58 research outputs found
Liquid-Infused Surfaces for Anti–Thrombogenic Cardiovascular Medical Devices
Tethered-Liquid Perfluorocarbon (TLP) are a class of lubricant-infused surface coatings that, once
infused with perfluorinated lubricants, show promise to reduce adverse reactions in medical devices
implanted into the body such as reducing blood clot formation (thrombosis). A vapour phase
silanisation reaction and the self-assembling properties of a fluorinated silane are exploited to form
tethered perfluorocarbon (TP) layers containing nanostructured, bumpy aggregates. The vapour
phase method compares favourably to the previously established liquid phase deposition method
(LPD) to reproducibly create slippery coatings, without the need to control humidity conditions that
often plague LPD methods. The TP layer retains perfluorinated lubricants when exposed to flow
conditions seen in some medical devices, with a higher viscosity lubricant being more resistant to
shear flow-induced depletion. TLP infused with more viscous lubricant, was equally effective in
reducing adhesion of fibrin from human whole blood. Further in vitro biological assays revealed the
wettability dependence of the intrinsic pathway of coagulation is applicable to TLP, based on factor
XIIa activity and rate of plasma coagulation. Reduced adhesion of blood and loose packing of fibrin
fibers on TLP coatings is attributed to the combined effects of low contact activation and enhanced
mobility at the lubricant interface. Lubricant depletion dynamics under external flow was tested with a
microfluidic device, combined with a dual-wavelength reflection interference contrast microscopy
technique, enabling quantitative analysis of the lubricant on the nanoscale. The microfluidic platform
also revealed reduced fibrin and platelet adhesion to TLP coatings exposed to blood flow. Optimised
TLP coatings and greater understandings of anti-thrombogenic mechanisms open new avenues to
assess TLP under blood flow for further translational development towards the next generation of
blood-contacting medical devices
Mechanical characterisation of biological cells and biofunctional interfaces
Biological cells sense the mechanical properties of their surrounding environment and adapt their
shape and function. Moreover, the mechanical properties of cells and tissues tightly correlate with
their functions. The main thrust of this thesis is to quantitatively determine the mechanical proper-
ties of cells and cell-repellent coating materials by the combination of unique experimental techniques
by covering different spatio-temporal domains.
In chapter 7 the viscoelastic shape relaxation of malaria-infected human red blood cells with a di-
ameter of about 10 μm was monitored by the combination of a custom-designed microfluidic device
and a high-speed imaging platform under collaboration with Prof. Dr. M. Lanzer (Center for Inte-
grative Infectious Diseases, Heidelberg University). Using the binarised cell rims extracted from the
live-cell images, the shape recovery of red blood cells upon the ejection from the narrow constriction
was monitored with a time resolution of 30 μs per frame. The mechanical responses of the malaria-
infected red blood cells were monitored through the entire life cycle of parasites. The systematic
comparison of the red blood cells with genetically mutated hemoglobin (hemoglobinopathie) with
normal red blood cells indicated a less pronounced change in the relaxation time in hemoglobinopa-
thetic red blood cells, which might correlate with delayed protein synthesis in hemoglobinopathetic
red blood cells.
In chapter 8 the film elastic properties and internal structures of the monolayers of oligoethylene
glycol-based dendrons for the coating of iron-oxide nanoparticles were studied by the combination
of high energy X-ray reflectivity and high-speed atomic force microscopy. To achieve higher film sta-
bility in blood stream, the dendrons, synthesized by the group of Prof. Dr. Felder-Flesch (Institut
de Physique et Chimie des Materiaux , Univ. Strasbourg) were coupled to the oxide surface via two
phosphonate groups. The interfacial force measurements were performed on planar silicon dioxide
surfaces instead of iron oxide nanoparticle surfaces due to the technical limitations. The internal
structures of dendron monolayers in water were probed by high energy specular X-ray reflectivity.
An analytical model considering the transition from a soft layer to a hard layer was introduced to cal-
culate the Young’s modulus from nm-thick monolayers. To gain deeper insights into the interfacial
force interactions, the coarse-scale surface force-distance curves were measured by a cell-sized particle
attached to an atomic force cantilever cantilever, while the size and distribution of nanoscopic pin-
ning centers were monitored by fast force mapping with a pixel rate of 200 Hz. The capability of
the dendron coating to prevent the platelet aggregation was assessed by observing the non-specific
adhesion of human platelets on dendron-coated substrates. The dynamic uptake and localisation
of fluorescent dendron-coated iron oxide nanoparticles into hypoxic mouse breast cancer cells was
tracked using fluorescence imaging and cryo-transmission electron microscopy. Together, these meth-
ods revealed a continuous uptake of iron oxide nanoparticles into in intracellular compartments such
as endosomes via endocytosis. The iron oxide particles were found either agglomerated or as single
nanoparticles
Systems Radiology and Personalized Medicine
Medicine has evolved into a high level of specialization using the very detailed imaging of organs. This has impressively solved a multitude of acute health-related problems linked to single-organ diseases. Many diseases and pathophysiological processes, however, involve more than one organ. An organ-based approach is challenging when considering disease prevention and caring for elderly patients, or those with systemic chronic diseases or multiple co-morbidities. In addition, medical imaging provides more than a pretty picture. Much of the data are now revealed by quantitating algorithms with or without artificial intelligence. This Special Issue on “Systems Radiology and Personalized Medicine” includes reviews and original studies that show the strengths and weaknesses of structural and functional whole-body imaging for personalized medicine
Computed tomography and positron emission tomography in the assessment of aortic valve disease
Introduction
Native and bioprosthetic aortic valve diseases are an increasingly common clinical challenge as a consequence of the ageing demographic and the expansion of new valve technology. In both conditions, there remains substantial scope to broaden our understanding of the pathophysiology, improve diagnostic sensitivity and accuracy, and develop new markers of disease activity with which to measure therapeutic effect. Computed tomography (CT) and positron emission tomography (PET) are non-invasive imaging assessments that combine high resolution anatomical detail with real-time functional information about disease activity, and as such are ideally suited to complement echocardiography in the investigation of native and bioprosthetic aortic valve diseases.
Methods
Aortic Stenosis
Volunteers with aortic stenosis (n=143) across a range of severity underwent echocardiography, CT aortic valve calcium scoring and contrast-enhanced CT angiography. Aortic valve fibrosis and calcification were quantified to produce two novel measures: the fibro-calcific ratio and fibro-calcific burden. From the same study population, a subset of 15 volunteers underwent hybrid 18F-fluoride PET/CT on two separate occasions and we investigated different methods of image analysis to optimise accuracy and reproducibility.
Bioprosthetic Valves
Explanted degenerated bioprosthetic valves (n=16) were examined ex vivo using histopathology and preclinical 18F-fluoride PET/CT. Patients with bioprosthetic aortic valves (n=78) were then recruited into two cohorts, with and without prosthetic valve dysfunction, and underwent in-vivo contrast-enhanced CT angiography, 18F-fluoride PET, and serial echocardiography over 2 years of follow-up.
Results
Aortic Stenosis
Contrast-enhanced CT calcium volume correlated closely with conventional CT calcium score in the aortic valve (r=0.86, p=<0.001). Fibrosis dominated in mild aortic stenosis while calcification dominated in severe stenosis (fibro-calcific ratio: 1.33 [0.91-2.4]) versus 0.53 [0.35-1.05] respectively; p=0.001). Males exhibited more calcium than fibrosis, with the reverse true for females (fibro-calcific ratio: 0.89 [0.45-1.54] versus 1.49 [0.82-5.74] respectively; p=0.001). The fibro-calcific burden demonstrated the strongest correlation with peak aortic-jet velocity (r=0.71, p<0.001), especially in women (r=0.77, p=0.001) where it outperformed CT calcium score (p=0.027). In our investigation of 18F-fluoride-PET/CT, contrast-enhanced, ECG-gated PET/CT provided superior spatial localisation of 18F-fluoride uptake. Scan-rescan reproducibility was markedly improved using enhanced analysis techniques leading to a reduction in variability from 25% to <10%.
Bioprosthetic Valves
In degenerated bioprosthetic valves ex vivo, calcification was the most prevalent pathological feature (87%), whilst thrombus (40%) and pannus overgrowth (47%) were other common findings. All valves exhibited 18F-fluoride uptake on PET, with a strong positive correlation between 18F-fluoride uptake and calcium volume (r=0.73, p=0.0031). 18F-Fluoride uptake was highest in regions of leaflet calcification but also localised to regions of organised thrombus, fibrosis and features of matrix degradation on histopathology.
In the cohort study of patients with bioprosthetic aortic valves, all those with recognised valve dysfunction exhibited abnormalities on CT and high 18F-fluoride uptake. In the 71 patients without valve dysfunction, 20% had leaflet pathology on CT and 34% had increased 18F-fluoride uptake (target-to-background ratio 1.55 [1.44-1.88]). Patients with increased 18F-fluoride uptake exhibited more rapid deterioration in valve function than those without (annualised change in peak transvalvular velocity: 0.30 [0.13-0.61] versus 0.01 [-0.05-0.16] ms-1/year, p<0.001). 18F-Fluoride uptake correlated with deterioration in all echocardiographic measures of valve function (e.g. change in peak velocity, r=0.72; p<0.001) and, on multivariable analysis, was the only independent predictor of future bioprosthetic dysfunction.
Conclusions
In both native aortic valve disease and bioprosthetic valve disease, CT and 18F-fluoride PET afford valuable insights into disease mechanisms, inform patient risk stratification and prognosis, and provide biomarkers of disease activity that may be used for the development of future therapeutic interventions
CT Scanning
Since its introduction in 1972, X-ray computed tomography (CT) has evolved into an essential diagnostic imaging tool for a continually increasing variety of clinical applications. The goal of this book was not simply to summarize currently available CT imaging techniques but also to provide clinical perspectives, advances in hybrid technologies, new applications other than medicine and an outlook on future developments. Major experts in this growing field contributed to this book, which is geared to radiologists, orthopedic surgeons, engineers, and clinical and basic researchers. We believe that CT scanning is an effective and essential tools in treatment planning, basic understanding of physiology, and and tackling the ever-increasing challenge of diagnosis in our society
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Toward Growth-Accommodating Polymeric Heart Valves with Graphene-Network Reinforcement
Graphene is a 2D material well known for its high intrinsic strength of 100 GPa and Young’s modulus of 1 TPa. Because of its 2D nature, the most promising avenues to utilize graphene as a mechanical material include incorporating it as reinforcement in a nanocomposite and creating free-standing foams and aerogels. However, the current techniques are not well-controlled – the reinforcing graphene particles are often discontinuous and randomly dispersed – making it difficult to accurately model and predict the resulting material properties.
Here we aim to develop a framework for a new class of nanocomposites reinforced not by discrete nanoparticles, but by a continuous 3D graphene network. These 3D graphene networks were formed by chemical vapor deposition of graphene on periodic metallic microlattices, thereby providing mechanical reinforcement for the lattices. To assist in the lattice design, analytical models were derived for the mechanical properties of core/shell composite lattices and experimentally validated through compression testing of polymer lattices coated with electroless Ni-P. The models and experiments showed good agreement at lower shell thicknesses, while there was divergence at higher thicknesses, likely due to fabrication imperfections. The analytical models were also applied to hollow metallic lattices coated with graphene and compared to experimental data. The results showed that the models are plausible and suggest that graphene has a significant strengthening effect on the microlattices. These studies represent a paradigm shift in the design and fabrication of nanocomposites as one may now precisely prescribe the placement of the reinforcing nanomaterials. On a broader scale, this work also lays the framework for using a 2D material to span 3D space, enabling further exploration of 2D material properties and applications.
One potential application area for a graphene-reinforced polymer composite is in prosthetic heart valves. The tissue of a human heart valve leaflet is heavily reinforced with networks of collagen and elastin fibers. One could similarly incorporate a graphene network as reinforcement within the polymeric leaflets of a prosthetic valve. One promising application of polymeric valves is in growth-accommodating implants for pediatric patients. Here we aim to develop a polymeric valved conduit that can be expanded by transcatheter balloon dilation to match a child’s growth. We designed the valve, characterized and selected materials, fabricated the devices and performed benchtop in vitro testing. The first generation of an expandable biostable valved conduit displayed excellent hydrodynamic performance before and after permanent balloon dilation from 22 to 25 mm. The second generation has shown the potential for a greater dilation from 12 to 24 mm. These results demonstrate concept feasibility and motivate further development of a polymeric balloon-expandable device to replace valves in children and avoid reoperations
Frameshift mutations at the C-terminus of HIST1H1E result in a specific DNA hypomethylation signature
BACKGROUND: We previously associated HIST1H1E mutations causing Rahman syndrome with a specific genome-wide methylation pattern. RESULTS: Methylome analysis from peripheral blood samples of six affected subjects led us to identify a specific hypomethylated profile. This "episignature" was enriched for genes involved in neuronal system development and function. A computational classifier yielded full sensitivity and specificity in detecting subjects with Rahman syndrome. Applying this model to a cohort of undiagnosed probands allowed us to reach diagnosis in one subject. CONCLUSIONS: We demonstrate an epigenetic signature in subjects with Rahman syndrome that can be used to reach molecular diagnosis
Making sense of outcome after congenital left ventricular outflow tract surgery
This thesis aims to make sense of outcome after congenital left ventricular outflow tract surgery and improve evidence-based decision-making, patient information and patient involvement by investigating the following research questions:
- __What is long-term outcome after congenital left ventricular outflow tract surgery?__
- __How can evidence on outcome be effectively conveyed to physicians and patients for implementation of informed shared decision-making in practice?_
- …