AbstractBlood-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.

Abstract
AIMS:
Simple surface modifications can enhance coronary stent performance. Ultra-hydrophilic surface (UHS) treatment of contemporary bare metal stents (BMS) was assessed in vivo to verify whether such stents can provide long-term efficacy comparable to second-generation drug-eluting stents (DES) while promoting healing comparably to BMS.

METHODS AND RESULTS:
UHS-treated BMS, untreated BMS and corresponding DES were tested for three commercial platforms. A thirty-day and a 90-day porcine coronary model were used to characterise late tissue response. Three-day porcine coronary and seven-day rabbit iliac models were used for early healing assessment. In porcine coronary arteries, hydrophilic treatment reduced intimal hyperplasia relative to the BMS and corresponding DES platforms (1.5-fold to threefold reduction in 30-day angiographic and histological stenosis; p<0.04). Endothelialisation was similar on UHS-treated BMS and untreated BMS, both in swine and rabbit models, and lower on DES. Elevation in thrombotic indices was infrequent (never observed with UHS, rare with BMS, most often with DES), but, when present, correlated with reduced endothelialisation (p<0.01).

CONCLUSIONS:
Ultra-hydrophilic surface treatment of contemporary stents conferred good healing while moderating neointimal and thrombotic responses. Such surfaces may offer safe alternatives to DES, particularly when rapid healing and short dual antiplatelet therapy (DAPT) are crucial.

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¹ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.

EuroIntervention. 2017 Apr 20;12(17):2148-2156. doi: 10.4244/EIJ-D-15-00497.

Abstract
AIMS:
In preclinical studies, a bare metal cobalt-chromium stent with an active surface oxide layer modification (BMSmod) has been shown to inhibit neointimal hyperplasia effectively. We sought to assess both the clinical safety and feasibility of the BMSmod.

METHODS AND RESULTS:
In this prospective, non-randomised, first-in-man multicentre study, a total of 31 patients with de novo coronary lesions, reference lumen diameters of 2.5-3.5 mm and lesion length ≤16 mm, were enrolled. Quantitative coronary angiography and optical coherence tomography (OCT) were performed at baseline and six-month follow-up. Primary angiographic and OCT endpoints included in-stent late lumen loss (LLL) and mean neointimal thickness at six months. The device-oriented composite endpoint (DoCE), defined as cardiac death, myocardial infarction not clearly attributable to a non-intervention vessel, and clinically indicated target lesion revascularisation (CI-TLR), was analysed according to the intention-to-treat principle. In 31 patients (33 lesions), the procedural success rate was 93.5%. At six months, angiographic LLL was 0.91±0.45 mm and binary angiographic restenosis occurred in 23.3% of lesions. Out of 33 lesions, OCT was performed in 27 lesions at both time points. Mean neointimal thickness amounted to 348±116 µm. At six months, the DoCE was 19.4% due to the occurrence of CI-TLR in five patients (including one late definite stent thrombosis of a non-study stent).

CONCLUSIONS:
In contrast to previous preclinical pathophysiological work, the BMSmod did not prevent neointimal hyperplasia in a first-in-man clinical setting.

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¹Thoraxcenter, Erasmus Medical Center, Rotterdam, the Netherlands.

EuroIntervention. 2017 Apr 20;12(17):2118-2127. doi: 10.4244/EIJ-D-16-00975.

CoCr alloys, in particular MP35N and L605, are extensively used in biomedical implants, for example for coronary stents. In practice, these alloys present a moderately hydrophobic surface which leads to significant platelet adhesion and consequently to risk of early thrombosis or in-stent restenosis. Surface modification of biomedical implants is known to alter their biological performances. In this study we focused on the alteration of in vitro biological responses of human cells contacting CoCr surfaces with engineered oxide layers. XPS analysis was performed to determine the composition of the oxide layer of differently treated CoCr while the bulk properties were not modified. An extensive characterization of the surfaces was performed looking at surface roughness, wettability and charge. After static exposure to blood, strongly reduced platelet and increased polymorphonuclear neutrophil adhesion were observed on treated versus untreated surfaces. Comparisons of treated and untreated samples provide evidence for wettability being an important player for platelet adhesion, although multiple factors including surface oxide chemistry and charge might control polymorphonuclear neutrophil adhesion. The differently treated surfaces were shown to be equally suitable for endothelial cell proliferation. We herein present a novel approach to steer biological properties of CoCr alloys. By adjusting their oxide layer composition, substrates were generated which are suitable for endothelial cell growth and at the same time show an altered (reduced) blood contact activation. Such treatments are expected to lead to stents of highly reproducible quality with minimal thrombogenicity and in-stent restenosis, while maintaining rapid re-endothelialization after coronary angioplasty. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2014.

Abstract

Biomaterials upon implantation are immediately covered by blood proteins which direct the subsequent blood activation. These early events determine the following cascade of biological reactions and consequently the long-term success of implants. The ability to modulate surface properties of biomaterials is therefore of considerable clinical significance.

Goal of this study was an in-depth understanding of the biological response to cobalt chromium stent alloys with engineered surface oxide layers, which showed altered body reactions in vivo. We analyzed in vitro the biological events following initial blood contact on engineered cobalt chromium surfaces featuring said oxide layers. Surface-specific blood reactions were confirmed by scanning electron microscopy and the adsorbed protein layers were characterized by mass spectrometry. This powerful proteomics tool allowed the identification and quantification of over hundred surface-adhering proteins. Proteins associated with the coagulation cascade, platelet adhesion and neutrophil function correlated with the various blood surface activations observed. Furthermore, results of pre-coated surfaces with defined fibrinogen–albumin mixtures suggest that neutrophil adhesion was controlled by fibrinogen orientation and conformation rather than quantity. This study highlights the importance of controlling the biological response in the complex protein–implant surface interactions and the potential of the surface modifications to improve the clinical performance of medical implants.

Statement of Significance

The blood contact activation of CoCr alloys is determined by their surface oxide layer properties. Modifications of the oxide layer affected the total amount of adsorbed proteins and the composition of the adsorbed protein layer. Additionally fibrinogen coatings mediated the surface-dependent neutrophil adhesion in a concentration-independent manner, indicating the influence of conformation and/or orientation of the adsorbed protein. Despite the complexity of protein–implant interactions, this study highlights the importance of understanding and controlling mechanisms of protein adhesion in order to improve and steer the performance of medical implants. It shows that modification of the surface oxide layer is a very attractive strategy to directly functionalize metallic implant surfaces and optimize their blood interaction for the desired orthopedic or cardiovascular applications. © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

The QBM surface significantly reduced neointimal hyperplasia in swine coronaries compared to both BMS and DES, independently from stent design and/or alloy, without adverse vascular healing effects. In-Vitro data indicate that those results may be related to a significant reduction of adherent platelets combined with enhanced neutrophil adhesion, which promote reendothelialization and decrease neointimal hyperplasia by locally regulating acute inflammatory response and endothelial recovery. Therefore, this novel approach may be an effective alternative to DES in reducing clinical in-stent restenosis.

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