Bivalirudin Research Articles

Poly(L-lactide-co-ɛ-caprolactone)/gelatin-based small-diameter vascular grafts: Salutatory effect of the BVLD and EGCG-Cu to promote hemocompatibility and nitric oxide production for in situ blood vessel regeneration

Polymeric small-diameter vascular grafts (SDVGs, inner diameter, < 6 mm) with characteristics, such as thrombo-protection and adequate short-term as well as long-term patency are still in the development and exploration stage. In this study, based on the gas signaling molecule release strategy, SDVGs were prepared by electrospinning using poly(L-lactide-co-ɛ-caprolactone) (PLCL) and gelatin (Gel). Bivalirudin (BVLD) and epigallocatechin gallate-copper (EGCG-Cu) complex were loaded into SDVGs to improve hemocompatibility and nitric oxide (NO) release, respectively. Vascular grafts manifested drug release for up to 40 days in vitro; BVLD effectively inhibited thrombosis while the EGCG-Cu complex catalyzed the NO production from endogenous donors (S-nitroso glutathione (GSNO) and glutathione (GSH)), thereby conferring vascular grafts with functions similar to that of the natural vascular endothelium layer. Both in vitro and in vivo tests demonstrated that SDVGs co-loaded with BVLD and EGCG-Cu (PG-EB) could effectively inhibit thrombosis, alleviate inflammation, and suppress the proliferation of smooth muscle cells (SMCs) while promoting the proliferation of endothelial cells (ECs), and finally regenerate vascular tissues. In vivo animal experiments demonstrated that vascular grafts could promote endothelialization and vascular remodeling. In summary, our simultaneous utilization of BVLD and EGCG-Cu may offer a promising avenue for the fabrication of in situ regenerable SDVGs.

Bivalirudin-hydrogel coatings of polyvinyl chloride on extracorporeal membrane oxygenation for anticoagulation.

Thromboembolic events associated with extracorporeal membrane oxygenation (ECMO) in clinical treatment are typical. Heparin coating has been widely employed as a surface modification strategy for ECMO tubes. However, its clinical application is often accompanied by unavoidable complications due to its mechanism of action. As a direct thrombin inhibitor with a single target, Bivalirudin (BV) has exhibited a lower incidence of adverse events and superior pharmacokinetic performance compared to heparin. A gelatin methacrylate hydrogel (GelMA) coating layer with BV was successfully synthesized on polyvinyl chloride, and the drug release ratio was close to complete release within 7 days. Simulated extracorporeal circulation experiments using roller pumps in vitro and jugular arteriovenous bypass experiments in rabbits demonstrated its outstanding anticoagulant efficacy. The systemic anticoagulant assay proved that BV hydrogel coating does not affect the coagulation level, and reduces the risk of complications such as systemic bleeding compared to intravenous injection. BV-Coating GelMA hydrogel tube has exhibited good biocompatibility and significantly improved anticoagulant performance, making it an optimal choice for surface materials used in blood-contacting medical devices.

Abstract 12314: Bivalirudin versus Unfractionated Heparin During Percutaneous Intervention for Chronic Total Occlusion: A Systematic Review and Meta-Analysis

Introduction: Chronic total occlusion (CTO) percutaneous intervention (PCI) is an evolving challenge within interventional cardiology. Anticoagulation during percutaneous intervention remains part of the standard of care for patients undergoing PCI to prevent thrombotic complications peri-procedurally. Unfractionated heparin (UFH) is a commonly used for CTO PCI-related anticoagulation. However, bivalirudin (BV), a synthetic, reversible, direct thrombin inhibitor, has been utilized as an alternative to UFH in CTO patients undergoing PCI. This meta-analysis aims to investigate the efficacy and safety of bivalirudin versus UFH for CTO PCI. Methods: We performed a comprehensive literature search using PubMed, Embase, and Cochrane Library databases through May 2022 for all studies evaluating efficacy and safety of bivalirudin versus UFH in CTO patients undergoing PCI. The primary outcome was mortality. Secondary outcomes were major adverse cardiac events (MACE), major bleeding events, peri-procedure myocardial infarction (MI), in-stent thrombosis, and unplanned revascularization. Pooled risk ratio (RR) and 95% confidence intervals (CIs) were obtained by the Mantel-Haenszel method within a random-effects model. Heterogeneity was assessed by I2 statistic. Results: A total of 5 studies containing 1347 patients with CTO undergoing PCI on anticoagulation (631 BV versus 716 UFH) were included. No significant difference existed between BV and UFH regarding mortality [RR: 0.54 (95% CI: 0.19-1.56); P 0.26 , I2 0%]. Major bleeding events were significantly lower in BV compared with UFH [RR: 0.33 (95% CI: 0.19-0.66); P 0.001, I2 0%]. MACE [RR: 0.75 (95% CI: 0.55-1.00); P 0.05, I2 2%], peri-procedure MI [RR: 0.80 (95% CI: 0.56-1.15); P 0.24, I2 0%], in-stent thrombosis [RR: 0.68 (95% CI: 0.19-2.39); P 0.55, I2 17%] and unplanned revascularization [OR: 0.77 (95% CI: 0.29-2.07); P 0.61, I2 0%] were similar between the two groups. Conclusions: BV seems to be safer than UFH in preventing major bleeding in anticoagulated patients with CTO undergoing PCI; there is no significant difference between groups in terms of mortality, MACE, peri-procedure MI, in-stent thrombosis, or unplanned revascularization. Future randomized controlled trials are needed.

Outcomes of systemic bivalirudin and sodium bicarbonate purge solution for Impella 5.5.

Impella 5.5 (Abiomed; Danvers, MA) (IMP5) is a commonly used, surgically implanted, tMCS device that requires systemic anticoagulation and purge solution to avoid pump failure. To avoid heparin-induced thrombocytopenia (HIT) from unfractionated heparin (UFH) use, our program has explored the utility of bivalirudin (BIV) for systemic anticoagulation and sodium bicarbonate-dextrose purge solution (SBPS) in IMP5.5. This single center, retrospective study included 34 patients supported on IMP5.5 with BIV based AC and SBPS between December 1st 2020 to December 1st 2021.The efficacy and safety end points were incidence of development of HIT, Tissue Plasminogen Activator (tPA) use for suspected pump thrombosis, stroke, and device failure as well as clinically significant bleeding. The median duration of IMP5.5 support was 9.8 days (IQR: 6-15). Most patients were bridged to HTX (58%) followed by recovery (27%) and LVAD implantation (15%). Patients were therapeutic on bivalirudin for 64% of their IMP5.5 support. One patient (2.9%) suffered from ischemic stroke and 26.5% (9) patients developed clinically significant bleeding. tPA was administered to 7(21%) patients. One patient in the entire cohort developed HIT. Our experience supports the use of systemic BIV and SBPS as a method to avoid heparin exposure in a patient population predisposed to the development of HIT.

Surface modification of polycarbonate urethane by grafting polyethylene glycol and bivalirudin drug for improving hemocompatibility

AbstractAs the clinical demand for blood‐contacting materials increases, higher requirements are placed on their physicochemical properties, durability and hemocompatibility in vivo. In this work, a multiple functionalized material was developed through a facile modification process. Herein, polycarbonate urethane (PCU) surface was co‐modified with polyethylene glycol (PEG) and bivalirudin (BVLD). PCU provides excellent physical and mechanical properties, PEG and BVLD, especially BVLD, enable the surface with outstanding anticoagulant capacity. Specifically, PCU surface was first treated with hexamethylene diisocyanate to introduce active isocyanate groups onto the surface, followed by hydroxy‐PEG grafting to improve the hydrophilicity. Finally, BVLD was immobilized on the surface via Michael addition reaction to improve antithrombotic properties. Attenuated total reflection Fourier transforms infrared spectroscopy and UV spectrophotometers were used to confirm the modified surfaces. The hydrophilicity was characterized by static water contact angle measurement, the morphology of the modified surfaces was observed by scanning electron microscopy. Blood compatibility of the modified surfaces was characterized by the hemolysis rate, platelet adhesion assay and cell culture test. The results showed that the BVLD immobilized surface has excellent anticoagulant properties, good fibrin‐bound thrombin inhibition, and good resistance against non‐specific adhesion of proteins. Hence, the co‐modification with PEG and BVLD was proved an encouraging strategy for improving hemocompatibility.

Effects of systemic anticoagulation in a murine model of compensatory lung growth.

Neonates with congenital diaphragmatic hernia (CDH) suffer from pulmonary hypoplasia (PH) and may require extracorporeal membrane oxygenation (ECMO) and anticoagulation, often with unfractionated heparin (UFH). UFH interacts with vascular endothelial growth factor (VEGF), a factor important in lung development. We investigated the effects of UFH, low molecular weight heparin (LMWH), and bivalirudin (BV) on a murine model of compensatory lung growth (CLG). Proliferation and apoptosis were assessed in microvascular lung endothelial cells (HMVEC-L) treated with anticoagulants. Eight-week-old C57Bl/6J mice underwent left pneumonectomy and anticoagulation with low- or high-dose UFH, LMWH, BV, or saline control. Lung volume, pulmonary function tests, morphometrics, treadmill exercise tolerance, and pulmonary protein expression were examined. UFH and LMWH inhibited HMVEC-L proliferation. BV promoted proliferation and decreased apoptosis. UFH and LMWH-treated mice had reduced lung volume, total lung capacity, alveolar volume, and septal surface area compared to controls, while BV did not affect these measures. UFH and LMWH-treated mice had lower exercise tolerance compared to controls. UFH and LMWH impair pulmonary growth, alveolarization, and exercise tolerance, while BV does not. Alternative anticoagulants to heparin may be considered to improve functional outcomes for neonates with CDH and pulmonary hypoplasia. Unfractionated heparin and low molecular weight heparin may modify compensatory lung growth by reducing microvascular lung endothelial cell proliferation and affecting pulmonary angiogenic signaling. Functional effects of unfractionated heparin and low molecular weight heparin on murine compensatory lung growth include reduction in exercise tolerance. Bivalirudin, a direct thrombin inhibitor, may increase microvascular lung endothelial cell proliferation and preserves lung volume, alveolarization, and exercise tolerance in a murine compensatory lung growth model. Anticoagulants alternative to heparin should be further investigated for use in neonates with pulmonary hypoplastic diseases to optimize lung growth and development and improve outcomes.

Bivalirudin exerts antiviral activity against respiratory syncytial virus-induced lung infections in neonatal mice.

Respiratory syncytial virus (RSV) is the most common cause of small airways inflammation in the lungs (bronchiolitis) in neonates and immunocompromised adults. The deregulation of cellular and plasma components leads to increased morbidity and mortality. The activation of the clotting cascade plays a key role in the progression of disease severity during viral infection. The current investigation studied the effect of bivalirudin (BR) on the progression and cellular effects of RSV-induced infection in the neonatal mice model. Mice (5-7 days old) were inoculated intranasally with RSV with or without BR administration (2 mg kg-1 day-1, i.v.) for 2 weeks. Tissue histopathology, inflammatory signalling genes such as TLR, and cytokines were analyzed. The results showed pneumocytes exhibiting nuclear pyknosis, cellular infiltration in lung tissue and increased lung titers in RSV-infected mice compared to the control. Furthermore, RSV-infected mice demonstrated altered clotting parameters such as D-dimer, soluble thrombomodulin, and increased inflammatory cytokines IL-5, 6, IFN-γ, IL-13, and CXCL1. Additionally, the mRNA expression analysis displayed increased levels of IL-33, TLR3, and TLR7 genes in RSV-infected lung tissue. Further, to delineate the role of micro RNAs, the qRT-PCR analysis was done, and the results displayed an increase in miR-136, miR-30b, and let-7i. At the same time, the down-regulated expression of miR-221 in RSV-infected mice compared to the control. BR treatment reduced the cellular infiltration with reduced inflammatory cytokines and normalized clotting indices. Thus, the study shows that RSV infection induces specific changes in lung tissue and the clotting related signalling mechanism. Additionally, BR treatment significantly reduces bronchiolitis and prevents the severity of the infections suggesting that BR can possibly be used to reduce the viral-mediated infections in neonates.

Direct thrombin inhibitor-bivalirudin improved the hemocompatibility of electrospun polycaprolactone vascular grafts

Synthetic artificial vascular grafts are hampered by their low patency rate in substituting small-caliber arteries (inner diameter <6 mm) because of their poor hemocompatibility . As compared to the heparin, bivalirudin (BV), a direct thrombin inhibitor, is a more reliable anticoagulant. In this study, BV-loaded polycaprolactone (PCL) grafts (PCL-BV) were fabricated by electrospinning. The loading rate of BV was approximately 87%. The PCL-BV grafts achieved the sustained release of BV for up to 30 days in vitro , but mainly released in the first 15 days. Scanning electron microscopy (SEM) and mechanical testing revealed that the BV loading did not affect the structure and mechanical properties of PCL grafts. In vitro coagulation analysis showed that the loading of the BV reduced thrombin activity, prolonged hemocompatibility parameters (activated partial thromboplastin time (APTT), prothrombin time (PT) and thromboplastin time (TT)), reduced blood coagulation, and inhibited the adhesion and activation of fibrinogen (FIB) and platelets. The assessment of vascular grafts in a rabbit arteriovenous (AV)-shunt ex vitro and carotid artery implantation in vivo indicated that BV significantly improved the antithrombogenicity and patency of PCL grafts. Overall, these results suggested that the incorporation of BV into electrospun grafts would be an effective approach to improve the hemocompatibility and patency rate of synthetic vascular grafts.

A Polyphenol-Network-Mediated Coating Modulates Inflammation and Vascular Healing on Vascular Stents.

Localized drug delivery from drug-eluting stents (DESs) to target sites provides therapeutic efficacy with minimal systemic toxicity. However, DESs failure may cause thrombosis, delay arterial healing, and impede re-endothelialization. Bivalirudin (BVLD) and nitric oxide (NO) promote arterial healing. Nevertheless, it is difficult to combine hydrophilic signal molecules with hydrophobic antiproliferative drugs while maintaining their bioactivity. Here, we fabricated a micro- to nanoscale network assembly consisting of copper ion and epigallocatechin gallate (EGCG) via π-π interactions, metal coordination, and oxidative polymerization. The network incorporated rapamycin and immobilized BVLD by the thiol-ene "click" reaction and provided sustained rapamycin and NO release. Unlike rapamycin-eluting stents, those coated with the EGCG-Cu-rapamycin-BVLD complex favored competitive endothelial cell (EC) growth over that of smooth muscle cells, exhibited long-term antithrombotic efficacy, and attenuated the negative impact of rapamycin on the EC. In vivo stent implantation demonstrated that the coating promoted endothelial regeneration and hindered restenosis. Therefore, the polyphenol-network-mediated surface chemistry can be an effective strategy for the engineering of multifunctional surfaces.

Bivalirudin vs. heparin in paediatric and adult patients on extracorporeal membrane oxygenation: A meta-analysis.

Unfractionated heparin (UFH) has been the primary anticoagulant of choice on extracorporeal membrane oxygenation (ECMO). However, it is debatable whether bivalirudin (BIV), a direct thrombin inhibitor, may be considered a better alternative anticoagulant option. We searched Embase, Pubmed, Cochrane library, Clinicaltrials.gov, CNKI and Wanfang databases up to 15 June 2021. Randomized controlled trials and observational studies were considered eligible for inclusion. Random-effects meta-analyses, including subgroup analyses, were conducted. A total of 9 studies containing 994 patients were enrolled. All articles were retrospective cohort studies. Compared with UFH, BIV was associated with lower risks of major bleeding (risk ratio [RR]: 0.32, 95% confidence interval [CI] 0.22-0.49), ECMO in-circuit thrombosis (RR: 0.57, 95% CI 0.43-0.74), stroke (RR: 0.52, 95% CI 0.29-0.95) and in-hospital mortality (RR: 0.82, 95% CI 0.69-0.99), and higher rates of survival to ECMO decannulation (RR: 1.18, 95% CI 1.03-1.34). Pooled risk estimates did not show a significant association with clinical thrombotic events (RR: 0.69, 95% CI 0.45-1.07). Moreover, BIV was associated with a lower risk of ECMO in-circuit thrombosis and in-hospital mortality in the adult subgroup but not in the paediatric subgroup. However, leave-one-out sensitivity analyses indicated that the results of stroke, survival to ECMO decannulation and in-hospital mortality should be interpreted with caution. BIV appears to be a potential alternative to UFH in paediatric and adult patients requiring ECMO.

Outcomes of systemic anticoagulation with bivalirudin for Impella 5.0.

Temporary mechanical circulatory support (tMCS) devices are used for the management of cardiogenic shock. The Impella 5.0 (Abiomed; Danvers, MA) (IMP5) is a commonly used, surgically implanted, tMCS device that requires systemic anticoagulation and purge solution to avoid pump failure. To avoid heparin-induced thrombocytopenia (HIT) from unfractionated heparin (UFH) use, our program has explored the utility of bivalirudin (BIV) for systemic anticoagulation in IMP5. This single center, retrospective study included patients supported on IMP5 with BIV based AC. The efficacy and safety end points were recovery, bridge to left ventricular assist device (LVAD), cardiac transplant (HTX), or death as well as clinically significant bleeding, incidence of Tissue Plasminogen Activator (tPA) use for suspected pump thrombosis, stroke, and device failure. There were 31 patients included, and 26 (84%) received BIV purge solutions. The median duration of IMP5 was 6 (IQR 4-10) days. Most patients were bridged to LVAD (39%, 12); 16% (5) were bridged to HTX, 16% (5) recovered, and 29% (9) died. One patient (3%) suffered from ischemic stroke and 12% (4) patients developed clinically significant bleeding. tPA was administered to 8 (26%) patients. Logistic regression analysis demonstrated that duration of IMP5 was a significant predictor of tPA use (OR 1.28; 95% Confidence Interval 1.04-1.56). There were no cases of pump failure. Our experience highlights the feasibility of utilizing BIV for routine AC use in IMP5.

Bivalirudin: Are kids just adults to the ¾ power?

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Electrochemical-spectroscopic-chemometric investigation of binding and inhibition of myeloperoxidase by bivalirudin: Application to determination of myeloperoxidase as a biomarker for acute coronary syndrome

In this paper, we are going to report results of one of our projects in which we have investigated binding and inhibition of myeloperoxidase (MO) by bivalirudin (BV) with the help of electrochemical and spectroscopic techniques assisted by chemometric methods. Different electrochemical and spectroscopic data were combined or individually used to justify binding and inhibition of the MO by BV. Hard and soft modeling chemometric methods were used to the analysis of experimental data to extract concentration profiles, pure instrumental signal profiles and binding constant value (Kb). Results of conventional and chemometric analyses confirmed a relatively strong binding of BV with MO which inhibited it. Concentration and pure instrumental signal profiles revealed interaction and binding of BV with MO and formation of one complex species. Inhibition of the MO by BV helped us to exploit a quantitative concept for electrochemical determination of the MO based on its binding with BV. Determination of the MO was performed by electrochemical impedance spectroscopy (EIS) and differential pulse voltammetry (DPV) and the results of the EIS were better than DPV which can be suggested for the analysis of serum samples with the aim of evaluation of patients with acute coronary syndrome.

Outcomes of Systemic Anticoagulation with Bivalirudin for Impella 5.0

<h3>Purpose</h3> The Impella 5.0 (IMP5) is a surgically implanted axial flow pump used in cardiogenic shock. Anticoagulation (AC) strategy with unfractionated heparin (UFH) is used for pump patency. Alternative AC strategies have not been well defined. This study examines the outcomes of patients treated with bivalirudin (BIV) for AC during IMP5 utilization. <h3>Methods</h3> This single center, retrospective study included patients supported on IMP5 with BIV based AC. The primary end points were recovery, bridge to left ventricular assist device (LVAD), cardiac transplant (HTX), or death. Secondary end points included clinically significant bleeding (TIMI major or minor), incidence of tPA (Tissue Plasminogen Activator) use for suspected pump thrombosis, stroke, and device outcomes. <h3>Results</h3> 31 patients were included with a mean age of 57.4 years and 19.4% female. 26 patients (84%) received BIV purge solution. The median duration of IMP5 was 6 days. Most patients (38.7%) were bridged to LVAD; 16.1% were bridged to HTX, 16.1% recovered, and 29% died. 1 patient (3.2%) suffered ischemic stroke and 12 patients (38.7%) developed TIMI major or minor bleeding. . tPA was administered to 8/31 (25.8%) of patients. There was no difference in time to therapeutic AC between patients given or not given tPA(p=0.18). Of those given tPA, 37.5% had therapeutic aPTTs (61-75 seconds) immediately prior to tPA. 17/23 (73.9%) of patients not given tPA had therapeutic aPTTs (Fig. 1). Overall time to therapeutic range for all subjects is displayed in Figure 2. Logistic regression analysis demonstrated that duration of IMP5 was a significant predictor of tPA use (OR 1.28; 1.04-1.56). There were no cases of pump failure. <h3>Conclusion</h3> Use of BIV as an alternative to UFH for IMP5 was proven to be feasible with most patients surviving to recovery, LVAD, or HTX.

Bivalirudin and sirolimus co-eluting coronary stent: Potential strategy for the prevention of stent thrombosis and restenosis

Localized drug delivery with sustained elution characteristics from nanocarrier coated stents represents a viable therapeutic approach to circumvent concerns related to coronary stent therapy. We fabricated a Sirolimus (SRL) and Bivalirudin (BIV) releasing nanoparticles (NPs) coated stent for concurrent mitigation of vascular restenosis and acute stent thrombosis. SRL NPs were prepared by nanoprecipitation method whereas the BIV vesicles were generated using hydrophobic ion pair approach followed by micellization phenomenon. MTT assay and confocal microscopic analysis indicated superior anti-proliferative activity and higher cellular uptake of SRL NPs into human coronary artery smooth muscle cells, respectively. DSC and ATR-FTIR techniques confirmed the formation of complex between BIV and phosphatidylglycerol via some weak physical interactions. More than 2 fold rise in log P value was obtained for DSPG-BIV at 3:1 M ratio compared with native BIV solution. The SAXS analysis indicated formation of oligolamellar vesicles of DSPG-BIV complex which was preferentially entrapped into lipophilic lamellae of vesicles. APTT, PT, and TT tests revealed that the BIV vesicles caused significant prolongation of clotting time compared to native BIV solution. The SEM analysis showed uniform and defect free stent coating. In vitro release study demonstrated that SRL and BIV were eluted in a sustained manner from coated stents.

Vascular transplantation with dual-biofunctional ePTFE vascular grafts in a porcine model.

Cardiovascular disease (CVD) poses serious health concerns worldwide. The lack of transplantable vascular grafts is an unmet clinical need in the surgical treatment of CVD. Although expanded polytetrafluoroethylene (ePTFE) vascular grafts have been used in clinical practice, a low long-term patency rate in small-diameter transplantation application is still the biggest challenge. Thus, surface modification of ePTFE is sought after. In this study, polydopamine (PDA) was used to improve the hydrophilia and provide immobilization sites in ePTFE. Bivalirudin (BVLD), a direct thrombin inhibitor, was used to enhance the anti-thrombotic activity of ePTFE. The peptides derived from extracellular matrix proteins were used to elevate the bioactivity of ePTFE. The morphology, chemical composition, peptide modified strength, wettability, and hemocompatibility of modified ePTFE vascular grafts were investigated. Then, an endothelial cell proliferation assay was used to evaluate the best co-modification strategy of the ePTFE vascular graft in vitro. Since a large animal could relatively better mimic human physiology, we chose a porcine carotid artery replacement model in the current study. The results showed that the BVLD/REDV co-modified ePTFE vascular grafts had a satisfactory patency rate (66.7%) and a higher endothelial cell coverage ratio (70%) at 12 weeks after implantation. This may offer an opportunity to produce a multi-biofunctional ePTFE vascular graft, thereby yielding a potent product to meet the clinical needs.

Phenolic-amine chemistry mediated synergistic modification with polyphenols and thrombin inhibitor for combating the thrombosis and inflammation of cardiovascular stents

Antithrombogenicity, anti-inflammation, and rapid re-endothelialization are central requirements for the long-term success of cardiovascular stents. In this work, a plant-inspired phenolic-amine chemistry strategy was developed to combine the biological functions of a plant polyphenol, tannic acid (TA), and the thrombin inhibitor bivalirudin (BVLD) for tailoring the desired multiple surface functionalities of cardiovascular stents. To realize the synergistic modification of TA and BVLD on a stent surface, an amine-bearing coating of plasma polymerized allylamine was firstly prepared on the stent surface, followed by the sequential conjugation of TA and BVLD in alkaline solution based on phenolic-amine chemistry (i.e., Michael addition reaction). TA and BVLD were successfully immobilized onto the stent surface with considerable amounts of 330 ± 12 and 930 ± 80 ng/cm2, respectively. The abundant phenolic hydroxyl groups of TA imparted the stent with ability to suppress inflammation. Meanwhile, BVLD provided an antithrombogenic and endothelial-friendly microenvironment. As a result, the combined functions of the TA and BVLD facilitate the rapid stent re-endothelialization for reduced intimal hyperplasia in vivo, and may be a promising strategy to address the clinical complications associated with restenosis and late stent thrombosis.

Using a Modified CPD Blood Bag to Store Blood from either ECMO or RRT Circuit Blood in Pediatric Patients.

By adapting a citrate phosphate dextrose (CPD) whole blood storage bag, residual blood from a renal replacement therapy (RRT) circuit can be saved in pediatric patients, decreasing in donor exposure later. The techniques used for autologous preoperative blood storage are the basis of storing the RRT circuit blood. The CPD anticoagulant has a benefit of having a commonly used reversal agent for its anticoagulant properties, i.e., calcium. Also, unlike the traditional anticoagulants used in extracorporeal membrane oxygenation (ECMO), i.e., heparin, and direct thrombin inhibitors, i.e., bivalirudin, there is no increase in anticoagulation laboratory parameters after administration. The CPD volume in the bag is reduced but keeps the original ratio the same between CPD and blood. This is accomplished by removing all CPD from the bag, adding back only the exact amount of CPD needed for the smaller amount of blood being transferred from the circuit. The RRT circuit managed at our institution uses 23 mL of CPD for 165 mL of circuit blood when stored with this technique. This calculation assumes a normal patient calcium level. This technique has been used successfully multiple times in more than 30 pediatric patients without incident for 7 years at our center. The CPD bag can also be used to store the residual blood from ECMO circuits after removal of ECMO to allow the blood to be given back to the patient at a later time by keeping the same citrate-to-blood ratio.

Metal-catechol-(amine) networks for surface synergistic catalytic modification: Therapeutic gas generation and biomolecule grafting

Regarding the high requirement of cardiac and vascular implants in tissue engineering, a novel concept of surface chemistry strategy featuring multiple functions is proposed in this study, which provides glutathione peroxidase (GPx)-like catalytic activity and allows secondary reactions for grafting functional biomolecules. The suggested strategy is the fabrication of a metal-catechol-(amine) network (MCAN) containing copper ions with GPx-like activity, amine-bearing hexamethylenediamine (HD) and wet adhesive catechol dopamine (DA). With a simple one-step molecular/ion co-assembly, the developed copper-DA-HD (CuII-DA/HD) network can be used to catalyze the generation of therapeutic nitric oxide (NO) gas in a durable and dose-controllable manner. The primary amine groups in the CuII-DA/HD network facilitate the secondary immobilization of bivalirudin (BVLD) to further provide an antithrombotic activity as supplement to the functions of NO. The CuII-DA/HD + BVLD coating functionalized on cardiovascular stents successfully improved thromboresistance, anti-restenosis, and promotes re-endothelialization in vivo. With regard to the ease of operation and low cost, the synergetic modification using MCAN strategy is of great potential for developing multifunctional blood-contacting materials/devices.

From surface to bulk modification: Plasma polymerization of amine-bearing coating by synergic strategy of biomolecule grafting and nitric oxide loading

Integration of two or more biomolecules with synergetic and complementary effects on a material surface can help to obtain multi-functions for various biomedical applications. However, the amounts of biomolecules integrated and their physiological functions are compromised due to the limited surface anchoring sites. Herein, we propose a novel concept of film engineering strategy “from surface to bulk synergetic modification”. This new concept is realized by employing the surface amine groups of plasma polymerized allylamine (PPAm) film for grafting a molecule e.g., thrombin inhibitor, bivalirudin (BVLD), meanwhile its bulk amine groups is used as a universal depot for storing and releasing therapeutic nitric oxide (NO) gas as supplement to the functions of BVLD. It is demonstrated that such a “from surface to bulk synergetic modification” film engineering can impart the modified-substrates with anti-platelet and anti-coagulant dual functions, giving rise to a highly endothelium-mimetic thromboresistant property. We believe that our research provides a very promising strategy to deliver multifunctional surface versatilely that require NO release in combination with other properties, which will find broad biomedical applications in blood-contacting devices, and et al. Moreover, it also provides a brand-new film engineering strategy for tailoring surface multi-functionalities of a wide range of materials.