Thrombogenic potential of Innovia polymer valves versus Carpentier-Edwards Perimount Magna aortic bioprosthetic valves.

Trileaflet polymeric prosthetic aortic valves (AVs) produce hemodynamic characteristics akin to the natural AV and may be most suitable for applications such as transcatheter implantation and mechanical circulatory support (MCS) devices. Their success has not yet been realized due to problems of calcification, durability, and thrombosis. We address the latter by comparing the platelet activation rates (PARs) of an improved polymer valve design (Innovia LLC) made from poly(styrene-block-isobutylene-block-styrene) (SIBS) with the commercially available Carpentier-Edwards Perimount Magna Aortic Bioprosthetic Valve. We used our modified prothrombinase platelet activity state (PAS) assay and flow cytometry methods to measure platelet activation of a pair of 19 mm valves mounted inside a pulsatile Berlin left ventricular assist device (LVAD). The PAR of the polymer valve measured with the PAS assay was fivefold lower than that of the tissue valve (p = 0.005) and fourfold lower with flow cytometry measurements (p = 0.007). In vitro hydrodynamic tests showed clinically similar performance of the Innovia and Magna valves. These results demonstrate a significant improvement in thrombogenic performance of the polymer valve compared with our previous study of the former valve design and encourage further development of SIBS for use in heart valve prostheses.

In-vivo assessment of a novel polymer (SIBS) trileaflet heart valve.

BACKGROUND AND AIM OF THE STUDY: A novel trileaflet polymer valve, which is a composite design of a biostable and biocompatible polymer poly(styrene-block-isobutylene-block-styrene) (SIBS) with an embedded reinforcement polyethylene terephthalate (PET) fabric, is being developed with the intention of providing a valve that has low thrombogenicity, high durability and favorable hemodynamic performance. The study aim was to investigate the biocompatibility and performance of this SIBS valve prototype under physiological loading conditions similar to humans, using a large-animal model. METHODS: Four SIBS valves (two with surface modification using dimyristoyl phosphatidylcholine, DMPC), and two commercial Magna tissue valves, were implanted into sheep. Hemodynamic and blood chemistry measurements were performed periodically during the postoperative period. The explanted SIBS valves were extensively evaluated using macroscopic, histological, radiographical and scanning electron microscopy/energy-dispersive spectroscopy analysis. RESULTS: Three animals, one with the DMPC-coated SIBS valve, and two with the Magna valves, reached the end of the study in satisfactory clinical condition, and were euthanized after 20 weeks. The other three animals (two with SIBS valves, one with a DMPC-coated SIBS valve) died at 6, 6.5, and 10 weeks due either to material failure or myocardial infarction. The explanted valves exhibited stent deformation and cracks on the leaflets, which exposed the underlying PET fabric and resulted in severe blood and tissue reactions. Extrinsic calcification was identified on the leaflets, and was associated with the regions of surface cracks. CONCLUSION: The SIBS valve failed in animal testing because of material failure and calcification. The physical properties of SIBS must be improved in order to provide the structural integrity required for long-term in-vivo use in the form of a heart valve.

A novel small animal model for biocompatibility assessment of polymeric materials for use in prosthetic heart valves.

A composite polymeric material, poly(styrene-block-isobutylene-block-styrene) (SIBS) with an embedded reinforcement polyethylene terephthalate (PET) fabric, is undergoing investigation for potential use in a novel heart valve. The purpose of this study was to develop and implement a small animal model to assess the biocompatibility of composite samples in a cardiovascular tissue and blood-contacting environment. Composite samples were manufactured using dip coating and solvent casting with two coating thicknesses (25 and 50 microm). A novel rat abdominal aorta model was developed to test the dip-coated samples in a similar pulsatile flow condition to its intended use, and both dip-coated and solvent-cast samples were tested using a rat subcutaneous model. Tissue response, defined by degree of cellular infiltration and encapsulation, was minimized when a smooth coating of SIBS shielded the PET fabric from exposure to blood and tissue, and the degree of tissue response was directly correlated with the degree of surface roughness. Surface modification using phospholipid further reduces the tissue response. We have demonstrated the applicability of using a novel rat abdominal aorta model for biocompatibility assessment of polymeric materials that will be used in cardiovascular implants. For the purpose of this study, our results indicate that solvent casting with a 25-microm SIBS coating thickness will provide optimal biocompatibility for the SIBS valve.

Development and evaluation of a novel artificial catheter-deliverable prosthetic heart valve and method for in vitro testing.

BACKGROUND: This work presents a novel artificial prosthetic heart valve designed to be catheter or percutaneously deliverable, and a method for in vitro testing of the device. The device is intended to create superior characteristics in comparison to tissue-based percutaneous valves. METHODS: The percutaneous heart valve (PhV) was constructed from state-of-the-art polymers, metals and fabrics. It was tested hydrodynamically using a modified left heart simulator (Lhs) and statically using a tensile testing device. RESULTS: The PhV exhibited a mean transvalvular pressure gradient of less than 15 mmhg and a mean regurgitant fraction of less than 5 percent. It also demonstrated a resistance to migration of up to 6 N and a resistance to crushing of up to 25 N at a diameter of 19 mm. The PhV was crimpable to less than 24 F and was delivered into the operating Lhs via a 24 F catheter. CONCLUSION: An artificial PhV was designed and optimized, and an in vitro methodology was developed for testing the valve. The artificial PhV compared favorably to existing tissue-based PhVs. The in vitro test methods proved to be reliable and reproducible. The PhV design proved the feasibility of an artificial alternative to tissue based PhVs, which in their traditional open-heart implantable form are known to have limited in vivo durability.

Comparison of near-wall hemodynamic parameters in stented artery models.

Four commercially available stent designs (two balloon expandable-Bx Velocity and NIR, and two self-expanding-Wallstent and Aurora) were modeled to compare the near-wall flow characteristics of stented arteries using computational fluid dynamics simulations under pulsatile flow conditions. A flat rectangular stented vessel model was constructed and simulations were carried out using rigid walls and sinusoidal velocity input (nominal wall shear stress of 10+/-5 dyn/cm2). Mesh independence was determined from convergence (<10%) of the axial wall shear stress (WSS) along the length of the stented model. The flow disturbance was characterized and quantified by the distributions of axial and transverse WSS, WSS gradients, and flow separation parameters. Normalized time-averaged effective WSS during the flow cycle was the smallest for the Wallstent (2.9 dyn/cm2) compared with the others (5.8 dyn/cm2 for the Bx Velocity stent, 5.0 dyn/cm2 for the Aurora stent, and 5.3 dyn/cm2 for the NIR stent). Regions of low mean WSS (<5 dyn/cm2) and elevated WSS gradients (>20 dyn/cm3) were also the largest for the Wallstent compared with the others. WSS gradients were the largest near the struts and remained distinctly nonzero for most of the region between the struts for all stent designs. Fully recirculating regions (as determined by separation parameter) were the largest for the Bx Velocity stent compared with the others. The most hemodynamically favorable stents from our computational analysis were the Bx Velocity and NIR stents, which were slotted-tube balloon-expandable designs. Since clinical data indicate lower restenosis rates for the Bx Velocity and NIR stents compared with the Wallstent, our data suggest that near-wall hemodynamics may predict some aspects of in vivo performance. Further consideration of biomechanics, including solid mechanics, in stent design is warranted.

A phospholipid-modified polystyrene-polyisobutylene-polystyrene (SIBS) triblock polymer for enhanced hemocompatibility and potential use in artificial heart valves.

Poly(styrene-block-isobutylene-block-styrene) ('SIBS') is selected for a novel tri-leaflet heart valve due to its high resistance to oxidation, hydrolysis, and enzyme attack. SIBS is modified using six different phospholipids and its mechanical properties characterized by tensile stress, peel strength, shear strength, contact angle, and surface energy, and then for hemocompatibility by studying the adhesion of fluorescently labeled platelets in a parallel plate chamber under physiological flow conditions. Phospholipid modification decreases SIBS tensile stress (at 45% strain) by 30% and reduces platelet adhesion by a factor of 10, thereby improving its hemocompatibility and its potential use as a synthetic heart valve.

Effects of stent geometry on local flow dynamics and resulting platelet deposition in an in vitro model.

Platelet deposition has been shown previously to depend on convective transport patterns, visualized by the instantaneous streamlines. Previous attempts to quantify hemodynamic studies of platelet deposition have been limited to 2D geometries. This study provides a physiologic assessment of the effects of stent geometry on platelet deposition by using actual 3D stents. Human blood with fluorescently labeled platelets was circulated through an in vitro system producing physiologic pulsatile flow in a compliant tube in which Bx Velocity, Wallstent and Aurora stents were implanted. Computational fluid dynamic models of the stents provided flow data to aid in explaining localized platelet deposition. Regions of constant flow separation proximal and distal to the strut exhibited very low platelet deposition. Platelet deposition was highest just downstream of flow stagnation regions due to convection towards the wall, then decreased with axial distance from the strut as flow streamlines became locally parallel to the wall. The nearly helically recirculating regions near the Bx Velocity stent connectors exhibited complex fluid dynamics with more platelet deposition, than the smaller separation regions. Localized platelet deposition was heavily dependent on flow convection, suggesting that arterial reaction to stents can be modulated in part by altering the hemodynamics associated with stent design.

Exploring electron transfer between heme proteins of cytochrome C super family in biosensors: a molecular mechanics study.

Electron transfer between heme proteins with mediators plays an important role in the fabrication of sensitive bio-nano sensors. Heme protein Cytochrome c (pdb code - 1HRC) was chosen as the mediator with Cytochrome c' (pdb code - 1A7V) as the probe protein for our investigation on the electron transfer process. We used the software GRAMM, HEX, and MACRODOX to build the protein complex with further evaluation by GROMACS potential. After molecular mechanics refinement by GROMACS the protein complexes were evaluated in terms of the following criteria: Hydrophobic packing, proximity of the hemes, hydrogen bonds, enthalpy and entropy of binding. The free energy was calculated for each complex to derive the feasible stable models. The combined electron transport of the chosen geometric models was evaluated to choose the possible models. Electrostatic potential was calculated using the program APBS around the heme in the presence and absence of other proteins. From our studies, we derived multiple feasible models and possible electronic path. These studies helped us to understand the relay mechanism between the two proteins and to design mutant proteins by rational site directed mutagenesis to enhance the redox potential and thereby improving the signal to noise ratio in amperometric bionano sensors.

Large scale motions in a biosensor protein glucose oxidase: a combined approach by QENS, normal mode analysis, and molecular dynamics studies.

The characteristics of the glucose oxidase were studied using a combination of experimental and theoretical techniques. Quasi elastic neutron scattering experiments were used to obtain the vibrational frequencies of the protein. These were compared to theoretical results obtained by normal mode analysis. Results indicate a good match between the experimental and theoretical values. Molecular dynamic simulation with covariant analysis was used to study the structure and dynamics of glucose oxidase. Various parameters like the radius of gyration, root mean square fluctuations, solvent accessibility were studied for evaluating the structural stability of the protein. The frequency of vibration calculated from the three methods is used to derive the large scale motions. Theses studies were used to predict the suitable lysine residues for linkage with carbon nanotubes.

Medical applications of poly(styrene-block-isobutylene-block-styrene) ("SIBS").

Poly(Styrene-block-IsoButylene-block-Styrene) ("SIBS") is a biostable thermoplastic elastomer with physical properties that overlap silicone rubber and polyurethane. Initial data collected with SIBS stent-grafts and coatings on metallic stents demonstrate hemocompatibility, biocompatibility and long-term stability in contact with metal. SIBS has been used successfully as the carrier for a drug-eluting coronary stent; specifically Boston Scientific's TAXUS stent, and its uses are being investigated for ophthalmic implants to treat glaucoma, synthetic heart valves to possibly replace tissue valves and other applications. At present, researchers developing medical devices utilizing SIBS have found the following: (1) SIBS does not substantially activate platelets in the vascular system; (2) polymorphonuclear leukocytes in large numbers are not commonly observed around SIBS implants in the vascular system or in subcutaneous implants or in the eye; (3) myofibroblasts, scarring and encapsulation are not clinically significant with SIBS implanted in the eye; (4) embrittlement has not been observed in any implant location; (5) calcification within the polymer has not been observed; and (6) degradation has not been observed in any living system to date. Some deficiencies of SIBS that need to be addressed include creep deformation in certain load-bearing applications and certain sterilization requirements. The reason for the excellent biocompatibility of SIBS may be due to the inertness of SIBS and lack of cleavable moieties that could be chemotactic towards phagocytes.

Effect of fiber orientation on the stress distribution within a leaflet of a polymer composite heart valve in the closed position.

Polymer trileaflet valves offer natural hemodynamics with the potential for better durability than commercially available tissue valves. Strength and durability of polymer-based valves may be increased through fiber reinforcement. A finite element analysis of the mechanics of a statically loaded polymer trileaflet aortic heart valve has been conducted. A parametric analysis was performed to determine the effects of fiber orientation and volume density in a single and double ply model. A maximum stress value of 1.02MPa was obtained in the non-reinforced model for a transvalvular load (downstream-upstream) of 120mmHg. The maximum stress on the downstream side of the leaflet was approximately twice the maximum stress on the upstream side, and always occurred on the interface with the valve stent. The single ply model reduced the stress on the polymer matrix, with the maximum reduction of at least 64% occurring when the fiber orientation was such that the fibers ran perpendicular to the stent edge. The double ply model further reduced the stress on the polymer matrix, with the maximum reduction of greater than 86% now occurring when the fibers are oriented most perpendicular to one another.

A novel polymer for potential use in a trileaflet heart valve.

A novel polyolefin, poly(styrene-b-isobutylene-b-styrene) (Quatromer), is being proposed as a viable polymer for use in trileaflet heart valves because of its oxidative stability. The current study was designed to assess the polymer's hemocompatibility and mechanical durability. Mechanical characterization included static tensile tests and dynamic tension-tension and bending fatigue tests, where the properties of isotropic and composite (polypropylene (PP) embedded) Quatromer specimens were compared with those of a polyurethane (PUR) approved for cardiovascular applications. It was found that by embedding PP fibers into the Quatromer matrix, the tensile and fatigue properties of the polymer could be improved, making them comparable, if not better than the PUR. The thrombotic potential of Quatromer was compared with the PUR, glutaraldehyde-fixed porcine valve material, and a positive and negative control by measuring platelet deposition with radiolabeled platelets in a parallel plate flow configuration. The porcine valve material was found to have significantly higher platelet deposition under all flow regimes, while no significant difference existed between Quatromer and PUR. In conclusion, Quatromer is shown to have suitable hemocompatibility and mechanical durability for use in polymer trileaflet heart valves, and fiber reinforcement can effectively be used to tailor the mechanical properties.

Flow-induced platelet activation in a St. Jude mechanical heart valve, a trileaflet polymeric heart valve, and a St. Jude tissue valve.

Polymer heart valves have been under investigation since the 1960s, but their success has been hampered by an overall lack of durability mainly due to calcification of the leaflets and a relatively high rate of thromboembolic complications. A new polymer (Quatromer) trileaflet design was tested for its thrombogenic potential and was compared to that of existing prosthetic heart valves routinely implanted in patients: a St. Jude Medical bileaflet mechanical heart valve (MHV) and a St. Jude porcine bioprosthetic tissue valve. The valves were mounted in a left ventricular assist device and the procoagulant activity of the platelets was measured using a platelet activation state (PAS) assay. The PAS measurements indicated that the platelet activation level induced by the polymeric valve was very similar to that induced by the St. Jude Medical MHV and the St. Jude tissue valve. No significant difference was observed between the three valves, indicating that they have a comparable thrombogenic potential.

Spatial distribution of platelet deposition in stented arterial models under physiologic flow.

This paper presents dynamic flow experiments with fluorescently labeled platelets to allow for spatial observation of wall attachment in inter-strut spacings, to investigate their relationship to flow patterns. Human blood with fluorescently labeled platelets was circulated through an in vitro system that produced physiologic pulsatile flow in a parallel plate flow chamber that contained three different stent designs that feature completely recirculating flow, partially recirculating flow (intermediate strut spacing), and completely reattached flow. Highly resolved spatial distribution of platelets was obtained by imaging fluorescently labeled platelets between the struts. Platelet deposition was higher in areas where flow is directed towards the wall, and lower in areas where flow is directed away from the wall. Flow detachment and reattachment points exhibited very low platelet deposition. Platelet deposition within intermediate strut spacing continued to increase throughout the experimental period, indicating that the deposition rate had not plateaued unlike other strut spacings. The spatial uniformity and temporal increase in platelet deposition for the intermediate strut spacing confirms and helps explain our previous finding that platelet deposition was highest with this strut spacing. Further experimental investigations will include more complex three-dimensional geometries.

Platelet adhesion to simulated stented surfaces.

PURPOSE: To determine if the protrusion of stent struts into the flow stream, which creates stagnation along the wall dependent on the strut spacing, has an effect on platelet adhesion. METHODS: Three 2-dimensional stents with different strut spacings were placed in a flat-plate flow chamber. Human blood was collected and platelets were labeled with indium 111. The blood with radioactive platelets was pumped through the flow chamber for 30 minutes to produce a pulsatile wall shear stress of 10+/-5 dynes/cm2 (mean +/- amplitude at 1 Hz). A gamma counter measured radioactivity along the surface and on the stents. Computational flow simulations provided specific data on flow separation and wall shear stress for each stent strut spacing tested (2.5, 4.0, and 7.0 times the strut height). RESULTS: The presence of any stent provoked an elevation in platelet adhesion within the stented region (p<0.05). The stents with larger strut spacing had higher platelet adhesion on the substrate in the stented region (1.71+/-0.63 normalized platelet deposition for the 7.0 model and 2.11+/-1.02 for the 4.0 model) than stents with smaller strut spacing (1.37+/-0.68 for the 2.5 model, p<0.05). The stents themselves showed platelet adhesion levels that were 3 to 7 times higher than the substrates, with a similar dependence on stent strut spacing. CONCLUSIONS: Additional knowledge of the role of mechanical factors in stent restenosis will aid in designing stents that minimize intimal hyperplasia and restenosis. The results of this study demonstrate the importance of stent design-mediated blood flow patterns, with smaller strut spacings minimizing platelet adhesion per unit strut area.