Visions of TAVR Future: Development and Optimization of a Second Generation Novel Polymeric TAVR.

Tissue-based transcatheter aortic valve (AV) replacement (TAVR) devices have been a breakthrough approach for treating aortic valve stenosis. However, with the expansion of TAVR to younger and lower risk patients, issues of long-term durability and thrombosis persist. Recent advances in polymeric valve technology facilitate designing more durable valves with minimal in vivo adverse reactions. We introduce our second-generation polymeric transcatheter aortic valve (TAV) device, designed and optimized to address these issues. We present the optimization process of the device, wherein each aspect of device deployment and functionality was optimized for performance, including unique considerations of polymeric technologies for reducing the volume of the polymer material for lower crimped delivery profiles. The stent frame was optimized to generate larger radial forces with lower material volumes, securing robust deployment and anchoring. The leaflet shape, combined with varying leaflets thickness, was optimized for reducing the flexural cyclic stresses and the valve's hydrodynamics. Our first-generation polymeric device already demonstrated that its hydrodynamic performance meets and exceeds tissue devices for both ISO standard and patient-specific in vitro scenarios. The valve already reached 900 × 106 cycles of accelerated durability testing, equivalent to over 20 years in a patient. The optimization framework and technology led to the second generation of polymeric TAV design- currently undergoing in vitro hydrodynamic testing and following in vivo animal trials. As TAVR use is rapidly expanding, our rigorous bio-engineering optimization methodology and advanced polymer technology serve to establish polymeric TAV technology as a viable alternative to the challenges facing existing tissue-based TAV technology.

Electronic sensor and actuator webs for large-area complex geometry cardiac mapping and therapy.

Curved surfaces, complex geometries, and time-dynamic deformations of the heart create challenges in establishing intimate, nonconstraining interfaces between cardiac structures and medical devices or surgical tools, particularly over large areas. We constructed large area designs for diagnostic and therapeutic stretchable sensor and actuator webs that conformally wrap the epicardium, establishing robust contact without sutures, mechanical fixtures, tapes, or surgical adhesives. These multifunctional web devices exploit open, mesh layouts and mount on thin, bio-resorbable sheets of silk to facilitate handling in a way that yields, after dissolution, exceptionally low mechanical moduli and thicknesses. In vivo studies in rabbit and pig animal models demonstrate the effectiveness of these device webs for measuring and spatially mapping temperature, electrophysiological signals, strain, and physical contact in sheet and balloon-based systems that also have the potential to deliver energy to perform localized tissue ablation.

Core-shell nanofibers: Integrating the bioactivity of gelatin and the mechanical property of polyvinyl alcohol.

Coaxial electrospinning is used to fabricate nanofibers with gelatin in the shell and polyvinyl alcohol (PVA) in the core in order to derive mechanical strength from PVA and bioactivity from gelatin. At a 1:1 PVA/gelatin mass ratio, the core-shell nanofiber scaffolds display a Young's modulus of 168.6 ± 36.5 MPa and a tensile strength of 5.42 ± 1.95 MPa, which are significantly higher than those of the scaffolds composed solely of gelatin or PVA. The Young's modulus and tensile strength of the core-shell nanofibers are further improved by reducing the PVA/gelatin mass ratio from 1:1 to 1:3. The mechanical analysis of the core-shell nanofibers suggests that the presence of the gelatin shell may improve the molecular alignment of the PVA core, transforming the semi-crystalline, plastic PVA into a more crystallized, elastic PVA, and enhancing the mechanical properties of the core. Lastly, the PVA/gelatin core-shell nanofibers possess cellular viability, proliferation, and adhesion similar to these of the gelatin nanofibers, and show significantly higher proliferation and adhesion than the PVA nanofibers. Taken together, the coaxial electrospinning of nanofibers with a core-shell structure permits integration of the bioactivity of gelatin and the mechanical strength of PVA in single fibers.

In vitro evaluation of a novel hemodynamically optimized trileaflet polymeric prosthetic heart valve.

Calcific aortic valve disease is the most common and life threatening form of valvular heart disease, characterized by stenosis and regurgitation, which is currently treated at the symptomatic end-stages via open-heart surgical replacement of the diseased valve with, typically, either a xenograft tissue valve or a pyrolytic carbon mechanical heart valve. These options offer the clinician a choice between structural valve deterioration and chronic anticoagulant therapy, respectively, effectively replacing one disease with another. Polymeric prosthetic heart valves (PHV) offer the promise of reducing or eliminating these complications, and they may be better suited for the new transcatheter aortic valve replacement (TAVR) procedure, which currently utilizes tissue valves. New evidence indicates that the latter may incur damage during implantation. Polymer PHVs may also be incorporated into pulsatile circulatory support devices such as total artificial heart and ventricular assist devices that currently employ mechanical PHVs. Development of polymer PHVs, however, has been slow due to the lack of sufficiently durable and biocompatible polymers. We have designed a new trileaflet polymer PHV for surgical implantation employing a novel polymer-xSIBS-that offers superior bio-stability and durability. The design of this polymer PHV was optimized for reduced stresses, improved hemodynamic performance, and reduced thrombogenicity using our device thrombogenicity emulation (DTE) methodology, the results of which have been published separately. Here we present our new design, prototype fabrication methods, hydrodynamics performance testing, and platelet activation measurements performed in the optimized valve prototype and compare it to the performance of a gold standard tissue valve. The hydrodynamic performance of the two valves was comparable in all measures, with a certain advantage to our valve during regurgitation. There was no significant difference between the platelet activation rates of our polymer valve and the tissue valve, indicating that similar to the latter, its recipients may not require anticoagulation. This work proves the feasibility of our optimized polymer PHV design and brings polymeric valves closer to clinical viability.

Non-antibacterial tetracyclines modulate mediators of periodontitis and atherosclerotic cardiovascular disease: a mechanistic link between local and systemic inflammation.

Periodontitis, one of the most common chronic inflammatory diseases afflicting man, is increasingly being recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD). Non-antimicrobial tetracyclines are known to have inhibitory effects on inflammatory mediators and effector molecules, including cytokines and matrix metalloproteinases (MMPs), associated with both diseases. In this paper, we discuss the evidence that doxycycline and related non-antibiotic chemically modified tetracyclines (e.g., CMT-3) can effectively reduce cytokine (TNF-α, IL-6, and MCP-1) production by human mononuclear inflammatory cells when stimulated either by endotoxin (LPS) or by a complex of C-reactive protein/oxidized LDL cholesterol relevant to the pathogenesis of periodontal disease and ASCVD, respectively. This inhibition by tetracycline compounds appears to be mediated at least in part by a suppression of the phosphorylation/activation of the NFκB cell signaling pathway. We are currently conducting clinical trials on patients who exhibit both diseases, and our preliminary data suggest that virtually all acute coronary syndrome (ACS) patients exhibit moderate-to-severe periodontitis, a higher incidence of this oral inflammatory disease than that seen in the population at large. In other studies, a non-antimicrobial formulation of doxycycline (SDD) has been found to dramatically reduce hsCRP, IL-6 and MMP-9 levels in plasma of ACS patients, and SDD has also been found to significantly increase serum levels of both cardio-protective HDL cholesterol and its core molecule apolipoprotein A-I in ASCVD-vulnerable patients with periodontitis. Our current research suggests that one mechanism involved may be the ability of SDD to inhibit MMP-mediated HDL loss by protecting apolipoprotein A-I from proteinase attack. These pleiotropic mechanisms of non-antimicrobial tetracyclines provide significant therapeutic potential to treat chronic inflammatory diseases including both periodontitis and ASCVD.

Characterization of the competing role of surface-contact and shear stress on platelet activation in the setting of blood contacting devices.

Supraphysiological shear stress and surface-contact are recognized as driving mechanisms of platelet activation (PA) in blood contacting devices (BCDs). However, the competing role of these mechanisms in triggering thrombogenic events is poorly understood. Here, we characterized the dynamics of PA in response to the combined effect of shear stress and material exposure. Human platelets were stimulated with different levels of shear stress (500, 750, 1000 dynes/cm2) over a range of exposure times (10, 20, and 30 min) within capillary tubes made of various polymeric materials. Polyethylene (PE), polytetrafluoroethylene (PTFE), ethylene tetrafluoroethylene (ETFE), and polyether ether ketone (PEEK), used for BCDs fabrication, were investigated as compared to glass and thromboresistant Sigma™-coated glass. PA was quantified using the Platelet Activity State assay. Our results indicate that mechanical stimulation and polymer surface-contact both significantly contribute to PA. Notably, the contribution of the mechanical stimulus ranges between +36% and +43%, while that associated with polymer surface-contact ranges from +48% to +59%, depending on the exposure time. In more detail, our results indicate that: (i) PA increases with increasing shear stress magnitude; (ii) PA has a non-linear, time-dependent relationship to exposure time; (iii) PA is largely influenced by biomaterials, with PE and PEEK having respectively the lowest and highest prothrombotic potential; (iv) the effects of polymer surface-contact and shear stress are not correlated and can be studied separately. Our results suggest the importance of incorporating the evaluation of platelet activation driven by the combined effect of shear stress and polymer surface-contact for the comprehensive assessment, and eventually minimization, of BCDs thrombogenic potential.

Patterned Electrospinning: A Method of Generating Defined Fibrous Constructs Influencing Cell Adhesion and Retention.

A critical component of tissue engineering is the ability to functionally replace native tissue stroma. Electrospinning is a technique capable of forming fibrous constructs with a high surface area for increased cell-material interaction and enhanced biocompatibility. However, physical and biological properties of electrospun scaffolds are limited by design controllability on a macroscale. We developed a methodology for generating electrospun scaffolds with defined patterns and topographic features to influence physical properties and biological interactions. Five unique design electrospinning target collectors were fabricated to allow for generation of defined polymeric scaffold patterns including lines, sinusoids, squares, zigzags, and solid. Poly(lactic-co-glycolic) acid was electrospun under identical conditions utilizing these varied targets, and constructs generated were examined as to their physical configuration, mechanical and chemical properties, and their ability to foster vascular smooth muscle cell adhesion and retention at 24 h. Modifying collector designs led to significant differences in fiber target coverage ranging from 300 mm2 for solid (100% of the target area) to 217.8 mm2 for lines (72.6% of the target area). Measured fiber excess, residual open area, and contact angle (hydrophobicity) followed the same trend as fiber target coverage with respect to the collector pattern: lines > sinusoids > squares > zigzags > solid. Similarly, the line design allowed for the greatest cell adhesion and retention (258 ± 31 cells), whereas solid exhibited the lowest (150 ± 15 cells); p < 0.05. There was a strong direct correlation of cell adhesion to construct residual open area (R2 = 0.94), normalized fiber excess (R2 = 0.99), and fiber grammage (R2 = 0.72), with an inverse relationship to fiber target coverage (R2 = 0.94). Our results demonstrate the ability to utilize patterned collectors for modifying macroscopic and microscopic electrospun scaffold features, which directly impact cell adhesion and retention, offering translational utility for designing specific tissue constructs.

Stretchable Electronic Wearable Motion Sensors Delineate Signatures of Human Motion Tasks.

Digital tracking of human motion offers the potential to monitor a wide range of activities detecting normal versus abnormal performance of tasks. We examined the ability of a wearable, conformal sensor system, fabricated from stretchable electronics with contained accelerometers and gyroscopes, to specifically detect, monitor, and define motion signals and "signatures," associated with tasks of daily living activities. The sensor system was affixed to the dominant hand of healthy volunteers (n = 4) who then completed four tasks. For all tasks examined, motion data could be captured, monitored continuously, uploaded to the digital cloud, and stored for further analysis. Acceleration and gyroscope data were collected in the x-, y-, and z-axes, yielding unique patterns of component motion signals for each task studied. Upon analysis, low-frequency (<10 Hz) tasks (walking, drinking from a mug, and opening a pill bottle) showed low intersubject variability (<0.3g difference) and low interrepetition variability (<0.1g difference) when comparing the acceleration of each axis for a single task. High-frequency (≥10 Hz) activity (brushing teeth) yielded low intersubject variability of peak frequencies in acceleration of each axis. Each motion task was readily distinguishable and identifiable (with ≥70% accuracy) by independent observers from motion signatures alone, without the need for direct visual observation. Stretchable electronic technologies offer the potential to provide wireless capture, tracking, and analysis of detailed directional components of motion for a wide range of individual activities and functional status.

Physical Characterization and Platelet Interactions under Shear Flows of a Novel Thermoset Polyisobutylene-based Co-polymer.

Over the years, several polymers have been developed for use in prosthetic heart valves as alternatives to xenografts. However, most of these materials are beset with a variety of issues, including low material strength, biodegradation, high dynamic creep, calcification, and poor hemocompatibility. We studied the mechanical, surface, and flow-mediated thrombogenic response of poly(styrene-coblock-4-vinylbenzocyclobutene)-polyisobutylene-poly(styrene-coblock-4-vinylbenzocylcobutene) (xSIBS), a thermoset version of the thermoplastic elastomeric polyolefin poly(styrene-block-isobutylene-block-styrene) (SIBS), which has been shown to be resistant to in vivo hydrolysis, oxidation, and enzymolysis. Uniaxial tensile testing yielded an ultimate tensile strength of 35 MPa, 24.5 times greater than that of SIBS. Surface analysis yielded a mean contact angle of 82.05° and surface roughness of 144 nm, which was greater than for poly(ε-caprolactone) (PCL) and poly(methyl methacrylate) (PMMA). However, the change in platelet activation state, a predictor of thrombogenicity, was not significantly different from PCL and PMMA after fluid exposure to 1 dyn/cm(2) and 20 dyn/cm(2). In addition, the number of adherent platelets after 10 dyn/cm(2) flow exposure was on the same order of magnitude as PCL and PMMA. The mechanical strength and low thrombogenicity of xSIBS therefore suggest it as a viable polymeric substrate for fabrication of prosthetic heart valves and other cardiovascular devices.

Hemodynamic and thrombogenic analysis of a trileaflet polymeric valve using a fluid-structure interaction approach.

Surgical valve replacement in patients with severe calcific aortic valve disease using either bioprosthetic or mechanical heart valves is still limited by structural valve deterioration for the former and thrombosis risk mandating anticoagulant therapy for the latter. Prosthetic polymeric heart valves have the potential to overcome the inherent material and design limitations of these valves, but their development is still ongoing. The aim of this study was to characterize the hemodynamics and thrombogenic potential of the Polynova polymeric trileaflet valve prototype using a fluid-structure interaction (FSI) approach. The FSI model replicated experimental conditions of the valve as tested in a left heart simulator. Hemodynamic parameters (transvalvular pressure gradient, flow rate, maximum velocity, and effective orifice area) were compared to assess the validity of the FSI model. The thrombogenic footprint of the polymeric valve was evaluated using a Lagrangian approach to calculate the stress accumulation (SA) values along multiple platelet trajectories and their statistical distribution. In the commissural regions, platelets were exposed to the highest SA values because of highest stress levels combined with local reverse flow patterns and vortices. Stress-loading waveforms from representative trajectories in regions of interest were emulated in our hemodynamic shearing device (HSD). Platelet activity was measured using our platelet activation state (PAS) assay and the results confirmed the higher thrombogenic potential of the commissural hotspots. In conclusion, the proposed method provides an in depth analysis of the hemodynamic and thrombogenic performance of the polymer valve prototype and identifies locations for further design optimization.

Core-shell PVA/gelatin electrospun nanofibers promote human umbilical vein endothelial cell and smooth muscle cell proliferation and migration.

Cardiovascular disease is the leading cause of death in the world. In this study, coaxial electrospinning is employed to fabricate fibers in a core-shell structure with polyvinyl alcohol (PVA) in the core and gelatin in the shell for evaluation as a potential vascular tissue engineering construct. PVA, a synthetic polymer, provides mechanical strength to the biocompatible and weak gelatin sheath. The HUVEC (human umbilical vein endothelial cells) and rSMC (rat smooth muscle cells) demonstrated a flattened morphology with multiple attachment sites on the gelatin and coaxial scaffolds, with an increase in cell spreading seen as mechanical stiffness of the scaffold increased. Additionally, HUVEC had an increase in migration on the coaxial scaffolds, which was attributed to the increase in stiffness; however, this increase in migration was not seen with the rSMC, which had the highest outward migration on the flat surfaces (tissue culture polystyrene and gelatin film). Overall, these scaffolds are appealing substrates for vascular tissue engineering applications. STATEMENT OF SIGNIFICANCE: The worldwide burden of cardiovascular disease presents an ongoing need and opportunity for creating a variety of vascular prostheses. Fabrication of novel scaffolds and constructs for these are needed, providing strength and biological properties facilitating endothelial (EC) and smooth muscle (SMC) cell attachment, migration, and integration. Using electrospinning we formed 3D core:shell nanofibers and examined their effectiveness as substrates for EC and SMC attachment and growth, compared to a 2D (flat) substrate. We found that ECs attached and grew best on 3D core:shell fibers, whereas SMCs favored 2D gelatin surfaces. Interestingly, we found that EC attachment, migration and growth correlated and improved with increasing fiber stiffness. These materials and insights may foster novel vascular prostheses development.

Hemocompatibility of Poly(vinyl alcohol)-Gelatin Core-Shell Electrospun Nanofibers: A Scaffold for Modulating Platelet Deposition and Activation.

In this study, we evaluate coaxial electrospun nanofibers with gelatin in the shell and poly(vinyl alcohol) (PVA) in the core as a potential vascular material by determining fiber surface roughness, as well as human platelet deposition and activation under varying conditions. PVA scaffolds had the highest surface roughness (Ra=65.5±6.8 nm) but the lowest platelet deposition (34.2±5.8 platelets) in comparison to gelatin nanofibers (Ra=36.8±3.0 nm and 168.9±29.8 platelets) and coaxial nanofibers (1 Gel:1 PVA coaxial, Ra=24.0±1.5 nm and 150.2±17.4 platelets. 3 Gel:1 PVA coaxial, Ra=37.1±2.8 nm and 167.8±15.4 platelets). Therefore, the chemical structure of the gelatin nanofibers dominated surface roughness in platelet deposition. Due to their increased stiffness, the coaxial nanofibers had the highest platelet activation rate, rate of thrombin formation, in comparison to gelatin and PVA fibers. Our studies indicate that mechanical stiffness is a dominating factor for platelet deposition and activation, followed by biochemical signals, and lastly surface roughness. Overall, these coaxial nanofibers are an appealing material for vascular applications by supporting cellular growth while minimizing platelet deposition and activation.

Description and evaluation of a ventriculo-coronary artery bypass device that provides bi-directional coronary flow.

OBJECTIVE: The objective of this study was to assess acute patency of a new myocardial revascularization device that connects the left ventricular cavity to a coronary artery (termed ventriculo-coronary artery bypass, VCAB) thereby providing proximal and distal blood flow from the site of the anastomosis. METHODS: A device made of expanded polytetrafluoroethylene and low density polyethylene was implanted from the base of the left ventricle to the mid left anterior descending coronary artery (LAD) in 11 juvenile domestic pigs using a beating heart approach. Flow rates were measured in the distal LAD before and after implant using ultrasonic flow techniques, and patency was assessed at explant at either 2 or 4 weeks post-implantation. Myocardial perfusion using positron emission tomography (PET) was assessed in a separate set of pigs (n=2) revascularized by VCAB 2 weeks post-implant. RESULTS: Net forward flow distal to the implanted device was 73 +/- 15% of native LAD flow. PET demonstrated that the target myocardium was perfused at 85% of that seen in the remote, control myocardium. Device patency rate was 80% (4/5) at 2 weeks in one set of pigs and 83% (5/6) at 4 weeks in a second set of pigs. Histologic analysis showed formation of neointima along the extraventricular segment of the device. CONCLUSIONS: This study demonstrates the promise of perfusing ischemic myocardium using a VCAB approach with a device that provides blood flow both proximal and distal to the anastomosis. Patency of the transmyocardial device was encouraging at 2 and 4 weeks and warrants further investigation.

Local hemostasis during laparoscopic partial nephrectomy using biodegradable hydrogels: initial porcine results.

BACKGROUND AND PURPOSE: Despite the advance of laparoscopic partial nephrectomy, significant technical limitations remain with regard to control of bleeding and closure of the collecting system. An attractive approach on the horizon for local hemostatic and wound control is the use of local tissue sealants. To date, sealants remain largely derived from natural biologic products and are difficult to apply laparoscopically with precise local control. In this study, we examined the novel strategy of forming occlusive tissue-adherent hydrogels utilizing a synthetic biodegradable polyethylene glycol-lactide copolymer (PEG-lactide) as an in situ occlusive barrier for hemostasis and wound control. Specifically, the objects of this study were to determine if PEG-lactide hydrogels could be formed intraperitoneally on renal tissue, to test the adhesiveness of the hydrogels to injured renal parenchyma, and to evaluate the ability of adherent hydrogel barriers to limit renal parenchymal bleeding and collecting system leakage following renal pole amputation or wedge excision. MATERIALS AND METHODS: Five kidneys from three female pigs were used in a nonsurvival study. A standardized model for laparoscopic partial nephrectomy was created by performing wedge excision or polar amputation under vascular control using a laparoscopic Satinsky clamp. Bleeding briskness following injury was assessed utilizing a scoring system and free blood quantitated comparing a conventional "clamp and wait" strategy with an adherent hydrogel strategy. For the hydrogel group, PEG-lactide hydrogel primer and macromer were applied through laparoscopic ports. The hydrogel was polymerized using a xenon light source, and the pedicle clamp was released to observe for bleeding. A subsequent opposite polar injury was created to confirm renal perfusion and the sites were compared. The kidneys were removed, and the adhesion of the hydrogel to the renal parenchyma was examined. RESULTS: The PEG-lactide macromer was effectively applied to five kidneys following partial nephrectomy. In all cases, successful intraperitoneal in situ polymerization was achieved, with resultant hydrogel formation. Polymeric hydrogel adhesion to the cut renal parenchyma was assessed semiquantitatively following vigorous cyclic washing. In all cases, polymer gels remained adherent without any evidence of peeling, delamination, or separation from the underlying tissue surface. In the control group, the mean bleeding score was 2.63 +/- 0.48 v 0.00 +/- 0.00 in the gel-treated group (P < 0.001). Blood loss in the control group was 56 +/- 5 ml v 0.00 +/- 0.00 in the gel-treated group (P < 0.001). In an ex vivo retrograde ureteral perfusion, no leakage was observed at pressure as high as 100 mm Hg. CONCLUSIONS: In this feasibility study, a biodegradable PEG-lactide polymer system photopolymerized rapidly in situ on exposed renal parenchymal surfaces, forming adherent hydrogel barriers. When applied during vascular clamping, an adequate physical bond and patch-like cap was created to prevent bleeding at physiologic renal perfusion pressures. Use of locally applied occlusive hydrogels holds promise for hemostasis and local wound control during laparoscopic urologic procedures.

Linear fibroblast alignment on sinusoidal wave micropatterns.

Micrometer and nanometer grooved surfaces have been determined to influence cellular orientation, morphology, and migration through contact guidance. Cells typically elongate along the direction of an underlying groove and often migrate with guidance provided by constraints of the pattern. This phenomenon has been studied primarily using linear grooves, post, or well patterns. We investigated the behavior of mouse embryonic fibroblasts on non-linear, sinusoidal wave grooves created via electron beam lithography on a polymethyl methacrylate (PMMA) substrate that was spin-coated onto a positively charged glass surface. Three different wave patterns, with varying wavelengths and amplitudes, and two different line patterns were created. Cell orientation and adhesion was examined after 4, 24, and 48 h after cell seeding. Attachment strength was studied via subjecting cells on substrates to centrifugal force following a 24-h incubation period. For all wave patterns studied, it was noted that cells did not reside within the groove, rather they were observed to cross over each groove, residing both inside and outside of each wave pattern, aligning linearly along the long axis of the pattern. For the linear patterns, we observed that cells tended to reside within the grooves, consistent with previous observations. The ability to add texture to a surface to manipulate cell adhesion strength and growth with only localized attachment, maintaining free space in curvilinear microtopography underlying the cell, may be a useful addition for tissue engineering and the fabrication of novel biomedical devices.

Toward optimization of a novel trileaflet polymeric prosthetic heart valve via device thrombogenicity emulation.

Aortic stenosis is the most prevalent and life-threatening form of valvular heart disease. It is primarily treated via open-heart surgical valve replacement with either a tissue or a mechanical prosthetic heart valve (PHV), each prone to degradation and thrombosis, respectively. Polymeric PHVs may be optimized to eliminate these complications, and they may be more suitable for the new transcatheter aortic valve replacement procedure and in devices like the total artificial heart. However, the development of polymer PHVs has been hampered by persistent in vivo calcification, degradation, and thrombosis. To address these issues, we have developed a novel surgically implantable polymer PHV composed of a new thermoset polyolefin called cross-linked poly(styrene-block-isobutylene-block-styrene), or xSIBS, in which key parameters were optimized for superior functionality via our device thrombogenicity emulation methodology. In this parametric study, we compared our homogeneous optimized polcymer PHV to a prior composite polymer PHV and to a benchmark tissue valve. Our results show significantly improved hemodynamics and reduced thrombogenicity in the optimized polymer PHV compared to the other valves. These results indicate that our new design may not require anticoagulants and may be more durable than its predecessor, and validate the improvement, toward optimization, of this novel polymeric PHV design.

Polymeric trileaflet prosthetic heart valves: evolution and path to clinical reality.

Present prosthetic heart valves, while hemodynamically effective, remain limited by progressive structural deterioration of tissue valves or the burden of chronic anticoagulation for mechanical valves. An idealized valve prosthesis would eliminate these limitations. Polymeric heart valves (PHVs), fabricated from advanced polymeric materials, offer the potential of durability and hemocompatibility. Unfortunately, the clinical realization of PHVs to date has been hampered by findings of in vivo calcification, degradation and thrombosis. Here, the authors review the evolution of PHVs, evaluate the state of the art of this technology and propose a pathway towards clinical reality. In particular, the authors discuss the development of a novel aortic PHV that may be deployed via transcatheter implantation, as well as its optimization via device thrombogenicity emulation.

Nuclear factor kappa B (NF-κB): a novel cause for diabetes, coronary artery disease and cancer initiation and promotion?

Obesity is a growing epidemic in the United States (US). Obesity has been recognized as a modifiable risk factor for many diverse diseases including diabetes, cardiovascular disease and cancer burden. Common contributors to obesity include a high fat diet, smoking and physical inactivity. Systemic effects of obesity include increased micro-inflammatory molecules such as nuclear factor kappa B (NF-κB) that influence the both endothelial and epithelial layers as well as the supportive stroma. An emerging risk factor for micro-inflammation also includes periodontal disease. These pro-inflammatory states are hypothesized to contribute to diabetes as well as cardiovascular disease and cancer through the direct activation of NF-κB. Therefore, a comprehensive health care strategy would include reduction of diabetes, cardiovascular and cancer risk through the decrease in micro-inflammation.

The effect of subantimicrobial-dose-doxycycline periodontal therapy on serum biomarkers of systemic inflammation: a randomized, double-masked, placebo-controlled clinical trial.

BACKGROUND: Periodontitis has been reported to be associated with coronary artery disease (CAD). Research is needed to determine if therapies that improve periodontal health also reduce systemic measures of inflammation associated with both diseases. METHODS: The study registrar randomly assigned 128 eligible postmenopausal women with chronic periodontitis to a twice-daily regimen of subantimicrobial-dose-doxycycline (SDD) or placebo tablets for two years as an adjunct to periodontal maintenance therapy. Through a supplement to the main trial, in which they investigated alveolar bone and clinical attachment level changes, the authors assayed inflammatory mediators and lipid profiles in baseline, one-year and two-year serum samples. The authors analyzed the data by using generalized estimating equations. RESULTS: In the intent-to-treat analysis across two years, SDD treatment reduced median high-sensitivity C-reactive protein (hs-CRP) by 18 percent (primary outcome; P = .02) and reduced serum matrix metalloproteinase (MMP)-9 (92 kilodalton gelatinase; difference in mean scanning units, -28.44; P < .001), with no significant effect on serum lipids. However, in women more than five years postmenopausal, SDD elevated the level of high-density lipoprotein (HDL) cholesterol (difference in means [milligrams per deciliter], 5.99; P = .01). CONCLUSION: A two-year SDD regimen in postmenopausal women significantly reduced the serum inflammatory biomarkers hs-CRP and MMP-9 and, among women more than five years postmenopausal, increased the HDL cholesterol level. CLINICAL IMPLICATIONS: SDD significantly reduced the systemic inflammatory biomarkers hs-CRP and MMP-9. More research is needed to determine whether SDD has a role in managing the care of patients at risk of developing CAD.