the COMBO and Nano stents, with TLF rates of 9.3% and 7.9% (p = .61) at 12 months, and 9.4% and 8.0% (p = .62) at 24 months, respectively. The PoCE rate was 14.8% and 10.6% (p = .19) at 12 months, and 16.0% and 11.3% (p = .16) at 24 months, respectively. Ischemia-driven target lesion revascularization rates were 6.0% and 3.7% (p = .26) at 12 months, and 6.2% and 3.8% (p = .26) at 24 months, respectively. No case of ST occurred in either group. The RECOVERY trial has shown the COMBO stent was effective, meeting the primary non-inferiority angiographic endpoint, and safe, with an overall low rate of clinical events in both stent groups, including no ST for up to 2 years.

Construction of biological factor-coated stent and its effect on promoting endothelialization

Recently, just taking endothelialization of stent as an interventional treatment of aneurysms is unsatisfactory. This treatment also has impacts the occlusion rate of the aneurysm. In accordance with that, the authors aims to construct a novel biological factor-coated stent with dual biological effects of anticoagulation and endothelialization for the improvement of the occlusion rate of aneurysms and reduction of the risk for treatment of aneurysm with intravascular interventional therapy. The Ni-Ti alloy sheets loaded with VEGF and anti-CD34 antibody were put into use for stimulating the construction of the biological factor-coated stents, for the Ni-Ti alloy sheets could help improve the proliferation of endothelial cell (EC), recognize effectively and adhere to endothelial progenitor cell (EPC). Blood compatibility characterization methods (water contact angle, platelet activation test, clotting time evaluation and protein adsorption test) were applied for study the influence of the interaction between the Ni-Ti alloy sheets and blood. Cell experiments (HUVEC proliferation experiment, migration experiment and EPC capture experiment) were resorted to investigate the ability of the sheets to promote the proliferation of HUVEC and to capture EPCs. With the mature of the construction technology, the Enterprise stent with the biological factors were optimized accordingly, the biological function of that were verified by cell experiments. Studies showed that Ni-Ti alloy sheets and enterprise stents can successfully load with VEGF and anti-CD34 antibody. The below achievements can be realized including a better blood compatibility and effects of the constructed sheets and enterprise stents on promoting HUVEC proliferation and adhesion of EPC. It was meaningful of conversion to clinical application to improve the cure rate of the aneurysm and the safety of the intravascular treatment.

One-Year COMBO Stent Outcomes in Acute Coronary Syndrome: from the COMBO Collaboration.

The COMBO biodegradable polymer sirolimus-eluting stent includes endothelial progenitor cell capture (EPC) technology for rapid endothelialization, which may offer advantage in acute coronary syndromes (ACS). We sought to analyze the performance of the COMBO stent by ACS status and ACS subtype. The COMBO collaboration (n = 3614) is a patient-level pooled dataset from the MASCOT and REMEDEE registries. We evaluated outcomes by ACS status, and ACS subtype in patients with ST segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) versus unstable angina (UA). The primary endpoint was 1-year target lesion failure (TLF), composite of cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization. Secondary outcomes included stent thrombosis (ST). We compared 1965 (54%) ACS and 1649 (46.0%) non-ACS patients. ACS presentations included 40% (n = 789) STEMI, 31% (n = 600) NSTEMI, and 29% (n = 576) UA patients. Risk of 1-year TLF was greater in ACS patients (4.5% vs. 3.3%, HR 1.51 95% CI 1.01-2.25, p = 0.045) without significant differences in definite/probable ST (1.1% vs 0.5%, HR 2.40, 95% CI 0.91-6.31, p = 0.08). One-year TLF was similar in STEMI, NSTEMI, and UA (4.8% vs 4.8% vs. 3.7%, p = 0.60), but definite/probable ST was higher in STEMI patients (1.9% vs 0.5% vs 0.7%, p = 0.03). Adjusted outcomes were not different in MI versus UA patients. Despite the novel EPC capture technology, COMBO stent PCI was associated with somewhat greater risk of 1-year TLF in ACS than in non-ACS patients, without significant differences in stent thrombosis. No differences were observed in 1-year TLF among ACS subtypes.

Final 5-year results of the TRIAS-LR: a multi-centre, randomized trial comparing the Genous endothelial progenitor cell capturing stent with bare metal stents in patients with low risk for restenosis

Abstract Introduction The Genous stent is a bare metal stent (BMS) together with a technique of capturing endothelial progenitor cells. The successor of the Genous endothelial progenitor cell capturing (EPC) stent, the COMBO stent, combines this technique with the drug eluting polymer. The current studies showed promising results of the COMBO stent, however the additional value of EPC technique in overcoming neointimal hyperplasia has yet to be proven. Purpose This study sought to evaluate the efficacy and safety of the Genous EPC stent compared to BMS in a patient population with low risk for restenosis. Methods TRIAS-LR was an investigator-initiated, prospective, multicentre, single blind trial randomizing patients with low risk of restenosis 1:1 to Genous ECS or BMS. Patients were recruited between 2007 and 2014 at 31 sites across Europe. The study enrolment was terminated at 70% of the planned inclusion due to slow enrolment and change of guidelines. Patients or lesions were considered low risk if all of the following criteria were met: 1) reference vessel diameter &amp;gt;2.8mm, 2) lesion length &amp;lt;20mm, 3) no thrombolysis in myocardial infarction (TIMI) flow of 0, and 4) patient without diabetes mellitus. Clinical follow-up was obtained yearly. The trial was monitored and independent clinical event committee adjudicated serious adverse clinical events. The primary endpoint was target lesion failure (TLF), composite of cardiac death, target-vessel myocardial infarction (TV-MI) or target lesion revascularization (TLR) at 1 year. Secondary endpoint included the composite of death or MI at 5-year follow-up. Results In total, 838 patients were enrolled of whom 422 patients with 476 lesions were randomly assigned to Genous EPC stent and 416 patients with 480 lesions to BMS. The mean age was 64 years, 74% were males and in 76% patients were treated in elective setting. At 1 year TLF had occurred in 3.6% (n=15) of the Genous arm and in 6.1% (n=25) of the BMS arm (p=0.094; risk difference of −2.5%). However, this difference disappeared, at 5-years of follow-up; TLF rate was 12.6% (n=51) in the Genous arm versus 14.3% (n=58) in the BMS arm (p=0.385; risk difference of −1.7%). The secondary objective of the composite death or MI at 5 years occurred in 11.6% (n=47) in the Genous arm and 9.9% (n=40) in the BMS arm (p=0.479; risk difference of 1.7%). At 5 years definite stent thrombosis (ST) occurred in 0.5% (n=2) of the Genous arm, no definite ST had occurred in the BMS arm (p=0.162). Conclusion TRIAS-LR trial showed no differences between Genous EPC and BMS throughout 5-year follow-up in patients considered as low risk of restenosis. Kaplan-Meier plot of composite endpoints Funding Acknowledgement Type of funding source: Private company. Main funding source(s): OrbusNeich Medical BV

One-year clinical outcomes in patients with chronic kidney disease treated with COMBO stents: From the COMBO collaboration.

Chronic kidney disease (CKD) patients undergoing percutaneous coronary intervention (PCI) experience greater ischemic events including clinically driven target lesion revascularization (CD-TLR). Whether the COMBO biodegradable-polymer sirolimus-eluting stent promotes better outcomes in these patients by virtue of endothelial progenitor cell capture technology is unknown. We examined one-year outcomes by CKD status from the COMBO collaboration. The COMBO collaboration was a patient-level pooled dataset from the REMEDEE and MASCOT registries (3,614 patients) of all-comers undergoing attempted COMBO stent PCI. The primary endpoint was one-year target lesion failure (TLF), composite of cardiac death, target-vessel myocardial infarction (TV-MI) or CD-TLR. Secondary endpoints included stent thrombosis (ST). The study included 6.4% (n = 231) CKD and 93.6% (n = 3,361) non-CKD patients. CKD patients were older and included more women with greater prevalence of several comorbidities but similar rate of acute coronary syndrome (50.6% vs. 54.5%, p = .26). CKD patients underwent radial PCI less often (56.1% vs. 70.3%, p < .001) and received clopidogrel (78.6% vs. 68.3%) more often (p = .004). One-year TLF occurred in 7.9% CKD vs. 3.7% non-CKD patients, p = .001. CKD patients also demonstrated greater incidence of cardiac death (6.2% vs. 1.2%, p < .0001), TV-MI (2.7% vs. 1.1%, p = .04) but similar CD-TLR (2.7% vs 2.2%, p = .61) and definite/probable ST (1.4% vs. 0.8%, p = .42), compared to non-CKD patients. CKD patients treated with COMBO stents had significantly greater incidence of one-year TLF compared to non-CKD patients driven by cardiac death and to a lesser extent TV-MI but not CD-TLR. They had similar rates of definite/probable ST.

1-Year COMBO stent outcomes stratified by the PARIS bleeding prediction score: From the MASCOT registry.

BackgroundThe COMBO stent is a biodegradable-polymer sirolimus-eluting stent with endothelial progenitor cell capture technology for faster endothelialization.ObjectiveWe analyzed COMBO stent outcomes in relation to bleeding risk using the PARIS bleeding score.MethodsMASCOT was an international registry of all-comers undergoing attempted COMBO stent implantation. We stratified patients as low bleeding-risk (LBR) for PARIS score ≤ 3 and intermediate-to-high (IHBR) for score > 3 based on baseline age, body mass index, anemia, current smoking, chronic kidney disease and need for triple therapy. Primary endpoint was 1-year target lesion failure (TLF), composite of cardiac death, myocardial infarction (MI) not clearly attributed to a non-target vessel or clinically-driven target lesion revascularization (TLR). Bleeding was adjudicated using the Bleeding Academic Research Consortium (BARC) definition. Dual antiplatelet therapy (DAPT) cessation was independently adjudicated.ResultsThe study included 56% (n = 1270) LBR and 44% (n = 1009) IHBR patients. Incidence of 1-year TLF was higher in IHBR patients (4.1% vs. 2.6%, p = 0.047) driven by cardiac death (1.7% vs. 0.7%, p = 0.029) with similar rates of MI (1.8% vs. 1.1%, p = 0.17), TLR (1.5% vs. 1.6%, p = 0.89) and definite/ probable stent thrombosis (1.2% vs. 0.6%, p = 0.16). Incidence of 1-year major BARC 3 or 5 bleeding was significantly higher in IHBR patients (2.3% vs. 0.9%, p = 0.0094), as was the incidence of DAPT cessation (29.3% vs. 22.8%, p < 0.01), driven by physician-guided discontinuation.ConclusionsPatients with intermediate-to-high PARIS bleeding risk in the MASCOT registry experienced greater incidence of 1-year TLF, major bleeding and DAPT cessation than LBR patients, without significant differences in stent thrombosis.

Comparison of One-Year Outcomes in Patients >75 Versus ≤75 Years With Coronary Artery Disease Treated With COMBO Stents (From The MASCOT Registry)

Older patients who undergo coronary interventions are at greater risk of ischemic events and less likely to tolerate prolonged dual antiplatelet therapy (DAPT) due to bleeding risk. The COMBO biodegradable polymer sirolimus-eluting stent promotes rapid endothelialization through endothelial progenitor cell capture technology which may be advantageous in elderly patients. We compared 1-year clinical outcomes and DAPT cessation events in patients >75 versus ≤75 years from the MASCOT registry. MASCOT was a prospective, multicenter cohort study of all-comers undergoing attempted COMBO stenting. The primary endpoint was 1-year target lesion failure (TLF), composite of cardiac death, myocardial infarction (MI) not clearly attributed to a nontarget vessel or clinically driven target lesion revascularization. Bleeding was adjudicated using the Bleeding Academic Research Consortium criteria. Adjusted outcomes were analyzed using Cox regression methods. The study included 18% (n = 479) patients >75 years and 72% (n = 2,135) patients ≤75 years. One-year TLF occurred in 4.6% patients >75 years versus 3.1% patients ≤75years of age, p = 0.10; adj hazard ratio 1.36, 95% confidence intervals 0.77 to 2.38, p = 0.29. There were no significant differences in cardiac death (1.7% vs 1.3%, p = 0.55), MI (2.1% vs 1.2%, p = 0.14), target lesion revascularization (1.7% vs 1.4%, p = 0.60) and definite stent thrombosis (0.8% vs 0.4%, p = 0.19). Major Bleeding Academic Research Consortium 3,5 bleeding (3.1% vs 1.5%, p = 0.01) and DAPT cessation rates (32.4% vs 23.0%, p <0.001) were significantly higher in elderly patients. In conclusion, elderly patients >75 years treated with COMBO stents had similar TLF but significantly greater incidence of bleeding than younger patients and DAPT cessation in one-third of patients over 1 year.

Sex differences in 1-year clinical outcomes after percutaneous coronary intervention with COMBO stents: From the COMBO collaboration.

The COMBO drug eluting stent is a novel device with luminal endothelial progenitor cell capture technology for rapid homogeneous endothelialization. We examined for sex differences in 1-year outcomes after COMBO stenting from the COMBO collaboration, a pooled patient-level dataset from the MASCOT and REMEDEE multicenter registries. The primary endpoint was 1-year target lesion failure (TLF), composite of cardiac death, target vessel-myocardial infarction (TV-MI), or clinically driven target lesion revascularization (CD-TLR). Secondary outcomes included stent thrombosis (ST). Adjusted outcomes were assessed using Cox regression methods. The study included 861 (23.8%) women and 2,753 (76.2%) men. Women were older with higher prevalence of several comorbidities including diabetes mellitus. Risk of 1-year TLF was similar in both sexes (3.8% vs. 3.9%, HR 0.92, 95% CI 0.59-1.42, p = .70), without sex differences in the incidence of cardiac death (1.6% vs. 1.5%, p = .78), TV-MI (1.5% vs. 1.1%, p = .32), or CD-TLR (2.0% vs. 2.2%, p = .67). Definite or probable ST occurred in 0.4% women and 1.0% men (HR 0.26, 95% CI 0.06-1.11, p = .069). Despite greater clinical risks at baseline, women treated with COMBO stents had similarly low 1-year TLF and other ischemic outcomes compared to men.

Anti-CD34-Grafted Magnetic Nanoparticles Promote Endothelial Progenitor Cell Adhesion on an Iron Stent for Rapid Endothelialization.

Iron stents, with superior mechanical properties and controllable degradation behavior, have potential for use as feasible substitutes for nondegradable stents in the treatment of coronary artery occlusion. However, corrosion renders the iron surface hard to modify with biological molecules to accelerate endothelialization and solve restenosis. The objective of this study is to demonstrate the feasibility of using endothelial progenitor cells (EPCs) to rapidly adhere onto iron surfaces with the assistance of anti-CD34-modified magnetic nanoparticles. Transmission electron microscopy, Fourier transform infrared spectroscopy, Thermogravimetric analysis, XRD, and anti-CD34 immunofluorescence suggested that anti-CD34 and citric acid were successfully modified onto Fe3O4, and Prussian blue staining demonstrated the selectivity of the as-prepared nanoparticles for EPCs. Under an external magnetic field (EMF), numerous nanoparticles or EPCs attached onto the surface of iron pieces, particularly the side of the iron pieces exposed to flow conditions, because iron could be magnetized under the EMF, and the magnetized iron has an edge effect. However, the uniform adhesion of EPCs on the iron stent was completed because of the weakening edge effect, and the sum of adherent EPCs was closely linked with the magnetic field (MF) intensity, which was validated by the complete covering of EPCs on the iron stent upon exposure to a 300 mT EMF within 3 h, whereas almost no cells were observed on the iron stent without an EMF. These results verify that this method can efficiently promote EPC capture and endothelialization of iron stents.

P954Value of a single bolus erythopoetin in STEMI patients treated with the Genous endothelial progenitor cell capture stent

Abstract Background The Endothelial Progenitor Cell (EPC) stent was designed to capture circulating EPCs and promote early stent re-endothelization. Erythropoietin (EPO) stimulates mobilization of EPC from the bone marrow. Combination of EPO and the EPC stent in the setting of ST-segment elevation myocardial infarction (STEMI) has never been investigated. Methods STEMI patients enrolled in the HEBE-III trial were randomized to a single bolus of EPO or No-EPO after implantation of the EPC capture stent. Late lumen loss (LLL) was determined at 9-month angiographic follow-up. Clinical data was collected at 30 days and 12 months. Results 196 patients were randomized to EPO (n=100) or No-EPO (n=96). No significant difference in baseline characteristics was observed between the two groups. A significant reduction in angiographic LLL was observed with EPO (0.43±0.57mm) as compared to No-EPO (0.74±0.63mm) (p=0.011). At 12 months follow up, no difference with regard to death or re- infarction was observed in both groups, whereas significant reduction in the need for target vessel revacularization for the EPO versus No-EPO was observed with rates of 7.1% and 19.1% respectively (p=0.013). Angiographic and clinical results EPO (n=39) No-EPO (n=45) P-value Angiography Lume late loss 0.43±0.57 0.74±0.63 0.011 12 months clinical Death 0 0 ns Re infarction 0 1 (2.2%) ns Additional PCI 4 (10.3%) 17 (37.8%) 0.004 CABG 2 (5.1%) 2 (4.4%) ns CVA 0 0 ns Bleeding 3 (7.7%) 4 (8.9%) ns ns = not significant; CVA = cerebrovascular accident; CABG = coronary bypass graft; PCI = percutaneous coronary intervention. Conclusion In STEMI patients treated with EPC capture stent, additional EPO can further improve angiographic LLL

Co-immobilization of CD133 antibodies, vascular endothelial growth factors, and REDV peptide promotes capture, proliferation, and differentiation of endothelial progenitor cells

Capture of endothelial progenitor cells (EPCs) in situ has been considered as a promising strategy for the rapid endothelialization and long-term patency of artificial blood vessels and implant devices. In this study, a CD133+ EPC capture surface was fabricated by grafting CD133 antibody (a more specific EPC surface marker than CD34) and Arg-Glu-Asp-Val (REDV) peptideon the methacrylate-grafted hyaluronic acid (MA-HA) and heparin-hybridized (MA-HA&Heparin) resisting layer. Vascular endothelial growth factor (VEGF) was further conjugated to the immobilized heparin. This engineered surface showed good hemocompatibility and significantly higher ability of capturing CD133+ EPCs from human peripheral blood mononuclear cells (PBMCs) and obviously upregulated the expression of endothelial cell (EC) marker genes of EPCs such as VEGF receptor 2 (VEGFR2), CD31, VE-cadherin, and von Willebrand factor (vWF), facilitating the differentiation of EPCs into ECs. The dramatically enhanced EPC proliferation on this surface was dependent on the integrin-VEGFR synergistic signaling, as ERK1/2 phosphorylation was only significantly enhanced on the REDV and VEGF co-immobilized surface. This study highlights a new surface coating strategy for blood-contact materials based on the specific EPC capturing and rapid endothelialization. Statement of SignificanceCapture of endothelial progenitor cells (EPCs) in situ is a promising strategy for the rapid endothelialization and long-term patency of artificial blood vessels and scaffolds. More specific capture of EPCs by targeting CD133 rather than CD34 can better reduce the risk of inflammation and restenosis. On the other hand, an appropriate microenvironment for EPC proliferation is equally important for endothelialization, which is rarely considered by the existing EPC capture strategies. In this study, the capture ratio of EPCs was significantly increased by simultaneously grafting CD133 antibody and VEGF on a MA-HA and heparin-hybridized antifouling layer. Further, proliferation of EPCs after capture was significantly promoted by grafting VEGF and REDV peptide through the integrin–VEGFR synergistic signaling. This study highlights a new strategy for the surface coating of blood-contact materials based on specific EPC capture and rapid endothelialization.

Prevention of in-stent restenosis with endothelial progenitor cell (EPC) capture stent placement combined with regional EPC transplantation: An atherosclerotic rabbit model.

Even with drug-eluting stents, the risk of in-stent restenosis (ISR) remains high. The goal of this study was to investigate the use of an endothelial progenitor cell (EPC) capture stent plus regional EPC transplantation to reduce the ISR rate. Endothelial progenitor cell capture stents were fabricated using fibrin gel and anti-CD34 plus anti-VEGFR-2 dual antibodies. Twenty male New Zealand white rabbits established as an atherosclerotic model were randomly divided into two groups: group 1 (n = 10), in which EPC capture stents were deployed into the right iliac artery; and group 2 (n = 10), in which sirolimus-eluting stents were placed. In both groups, EPCs were transplanted into target vessels beyond the stents, with outflow blocked. Radiologic-pathologic correlation outcomes were reviewed after 2 months. The technical success rate of EPC capture stent placement plus EPC transplantation was 100%. The ISR rate in group 1 was lower than in group 2 (1/10 vs. 4/10; p > 0.05). Minimal luminal diameters were larger in group 1 than in group 2 (computed tomographic angiography, 1.85 ± 0.15 mm vs. 1.50 ± 0.20 mm; duplex ultrasound, 1.90 ± 0.10 mm vs. 1.70 ± 0.30 mm; p > 0.05). Transplanted EPCs were tracked positively only in group 1. Pathologic analysis demonstrated neointimal hyperplasia thickness of 0.21 ± 0.09 mm in group 1 vs. 0.11 ± 0.07 mm in group 2 (p < 0.05). Endothelial progenitor cell capture stent placement plus local EPC transplant decreases the ISR rate through thrombosis reduction rather than through neointimal hyperplasia inhibition.

Functionalization with a VEGFR2-binding antibody fragment leads to enhanced endothelialization of a cardiovascular stent in vitro and in vivo.

Rapid endothelialization of cardiovascular stents is critical to prevent major clinical complications such as restenosis. Reconstruction of the native endothelium on the stent surface can be achieved by the capture of endothelial progenitor cells (EPCs) or neighboring endothelial cells (ECs) in vivo. In this study, stainless steel cardiovascular stents were functionalized with recombinant scFv antibody fragments specific for vascular endothelial growth factor receptor-2 (VEGFR2) that is expressed on EPCs and ECs. Anti-VEGFR2 scFvs were expressed in glycosylated form in Escherichia coli and covalently attached to amine-functionalized, titania-coated steel disks and stents. ScFv-coated surfaces exhibited no detectable cytotoxicity to human ECs or erythrocytes in vitro and bound 15 times more VEGFR2-positive human umbilical vein ECs than controls after as little as 3 min. Porcine coronary arteries were successfully stented with scFv-coated stents with no adverse clinical events after 30 days. Endovascular imaging and histology revealed coverage of the anti-VEGFR2 scFv-coated stent with a cell layer after 5 days and the presence of a neointima layer with a minimum thickness of 80 μm after 30 days. Biofunctionalization of cardiovascular stents with endothelial cell-capturing antibody fragments in this manner offers promise in accelerating stent endothelialization in vivo. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 108B:213-224, 2020.

Safety and efficacy of the COMBO bio-engineered stent in an all-comer PCI cohort: 1-Year final clinical outcomes from the MASCOT post-marketing registry

BackgroundThe COMBO stent (OrbusNeich Medical, Ft. Lauderdale, Florida) is a new-generation bio-engineered drug eluting stent, combining an abluminal coating of a bioabsorbable polymer matrix for sustained release of sirolimus and luminal anti-CD34 coating for endothelial progenitor cell capture and rapid endothelialization. MethodsThe Multinational Abluminal Sirolimus Coated BiO-Engineered StenT (MASCOT) registry was a prospective post-marketing study conducted from June 2014–May 2017 across 60 centers globally. Patients were eligible if COMBO stent implantation was attempted, and they received dual antiplatelet therapy (DAPT) per local guidelines. Follow-up was conducted by trained research staff at 1, 6 and 12 months by phone or clinic visit to capture clinical events and DAPT cessation events. The primary endpoint was 1-year target lesion failure (TLF), composite of cardiac death, non-fatal myocardial infarction not clearly attributable to a non-target vessel, or ischemia-driven target lesion revascularization. ResultsA total of 2614 patients were enrolled over the study period with 96.7% completion of 1-year follow-up. The mean age of enrolled patients was 62.9 ± 11.2 years and 23.0% were female. Diabetes mellitus was present at baseline in 33.5%. A total of 56.1% patients underwent PCI for acute coronary syndrome (ACS). The 1-year primary endpoint of TLF occurred in 3.4% patients (n = 88). Definite stent thrombosis occurred in 0.5% patients (n = 12). ConclusionThe MASCOT post marketing registry provides comprehensive safety and efficacy outcomes following contemporary PCI using the novel COMBO stent in an all-comer population. This platform is associated with low rates of 1-year TLF and ST. Clinicaltrials.gov identifierNCT02183454.