Phenoxaphosphonium Mixed Ylides in Ring Expansion Reaction.

Treatment of mixed phosphonium-iodonium ylides featuring a six-membered phenoxaphosphonium fragment with aqueous tetrafluoroboronic acid induces a rearrangement, resulting in expansion of the phosphacycle and oxidation of the phosphorus atom. The target difficult-to-access dibenzo[b,f][1,4]oxaphosphepine oxides (3 examples) were isolated in excellent yields (up to 95%) as mixtures of stereoisomers. Hydrolysis of a five-membered mixed ylide, a dibenzophosphole derivative, predominantly preserves the phosphole system with cycle expansion occurring as a side process.

Comparison of the Patency and Regenerative Potential of Biodegradable Vascular Prostheses of Different Polymer Compositions in an Ovine Model.

The lack of suitable autologous grafts and the impossibility of using synthetic prostheses for small artery reconstruction make it necessary to develop alternative efficient vascular grafts. In this study, we fabricated an electrospun biodegradable poly(ε-caprolactone) (PCL) prosthesis and poly(3-hydroxybutyrate-co-3-hydroxyvalerate)/poly(ε-caprolactone) (PHBV/PCL) prosthesis loaded with iloprost (a prostacyclin analog) as an antithrombotic drug and cationic amphiphile with antibacterial activity. The prostheses were characterized in terms of their drug release, mechanical properties, and hemocompatibility. We then compared the long-term patency and remodeling features of PCL and PHBV/PCL prostheses in a sheep carotid artery interposition model. The research findings verified that the drug coating of both types of prostheses improved their hemocompatibility and tensile strength. The 6-month primary patency of the PCL/Ilo/A prostheses was 50%, while all PHBV/PCL/Ilo/A implants were occluded at the same time point. The PCL/Ilo/A prostheses were completely endothelialized, in contrast to the PHBV/PCL/Ilo/A conduits, which had no endothelial cells on the inner layer. The polymeric material of both prostheses degraded and was replaced with neotissue containing smooth-muscle cells; macrophages; proteins of the extracellular matrix such as type I, III, and IV collagens; and vasa vasorum. Thus, the biodegradable PCL/Ilo/A prostheses demonstrate better regenerative potential than PHBV/PCL-based implants and are more suitable for clinical use.

A new imaging concept in spin polarimetry based on the spin-filter effect.

The concept of an imaging-type 3D spin detector, based on the combination of spin-exchange interactions in the ferromagnetic (FM) film and spin selectivity of the electron-photon conversion effect in a semiconductor heterostructure, is proposed and demonstrated on a model system. This novel multichannel concept is based on the idea of direct transfer of a 2D spin-polarized electron distribution to image cathodoluminescence (CL). The detector is a hybrid structure consisting of a thin magnetic layer deposited on a semiconductor structure allowing measurement of the spatial and polarization-dependent CL intensity from injected spin-polarized free electrons. The idea is to use spin-dependent electron transmission through in-plane magnetized FM film for in-plane spin detection by measuring the CL intensity from recombined electrons transmitted in the semiconductor. For the incoming electrons with out-of-plane spin polarization, the intensity of circularly polarized CL light can be detected from recombined polarized electrons with holes in the semiconductor. In order to demonstrate the ability of the solid-state spin detector in the image-type mode operation, a spin detector prototype was developed, which consists of a compact proximity focused vacuum tube with a spin-polarized electron source [p-GaAs(Cs,O)], a negative electron affinity (NEA) photocathode and the target [semiconductor heterostructure with quantum wells also with NEA]. The injection of polarized low-energy electrons into the target by varying the kinetic energy in the range 0.5-3.0 eV and up to 1.3 keV was studied in image-type mode. The figure of merit as a function of electron kinetic energy and the target temperature is determined. The spin asymmetry of the CL intensity in a ferromagnetic/semiconductor (FM-SC) junction provides a compact optical method for measuring spin polarization of free-electron beams in image-type mode. The FM-SC detector has the potential for realizing multichannel 3D vectorial reconstruction of spin polarization in momentum microscope and angle-resolved photoelectron spectroscopy systems.

Calciprotein Particles Link Disturbed Mineral Homeostasis with Cardiovascular Disease by Causing Endothelial Dysfunction and Vascular Inflammation.

An association between high serum calcium/phosphate and cardiovascular events or death is well-established. However, a mechanistic explanation of this correlation is lacking. Here, we examined the role of calciprotein particles (CPPs), nanoscale bodies forming in the human blood upon its supersaturation with calcium and phosphate, in cardiovascular disease. The serum of patients with coronary artery disease or cerebrovascular disease displayed an increased propensity to form CPPs in combination with elevated ionised calcium as well as reduced albumin levels, altogether indicative of reduced Ca2+-binding capacity. Intravenous administration of CPPs to normolipidemic and normotensive Wistar rats provoked intimal hyperplasia and adventitial/perivascular inflammation in both balloon-injured and intact aortas in the absence of other cardiovascular risk factors. Upon the addition to primary human arterial endothelial cells, CPPs induced lysosome-dependent cell death, promoted the release of pro-inflammatory cytokines, stimulated leukocyte adhesion, and triggered endothelial-to-mesenchymal transition. We concluded that CPPs, which are formed in the blood as a result of altered mineral homeostasis, cause endothelial dysfunction and vascular inflammation, thereby contributing to the development of cardiovascular disease.

Meet the Cerium(IV) Phosphate Sisters: CeIV (OH)PO4 and CeIV 2 O(PO4 )2.

Two new cerium(IV) phosphates were obtained: cerium(IV) hydroxidophosphate, Ce(OH)PO4 , and cerium(IV) oxidophosphate, Ce2 O(PO4 )2 , which were shown to complement the classes of isostructural compounds M(OH)PO4 and R2 O(PO4 )2 , where M=Th, U and R=Th, U, Np, Zr. Ce2 O(PO4 )2 oxidophosphate is formed by elimination of H2 O from the crystal structure of Ce(OH)PO4 during its thermal decomposition. The structures of Ce(OH)PO4 and Ce2 O(PO4 )2 are related to each other with the same Cmce space group and similar unit cell parameters (a=6.9691(3) Å, b=9.0655(4) Å, c=12.2214(4) Å, V=772.13(8) Å3 , Z=8; a=7.0220(4) Å, b=8.9894(5) Å, c=12.544(1) Å, V=791.8(1) Å3 , Z=4, respectively).

Conjugation with RGD Peptides and Incorporation of Vascular Endothelial Growth Factor Are Equally Efficient for Biofunctionalization of Tissue-Engineered Vascular Grafts.

The blend of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) and poly(ε-caprolactone) (PCL) has recently been considered promising for vascular tissue engineering. However, it was shown that PHBV/PCL grafts require biofunctionalization to achieve high primary patency rate. Here we compared immobilization of arginine-glycine-aspartic acid (RGD)-containing peptides and the incorporation of vascular endothelial growth factor (VEGF) as two widely established biofunctionalization approaches. Electrospun PHBV/PCL small-diameter grafts with either RGD peptides or VEGF, as well as unmodified grafts were implanted into rat abdominal aortas for 1, 3, 6, and 12 months following histological and immunofluorescence assessment. We detected CD31⁺/CD34⁺/vWF⁺ cells 1 and 3 months postimplantation at the luminal surface of PHBV/PCL/RGD and PHBV/PCL/VEGF, but not in unmodified grafts, with the further observation of CD31⁺CD34-vWF⁺ phenotype. These cells were considered as endothelial and produced a collagen-positive layer resembling a basement membrane. Detection of CD31⁺/CD34⁺ cells at the early stages with subsequent loss of CD34 indicated cell adhesion from the bloodstream. Therefore, either conjugation with RGD peptides or the incorporation of VEGF promoted the formation of a functional endothelial cell layer. Furthermore, both modifications increased primary patency rate three-fold. In conclusion, both of these biofunctionalization approaches can be considered as equally efficient for the modification of tissue-engineered vascular grafts.

Vacuum Spin LED: First Step towards Vacuum Semiconductor Spintronics.

Improving the efficiency of spin generation, injection, and detection remains a key challenge for semiconductor spintronics. Electrical injection and optical orientation are two methods of creating spin polarization in semiconductors, which traditionally require specially tailored p-n junctions, tunnel or Schottky barriers. Alternatively, we introduce here a novel concept for spin-polarized electron emission/injection combining the optocoupler principle based on vacuum spin-polarized light-emitting diode (spin VLED) making it possible to measure the free electron beam polarization injected into the III-V heterostructure with quantum wells (QWs) based on the detection of polarized cathodoluminescence (CL). To study the spin-dependent emission/injection, we developed spin VLEDs, which consist of a compact proximity-focused vacuum tube with a spin-polarized electron source (p-GaAs(Cs,O) or Na2KSb) and the spin detector (III-V heterostructure), both activated to a negative electron affinity (NEA) state. The coupling between the photon helicity and the spin angular momentum of the electrons in the photoemission and injection/detection processes is realized without using either magnetic material or a magnetic field. Spin-current detection efficiency in spin VLED is found to be 27% at room temperature. The created vacuum spin LED paves the way for optical generation and spin manipulation in the developing vacuum semiconductor spintronics.

Photochemical synthesis of phosphinolines from phosphonium-iodonium ylides.

We describe three different series of experiments which were undertaken to test our hypothesis that during irradiation of phosphonium-iodonium ylides (1a, 1b) an electrophilic carbene is generated. By opposing the assumed intermediate to monosubstituted alkynes, we observed in the case of electron-rich substituents at the triple bond a domination of a 1,3-dipolar cycloaddition of the intermediate with the triple bond to yield furans. In the case of electron poorer substituents, the formation of phosphinolines prevails. A second series of experiments was carried out with mixed ylides in which one phenyl ring at the triarylphosphonium group was replaced by a thienyl group. In this case, we observe only an intramolecular reaction with the thienyl ring to yield the phosphinolines 21-23. In a third test, we replaced in the mixed ylides 1a, 1b the COR group by a CN substituent. This modification leads to phosphinolines only and avoids a 1,3-dipolar cycloaddition.

Tissue-Engineered Carotid Artery Interposition Grafts Demonstrate High Primary Patency and Promote Vascular Tissue Regeneration in the Ovine Model.

Tissue-engineered vascular graft for the reconstruction of small arteries is still an unmet clinical need, despite the fact that a number of promising prototypes have entered preclinical development. Here we test Poly(3-hydroxybutyrate-co-3-hydroxyvalerate)Poly(ε-caprolactone) 4-mm-diameter vascular grafts equipped with vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and stromal cell-derived factor 1α (SDF-1α) and surface coated with heparin and iloprost (PHBV/PCL[VEGF-bFGF-SDF]Hep/Ilo, n = 8) in a sheep carotid artery interposition model, using biostable vascular prostheses of expanded poly(tetrafluoroethylene) (ePTFE, n = 5) as a control. Primary patency of PHBV/PCL[VEGF-bFGF-SDF]Hep/Ilo grafts was 62.5% (5/8) at 24 h postimplantation and 50% (4/8) at 18 months postimplantation, while all (5/5) ePTFE conduits were occluded within the 24 h after the surgery. At 18 months postimplantation, PHBV/PCL[VEGF-bFGF-SDF]Hep/Ilo grafts were completely resorbed and replaced by the vascular tissue. Regenerated arteries displayed a hierarchical three-layer structure similar to the native blood vessels, being fully endothelialised, highly vascularised and populated by vascular smooth muscle cells and macrophages. The most (4/5, 80%) of the regenerated arteries were free of calcifications but suffered from the aneurysmatic dilation. Therefore, biodegradable PHBV/PCL[VEGF-bFGF-SDF]Hep/Ilo grafts showed better short- and long-term results than bio-stable ePTFE analogues, although these scaffolds must be reinforced for the efficient prevention of aneurysms.

A Brief Report on an Implantation of Small-Caliber Biodegradable Vascular Grafts in a Carotid Artery of the Sheep.

The development of novel biodegradable vascular grafts of a small diameter (<6 mm) is an unmet clinical need for patients requiring arterial replacement. Here we performed a pre-clinical study of new small-caliber biodegradable vascular grafts using a sheep model of carotid artery implantation. The 4 mm diameter vascular grafts were manufactured using a mix of polyhydroxybutyrate/valerate and polycaprolactone supplemented with growth factors VEGF, bFGF and SDF-1α (PHBV/PCL-GFmix) and additionally modified by a polymer hydrogel coating with incorporation of drugs heparin and iloprost (PHBV/PCL-GFmixHep/Ilo). Animals with carotid artery autograft implantation and those implanted with clinically used GORE-TEX® grafts were used as control groups. We observed that 24 h following surgery, animals with carotid artery autograft implantation showed 87.5% patency, while all the PHBV/PCL-GFmix and GORE-TEX® grafts displayed thrombosis. PHBV/PCL-GFmixHep/Ilo grafts demonstrated 62.5% patency 24 h following surgery and it had remained at 50% 1 year post-operation. All the PHBV/PCL grafts completely degraded less than 1 year following surgery and were replaced by de novo vasculature without evidence of calcification. On the other hand, GORE-TEX® grafts displayed substantial amounts of calcium deposits throughout graft tissues. Thus, here we report a potential clinical usefulness of PHBV/PCL grafts upon their additional modification by growth factors and drugs to promote endothelialization and reduce thrombogenicity.

Biodegradable Patches for Arterial Reconstruction Modified with RGD Peptides: Results of an Experimental Study.

Modification by Arg-Gly-Asp (RGD) peptides is a promising approach to improve the biocompatibility of biodegradable vascular patches for arteriotomy. In this study, we evaluated the performance of vascular patches electrospun using a blend of polycaprolactone (PCL) and polyhydroxybutyrate/valerate (PHBV) and additionally modified with RGDK, AhRGD, and c[RGDFK] peptides using 1,6-hexamethylenediamine or 4,7,10-trioxa-1,13-tridecanediamine (TTDDA) linkers. We examined mechanical properties and hemocompatibility of resulting patches before implanting them in rat abdominal aortas to assess their performance in vivo. Patches were explanted 1, 3, 6, and 12 months postoperation followed by histological and immunofluorescence analyses. Patches manufactured from the human internal mammary artery or commercially available KemPeriplas-Neo xenopericardial patches were used as a control. The tensile strength and F max of KemPeriplas-Neo patches were 4- and 16.7-times higher than those made of human internal mammary artery, respectively. Both RGD-modified and unmodified PHBV/PCL patches demonstrated properties similar to a human internal mammary artery patch. Regardless of RGD modification, experimental PHBV/PCL patches displayed fewer lysed red blood cells and resulted in milder platelet aggregation than KemPeriplas-Neo patches. Xenopericardial patches failed to form an endothelial layer in vivo and were prone to calcification. By contrast, TTDDA/RGDK-modified biodegradable patches demonstrated a resistance to calcification. Modification by TTDDA/RGDK and TTDDA/c[RGDFK] facilitated the formation of neovasculature upon the implantation in vivo.

Heterocycles from phosphonium-iodonium ylides. Photochemical synthesis of lambda(5)-phosphinolines.

A photochemical reaction of mixed phosphonium-iodonium ylides with acetylenes yielding lambda(5)-phosphinolines, a rare class of phosphorus heterocycles hardly accessible by other methods, was found. The yields of lambda(5)-phosphinolines vary from 35% to 80%. The structures of two phosphinolines were established by single-crystal X-ray diffraction. The X-ray diffraction and NMR spectra data indicate the superposition of ylidic and aromatic structures for phosphinolines.

Biocompatibility of Small-Diameter Vascular Grafts in Different Modes of RGD Modification.

Modification with Arg-Gly-Asp (RGD) peptides is a promising approach to improve biocompatibility of small-calibre vascular grafts but it is unknown how different RGD sequence composition impacts graft performance. Here we manufactured 1.5 mm poly(3-hydroxybutyrate-co-3-hydroxyvalerate)/poly(ε-caprolactone) grafts modified by distinct linear or cyclic RGD peptides immobilized by short or long amine linker arms. Modified vascular prostheses were tested in vitro to assess their mechanical properties, hemocompatibility, thrombogenicity and endothelialisation. We also implanted these grafts into rat abdominal aortas with the following histological examination at 1 and 3 months to evaluate their primary patency, cellular composition and detect possible calcification. Our results demonstrated that all modes of RGD modification reduce ultimate tensile strength of the grafts. Modification of prostheses does not cause haemolysis upon the contact with modified grafts, yet all the RGD-treated grafts display a tendency to promote platelet aggregation in comparison with unmodified counterparts. In vivo findings identify that cyclic Arg-Gly-Asp-Phe-Lys peptide in combination with trioxa-1,13-tridecanediamine linker group substantially improve graft biocompatibility. To conclude, here we for the first time compared synthetic small-diameter vascular prostheses with different modes of RGD modification. We suggest our graft modification regimen as enhancing graft performance and thus recommend it for future use in tissue engineering.

Bioabsorbable Bypass Grafts Biofunctionalised with RGD Have Enhanced Biophysical Properties and Endothelialisation Tested In vivo.

Small diameter arterial bypass grafts are considered as unmet clinical need since the current grafts have poor patency of 25% within 5 years. We have developed a 3D scaffold manufactured from natural and synthetic biodegradable polymers, poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) and poly(𝜀-caprolactone) (PCL), respectively. Further to improve the biophysical properties as well as endothelialisation, the grafts were covalently conjugated with arginine-glycine-aspartic acid (RGD) bioactive peptides. The biophysical properties as well as endothelialisation of PHBV/PCL and PCL 2 mm diameter bypass grafts were assessed with and without biofunctionalisation with RGD peptides in vitro and in vivo. Morphology of the grafts was assessed by scanning electron microscopy, whereas physico-mechanical properties were evaluated using a physiological circulating system equipped with a state of art ultrasound vascular wall tracking system. Endothelialisation of the grafts in vitro and in vivo were assessed using a cell viability assay and rat abdominal aorta replacement model, respectively. The biofunctionalisation with RGD bioactive peptides decreased mean fiber diameter and mean pore area in PHBV/PCL grafts; however, this was not the case for PCL grafts. Both PHBV/PCL and PCL grafts with RGD peptides had lower durability compared to those without; these durability values were similar to those of internal mammary artery. Modification of PHBV/PCL and PCL grafts with RGD peptides increased endothelial cell viability in vitro by a factor of eight and enhanced the formation of an endothelial cell monolayer in vivo 1 month postimplantation. In conclusion, PHBV/PCL small-caliber graft can be a suitable 3D scaffold for the development of a tissue engineering arterial bypass graft.

Vascular Endothelial Growth Factor Improves Physico-Mechanical Properties and Enhances Endothelialization of Poly(3-hydroxybutyrate-co-3-hydroxyvalerate)/Poly(ε-caprolactone) Small-Diameter Vascular Grafts In vivo.

The combination of a natural polymer poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) and a synthetic hydrophobic polymer poly(ε-caprolactone) (PCL) is promising for the preparation of biodegradable and biocompatible small-diameter vascular grafts for bypass surgery. However, physico-mechanical properties and endothelialization rate of PHBV/PCL grafts are poor. We suggested that incorporation of vascular endothelial growth factor (VEGF) into PHBV/PCL grafts may improve their physico-mechanical properties and enhance endothelialization. Here we compared morphology, physico-mechanical properties, and in vivo performance of electrospun small-diameter vascular grafts prepared from PHBV/PCL with and without VEGF. Structure of the graft surface and physico-mechanical properties were examined by scanning electron microscopy and universal testing machine, respectively. Grafts were implanted into rat abdominal aorta for 1, 3, and 6 months with the further histological, immunohistochemical, and immunofluorescence examination. PHBV/PCL grafts with and without VEGF were highly porous and consisted mostly of nanoscale and microscale fibers, respectively. Mean pore diameter and mean pore area were significantly lower in PHBV/PCL/VEGF compared to PHBV/PCL grafts (1.47 µm and 10.05 µm(2); 2.63 µm and 47.13 µm(2), respectively). Durability, elasticity, and stiffness of PHBV/PCL grafts with VEGF were more similar to internal mammary artery compared to those without, particularly 6 months postimplantation. Both qualitative examination and quantitative image analysis showed that three-fourths of PHBV/PCL grafts with VEGF were patent and had many CD31-, CD34-, and vWF-positive cells at their inner surface. However, all PHBV/PCL grafts without VEGF were occluded and had no or a few CD31-positive cells at the inner surface. Therefore, VEGF enhanced endothelialization and improved graft patency at all the time points in a rat abdominal aorta replacement model. In conclusion, PHBV/PCL grafts with VEGF have better biocompatibility and physico-mechanical properties compared to those without. Incorporation of VEGF improves graft patency and accelerates formation of endothelial cell monolayer.