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Spectroscopic and Morphological Characterization of Inflow Cannulas of Left Ventricular Assist Devices

Pappalardo, Federico*; Cristaldi, Domenico A.; Fragalà, Ignazio L.; Millesi, Salvatrice; De Bonis, Michele; Gulino, Antonino

doi: 10.1097/MAT.0000000000000169
Adult Circulatory Support

Despite the consistent clinical data on the positive effects of left ventricular assist devices (LVADs) in the treatment of refractory heart failure, unfortunately these devices yet show some limitations such as the risk of stroke, infection, and device malfunction. The complex interplay between blood and the foreign material has a major role in the occurrence of these complications and biocompatibility of the inflow cannula would be pivotal in these terms. In this study, we carried out an in-depth physicochemical characterization of two commercially available LVADs by means of field emission gun scanning electron microscopy, energy dispersive X-ray, and X-ray photoelectron spectra. Our results show that, despite both pumps share the same physicochemical concepts, major differences can be identified in the surface nature, morphology, and chemical composition of their inflow cannulas

From the *Department of Cardiothoracic Intensive Care, Vita-Salute University and INSTM UdR of the San Raffaele Hospital, Milano, Italy; Department of Chemistry, University of Catania and INSTM UdR of Catania, Catania, Italy; and Department of Cardiac Surgery, San Raffaele Hospital, Milano, Italy.

Dr. Pappalardo and Prof. Gulino are the leaders of the research groups of the San Raffaele Hospital and of the Department of Chemistry, University of Catania, respectively.

Disclosures: The authors have no conflicts of interest to report.

Correspondence: Antonino Gulino, Department of Chemistry, University of Catania and INSTM UdR of Catania, Viale Andrea Doria 6, 95125 Catania, Italy. Email:

Heart failure is one of the most important epidemics in health care of the third millennium and, because of the scarcity of organs for transplantation, the use of left ventricular assist devices (LVADs) is steadily increasing. Such devices have been shown to significantly improve the survival and rate of bridging to heart transplantation in patients awaiting for a donor graft and also in those patients considered ineligible for heart transplantation (Destination Therapy).1–16 Yet, this technology, despite the significant improvements in the last decade, has some limitations such as the risk of stroke, infection, and device malfunction.

These devices can interfere with the coagulation system as the foreign material is a trigger for activation of the hemostatic cascade; moreover, LVADs also activate the inflammatory and immune systems, which crosstalk with coagulation further promoting thrombosis. Thromboembolic events (stroke, pump thrombosis, and peripheral thromboembolism) may occur in up to 20% of patients with LVADs.1–9 The inflow cannula in the left ventricle not only is the largest foreign surface of the pump but is also exposed to a peculiar fluidodynamic milieu: this would entail a major role for the interplay with coagulation and therefore the risk for thrombus formation and ingestion into the pump.

The biocompatibility of metal alloys used in manufacturing LVADs is not optimal and therefore patients require lifelong anticoagulants and antiplatelets. Physicochemical characterization of LVAD surfaces might be a pivotal step forward for the improvement of biocompatibility and therefore reduction of thromboembolic complications: the observation of any structural imperfection of the surface might eventually provide a valuable aid in the interpretation of the processes of nucleation and growth of thrombi in vivo.

The main purpose of this study is to characterize the physicochemical properties of the inflow cannulas of two commercially available LVADs, to eventually address any issue which would prompt the need for improving the biocompatibilty of these materials.17 The X-ray photoelectron spectroscopy (XPS) technique is attractive for an in-depth chemical characterization as it has optimal high vertical resolution, provides information on the bonding states of molecules, and allows the assessment of the elemental composition of the surfaces.

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Materials and Methods

In this study, we analyzed the inflow cannulas of the currently most worldwide used LVADs: the HeartMate II (Thoratec, Pleasanton, California) and the HeartWare LVAD (HeartWare Inc., Framingham, Massachusetts).

We received the samples in a standard packaging for clinic use. The cutting procedure to obtain cannula pieces suited for the spectroscopic analyses was performed at the workshop of the Physical Department of the University of Catania and involved the use of high precision cutting tools typically used for the silicon microelectronic devices. Afterward we just washed the cannulas with isopropyl alcohol before our investigations.

X-ray photoelectron spectroscopy is the most appropriate technique for surface studies of solids and present spectra were measured at 45° takeoff angle relative to the surface normal with a PHI 5600 Multi Technique System (base pressure of the main chamber 2 × 10−10 Torr) using the monochromatized Al-Kα X-ray radiation. The analyzer pass energy was set at 5.85 eV.18–21 No sample charging effect was observed.

The chemical composition was analyzed by energy dispersive X-ray (EDX) analysis using an INCA Energy Oxford solid state detector (Oxford Instruments, Abingdon, Oxfordshire, United Kingdom). Morphologies were examined through field emission gun scanning electron microscopy using a Zeiss SUPRA 55 VP microscope (Carl Zeiss AG, Oberkochen, Germany).

The roughness measurements have been performed using an Olympus LEXT confocal laser scanning microscope OLS 3000 (Olympus Corporation, Shinjuku Monolith, 3-1 Nishi-Shinjuku 2-chome, Shinjuku-ku, Tokyo, Japan).

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The surface morphology and composition of the different LVADs cannulas were investigated by scanning electron microscopy (SEM) and EDX analyses. These precise analyses allowed to obtain information on the composition, surface morphology as well as the mechanical stress suffered by these LVADs during their manufacturing.

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Scanning Electron Microscopy and Energy Dispersive X-Ray of the Internal Surface of the HeartWare Left Ventricular Assist Device Cannula

Scanning electron microscopy analysis of the internal surface of the HeartWare LVAD cannula is shown in Figure 1. The surface appears rather not homogeneous because many surface imperfections and metal fragments bound to the surface (Figure 1A). Moreover, long, linear, and dense streaks typical of a turned metal surface can be recognized (Figure 1B). The EDX analysis of large areas of this sample displayed the following chemical composition: Ti = 92.1%, Al = 6.0%, V = 1.9%. The Ti content was consistent in all different surface areas analyzed; in contrast, both light (large ellipse) and dark (small ellipse) surface features revealed higher vanadium and less aluminum contents (Table 1).

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Scanning Electron Microscopy and Energy Dispersive X-ray of the External Surface of the HeartWare Left Ventricular Assist Device Cannula

The external surface of the HeartWare LVAD cannula shows to the naked eye two differently worked parts that hereafter will be called external smooth and external rough surfaces (see Figure S1, Supplemental Digital Content 1, Scanning electron microscopy images of the external smooth surface show a striped morphology characterized by parallel furrows 8.7 μm distant each other and 4.4 μm tall (Figure 2). These features may be a result of an argon plasma etching, often used to manufacture micropatterns on titanium oxide films.22 The EDX analysis of large areas of this external smooth surface resulted in the following chemical composition: Ti = 92.3%, Al = 5.5%, V = 3.2% which strongly resembles that of the internal part.

The SEM analysis of the external rough surface of the HeartWare LVAD cannula shows a different morphology (Figure 3). The surface is totally covered by microspheres of mean diameter of ~115 μm. These microspheres seem to have undergone a sintering process and are partially melted each other. The EDX analysis of selected microspheres resulted in the following chemical composition: Ti = 87.7%, Al = 7.4%, V = 5.0%. Moreover, it is possible to spot a large quantity of a chemical residue interposed between the microspheres. The EDX composition of this residue (ellipse in Figure 3B) is as follows: O = 59.1%, K = 10.4%, Cl = 11.1%, Ti = 7.1%, and Na = 12.3%. It could be likely that this is a residue of the molten salt mixture used to decrease the sintering temperature of the ternary microspheres made by the Ti, Al, V alloy.

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Scanning Electron Microscopy and Energy Dispersive X-Ray of the HeartMate II Cannula

The HeartMate II inflow cannula has identical internal and external surfaces as shown in Figure S2 (see Supplemental Digital Content 1, Scanning electron microscopy analysis shows a rough surface characterized by a large number of microspheres that underwent a sintering process (Figure 4). As compared to the surface of the rough external HeartWare cannula, there is no material left after the sintering process and the surface is much more clean. The SEM image at higher magnification (Figure 5) shows that each microsphere has some surface cavities, probably because of strong impacts between the microspheres themselves. These impact areas (shape and morphology) are caused by the process used to cover the surface beneath. The mean diameter of each microsphere is about 140 μm, somewhat larger than those observed for the HeartWare cannula, and the microspheres are partially melted to each other and the surface cavities, due to possible collision events, are now much more evident (Figure 5B). The EDX analysis demonstrated a Ti (85.4 %), Al (2.0 %), and V (11.6 %) composition.23

The HeartWare cannula has shown roughness of 8.0 and 6.1 μm for the internal and the external surfaces, respectively. In contrast, the HeartMate II cannula showed a 374.3 μm roughness in both surfaces.

As a general indication, the Ti alloy used to manufacture the VAD cannulas is the Ti6Al4V alloy approved from the FDA. The thermal treatments used to fabricate and model the inflow cannulas are responsible of some metal segregation that modifies the composition of the cannula surfaces. In addition, also the Ti6Al4V alloy can contain other metals in low concentrations that, because of the thermodynamic surface segregation phenomenon, can be evidenced only with a surface-sensitive technique (XPS).

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X-Ray Photoelectron Spectroscopy

X-ray photoelectron spectroscopy measurements have been performed to characterize the chemical composition of the surfaces. XPS enables in-depth chemical and structural characterizations and allows for a qualitative and quantitative analysis of elemental composition as well as oxidation states. It is important to bear in mind that XPS probes a few tenth of angstroms of surface. Therefore, the XPS composition can show major differences with respect to EDX results.

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X-Ray Photoelectron Spectroscopy of the HeartMate II Cannula

Figure 6 shows the XPS of the internal surface of the HeartMate II cannula in the Ti 2p energy region. There are two strong and clear signals at 458.6 and 464.4 eV, typical of Ti 2p5/2 and Ti 2p3/2 spin–orbit components of the TiO2 phase.24–26 This result is rather important because the surface that will be in strong contact with the blood is TiO2 instead of Ti. The XPS atomic concentration analysis reveals also a relevant presence of silicon,17 being the surface ratio Si/Ti = 0.38, and some Al, being the ratio Al/Si = 0.05. No evidence of S was found. Therefore, the Ti6Al4V alloy used to manufacture the cannula contained some Si that segregated onto this cannula surface.

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X-Ray Photoelectron Spectroscopy of the HeartWare Left Ventricular Assist Device Cannula

The XPS atomic concentration analysis of the HeartWare internal cannula reveals increased Si and Al surface concentrations Si/Ti = 0.41 and Al/Si = 0.14 as compared to the HeartMate II. No Si presence was observed with EDX analyses in both HeartMate II and HeartWare cannulas. Therefore, the Si presence is confined to the topmost surface layers. Titanium is present only as TiO2 on the surface.27,28 In addition, a small but evident presence of lead, Pb/Ti = 0.01, was also found on the internal surface (Figure 7A) with the Pb 4f7/2 and Pb 4f5/2 spin–orbit components at 138.5 and 143.4 eV, respectively, and typical of the PbO phase.29

Importantly, Figure 7B shows the XPS of the HeartWare cannula in the S 2p energy region. There is a strong and clear signal at 169.1 eV typical of the SO4- group, as expected for a thin heparin film.30 This signal was absent in the HeartMate II cannula.

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Our study is the first addressing the physicochemical characterization of LVADs’ surfaces with techniques that allow high vertical resolution, providing information on the bonding states of molecules and on the elemental composition of the surfaces; moreover, morphological and quantitative results have been obtained.

Thromboembolic complications may result from ingestion of thrombi grown around the inflow cannula at the implant site in the left ventricle, especially in the presence of stasis or suction.

To improve the biocompatibility of the foreign material, pseudo-endothelial artificial surfaces have been implemented in LVADs. Two major groups of coating can be distinguished: bioactive (heparin, nitric oxide) and biopassive (albumin, phosphorylcholine). Heparin interferes with the physiological hemostasis but the duration of the immobilized heparin on the surfaces of the LVAD is not known over the time and phenomena of superficial thrombosis are often observed on LVAD surfaces and no consistent benefits of coating of artificial surfaces has yet been shown.

Few data are available on the role of the physicochemical properties of foreign surfaces and thrombosis: Ellingensen27 reported that oxide layers increase the surface hydrophobicity thus causing greater adsorption of proteins. In contrast to this view, other authors indicated an increased compatibility of blood with the titania layer.28

The rates of pump thrombosis in the HeartMate II and HeartWare series have been identified as major issues.31,32 In the HeartWare LVAD ADVANCE trial, these events prompted the introduction of sintering with titanium microspheres and the intensification of antiplatelets. Exchange rates for suspected pump thrombus were analyzed for those events occurring before the anticoagulation adjustment and device design enhancements (on or before March 15, 2011) compared with those occurring post-adjustment and design enhancements (after March 15, 2011 through July 30, 2012). The total number of patients at risk pre-adjustment was n = 253, and the total number at risk post-adjustment was n = 211. Event rates decreased from 0.065 event/person per year (PPY) to 0.028/PPY.31,32

Similarly, Starling et al.33 observed an increasing incidence of early thrombosis with the HeartMate II. The occurrence of confirmed pump thrombosis increased steeply after approximately March 2011, from 2.2% (95% confidence interval [CI]: 1.5–3.4) at 3 months after implantation to 8.4% (95% CI: 5.0 to 13.9) by January 2013. The risk of pump thrombosis peaked at 1.4% per month within 1 month after implantation before decreasing to a constant risk of 0.4% per month, with estimated occurrences of 4.7% during HeartMate II support for 6 months, 7.5% during 12 months of support and 12.3% during 24 months of support.

Our study has shown major differences between the HeartWare and HeartMate II. First, as far as the external surfaces, its roughness is much more pronounced for the HeartMate II device. Moreover, the HeartMate II cannula is totally covered with Ti nanospheres, while the HeartWare cannula shows only the lower external aspect covered with Ti sintered microspheres. In addition, the internal surfaces of the cannulas of these two devices are totally different: in fact, the HeartWare system shows no Ti microspheres and the surface roughness is ~8.0 μm while the HeartMate II cannula showed a ~374 μm roughness in both surfaces. Furthermore, no heparin was observed on the internal surface of the HeartMate II device.

In the light of these data, the HeartMate II and HeartWare LVAD have major differences in the physicochemical characteristics of their inflow cannula, albeit both sintered with titanium microspheres; whether these turn into major clinical outcomes warrants further studies. Structural inflow cannula changes and improvements of biocompatibility might turn into pivotal positive results in the clinical setting.

The combination of the analytical techniques applied in this study is unique in this field and could play interesting in evaluating innovations in structural changes and biocompatibility of artificial surfaces.

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In conclusion, this is the first study addressing the physicochemical characteristics of LVADs. Both HeartWare and HeartMate II LVADs show sintered titanium microspheres on the inflow cannulas. The two surfaces are, however, significantly different both macroscopically (in terms of design of the inner and outer side of the cannula and of smooth and rough surfaces) and microscopically (sintering of titanium microspheres). In both HeartWare and HeartMate II inflow cannulas the surface titanium is present as TiO2 with no zero-valent Ti. In the light of these data, further studies are warranted to address the interaction of the artificial surfaces of LVADs and blood coagulation, their correlations with thromboembolic complications, and eventually the optimization of anticoagulation.

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A. Gulino and F. Pappalardo thank INSTM and Regione Lombardia for the financial support of the BIOSUOVAD project, 2013. A. Gulino thanks the University of Catania. The authors are indebted to O. G. Turla, CCP, for his continuous support and for data collection.

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left ventricular assist device; X-ray photoelectron spectroscopy; scanning electron microscopy; energy dispersive X-ray; heart; thrombosis

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