Reduced Platelet Adhesion Research Articles

Stability and bioactivity of pepCD47 attachment on stainless steel surfaces

In-stent restenosis (ISR) and late stent thrombosis are the major complications associated with the use of metal stents and drug eluting stents respectively. Our lab previously investigated the use of peptide CD47 in improving biocompatibility of bare metal stents in a rat carotid stent model and our results demonstrated a significant reduction in platelet deposition and ISR. However, this study did not characterize the stability of the pepCD47 on metal surfaces post storage, sterilization and deployment. Thus, the objective of the present study was 1) to test the stability of the peptide post - storage, sterilization, exposure to shear and mechanical stress and 2) to begin to expand our current knowledge of pepCD47 coated metal surfaces into the preclinical large animal rabbit model. Our results show that the maximum immobilization density of pepCD47 on metal surfaces is approximately 350 ng/cm2. 100% of the pepCD47 was retained on the metal surface post 24 weeks of storage at 4 °C, exposure to physiological shear stress, and mechanical stress of stent expansion. The bioactivity of the pepCD47 was found to be intact post 24 weeks of storage and ethylene oxide sterilization. Finally our ex vivo studies demonstrated that compared to bare metal the rabbit pepCD47 coated surfaces showed - 45% reduced platelet adhesion, a 10-fold decrease in platelet activation, and 93% endothelial cell retention. Thus, our data suggests that pepCD47 coating on metal surfaces is stable and rabbit pepCD47 shows promising preliminary results in preventing thrombosis and not inhibiting the growth of endothelial cells. Statement of significanceBiocompatibility of bare metal stents is a major challenge owing to the significantly high rates of in-stent restenosis. Previously we demonstrated that peptide CD47 functionalization improves the biocompatibility of bare metal stents in rat model. A similar trend was observed in our ex vivo studies where rabbit blood was perfused over the rabbit pepCD47 functionalized surfaces. These results provide valuable proof of concept data for future in vivo rabbit model studies. In addition, we investigated stability of the pepCD47 on metal surface and observed that pepCD47 coating is stable over time and resistant to industrially relevant pragmatic challenges.

Novel high-strength thromboresistant poly(vinyl alcohol)-based hydrogel for vascular access applications

Adherence of proteins, cells, and microorganisms to the surface of biomaterials used for vascular access contribute to device failure by thrombosis, occlusions, and infections. Current technologies for inhibiting these complications are limited to coatings and additives that are limited in duration of efficacy and often induce adverse side effects. In this work, we developed a novel composite hydrogel structure comprising of a porous poly(vinyl alcohol) (PVA) that is impregnated with poly(acrylic acid) (PAA) and heat treated to create a physically cross-linked high-strength hydrogel material. The swelling and mechanical properties can be controlled by the temperature and duration of heat treatment to increase the cross-link density of the matrix. The heat treated composite PVA/PAA hydrogel exhibits both the mechanical strength and durability of thermoplastic polyurethanes (TPUs) and the inherently non-thrombogenic surface functionality of PVA-based hydrogels without the use of chemical cross-linking agents. The composite hydrogels were found to maintain their mechanical integrity and surface functionality after accelerated aging in a simulated-use in vitro model for 162.5 days real-time equivalent. Relative to commercial catheter materials, the composite PVA/PAA hydrogel exhibited up to an average of 97% reduction in platelet adhesion when exposed to an in vitro blood loop model and a lower rate of tip occlusion due to thrombosis. This high-strength thromboresistant hydrogel could have a major impact as a novel biomaterial for use in vascular access applications to improve patient health.

Antithrombotic, antimicrobial activities, and biocompatibility of surface-functionalized titanium

Abstract

Electrospun polyethylene terephthalate (PET) nanofibrous conduit for biomedical application

Nanostructured biomaterials have great potential in the field of biomedical engineering. Efforts for treatment of cardiovascular diseases focused on introducing vascular substitutes that are nonthrombogenic and have long‐term patency, but still there is not any perfect replacement for clinical use. In this study, nanostructure tubes of a commonly known biocompatible polymer, polyethylene terephthalate (PET), were prepared via electrospinning process using small diameter mandrel as a collector with two different speeds. The nanofibers (NFs) morphologies' physical and mechanical properties were investigated according to scanning electron microscope (SEM), water contact angle (WCA), porosity measurement, differential scanning calorimetry (DSC), and tensile test. Finer NFs, more percentage of crystallinity, and superior mechanical properties were observed for samples prepared by higher speed mandrel. Since both samples stimulated platelet adhesion and activation, further surface modification with sodium nitrate as nitric oxide (NO) donor was done using two different approaches: dip‐coating and electrospraying. The modified NFs were evaluated via SEM, WCA, tensile test, platelets, and cell adhesion. The results showed more hydrophilicity, reduction in platelet adhesion, and improved blood compatibility for eNO‐HS (electrosprayed NO for higher collector speed) compared with other samples implying the promising potential of this fabrication and modification technique for improving PET‐based cardiovascular substitutes.

Fungal Chitin Reduces Platelet Activation Mediated via TLR8 Stimulation.

Platelets play an important role in the innate immune response. During candidaemia, circulating fungal polysaccharides, including chitin, are released into the bloodstream and can interact with platelets and induce modulation of platelet activities. However, the role of circulating chitin in platelet modulation has not been investigated. The aims of the present study were to assess the effect of fungal chitin on activation, adhesion, aggregation and receptor expression of platelets and their impact on the host defense against Candida albicans. Platelets pre-treated with different concentrations of chitin (10–400 μg/mL) extracted from C. albicans were analyzed in terms of activation, Toll-like receptor (TLR) expression, aggregation and adhesion to C. albicans. Chitin treatment reduced platelet adhesion to C. albicans and neutrophils. P-selectin expression was significantly decreased in platelets challenged with chitin. Aggregation and intracellular Ca2+ influx were also decreased in platelets. TLR8 mRNA and proteins were expressed in platelets pre-treated with chitin when compared to untreated platelets. Overall, chitin purified from C. albicans reduced the adhesion, activation and aggregation of platelets mediated via TLR8 stimulation by decreasing intracellular Ca2+ influx and P-selectin expression.

Immobilization of Fibronectin-Loaded Polyelectrolyte Nanoparticles on Cardiovascular Material Surface to Improve the Biocompatibility

Vascular stent interventional therapy is the main method for clinical treatment of coronary artery diseases. However, due to the insufficient biocompatibility of cardiovascular materials, the implantation of stents often leads to serious adverse cardiac events. Surface biofunctional modification to improve the biocompatibility of vascular stents has been the focus of current research. In this study, based on the structure and function of extracellular matrix on vascular injury healing, a novel fibronectin-loaded poly-l-lysine/heparin nanoparticles was constructed for stent surface modification. In vitro blood compatibility evaluation results showed that the nanoparticles-modified surface could effectively reduce platelet adhesion and activation. In vitro cellular compatibility evaluation results indicated that the nanocoating may provide adequate efficacy in promoting the adhesion and proliferation of endothelial cells and thereby accelerate endothelialization. This study provides a new approach for the surface biological function modification of vascular stents.

Preparation and characterization of biodegradable and hemocompatible copolymers

In this study, we developed biodegradable polyesters with hemocompatibility and anti-thrombotic functions. First, we synthesized 3-benzyloxymethyl-6-methyl-1,4-dioxane-2,5-dione (LA-Bz). The ring opening polymerization of ε-caprolactone (CL), l-lactide (LA), and LA-Bz monomers provided poly(ε-caprolactone-ran-l-lactide-ran-3-benzyloxymethyl lactide) (PCLA-Bz) copolymers. Poly(ε-caprolactone-ran-l-lactide) (PCLA) was prepared as a control biodegradable copolymer. Subsequent deprotective benzyl reactions of PCLA-Bz and additional reactions with glutaric anhydride yielded PCLA copolymers with COOH pendant groups (PCLA-COOH). Afterward, methoxypolyethylene glycol (PCLA-MPEG) or heparin (PCLA-heparin) as an anti-thrombotic group was introduced in the pendant position of PCLA. The in vitro degradation and mechanical properties of PCLA, PCLA-COOH, PCLA-MPEG, and PCLA-heparin were examined over 8 weeks. In the hemocompatibility testing, PCLA-COOH, PCLA-MPEG, and PCLA-heparin exhibited hemocompatibility with little adherence of platelets. In addition, PCLA-heparin exhibited significantly reduced platelet adhesion and enhanced blood stability and thrombin inactivation. These results show that the introduction of anti-thrombotic groups in the pendant position of PCLA represents a useful approach to prepare biodegradable and hemocompatible copolymers.

PCL/sulfonated keratin mats for vascular tissue engineering scaffold with potential of catalytic nitric oxide generation.

Heparin-like polymers have a good anticoagulant effect due to some groups similar to heparin. Herein, sulfonated keratin(SK) was prepared by chain transfer radical polymerization of 3-sulfopropyl methacrylate(SPMA) to improve blood coagulation nature of keratin. Poly(ε-caprolactone)(PCL)/SK nanofibrous mats with the ratio of 7 and 3 were then fabricated by electrospinning. In vitro cytotoxicity and blood compatibility tests were performed to assess the biocompatibility. Viability of NIH 3T3 cells on PCL/SK mats was higher than that on the pristine PCL mats, indicating their good cytocompatibility. These sulfonated keratin-containing mats enhanced endothelial cell growth, while inhibited smooth muscle cell proliferation and reduced platelet adhesion in the presence of GSH and GSNO, as a result of NO generation. Furthermore, the biocomposite mats prolonged the activated partial thromboplastin time(APTT) effectively without hemolysis. Taken together, PCL/SK mats are potential for applications in vascular tissue engineering.

Early Inhibition of P-Selectin/P-Selectin Glycoprotein Ligand-1 Reduces Intimal Hyperplasia in Murine Vein Grafts through Platelet Adhesion.

Inflammatory processes contribute to intimal hyperplasia (IH) and long-term failure of vein grafts used in bypass surgery. Leukocyte recruitment on endothelial cells of vessels during inflammation is regulated by P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1), which also mediates the interaction between platelets and endothelial cells in vein grafts transferred to arteries. However, how this pathway causes IH in vein grafts is unclear. In this study, we used a murine model of vein grafting to investigate P-selectin-mediated platelet adhesion, followed by IH. On the luminal surface of the vein graft, leukocyte recruitment occurred mainly in areas with adhered platelets rather than on endothelial cells without adherent platelets 1 hour after vein grafting. Blockage of either P-selectin or PSGL-1 reduced platelet adhesion and leukocyte recruitment on the luminal surface of vein grafts. Inhibition of the P-selectin pathway in vein grafts significantly reduced platelet-mediated leukocyte recruitment and IH of vein grafts 28 days after surgery. The study demonstrates that functional blockage of the P-selectin/PSGL-1 pathway in the early inflammatory phase after vein grafting reduced leukocyte invasion in the vein graft wall and later IH development. The findings imply an attractive early time window for prevention of vein graft failure by manipulating platelet adhesion.

Effects of diameters and crystals of titanium dioxide nanotube arrays on blood compatibility and endothelial cell behaviors

Titanium dioxide nanotube arrays (TNTAs) have attracted extensive attention in the fields of biomaterials and biomedicine due to their unique tubular structure and good biocompatibility. In this paper, TNTAs with different nanotube diameters and lengths were in situ prepared on the titanium surface by the anodic oxidation, and their crystal structures were further changed by annealing treatment. The effects of TNTAs with different diameters and crystals on the blood compatibility and endothelial cell behaviors were investigated. The results showed that TNTAs with the diameter of 30∼90 nm can be obtained by controlling the anodization voltage, and annealing treatment did not obviously change the diameters and lengths of the nanotube arrays. However, annealing treatment can transform the amorphous TNTAs into the anatase structure. The diameter and crystal structure of the nanotube arrays played a key role in the surface wettability and protein adsorption. The nanotube array with larger diameter displayed better surface hydrophilicity as compared to the pristine titanium, and annealing treatment further enhanced the hydrophilicity. As compared to the pristine titanium, the nanotube array structure had the characteristic of selective protein adsorption, and the nanotube array can promote the bovine serum albumin (BSA) adsorption and prevent the fibrinogen (FIB) adsorption, however, the increase of nanotube diameter could reduce BSA adsorption and increase FIB adsorption. Besides, the nanotube array with anatase structure can promote BSA adsorption while reduce FIB adsorption. Therefore, the TNTAs with smaller diameter and anatase crystal had good blood compatibility and cell compatibility, they can not only reduce platelet adhesion and hemolysis rate but also increase endothelial cell adhesion and proliferation. In conclusion, the nanotube arrays of the present study can be used to improve the cell compatibility and blood compatibility of the titanium implants.

Multifunctional S-Nitroso-N-acetylpenicillamine-Incorporated Medical-Grade Polymer with Selenium Interface for Biomedical Applications.

Modern crises in implantable or indwelling blood-contacting medical devices are mainly due to the dual problems of infection and thrombogenicity. There is a paucity of biomaterials that can address both problems simultaneously through a singular platform. Taking cues from the body's own defense mechanism against infection and blood clotting (thrombosis) via the endogenous gasotransmitter nitric oxide (NO), both of these issues are addressed through the development of a layered S-nitroso-N-acetylpenicillamine (SNAP)-doped polymer with a blended selenium (Se)-polymer interface. The unique capability of the SNAP-Se-1 polymer composites to explicitly release NO from the SNAP reservoir as well as generate NO via the incorporated Se is reported for the first time. The NO release from the SNAP-doped polymer increased substantially in the presence of the Se interface. The Se interface was able to generate NO in the presence of S-nitrosoglutathione (GSNO) and glutathione (GSH), demonstrating the capability of generating NO from endogenous S-nitrosothiols (RSNO). Scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS) traced distribution of elemental Se nanoparticles on the interface and the surface properties were evaluated by surface wettability and roughness. The SNAP-Se-1 efficiently inhibited the growth of bacteria and reduced platelet adhesion while showing minimal cytotoxicity, thus potentially eliminating the risks of systemic antibiotic and blood coagulation therapy. The SNAP-Se-1 exhibited antibacterial activity of ∼2.39 and ∼2.25 log reductions in the growth of clinically challenging adhered Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli. SNAP-Se-1 also significantly reduced platelet adhesion by 85.5% compared to corresponding controls. A WST-8-based cell viability test performed on NIH 3T3 mouse fibroblast cells provided supporting evidence for the potential biocompatibility of the material in vitro. These results highlight the prospective utility of SNAP-Se-1 as a blood-contacting infection-resistant biomaterial in vitro which can be further tuned by application specificity.

Antidepressants: bleeding or thrombosis?

The contribution of depression to the pathogenesis of cardiovascular disease includes autonomic disturbances, endothelial dysfunction, inflammation, smoking, sedentary lifestyle, carbohydrate craving, and impaired fibrinolysis. There is evidence that serotonergic antidepressants (selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors) restore the fibrinolytic profile. Contrary to common belief, such antidepressants do not affect platelet aggregation induced by adenosine diphosphate or adrenaline but reduce platelet adhesion to collagen. Since platelet collagen receptor glycoprotein VI binds to fibrin, it is possible that fibrinolytic properties of serotonergic antidepressants could impair platelet adhesion to collagen. The profibrinolytic and antiplatelet properties of serotonergic antidepressants help explain the increased risk of gastrointestinal, intracranial, and surgical bleeding in patients using these medications. Studies evaluating the impact of antidepressants on thrombotic and cardiovascular risk have yielded contradictory results. Corroborating the hypothesis that serotonergic antidepressants have profibrinolytic and antiplatelet properties, some authors showed that these medications prevent both cardiovascular and thromboembolic events. Others showed an increased risk of ischemic stroke, cardiac events and thromboembolic disease. Silent brain infarction may present in some elders with depressive symptoms, so it is presumed that antidepressants are prescribed for subclinical stroke patients. Another explanation for the increased risk of cardiovascular and thromboembolic events reported by some authors in individuals taking antidepressants includes antidepressant side effects such as sedation and weight gain and depression comorbidities such as anxiety, obesity and hyperhomocysteinemia. In conclusion, we suggest that serotonergic antidepressants be considered weak anticoagulants. We also suggest that depressed patients with comorbidities increasing the risk of cardiovascular and thromboembolic disease be recommended to follow a balanced diet and engage in physical activity, such as daily walking.

Xinmailong Modulates Platelet Function and Inhibits Thrombus Formation via the Platelet αIIbβ3-Mediated Signaling Pathway.

Background: Xinmailong (XML), a bioactive composite extracted from Periplaneta americana, has been widely used to treat cardiovascular diseases such as congestive heart failure. However, it is unclear whether XML has antiplatelet and antithrombotic effects. Methods: The effects of XML on agonist-induced platelet aggregation, adhesion and spreading, granule secretion, integrin α II bβ3 activation, and thrombus formation were evaluated. Phosphorylation of Syk, PLCγ2, Akt, GSK3β, and MAPK signaling molecules was also studied on agonist-induced platelets. In addition, the antithrombotic effects of XML were observed in vivo using an acute pulmonary thrombosis mouse model. Results: XML dose-dependently inhibited in vitro platelet aggregation and granule secretion induced by thrombin, collagen, and arachidonic acid (AA). XML also greatly reduced platelet adhesion and spreading on both collagen- and fibrinogen-coated surfaces. Biochemical analysis revealed that XML inhibited thrombin-, collagen-, and AA-induced phosphorylation of Syk, PLCγ2, Akt, GSK3β, and MAPK. Additionally, XML significantly inhibited in vivo thrombus formation in a collagen–epinephrine-induced acute pulmonary thrombosis mouse model. Conclusions and General Significance: Here, we provide the first report showing that XML inhibits platelet function and that it possesses antithrombotic activity. This suggests that XML could be a potential therapeutic candidate to prevent or treat platelet-related cardiovascular diseases.

Abstract 770: Potential Explanation of the Mechanism for Loss of Function with G233D Mutation in Platelet Glycoprotein Ibα: Results fromMolecular Dynamics Simulation

Background: Platelet play crucial role for the onset of acute coronary syndrome. The initial binding following vessel injury is exclusively mediated by the binding of von Willebrand factor (VWF) and platelet glycoprotein (GP) Ib α . Previous biological experiments revealed loss of function of platelet expressing GPIb α with G233D mutation. Objective: To elucidate the mechanism underlining the loss of function in G233D mutant. Methods: Dynamic fluctuating three-dimensional structures and the Potential of Mean Force (PMF) were calculated for the binding of VWF and platelet GPIb α in wild-type or G233D mutant. PMF were calculated at each 0.5Å for 25 Å to 65 Å of mass center distance between GPIb α and VWF. The energy required to dissociate the bond between GPIb α and VWF was calculated by subtracting the lowest PMF from the PMF at 65 Å mass center distance. Chemistry at HARvard Molecular Mechanics (CHARMM) force field with NAnoscale Molecular Dynamics (NAMD) was used for calculation. The initial structure of each mutant was obtained by inducing single amino-acid substitution with Visual Molecular Dynamics (VMD) to the stable water-soluble binding structure of wild-type VWF and GPIb α . Results: The energetically most stable binding structure of VWF and GPIb α in wild-type and G233D did not differ substantially (Figure panel A). However, The energy required to dissociate the bond between GPIb α and VWF was 4.32 kcal/mol (19.5 %) lower for G233D mutant compared to wild-type (Figure panel B). Conclusions: Our results suggest that the reduction of dissociation energy of single molecule of G233D GPIb α mutant as a possible explanation for the reduced platelet adhesion under blood flow condition.

In vitro investigation of chemical properties and biocompatibility of neurovascular braided implants

Braiding of Nitinol micro wires is an established technology for the manufacturing of fine-meshed neurovascular implants for tortuous vessel geometries. Electropolishing of wires before the braiding process has the potential to improve the in vitro behaviour in terms of thrombogenicity and endothelial cell proliferation. In this study, we present the first in vitro investigation of braided electropolished/blue oxide Nitinol samples in a blood flow loop, showing a significantly lower activation of the coagulation pathway (represented by the TAT III marker) and a tendency towards reduced platelet adhesion. Furthermore, we applied the same surface treatment on flat disks and measured protein adhesion as well as endothelial cell proliferation. We compared our results to non-electropolished samples with a native oxide surface. While platelet deposition was reduced on electropolished/blue oxide surface, a significant increase of endothelial cell seeding was observed. Investigation of inflammatory marker expression in endothelial cells provided divergent results depending on the marker tested, demanding closer investigation. Surface analysis using Auger electron spectroscopy revealed a thin layer mainly consisting of titanium oxynitride or titanium oxide + titanium nitride as a potential cause of the improved biological performance. Translated to the clinical field of intracranial aneurysm treatment, the improved biocompatibility has the potential to increase both safety (low thrombogenicity) and effectiveness (aneurysm neck reconstruction).

Carboxymethyl kappa carrageenan-modified decellularized small-diameter vascular grafts improving thromboresistance properties.

The development of decellularized small-diameter vascular grafts is a potential solution for patients requiring vascular reconstructive procedures. However, there is a limitation for acellular scaffolds due to incomplete recellularization and exposure of extracellular matrix components to whole blood resulting in platelet adhesion. To address this issue, a perfusion decellularization method was developed using a custom-designed set up which completely removed cell nuclei and preserved three-dimensional structure and mechanical properties of native tissue (sheep carotid arteries). Afterwards, carboxymethyl kappa carrageenan (CKC) was introduced as a novel anticoagulant in vascular tissue engineering which can inhibit thrombosis formation. The method enabled uniform immobilization of CKC on decellularized arteries as a result of interaction between amine functional groups of decellularized arteries and carboxyl groups of CKC. The CKC modified graft significantly reduced platelet adhesion from 44.53 ± 2.05% (control) to 19.57 ± 1.37% (modified) and supported endothelial cells viability, proliferation, and nitric oxide production. Overall, the novel CKC modified scaffold provides a promising solution for thrombosis formation of small-diameter vessels and could be a potent graft for future in vivo applications in vascular bypass procedures. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1690-1701, 2019.

Constructing zwitterionic coatings on thin-film nanofibrous composite membrane substrate for multifunctionality

In this work, we construct zwitterionic multilayers on poly(vinyl alcohol) (PVA) thin-film nanofibrous composite (TFNC) substrate via a facile surface engineered layer-by-layer (LBL) assembly of poly (sulfobetaine methacrylate) (PSBMA) and tannic acid (TA, a polyphenol), which endowed the modified membranes with multifunctionality for filtration of proteins and dyes and potential biomedical application. Characterizations of surface chemical structure and morphology of the modified membranes confirmed the successful zwitterionic self-assembly modification. The LBL-assembled membranes showed superior separation performance for filtration of proteins and dyes. Especially when the number of TA/PSBMA bilayer was 6, the PVA-6BL-M possessed high permeate flux (311.7 Lm−2 h−1) and excellent rejection (99.9%) for 0.1 g/L Direct Red 80 solution at 0.6 MPa. After being covered more TA/PSBMA bilayers, the LBL-assembled membranes could not only sieve smaller molecules of proteins and dyes well, but also exhibit better anti-biofouling properties (higher water flux recovery ratio, negligible irreversible fouling and the less BSA, E. coli and S. aureus bacteria adsorption). In addition, the LBL-assembled membranes presented excellent blood compatibility (greatly reduced platelet adhesion, significantly increased clotting time and lower hemolysis ratio), which indicated great potential for biomedical application. This work provided a facile and efficient method for designing a multifunctional TFNC membrane for water treatment and biomedical engineering.

Translational Research and Early Favorable Clinical Results of a Novel Polyphosphazene (Polyzene-F) Nanocoating

This manuscript is a review of the preclinical and early clinical findings related to a unique fluorinated polyphosphazene nanolayer device surface modification. Polyzene-F (PzF) is a novel, high-molecular weight, highly pure polyphosphazene that was designed to enhance the biologic interface between a medical device surface and human tissue or blood. The polymer also has unique mechanical properties that for the first time allow implants to be paved with a coating that has a nanoscale thickness of < 50 nm. The coating has inherent thrombus resistant properties and takes on biomimetic properties soon after implant due to favorable protein adhesion. Over the last 1.5 decades, PzF has undergone extensive preclinical testing including benchtop endothelial cell migration and platelet adhesion studies followed by increasingly sophisticated evaluation in 16 different animal models. The coating consistently has shown reduced platelet adhesion, decreased clotting, reduced inflammation, and accelerated healing compared with different surfaces as well as uncoated controls. These preclinical findings have translated into early compelling clinical evidence that suggest enhanced healing and reduced thrombosis can be achieved with a PzF-coated implant. There are now two PzF nanocoated products approved by the US Food and Drug Association (FDA), embolic spheres, and a coronary stent. This is the first detailed overview of the history, preclinical findings, and current clinical results attributed to the PzF coating with emphasis on the coronary stent Cobra-PzF.Lay SummaryOver the last few decades, we have seen remarkable advances in medical technology including the development of less invasive surgical alternatives for the treatment of heart and vascular disease. One of the key advances in treating or preventing heart attack, stroke, and limb loss has been the development of stents. Stents are small, metallic, mesh-like devices that can be expanded within blocked vessels via small catheters placed through the groin or wrist. These stents provide structural support while the vessel heals. One of the challenges with stents and other permanent device implants is related to how our bodies react to foreign materials. One of the most feared complications of stents is clotting, which can result in abrupt closure of the treated artery. In the case of heart stents, abrupt closure can cause a heart attack or even sudden death whereas clotting within stents in the neck arteries (carotids) can cause stroke. Additional normal body defense mechanisms include complicated immune responses that trigger inflammation and can cause scarring resulting in early recurrence of the blockage or so-called “restenosis.” In an effort to eliminate restenosis, many stents are now coated with drugs that slow or prevent healing. The downside of this approach has been the need for long-term blood-thinning medications like Plavix and aspirin. In this article, we review the history and current clinical findings of a new way to potentially make medical implants invisible to the normal foreign body defense responses that cause subsequent complications. The innovation involves the development of a new compound called Polyzene-F (CeloNova BioSciences, San Antonio, TX) that can be placed on the surface of a device in a layer that is extremely thin. This new coating is so thin it cannot be seen with even the strongest available microscopes and falls into a new category of material science called nanotechnology. Nanotechnology involves materials that are measured on a molecular level rather than the traditional measurements used in the field of medical devices. We describe many experiments done on the benchtop alongside animal studies and early clinical results that support the hypothesis that an enhanced biologic response can be expected for implants coated with Polyzene-F. The initial types of heart disease patients being studied with this new coated stent (Cobra-PzF) are those at high risk for bleeding since we know these patients are less tolerant of blood-thinning medicine. This initial narrow focus was selected based on the experience from our team and others suggesting animal studies do not always predict how humans respond to new treatments coupled with the knowledge that drug-eluting stents are getting better each day. We do see signals in the completed Cobra-PzF clinical trials that clotting and recurrence (restenosis) are low, but these studies do not directly compare this device to alternative stents in a type of study we call a “randomized trial.” There is an ongoing large randomized trial comparing the Polyzene-F nanocoated stent (Cobra PzF) with contemporary drug-eluting stents in patients at high risk for bleeding, which should complete enrollment in 2019. At the same time, the US FDA-approved Polyzene-F-coated microbeads (Embozene, Boston Scientific, Marlborough, MA) are being studied for the treatment of tumors and cancer. If an enhanced biologic response is proven in the ongoing randomized trials being conducted on the currently approved Polyzene-F-coated devices, then this new surface enhancement may have broader application for a variety of medical device implants.

Peptide with endothelial cell affinity and antiplatelet adhesion property to improve hemocompatibility of blood‐contacting biomaterials

AbstractClinical applications of various blood‐contacting biomaterials have been limited by the complications associated with hemolysis and coagulation on material surfaces. We have been developing anticoagulant‐free polymeric mechanical heart valves with an expanded polytetrafluoroethylene (ePTFE) sewing cuff and have found that the insufficient hemocompatibility of ePTFE is one of the biggest problems to be overcome for their durability. In this work, we present a set of novel peptide sequences that bind selectively to endothelial cells (ECs) and have low platelet activation properties. Five 7mer‐oligopeptides selected from a phage display library were immobilized onto the ePTFE surface by a simple manufacturing protocol and evaluated in vitro. All sequences displayed a better EC‐binding property than the REDV. Two of the peptides displayed extremely low platelet adhesion and activation. In particular, HGGVRLY displayed the highest EC affinity and maximally reduced platelet adhesion. HGGVRLY is a promising peptide for modifying various types of blood‐contacting biomaterials.

Blood coagulation response and bacterial adhesion to biomimetic polyurethane biomaterials prepared with surface texturing and nitric oxide release

A dual functional polyurethane (PU) film that mimics aspects of blood vessel inner surfaces by combining surface texturing and nitric oxide (NO) release was fabricated through a soft lithography two-stage replication process. The fabrication of submicron textures on the polymer surface was followed by solvent impregnation with the NO donor, S-nitroso-N-acetylpenicillamine (SNAP). An in vitro plasma coagulation assay showed that the biomimetic surface significantly increased the plasma coagulation time and also exhibited reduced platelet adhesion and activation, thereby reducing the risk of blood coagulation and thrombosis. A contact activation assay for coagulation factor XII (FXII) demonstrated that both NO release and surface texturing also reduced FXII contact activation, which contributes to the inhibition of plasma coagulation. The biomimetic surface was also evaluated for bacterial adhesion in plasma and results demonstrate that this combined strategy enables a synergistic effect to reduce bacterial adhesion of Staphylococcus epidermidis, Staphylococcus aureus, and Pseudomonas aeruginosa microorganisms. The results strongly suggest that the biomimetic modification with surface texturing and NO release provides an effective approach to improve the biocompatibility of polymeric materials in combating thrombosis and microbial infection. Statement of significance(1) Developed a dual functional polyurethane (PU) film that mimics blood vessel inner surface by combining surface texturing and nitric oxide (NO) release for combatting biomaterial associated thrombosis and microbial infection. (2) Studied the blood coagulation response and bacterial adhesion to such biomimetic PU surfaces, and demonstrated that the combination of surface texturing and NO release synergistically reduced the platelet adhesion and bacterial adhesion in plasma, providing an effective approach to improve the biocompatibility of biomaterials used in blood-contacting medical devices. (3) The NO releasing surface significantly inhibits the plasma coagulation via the reduction of contact activation of FXII, indicating the multifunctional roles of NO in improving the biocompatibility of biomaterials in blood-contacting medical devices.