Engineering of a Microscale Niche for Pancreatic Tumor Cells Using Bioactive Film Coatings Combined with 3D-Architectured Scaffolds.

Two-photon polymerization has recently emerged as a promising technique to fabricate scaffolds for three-dimensional (3D) cell culture and tissue engineering. Here, we combined 3D-printed microscale scaffolds fabricated using two-photon polymerization with a bioactive layer-by-layer film coating. This bioactive coating consists of hyaluronic acid and poly(l-lysine) of controlled stiffness, loaded with fibronectin and bone morphogenic proteins 2 and 4 (BMP2 and BMP4) as matrix-bound proteins. Planar films were prepared using a liquid handling robot directly in 96-well plates to perform high-content studies of cellular processes, especially cell adhesion, proliferation, and BMP-induced signaling. The behaviors of two human pancreatic cell lines PANC1 (immortalized) and PAN092 (patient-derived cell line) were systematically compared and revealed important context-specific cell responses, notably in response to film stiffness and matrix-bound BMPs (bBMPs). Fibronectin significantly increased cell adhesion, spreading, and proliferation for both cell types on soft and stiff films; BMP2 increased cell adhesion and inhibited proliferation of PANC1 cells and PAN092 on soft films. BMP4 enhanced cell adhesion and proliferation of PANC1 and showed a bipolar effect on PAN092. Importantly, PANC1 exhibited a strong dose-dependent BMP response, notably for bBMP2, while PAN092 was insensitive to BMPs. Finally, we proved that it is possible to combine a microscale 3D Ormocomp scaffold fabricated using the two-photon polymerization technique with the bioactive film coating to form a microscale tumor tissue and mimic the early stages of metastatic cancer.

Hybrid integrated optical waveguides in glass for enhanced visible photoluminescence of nanoemitters.

Integrated optical devices able to control light-matter interactions on the nanoscale have attracted the attention of the scientific community in recent years. However, most of these devices are based on silicon waveguides, limiting their use for telecommunication wavelengths. In this contribution, we propose an integrated device that operates with light in the visible spectrum. The proposed device is a hybrid structure consisting of a high-refractive-index layer placed on top of an ion-exchanged glass waveguide. We demonstrate that this hybrid structure serves as an efficient light coupler for the excitation of nanoemitters. The numerical and experimental results show that the device can enhance the electromagnetic field confinement up to 11 times, allowing a higher photoluminescence signal from nanocrystals placed on its surface. The designed device opens new perspectives in the generation of new optical devices suitable for quantum information or for optical sensing.

Propagation losses and gain measurements in erbium-doped fluoride glass channel waveguides by use of a double-pass technique.

We have studied Er3+, Yb3+, and Ce3+ codoped microchannel waveguides that were developed by two methods: ionic exchange for heavy metal fluoride glasses [ZrF4-BaF2-AlF3-CeF3 (ZBAC)] and vapor phase deposition for transition metal fluoride glasses [PbF2-ZnF2-GaF3 (PZG)] by using a double-pass technique. For the first time to our knowledge, the measurement of propagation losses and amplification tests were carried out by use of the same experimental setup, leading to complete characterization of the waveguides. Net gains higher than 1 dB/cm were achieved in ZBAC Er/Ce single-mode fluoride glass waveguides.

An enantioselective access to 1-alkyl-1,2,3,4-tetrahydroisoquinolines. Application to a new synthesis of (-)-argemonine.

Potassium ferricyanide oxidation of salt 1 gave isoquinolinone 7 whose treatment with Grignard reagents resulted in a high-yield formation of substituted isoquinolinium salts 5. The selectivity of the reduction of these salts to give derivatives 6 has been studied. Particularly good selectivities (82-84%) were observed when R is a benzylic group. On the basis of these results, a practical and enantioselective synthesis of the natural alkaloid (-)-argemonine is presented.

Tetrahydroisoquinoline-3-carboxylate based matrix-metalloproteinase inhibitors: design, synthesis and structure-activity relationship.

The design, synthesis and structure-activity relationship (SAR) of a series of nonpeptidic 2-arylsulfonyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylates and-hydroxamates as inhibitors of the matrix metalloproteinase human neutrophil collagenase (MMP-8) is described here. Based on available X-ray structures of MMP-8/inhibitor complexes, our structure-based design strategy was directed to complement major protein-ligand interaction regions mainly in the S1' hydrophobic specificity pocket close to the catalytic zinc ion. Here, the rigid 1,2,3,4-tetrahydroisoquinoline scaffold (Tic) provides ideal geometry to combine hydroxamates and carboxylates as typical zinc complexing functionalities, with a broad variety of S1' directed mono- and biaryl substituents consisting of aromatic rings perfectly accommodated within this more hydrophobic region of the MMP-8 inhibitor binding site. The effect of different S1' directed substituents, zinc-complexing groups, chirality and variations of the tetrahydroisoquinoline ring-system is investigated by systematic studies. X-ray structure analyses in combination with 3D-QSAR studies provided an additional understanding of key determinants for MMP-8 affinity in this series. The hypothetical binding mode for a typical molecule as basis for our inhibitor design was found in good agreement with a 1.7 A X-ray structure of this candidate in complex with the catalytic domain of human MMP-8. After analysis of all systematic variations, 3D-QSAR and X-ray structure analysis, novel S1' directed substituents were designed and synthesized and biologically evaluated. This finally results in inhibitors, which do not only show high biological affinity for MMP-8, but also exhibit good oral bioavailability in several animal species.