Cardiovascular Implants Research Articles

Mimicking critical environment factors for a static in vitro biofilm formation model on blood-contact implant materials.

The prevention of implant infections is a major challenge for implant developers and clinicians. Understanding biofilm dynamics and favorable implant or environmental characteristics will help to prevent biofilm formation. Blood-contact implants, such as cardiovascular implants, are particularly susceptible to infections as the blood provides a favorable growth environment for bacteria due to its rich supply of micro- and macro substances, such as glucose and plasma proteins. In this context, Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis are the most reported causes accompanying foreign body-associated infections, mainly due to their ability to form an adherent, multilayered bacterial biofilm on a wide variety of surfaces. The present study demonstrates that the provision of glucose and human plasma to the growth medium or coating of the flask with human plasma differentially affects the biofilm formation of these three bacterial species, with human plasma being the most effective regulator. However, glucose supplementation promoted and stabilized biofilm formation of S. aureus and E. faecalis, while an opposite effect was observed for additional plasma. These findings highlight the urgent need to intensify studies on the impact of host soluble factors as risk factors promoting fitness and persistence of bacterial biofilms.

Properties and Applications of PDMS for Biomedical Engineering: A Review.

Polydimethylsiloxane (PDMS) is an elastomer with excellent optical, electrical and mechanical properties, which makes it well-suited for several engineering applications. Due to its biocompatibility, PDMS is widely used for biomedical purposes. This widespread use has also led to the massification of the soft-lithography technique, introduced for facilitating the rapid prototyping of micro and nanostructures using elastomeric materials, most notably PDMS. This technique has allowed advances in microfluidic, electronic and biomedical fields. In this review, an overview of the properties of PDMS and some of its commonly used treatments, aiming at the suitability to those fields’ needs, are presented. Applications such as microchips in the biomedical field, replication of cardiovascular flow and medical implants are also reviewed.

Cardiovascular Implant Durability Conference (CVID) Rescheduled to April

Cardiovascular Implant Durability Conference (CVID) Rescheduled to April

Immobilization of Glycogen Synthase Kinase-3β Inhibitor on 316L Stainless Steel via Polydopamine to Accelerate Endothelialization.

The coverage of stents with healthy endothelium is crucial to the success of cardiovascular stent implantation. Immobilizing bioactive molecules on stents is an effective strategy to generate such stents. Glycogen synthase kinase-3β inhibitor (GSKi) is a bioactive molecule that can effectively accelerate vascular endothelialization. In this work, GSKi was covalently conjugated on 316L stainless steel through polydopamine to develop a stable bioactive surface. Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and water contact angle results revealed the successful introduction of GSKi onto 316L stainless steel. The GSKi coating did not obviously affect the hemocompatibility of plates. The adhesion and proliferation of human coronary artery endothelial cells (HCAECs) on stainless steel was significantly promoted by the addition of GSKi. In summary, this work provides a universal and stable strategy of immobilizing GSKi on the stent surface. This method has the potential for widespread application in the modification of vascular stents.

Comparison of Surface Functionalization of PLGA Composite to Immobilize Extracellular Vesicles

Endothelialization by materials provides a promising approach for the rapid re-endothelialization of a cardiovascular implantation. Although previous studies have focused on improving endothelialization through the immobilization of bioactive molecules onto the surface of biodegradable implants, comparative studies of effective surface modification have not yet been reported. Here, we conducted a comparative study on the surface modification of poly(lactide-co-glycolide) (PLGA)-based composites to graft mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) using three different materials, fibronectin (FN), polyethylenimine (PEI), and polydopamine (PDA), which have different bond strengths of ligand–receptor interaction, ionic bond, and covalent bond, respectively. Further in vitro analysis exhibited that MSC-EVs released from all modified films sustainably, but the MSC-EVs grafted onto the surface coated with PEI are more effective than other groups in increasing angiogenesis and reducing the inflammatory responses in endothelial cells. Therefore, the overall results demonstrated that PEI is a desirable coating reagent for the immobilization of MSC-EVs on the surface of biodegradable implants.

Predicting the In Vivo Performance of Cardiovascular Biomaterials: Current Approaches In Vitro Evaluation of Blood-Biomaterial Interactions.

The therapeutic efficacy of a cardiovascular device after implantation is highly dependent on the host-initiated complement and coagulation cascade. Both can eventually trigger thrombosis and inflammation. Therefore, understanding these initial responses of the body is of great importance for newly developed biomaterials. Subtle modulation of the associated biological processes could optimize clinical outcomes. However, our failure to produce truly blood compatible materials may reflect our inability to properly understand the mechanisms of thrombosis and inflammation associated with biomaterials. In vitro models mimicking these processes provide valuable insights into the mechanisms of biomaterial-induced complement activation and coagulation. Here, we review (i) the influence of biomaterials on complement and coagulation cascades, (ii) the significance of complement-coagulation interactions for the clinical success of cardiovascular implants, (iii) the modulation of complement activation by surface modifications, and (iv) in vitro testing strategies.

Reduced thrombogenicity of surface-treated Nitinol implants steered by altered protein adsorption

Blood-contacting medical implants made of Nitinol and other titanium alloys, such as neurovascular flow diverters and peripheral stents, have the disadvantage of being highly thrombogenic. This makes the use of systemic (dual) anti-platelet/anticoagulant therapies inevitable with related risks of device thrombosis, bleeding and other complications. Meeting the urgent clinical demand for a less thrombogenic Nitinol surface, we describe here a simple treatment of standard, commercially available Nitinol that renders its surface ultra-hydrophilic and functionalized with phosphate ions. The efficacy of this treatment was assessed by comparing standard and surface-treated Nitinol disks and braids, equivalent to flow diverters. Static and dynamic (Chandler loop) blood incubation tests showed a drastic reduction of thrombus formation on treated devices. Surface chemistry and proteomic analysis indicated a key role of phosphate and calcium ions in steering blood protein adsorption and avoiding coagulation cascade activation and platelet adhesion. A good endothelialization of the surface confirmed the biocompatibility of the treated surface. STATEMENT OF SIGNIFICANCE: Titanium alloys such as Nitinol are biocompatible and show favorable mechanical properties, which led to their widespread use in medical implants. However, in contact with blood their surface triggers the activation of the intrinsic coagulation cascade, which may result in catastrophic thrombotic events. The presented results showed that a phosphate functionalization of the titanium oxide surface suppresses the activation of both coagulation cascade and platelets, avoiding the subsequent formation of a blood clot. This novel approach has therefore a great potential for mitigating the risks associated to either thrombosis or bleeding complications (due to systemic anticoagulation) in patients with cardiovascular implants.

Acute myocarditis with preserved ejection fraction: the role of CMR in long term follow up

Abstract Background Cardiac Magnetic Resonance (CMR) has an important role in subjects presenting with acute myocarditis and preserved ejection fraction (pEF); it is widely used as a non-invasive imaging test in patients with suspected myocarditis, both for diagnostic and prognostic purpose. Despite this, poor data is available regarding which parameters define a worst prognosis in acute myocarditis with pEF. Purpose The aim of this study was to analyze the role of CMR in acute myocarditis with pEF at long term follow up. Methods We retrospectively enrolled 61 patients admitted to our Cardiology Department with suspected acute myocarditis and pEF. In the acute phase we analyzed clinical parameters, blood sample tests, echocardiographic and CMR indices. Myocarditis was confirmed using the Lake-Louis criteria on CMR images. The patients were followed up for a median of 4.8 years for the development of two composite endpoints: the first including cardiovascular death, cardiac arrest and/or ICD implantation; the second hospitalization for acute heart failure and/or recurrence of myocarditis. Results The clinical presentation was infart-like in the 78% of subjects; they all had a NYHA class I and had a pEF at basal echocardiogram. CMR showed myocardial edema in 50 patients (83%) and late gadolinium enhancement (LGE) in 94% of subjects. LGE involved the inferolateral wall in the 70%, the interventricular septum in 25% and other walls in 5%. During follow up, the first composite endpoint occurred in the 8% of patients, while 7 subjects (11%) had a new hospitalization for cardiac causes (heart failure or recurrence of myocarditis). Those patients with events during follow up had a significantly higher LGE quantity (21±9,8 gr vs 12,8±6 gr; p=0.006 Figure 1) at basal CMR compared to the other group. Conclusions LGE quantification by CMR could represent a prognostic added tool at long-term follow up in patients presenting with acute myocarditis and left ventricular pEF. Funding Acknowledgement Type of funding sources: None. Figure 1

Evaluation and Implementation of Biocompatible Methods for the Cross-linking of Plasma Proteins

Abstract Autologous plasma proteins can be used to fabricate patient specific cardiovascular implants but need to be cross-linked to increase their mechanical strength and reduce water solubility. Glutaraldehyde is the state-of-the-art solution but its reaction products have been shown to be cytotoxic and pro-inflammatory. In this work, it has been shown, that cross-linking of plasma proteins with biocompatible alternatives to glutaraldehyde is possible. This was achieved by identifying four candidate substances (thrombin, transglutaminase, genipin, EDC) from current literature and investigating their ability to cross-link porcine plasma proteins in vitro. The degree of crosslinking was examined using calorimetric (DSC) and spectroscopic (FTIR, Raman) methods, mapping the influence of cross-linking on the denaturation temperature and primary amino-group content of the proteins. It could be shown that thrombin, genipin and EDC are able to cross-link plasma proteins to a satisfactory degree and thus represent useful alternatives to glutaraldehyde. Transglutaminase, on the other hand, could not sufficiently cross-link the plasma proteins and was therefore ruled out as an alternative.

Automation of online particle measurement during the simulated use of catheters and stent systems

Abstract The assessment of the coating integrity of cardiovascular implants such as catheters and stent systems is of crucial importance for device approval. Released particles may represent a potential health risk for the patients. Thus, an analysis of the particles released at simulated in-vivo conditions depending on their size and number is required by international standards (ISO, ASTM) as well as national authorities. In this study, an automated test bench for online particle measurement is presented. For software controlled automation, sensor data transmission and solenoid valves were implemented. A user interface was created for setting test parameters and data recording. The setup was validated by investigating standard particles as well as those released during the simulated application of non-industrial coated balloons. The measurement data were compared with results generated using the previous manual test routine. The results show an improvement in the reproducibility of the measurements, which can be attributed to the simplified handling for the user.

Effect of fluoroscopy frame rate on radiation exposure and in-hospital outcomes in cardiovascular implantable electronic device implantation procedures

ObjectiveTo assess the radiation exposure in cardiovascular implantable electronic device(CIED) implantation procedures, the effect of fluoroscopy frame rate on various radiation exposure indices, and in-hospital outcomes. MethodsData of CIED implantation procedures from September 2015 to December 2019 of all the CIED implantation procedures performed at our institute were retrospectively analyzed. The procedural data were divided into two groups: a) pre-group: procedures that were performed under fluoroscopy frame rate of 7.5 frames per second(fps); b) post-group: procedures that were performed under fluoroscopy frame rate of 3.75 fps. We compared procedure time, fluoroscopy time, Kerma air product, effective dose, and in-hospital outcomes between the two groups. ResultsA total of 2,225 procedures were included in the analysis with mean age of (62 ​± ​15) years. The procedures consisted of the implantation of single-chamber (n ​= ​1,436), double chamber (n ​= ​656), and biventricular devices (n ​= ​133). Procedure time and radiation indices showed a significant reduction over the study period (P ​< ​0.001). Reduction in the fluoroscopy frame rate was associated with a significant reduction in radiation exposure indices(P ​< ​0.001). In-hospital outcomes did not differ between the two groups. ConclusionsReduction in the fluoroscopy frame rate from 7.5 to 3.75 fps significantly decreased the radiation exposure in CIED implantation procedures. A framerate lower than 3.75 fps should be the default setting during such procedures.

Characterization and Validation of Fatigue Strains for Superelastic Nitinol Using Digital Image Correlation

Abstract Fatigue is a major challenge encountered in cardiovascular implant design. While the properly heat-treated Nitinol can exhibit up to 6–7% recoverable strains allowing for minimally invasive transcatheter delivery of cardiovascular implants, the cyclic in vivo loading can cause premature fracture of the implant if the fatigue strain is too high. Strain-based criteria have been adopted for the development of Nitinol fatigue resistance. Lacking experimental tools to characterize the local material fatigue strain, fatigue testing of Nitinol specimens has largely relied on the finite element analysis to compute the cyclic strain amplitude and mean strain based on experimentally derived constitutive parameters using phenomenological strain energy theory. Without a consistent computational standard, previous works have resulted in controversy and inconsistency in the impact of mean strain on the fatigue resistance of Nitinol in terms of strain amplitude limit at high cycle fatigue regime. In this paper, digital image correlation (DIC) technique is used to experimentally determine local material strains of Nitinol fatigue specimens using monotonic and cyclic loading conditions. These local strains are compared with strains computed from finite element analysis. It was found that strains from DIC and FEA are comparable in the single-phase states (pure austenitic or martensitic), whereas the measured strains can show significant difference from simulation computed strain during the transformation stage where both austenite and martensite phase co-exist. These observations have significant implications to nitinol fatigue testing and implant reliability assessment.

Cardiovascular Implant Durability Conference (CVID) to be Held in October

Cardiovascular Implant Durability Conference (CVID) to be Held in October

Safety study of malapposition of the bio-corrodible nitrided iron stent in vivo

Abstract To evaluate the safety of stent malapposition of corrodible nitride iron stent as biodegradable cardiovascular implants, a total of 108 stents were implanted into the abdominal aortas, iliac arteries, and iliac artery bifurcations of 36 New Zealand white rabbits separately. Each rabbit was implanted with three stents. After a follow-up period of 3 months, no thrombus and embolism were found in local and downstream vessels. And no other adverse events occurred either. Stent strut covered by endothelial layer started to show signs of degradation, while struts exposed to bifurcated blood flow covered by a layer of tissue and no rust particle was found on the surface. Also, there were no traces of thrombosis and traces of excess inflammation. The authors conclude that the risk brought by stent malapposition in less than 9 months is acceptable.

A Robot Mimicking Heart Motions: An Ex-Vivo Test Approach for Cardiac Devices

PurposeThe pre-clinical testing of cardiovascular implants gains increasing attention due to the complexity of novel implants and new medical device regulations. It often relies on large animal experiments that are afflicted with ethical and methodical challenges. Thus, a method for simulating physiological heart motions is desired but lacking so far.MethodsWe developed a robotic platform that allows simulating the trajectory of any point of the heart (one at a time) in six degrees of freedom. It uses heart motion trajectories acquired from cardiac magnetic resonance imaging or accelero-meter data. The rotations of the six motors are calculated based on the input trajectory. A closed-loop controller drives the platform and a graphical user interface monitors the functioning and accuracy of the robot using encoder data.ResultsThe robotic platform can mimic physiological heart motions from large animals and humans. It offers a spherical work envelope with a radius of 29 mm, maximum acceleration of 20 m/s2 and maximum deflection of ±19° along all axes. The absolute mean positioning error in x-, y- and z-direction is 0.21 ±0.06, 0.31 ±0.11 and 0.17 ±0.12 mm, respectively. The absolute mean orientation error around x-, y- and z-axis (roll, pitch and yaw) is 0.24 ±0.18°, 0.23 ±0.13° and 0.18 ±0.18°, respectively.ConclusionThe novel robotic approach allows reproducing heart motions with high accuracy and repeatability. This may benefit the device development process and allows re-using previously acquired heart motion data repeatedly, thus avoiding animal trials.

Effects of shear stress on differentiation of stem cells into endothelial cells.

Stem cell transplantation is an appealing potential therapy for vascular diseases and an indispensable key step in vascular tissue engineering. Substantial effort has been made to differentiate stem cells toward vascular cell phenotypes, including endothelial cells (ECs) and smooth muscle cells. The microenvironment of vascular cells not only contains biochemical factors that influence differentiation but also exerts hemodynamic forces, such as shear stress and cyclic strain. More recently, studies have shown that shear stress can influence the differentiation of stem cells toward ECs. A deep understanding of the responses and underlying mechanisms involved in this process is essential for clinical translation. This review highlights current data supporting the role of shear stress in stem cell differentiation into ECs. Potential mechanisms and signaling cascades for transducing shear stress into a biological signal are proposed. Further study of stem cell responses to shear stress will be necessary to apply stem cells for pharmacological applications and cardiovascular implants in the realm of regenerative medicine.

Dichloroacetate inhibits the degeneration of decellularized cardiovascular implants.

OBJECTIVESIntima hyperplasia is a major issue of biological cardiovascular grafts resulting in progressive in vivo degeneration that particularly decreases the durability of coronary and peripheral vascular bypasses. Previously, dichloroacetate (DCA) has been reported to prevent the formation of hyperplastic intima in injured arteries. In this study, the effect of DCA on the neointima formation and degeneration of decellularized small-caliber implants was investigated in a rat model.METHODSDonor rat aortic grafts (n = 22) were decellularized by a detergent-based technique, surface-coated with fibronectin (50 µl ml−1, 24 h incubation) and implanted via anastomoses to the infrarenal aorta of the recipients. Rats in the DCA group (n = 12) received DCA via drinking water during the whole follow-up period (0.75 g l−1), while rats without DCA treatment served as controls (n = 10). At 2 (n = 6 + 5) and 8 (n = 6 + 5) weeks, the grafts were explanted and examined by histology and immunofluorescence.RESULTSSystemic DCA treatment inhibited neointima hyperplasia, resulting in a significantly reduced intima-to-media ratio (median 0.78 [interquartile range, 0.51–1.27] vs 1.49 [0.67–2.39] without DCA, P < 0.001). At 8 weeks, neointima calcification, as assessed by an established von Kossa staining-based score, was significantly decreased in the DCA group (0 [0–0.25] vs 0.63 [0.06–1.44] without DCA, P < 0.001). At 8 weeks, explanted grafts in both groups were luminally completely covered by an endothelial cell layer. In both groups, inflammatory cell markers (CD3, CD68) proved negative.CONCLUSIONSSystemic DCA treatment reduces adverse neointima hyperplasia in decellularized small-caliber arterial grafts, while allowing for rapid re-endothelialization. Furthermore, DCA inhibits calcification of the implants.

Sol-gel coating loaded with inhibitor on ZE21B Mg alloy for improving corrosion resistance and endothelialization aiming at potential cardiovascular application

To improve the service performance of vascular stents, we designed/selected a series of organic compounds from commercial drugs, natural plants, and marine life as the potential corrosion inhibitors for ZE21B alloy. Paeonol condensation tyrosine (PCTyr) Schiff base was found to be the most efficient inhibitor among them. The biocompatible, self-healing, anti-corrosive sol-gel coating loaded with corrosion inhibitor was fabricated on the Mg substrate through a convenient dip-coating tactic. The corrosion resistance, self-healing ability, cytotoxicity, and hemocompatibility of the coated sample were evaluated. These results suggested the potentiality of Schiff base inhibitor-loaded sol-gel coating for enhanced corrosion protection and desired biocompatibility of bioabsorbable cardiovascular implants.

A multi-objective optimization of stent geometries

Stents are scaffolding cardiovascular implants used to restore blood flow in narrowed arteries. However, the presence of the stent alters local blood flow and shear stresses on the surrounding arterial wall, which can cause adverse tissue responses and increase the risk of adverse outcomes. There is a need for optimization of stent designs for hemodynamic performance. We used multi-objective optimization to identify ideal combinations of design variables by assessing potential trade-offs based on common hemodynamic indices associated with clinical risk and mechanical performance of the stents. We studied seven design variables including strut cross-section, strut dimension, strut angle, cell alignment, cell height, connector type and connector arrangement. Optimization objectives were the percentage of vessel area exposed to adversely low time averaged WSS (TAWSS) and adversely high Wall Shear Stress (WSS) assessed using computational fluid dynamics modeling, as well as radial stiffness of the stent using FEA simulation. Two multi-objective optimization algorithms were used and compared to iteratively predict ideal designs. Out of 50 designs, three best designs with respect to each of the three objectives, and two designs in regard to overall performance were identified.

Reveal crucial subtype of natural chondroitin sulfate on the functionalized coatings for cardiovascular implants

Surface functionalization is generally accepted as one of the most useful methods for endowing better biocompatibility of the cardiovascular implants. Chondroitin sulfate (CS) is a commercial drug applied for preventing cardiovascular diseases in clinics, suggesting a potential application for functionalized coatings. Our previous work demonstrated that the CS conjugated onto the poly-dopamine (PDA)/hexanediamine (HD) co-deposited 316L stainless steel (316L SS) could endow the surface stronger multi-functions for cardiovascular implants. However, the natural CS has two subtypes, CS A and CS C, while it is still unclear which subtype makes more contribution to the surface modification of cardiovascular implants. Thus, the present study focus on comparing CS A and CS C via preparing functionalized coatings on the cardiovascular implants. Our data suggested PDA/HD-CS C coating possessed better blood compatibility and pro-endothelialization function through controlling the phenotype and distribution of macrophages, smooth muscle cells and endothelial cells in time sequence and space sequence.