Mathieu Salaun

Confocal Fluorescence Endomicroscopy of the Human Airways

Confocal endomicroscopes aim at providing to the clinician microscopic imaging of a living tissue. The currently available microendoscopic devices use the principle of confocal fluorescent microscopy, in which the objective is replaced by an optical fiber and a miniaturized scanhead at the distal end of the endoscope or by a retractable bundle of optical fibers. Such systems have recently been applied to the explorations of several organs, including the gastrointestinal tract, and more recently to the proximal and distal airways in vivo. Respiratory fluorescence microendoscopes use 488 nm or 660 nm excitation laser light and thin flexible miniprobes that are introduced into the working channel of the bronchoscope. The devices have a lateral resolution of 3 microm, a field of view of 600 microm, and produce real-time imaging at 9 frames per second. For in vivo imaging, the miniprobe is applied onto the bronchial wall surface or advanced into a distal bronchiole down to the acinus. In nonsmokers, the 488-nm excitation device images the autofluorescence of the elastin that is contained in the basement membrane of the proximal airways and that participates to the axial backbone of the peripheral interstitial respiratory system. In smokers, a specific tobacco tar-induced fluorescence allows in vivo macrophage and alveolar wall imaging. Using 660 nm excitation and topical methylene blue, the technique enables cellular imaging of both bronchial epithelial layer and peripheral lung nodules. This article reviews the capabilities and possible limitations of confocal microendoscopy for in vivo proximal and distal lung explorations.

Pulsed Transfer Etching of PS–PDMS Block Copolymers Self-Assembled in 193 nm Lithography Stacks

This work presents the graphoepitaxy of high-χ block copolymers (BCP) in standard industry-like lithography stacks and their transfer into the silicon substrate The process includes conventional 193 nm photolithography, directed self-assembly of polystyrene-block-polydimethylsiloxane (PS-b-PDMS) and pulsed plasma etching to transfer the obtained features into the substrate. PS-b-PDMS has a high Flory-Huggins interaction parameter (high-χ) and is capable of achieving sub-10 nm feature sizes. The photolithography stack is fabricated on 300 mm diameter silicon wafers and is composed of three layers: spin-on-carbon (SoC), silicon-containing anti-reflective coating (SiARC) and 193 nm photolithography resist. Sixty-nanometer-deep trenches are first patterned by plasma etching in the SiARC/SoC stack using the resist mask. The PS-b-PDMS is then spread on the substrate surface. Directed self-assembly (DSA) of the BCP is induced by a solvent vapor annealing process and PDMS cylinders parallel to the substrate surface are obtained. The surface chemistry based on SoC permits an efficient etching process into the underlying silicon substrate. The etching process is performed under dedicated pulsed plasma etching conditions. Fifteen nanometer half-pitch dense line/space features are obtained with a height up to 90 nm.

Fabrication of highly ordered sub-20 nm silicon nanopillars by block copolymer lithography combined with resist design

The control of order and orientation of the self-assembly of cylinder-forming poly(styrene-b-dimethylsiloxane) block copolymer is demonstrated. Copolymer thin films are spun-cast onto topographically patterned (well-defined rectangular cross-section channels) polyhedral-silsesquioxane-type resist templates and annealed in solvent vapor. The templates used here are fabricated by UV-curing nanoimprint lithography and the surface properties of the resist are tuned by the ligands coordinated to the resists silsesquioxane cages. Depending on the resists composition and on the surface chemistry at the base of the trench (resist or silicon), various morphologies and orientations of the polydimethylsiloxane cylinders are observed without the use of a brush layer. Some surfaces are demonstrated to be neutral for the copolymer, without any wetting layer and, under favorable conditions, highly ordered features are observed over substrate areas of about 1 cm2 (scalable to larger surfaces). Also, the possibility of using solvents widely accepted in industry for polymer spin-coating and annealing is proved. Due to the high plasma etch resistance of the polydimethylsiloxane block, self-assembled patterns can be transferred to the silicon substrate producing silicon features with aspect ratios up to 2. We demonstrate that the methodology developed here could be integrated into conventional fabrication processes and scaled to wafer production.

Phase II Study of a Radiotherapy Total Dose Increase in Hypoxic Lesions Identified by 18 F-Misonidazole PET/CT in Patients with Non–Small Cell Lung Carcinoma (RTEP5 Study)

See an invited perspective on this article on page 1043. This multicenter phase II study investigated a selective radiotherapy dose increase to tumor areas with significant 18F-misonidazole (18F-FMISO) uptake in patients with non–small cell lung carcinoma (NSCLC). Methods: Eligible patients had locally advanced NSCLC and no contraindication to concomitant chemoradiotherapy. The 18F-FMISO uptake on PET/CT was assessed by trained experts. If there was no uptake, 66 Gy were delivered. In 18F-FMISO–positive patients, the contours of the hypoxic area were transferred to the radiation oncologist. It was necessary for the radiotherapy dose to be as high as possible while fulfilling dose-limiting constraints for the spinal cord and lungs. The primary endpoint was tumor response (complete response plus partial response) at 3 mo. The secondary endpoints were toxicity, disease-free survival (DFS), and overall survival at 1 y. The target sample size was set to demonstrate a response rate of 40% or more (bilateral α = 0.05, power 1-β = 0.95). Results: Seventy-nine patients were preincluded, 54 were included, and 34 were 18F-FMISO–positive, 24 of whom received escalated doses of up to 86 Gy. The response rate at 3 mo was 31 of 54 (57%; 95% confidence interval [CI], 43%–71%) using RECIST 1.1 (17/34 responders in the 18F-FMISO–positive group). DFS and overall survival at 1 y were 0.86 (95% CI, 0.77–0.96) and 0.63 (95% CI, 0.49–0.74), respectively. DFS was longer in the 18F-FMISO–negative patients (P = 0.004). The radiotherapy dose was not associated with DFS when adjusting for the 18F-FMISO status. One toxic death (66 Gy) and 1 case of grade 4 pneumonitis (>66 Gy) were reported. Conclusion: Our approach results in a response rate of 40% or more, with acceptable toxicity. 18F-FMISO uptake in NSCLC patients is strongly associated with poor prognosis features that could not be reversed by radiotherapy doses up to 86 Gy.

Direct top-down ordering of diblock copolymers through nanoimprint lithography

In this work, thermal nanoimprint lithography (NIL) is used on full 8 in. silicon wafers to imprint a thin PS-b-PMMA block copolymer (BCP) layer. The authors show that the imprinted BCP layer can thermally self-organize after the NIL process or during the NIL process itself, depending on experimental conditions used. Self-organized imprinted features with good graphoepitaxy alignment are obtained with a cylindrical BCP. Nevertheless, a standard fluorinated silane mold treatment is shown not to be neutral to the BCP. Then, if the line features do not have a thickness exactly commensurable to the natural self-organizing period of the polymer l0, a surface wetting layer is observed.

Fabrication and characterization of three-dimensional silver/air inverted opal photonic crystals

Photonic crystals made from noble metals such as silver are an interesting class of material for many applications such as chemical sensing, solar cells or photonics. Their fabrication suffers from a lack of reproducibility, and complicated and aggressive processes. In this paper we show a simple and reproducible method based on the black and white photography process, to get a self standing 3D silver photonic crystal. Their characterization by SEM and TEM allowed us to interpret the process, and optical analysis made in reflection and transmission were used to find out eventual coupling between surface plasmon polaritons and the photonics properties of the structure itself.

Multifunctional oxide nanostructures by metal-organic chemical vapor deposition (MOCVD)*

The development of thin films, in the context of ongoing reduction in the size of electronic systems, poses challenging questions for the materials sciences of multifunctional nanostructures. These include the limits of size reduction, integration of heterogeneous functions, and system characterization or process control at an atomic scale. We present here different studies devoted to perovskite oxide materials (or materials with derived structure), where in specific directions of the crystal structure the atomic organization decreases down to a few nanometers, thus building nanostructures. In these materials, very original physical phenomena are observed in multilayers or superlattices, nanowires (NWs) or nanodots, mainly because strain, surfaces, and interfaces play here a predominant role and can tune the physical properties. Metal-organic chemical vapor deposition (MOCVD) routes have been used for the synthesis of oxide materials. We first introduce the basic rules governing the choice of metal-organic precursors for the MOCVD reaction. Next we discuss the principles of the pulsed injection MOCVD system. A laser-assisted MOCVD system, designed to the direct growth of 2D and 3D photonic structures, will also be described. Selected case studies will finally be presented, illustrating the powerful development of different oxide nanostructures based on dielectric, ferroelectric, or superconducting oxides, manganites, and nickelates, as well as first results related to the growth of ZnO NWs.

Local Reorganization of Diblock Copolymer Domains in Directed Self-Assembly Monitored by in Situ High-Temperature AFM

In situ high-temperature AFM was used to locally follow dynamic processes, leading to directed self-assembly of copolymers in the context of graphoepitaxy. We focused on the effect of heating for temperatures much higher than the Tg of the used PS-b-PMMA polymer. We showed that such conditions favors the block rearrangement, leading to very regular and perfectly aligned structures in limited times. The use of in situ AFM allowed us to locally investigate the self-organization process at high temperature, thus bringing new insights into self-assembly of block copolymers by graphoepitaxy. In particular, we demonstrate that a slight increase of temperature between 180 and 200 °C allowed overpassing an energy barrier and considerably improves the long distance arrangement, even for relatively short times.

Electromigration-induced failure in operando characterization of 3D interconnects: microstructure influence

An accurate knowledge of the phenomenon is required to develop a predictive modeling of the electromigration failure. Thus, a hitherto unseen SEM in operando observation method is devised. The test structure with “high density” through silicon vias (TSV) is tested at 623 K with an injected current density of 1 MA/cm2. Regular shots of micrographs inform about the voids nucleation, forced in copper lines above the TSV, and about the scenario of their evolution. A clear relation is established between voids evolution and the one of the electrical resistance. The lack of impact of test conditions on the failure mechanism is demonstrated. Finally, the impact of microstructure on the depletion mechanism is discussed. Grain boundaries are preferential voids nucleation sites and influence the voids evolution. A probable effect of grain size and crystallographic orientation is revealed.

Nanopatterning via Self-Assembly of a Lamellar-Forming Polystyrene-block-Poly(dimethylsiloxane) Diblock Copolymer on Topographical Substrates Fabricated by Nanoimprint Lithography

The self-assembly of a lamellar-forming polystyrene-block-poly(dimethylsiloxane) (PS-b-PDMS) diblock copolymer (DBCP) was studied herein for surface nanopatterning. The DBCP was synthesized by sequential living anionic polymerization of styrene and hexamethylcyclotrisiloxane (D3). The number average molecular weight (Mn), polydispersity index (Mw/Mn) and PS volume fraction (φps) of the DBCP were MnPS = 23.0 kg mol−1, MnPDMS = 15.0 kg mol−1, Mw/Mn = 1.06 and φps = 0.6. Thin films of the DBCP were cast and solvent annealed on topographically patterned polyhedral oligomeric silsesquioxane (POSS) substrates. The lamellae repeat distance or pitch (λL) and the width of the PDMS features (dL) are ~35 nm and ~17 nm, respectively, as determined by SEM. The chemistry of the POSS substrates was tuned, and the effects on the self-assembly of the DBCP noted. The PDMS nanopatterns were used as etching mask in order to transfer the DBCP pattern to underlying silicon substrate by a complex plasma etch process yielding sub-15 nm silicon features.