Hemocompatibility and Preangiogenic Attributes of SiBxCyNzOm Coatings for Biomedical Applications.

In current clinical practices related to orthopedics, dental, and cardiovascular surgeries, a number of biomaterial coatings, such as hydroxyapatite (HAp), diamond-like carbon (DLC), have been used in combination with metallic substrates (stainless steel, Ti6Al4V alloy, etc.). Although SiBCN coatings are widely explored in material science for diverse applications, their potential remains largely unexplored for biomedical applications. With this motivation, the present work reports the development of SiBxCyNzOm coatings on a Ti6Al4V substrate, employing a reactive radiofrequency (RF) magnetron sputtering technique. Three different coating compositions (Si0.27B0.10C0.31N0.07O0.24, Si0.23B0.06C0.21N0.22O0.27, and Si0.20B0.05C0.19N0.20O0.35) were obtained using a Si2BC2N target and varying nitrogen flow rates. The hydrophilic properties of the as-synthesized coatings were rationalized in terms of an increase in the number of oxygen-containing functional groups (OH and NO) on the surface, as probed using XPS and FTIR analyses. Furthermore, the cellular monoculture of SVEC4-10 endothelial cells and L929 fibroblasts established good cytocompatibility. More importantly, the coculture system of SVEC4-10 and L929, in the absence of growth factors, demonstrated clear cellular phenotypical changes, with extensive sprouting leading to tube-like morphologies on the coating surfaces, when stimulated using a customized cell stimulator (StimuCell) with 1.15 V/cm direct current (DC) electric field strength for 1 h. In addition, the hemocompatibility assessment using human blood samples revealed clinically acceptable hemolysis, less erythrocyte adhesion, shorter plasma recalcification, and reduced risk for thrombosis on the SiBxCyNzOm coatings, when compared to uncoated Ti6Al4V. Taken together, the present study unambiguously establishes excellent cytocompatibility, hemocompatibility, and defines the preangiogenic properties of SiBxCyNzOm bioceramic coatings for potential biomedical applications.

Carbon-Rich Plasma-Deposited Silicon Oxycarbonitride Films Derived from 4-(Trimethylsilyl)morpholine as a Novel Single-Source Precursor.

4-(trimethylsilyl)morpholine O(CH2CH2)2NSi(CH3)3 (TMSM) was investigated as a single-source precursor for SiCNO films synthesis. Optical emission spectroscopy of plasma generated from TMSM/He, TMSM/H2, and TMSM/NH3 gas mixtures revealed the presence of N2, CH, H, CN, and CO species. The last two are suggested to be responsible for the lowering of carbon concentration in the films in comparison with the precursor. The refractive index ranged from 1.5 to 2.0, and bandgap varied from 2.0 to 4.6 eV, which pointed that some of the films can be used as antireflective coatings in silicon photovoltaic cell technologies and dielectric layers in electronic devices.

SiC/Graphene Film by Laser CVD as an Implantable Sensor Material for Dopamine Detection.

Implantable electrochemical sensor holds great promise in the real-time monitoring of dopamine (DA) to regulate body function. However, the real application of these sensors is limited by the weak current signal of DA in the human body and the poor compatibility of the on-chip microelectronic devices. In this work, a SiC/graphene composite film was fabricated using laser chemical vapor deposition (LCVD) and employed as a DA sensor. The graphene in the porous nanoforest-like SiC framework offered efficient channels for electronic transmission, leading to an enhanced electron transfer rate and consequently an increased current response for DA detection. The three-dimensional (3D) porous network also facilitated the exposure of more catalytic active sites toward DA oxidation. Besides, the wide distribution of graphene in the nanoforest-like SiC films reduced the interfacial resistance of the charge transfer. The SiC/graphene composite film exhibited excellent electrocatalytic activity toward DA oxidation with a low detection limit of 0.11 µM and a high sensitivity of 0.86 µA·µM-1·cm-2. The film electrode also showed a wide linear response for DA in 0.5-78 µM, along with good selectivity, repeatability, and reproducibility. Furthermore, the cell counting kit-8 (CCK-8) and live-dead assays revealed that the film is also biocompatible for biomedical applications. Therefore, the nanoforest-like SiC/graphene composite film via the CVD process enables a promising candidate for an integrated miniature DA biosensor with high detection performance.

Enhanced Wettability, Hardness, and Tunable Optical Properties of SiCxNy Coatings Formed by Reactive Magnetron Sputtering.

Silicon carbonitride films were deposited on Si (100), Ge (111), and fused silica substrates through the reactive magnetron sputtering of a SiC target in an argon-nitrogen mixture. The deposition was carried out at room temperature and 300 °C and at an RF target power of 50-150 W. An increase in the nitrogen flow rate leads to the formation of bonds between silicon and carbon atoms and nitrogen atoms and to the formation of SiCxNy layers. The as-deposited films were analyzed with respect to their element composition, state of chemical bonding, mechanical and optical properties, and wetting behavior. It was found that all synthesized films were amorphous and represented a mixture of SiCxNy with free carbon. The films' surfaces were smooth and uniform, with a roughness of about 0.2 nm. Depending on the deposition conditions, SiCxNy films within the composition range 24.1 < Si < 44.0 at.%, 22.4 < C < 56.1 at.%, and 1.6 < N < 51.9 at.% were prepared. The contact angle values vary from 37° to 67°, the hardness values range from 16.2 to 34.4 GPa, and the optical band gap energy changes from 1.81 to 2.53 eV depending on the synthesis conditions of the SiCxNy layers. Particular attention was paid to the study of the stability of the elemental composition of the samples over time, which showed the invariance of the composition of the SiCxNy films for five months.

Three novel metal-organic frameworks with different coordination modes for trace detection of anthrax biomarkers.

Dipicolinic acid (DPA) is an anthrax biomarker. Its serious consequences make its detection a great need. In this paper, three novel metal-organic frameworks (MOFs) with different coordination modes were synthesized by a simple solvothermal method, which can be used as highly efficient fluorescence sensors for the highly selective and sensitive trace detection of DPA. MOFs 1-3 showed rapid responses to DPA (<30 s), and the limits of detection (LODs) were calculated to be 1.01 × 10-6 M-1 (MOF 1), 1.17 × 10-6 M-1 (MOF 2) and 2.07 × 10-6 M-1 (MOF 3). DPA detection based on MOFs 1-3 in fetal bovine serum is highly reliable based on the high recovery rates (90% to 115%). Hence, the three MOF-based sensors can be used in the real-time detection of DPA.

Subcutaneous engineered factor VIIa marzeptacog alfa (activated) in hemophilia with inhibitors: Phase 2 trial of pharmacokinetics, pharmacodynamics, efficacy, and safety.

BACKGROUND: Marzeptacog alfa (activated) (MarzAA), a novel recombinant activated human factor VII (FVIIa) variant, was developed to provide increased procoagulant activity, subcutaneous (SC) administration, and longer duration of action in people with hemophilia. OBJECTIVES: To investigate if daily SC administration of MarzAA in subjects with inhibitors can provide effective prophylaxis. METHODS: This multicenter, open-label phase 2 trial (NCT03407651) enrolled men with severe congenital hemophilia with an inhibitor. All subjects had a baseline annualized bleeding rate (ABR) of ≥12 events/year. Subjects received a single 18 µg/kg intravenous dose of MarzAA to measure 24-hour pharmacokinetics (PK) and pharmacodynamics (PD), single 30 µg/kg SC dose to measure 48-hour PK/PD, then daily SC 30 µg/kg MarzAA for 50 days. If spontaneous bleeding occurred, the dose was sequentially escalated to 60, 90, or 120 µg/kg, with 50 days at the final effective dose without spontaneous bleeding to proceed to a 30-day follow-up. The primary end point was reduction in ABR. Secondary end points were safety, tolerability, and antidrug antibody (ADA) formation. RESULTS: In the 11 subjects, the mean ABR significantly reduced from 19.8 to 1.6, and the mean proportion of days with bleeding significantly reduced from 12.3% to 0.8%. Of a total of 517 SC doses, six injection site reactions in two subjects were reported. No ADAs were detected. One fatal unrelated serious adverse event occurred: intracerebral hemorrhage due to untreated hypertension. CONCLUSIONS: The data demonstrated that MarzAA was highly efficacious for prophylactic treatment in patients with inhibitors by significantly decreasing bleed frequency and duration of bleeding episodes.

SiCxNyOz Coatings Enhance Endothelialization and Bactericidal activity and Reduce Blood Cell Activation.

For biomedical applications, a number of ceramic coatings have been investigated, but the interactions with the components of living system remain unexplored for oxycarbonitride coatings. While addressing this aspect, the present study aims to provide an understanding of the biocompatibility of novel SiCxNyOz coatings that could validate the hypothesis that such coatings may not only enhance the cell-material interaction by re-endothelialization but also can help to reduce bacterial adhesion and activation of blood cells. This work reports the physicochemical properties, hemocompatibility, endothelialization, and antibacterial properties of novel amorphous SiCxNyOz coatings deposited on commercial pure titanium (Ti) by radiofrequency (RF) magnetron sputtering at varied nitrogen (N2) flow rates. A comparison is made with diamond-like carbon (DLC) coatings, which are clinically used. The surface roughness, surface wettability, nanoscale hardness, and surface energy of SiCxNyOz coatings were found to be dependent on the nitrogen (N2) flow rate. Importantly, the as-deposited SiCxNyOz coatings exhibited much better nanoscale hardness and scratch resistance than DLC coatings. Furthermore, Raman spectroscopy analysis of the SiCxNyOz coating deposited on Ti showed a change in the graphitic/disordered carbon content. Cytocompatibility and hemocompatibility properties of the as-deposited SiCxNyOz coating were evaluated using the Mus musculus lymphoid endothelial cell line (SVEC4-10) and rabbit blood in vitro. WST-1 assay analysis showed that these coatings, when compared to DLC, exhibited a better proliferation of endothelial cells, which can potentially result in improved surface endothelialization. Furthermore, qualitative and quantitative analyses of immunofluorescence images revealed a dense cellular layer of SVEC4-10 on SiCxNyOz coatings, deposited at 15 and 30 sccm nitrogen flow rates. As far as compatibility with rabbit blood is concerned, the hemolysis of the SiCxNyOz coatings was less than 4%, with slightly lower values for coatings deposited without N2 flow. The SiCxNyOz coatings support less platelet adhesion and aggregation, with no signature of morphological deformation, as compared to the uncoated titanium substrate or DLC coatings. Furthermore, SiCxNyOz coatings were also found to be effectively extending the blood coagulation time for a period of 60 min. The antimicrobial study of as-deposited SiCxNyOz coatings on E. coli and S. aureus bacteria revealed the effective inhibition of bacterial proliferation after 24 h of culture. An attempt has been made to explain the cyto- and hemocompatibility properties with antimicrobial efficacy of coatings in terms of the variation in the coating composition and surface energy. Taken together, we conclude that SiC1.3N0.76O0.87 coating having a roughness of 17 nm and a surface free energy of 54.0 ± 0.7 mN/m can exhibit the best combination of hardness, elastic modulus, scratch resistance, cytocompatibility, hemocompatibility, and bactericidal properties.

Three coordination polymers with regulated coordination interactions as fluorescent sensors for monitoring purine metabolite uric acid.

A facile optical sensor for uric acid (UA), an early pathological signature for the metabolic function of humans, was developed based on water-stable coordination polymers (CPs). Herein, three new isostructural fluorescent CPs, [Ln(TCPB)(DMF)3]n (Ln = La, CP 1; Ce, CP 2 and Pr, CP 3; H3TCPB = 1,3,5-tris(1-(2-carboxyphenyl)-1H-pyrazol-3-yl)benzene), with various metal ions were solvothermally synthesized. Significantly, by regulating the metal-organic coordination interactions, the fabricated CP 3 can quantitatively recognize UA with higher sensitivity compared with CP 1 and CP 2. The mechanism for the sensing properties further demonstrates the best performance of CP 3 and the excellent selectivity for UA monitoring. This work represents the strategy of designing fluorescent CP sensors to determine UA and provides a convenient approach for developing analysis platforms for the assessment of related disease progress and human health monitoring.

A Water-Stable Lanthanide Coordination Polymer as Multicenter Platform for Ratiometric Luminescent Sensing Antibiotics.

As a hot topic of global concern, the distinguishing and detecting of antibiotic pollution is crucial owing to its adverse effect on ecosystems and human health stemming from excessive use and poor management. Herein, a water-stable lanthanide coordination polymer sensor (Dy-TCPB) with multiple emitting centers is prepared. The versatile Dy-TCPB can conveniently differentiate various antibiotics, and displays a self-calibration luminescent response to nitrofurazone (NFZ) and furazolidone (FZD). Each antibiotic exhibits notable correlation to a unique combination of the two ligand-to-Dy ion emission intensity ratios, enabling two-dimensional fingerprint recognition. Furthermore, the novel self-calibration sensor demonstrates effective recognition of NFZ and FZD with excellent sensitivity and selectivity, and detection limits as low as 0.0476 and 0.0482 µm for NFZ and FZD, respectively. The synthetic approach for the fabrication of a singular coordination polymer exhibiting multiple emissions provides a promising strategy for the development of facile and effective ratiometric sensors.

Long-term safety and efficacy of the PI3K inhibitor copanlisib in patients with relapsed or refractory indolent lymphoma: 2-year follow-up of the CHRONOS-1 study.

Safety profiles of oral PI3K inhibitors have resulted in US FDA black box warnings regarding fatal/serious toxicities. The approved intravenous PI3K inhibitor copanlisib has low incidence of severe toxicities and no black box warnings, but chronic treatment effects were unknown. We provide an update on safety and efficacy of copanlisib with a minimum 2-year follow-up of the CHRONOS-1 study. A total of 142 patients with histologically confirmed indolent B-cell lymphoma who had relapsed after or were refractory to ≥2 prior treatments received intravenous copanlisib 60 mg on days 1, 8, and 15 (28-day cycle). The primary efficacy endpoint was objective response rate (ORR) after ≥4 cycles (independent assessment). The predominant histology was follicular lymphoma (n = 104). The ORR was 60.6% (seven additional complete responses since primary analysis). Secondary endpoints of median duration of response, progression-free survival, and overall survival were 14.1 months (median follow-up, 16.1 months), 12.5 months (median follow-up, 14.0 months), and 42.6 months (median follow-up, 31.5 months), respectively. Median safety follow-up was 6.7 months; 26% of patients received treatment for >1 year. Common treatment-emergent adverse events (TEAEs) (all grade/grade 3/grade 4) were transient hyperglycemia (50.0%/33.1%/7.0%), diarrhea (35.2%/8.5%/0%), transient hypertension (29.6%/23.9%/0%), and neutropenia (28.9%/9.2%/14.8%). Serious AEs were largely unchanged, with no new cases of pneumonitis (4.2%), diarrhea (2.8%), or grade 5 events. Note, TEAEs showed no evidence for increased incidence or worsening following longer exposure in patients treated >1 year. Long-term follow-up of patients with relapsed/refractory indolent B-cell lymphoma treated with intravenous copanlisib demonstrated durable, enhanced responses without evidence of worsening TEAEs, as reported for orally administered PI3K inhibitors.

Morphology controlling of 〈111〉-3C-SiC films by HMDS flow rate in LCVD.

Morphology of 〈111〉-oriented 3C-SiC films was transformed from mosaic to whisker to cauliflower-like with the increased flow rate (f) of hexametyldisilane (HMDS) in the process of laser chemical vapor deposition (LCVD). The SiC whiskers were naturally sharp hexagonal pyramids with average height of 250 nm and an aspect ratio in the range of 5 to 10, with a density of 1.3 × 108 mm-2. The influence mechanism of f on the surface morphology, as well as the growth mechanism of SiC whiskers, was discussed.

Phosphatidylinositol 3-Kinase Inhibition by Copanlisib in Relapsed or Refractory Indolent Lymphoma.

Purpose Phosphatidylinositol 3-kinase (PI3K) signaling is critical for the proliferation and survival of malignant B cells. Copanlisib, a pan-class I PI3K inhibitor with predominant activity against PI3K-α and -δ isoforms, has demonstrated efficacy and a manageable safety profile in patients with indolent lymphoma. Patients and Methods In this phase II study, 142 patients with relapsed or refractory indolent lymphoma after two or more lines of therapy were enrolled to receive copanlisib 60 mg intravenously on days 1, 8, and 15 of a 28-day cycle. The primary end point was objective response rate; secondary end points included duration of response, progression-free survival, and overall survival. In addition, safety and gene expression were evaluated. Results Median age was 63 years (range, 25 to 82 years), and patients had received a median of three (range, two to nine) prior regimens. The objective response rate was 59% (84 of 142 patients); 12% of patients achieved a complete response. Median time to response was 53 days. Median duration of response was 22.6 months, median progression-free survival was 11.2 months, and median overall survival had not yet been reached. The most frequent treatment-emergent adverse events were transient hyperglycemia (all grades, 50%; grade 3 or 4, 41%) and transient hypertension (all grades, 30%; grade 3, 24%). Other grade ≥3 events included decreased neutrophil count (24%) and lung infection (15%). High response rates to copanlisib were associated with high expression of PI3K/B-cell receptor signaling pathway genes. Conclusion PI3K-α and -δ inhibition by copanlisib demonstrated significant efficacy and a manageable safety profile in heavily pretreated patients with relapsed or refractory indolent lymphoma.

Boron nitride nanowalls: low-temperature plasma-enhanced chemical vapor deposition synthesis and optical properties.

Hexagonal boron nitride (h-BN) nanowalls (BNNWs) were synthesized by plasma-enhanced chemical vapor deposition (PECVD) from a borazine (B3N3H6) and ammonia (NH3) gas mixture at a low temperature range of 400 °C-600 °C on GaAs(100) substrates. The effect of the synthesis temperature on the structure and surface morphology of h-BN films was investigated. The length and thickness of the h-BN nanowalls were in the ranges of 50-200 nm and 15-30 nm, respectively. Transmission electron microscope images showed the obtained BNNWs were composed of layered non-equiaxed h-BN nanocrystallites 5-10 nm in size. The parallel-aligned h-BN layers as an interfacial layer were observed between the film and GaAs(100) substrate. BNNWs demonstrate strong blue light emission, high transparency (>90%) both in visible and infrared spectral regions and are promising for optical applications. The present results enable a convenient growth of BNNWs at low temperatures.

Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A.

Recombinant VIII (rVIII)-SingleChain is a novel B-domain-truncated recombinant factor VIII (rFVIII), comprised of covalently bonded factor VIII (FVIII) heavy and light chains. It was designed to have a higher binding affinity for von Willebrand factor (VWF). This phase 1/3 study investigated the efficacy and safety of rVIII-SingleChain in the treatment of bleeding episodes, routine prophylaxis, and surgical prophylaxis. Participants were ≥12 years of age, with severe hemophilia A (endogenous FVIII <1%). The participants were allocated by the investigator to receive rVIII-SingleChain in either an on-demand or prophylaxis regimen. Of the 175 patients meeting study eligibility criteria, 173 were treated with rVIII-SingleChain, prophylactically (N = 146) or on-demand (N = 27). The total cumulative exposure was 14 306 exposure days (EDs), with 120 participants reaching ≥50 EDs and 52 participants having ≥100 EDs. Hemostatic efficacy was rated by the investigator as excellent or good in 93.8% of the 835 bleeds treated and assessed. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.0, 2.4) and the median overall annualized bleeding rate (ABR) was 1.14 (Q1, Q3: 0.0, 4.2). Surgical hemostasis was rated as excellent/good in 100% of major surgeries by the investigator. No participant developed FVIII inhibitors. In conclusion, rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy in surgery and in the control of bleeding events, low ABR in patients on prophylaxis, and a favorable safety profile in this large clinical study. This trial was registered at www.clinicaltrials.gov as #NCT01486927.

Nondestructive and nonpreparative chemical nanometrology of internal material interfaces at tunable high information depths.

Improvement in the performance of functional nanoscaled devices involves novel materials, more complex structures, and advanced technological processes. The transitions to heavier elements and to thicker layers restrict access to the chemical and physical characterization of the internal material interfaces. Conventional nondestructive characterization techniques such as X-ray photoelectron spectroscopy suffer from sensitivity and quantification restrictions whereas destructive techniques such as ion mass spectrometry may modify the chemical properties of internal interfaces. Thus, novel methods providing sufficient sensitivity, reliable quantification, and high information depths to reveal interfacial parameters are needed for R&D challenges on the nanoscale. Measurement strategies adapted to nanoscaled samples enable the combination of Near-Edge X-ray Absorption Fine Structure and Grazing Incidence X-ray Fluorescence to allow for chemical nanometrology of internal material interfaces. Their validation has been performed at nanolayered model structures consisting of a silicon substrate, a physically vapor deposited Ni metal layer, and, on top, a chemically vapor deposited B(x)C(y)N(z) light element layer.

Analytical characterization of BC(x)N(y) films generated by LPCVD with triethylamine borane.

Triethylamine borane (TEAB) and He, N(2) or NH(3) were applied as additional reaction gases in the production of BC(x)N(y) layers by low-pressure chemical vapor deposition (LPCVD). These layers were deposited on Si(100) wafers and characterized chemically by X-ray photoelectron spectroscopy (XPS) and synchrotron radiation-based total-reflection X-ray fluorescence analysis combined with near-edge X-ray absorption fine-structure spectroscopy (TXRF-NEXAFS). The composition of the material produced without NH(3) was found to be dominated by B-C bonds with the stoichiometric formula B(2)C(3)N. B-N bonds with the formula B(2)CN(3) were preferred when NH(3) was added. A first attempt was made to compare the results obtained by applying trimethylamine borane and TEAB as single-source precursors.

Speciation of BC(x)N(y) films grown by PECVD with trimethylborazine precursor.

Films of BC(x)N(y) were produced in a plasma-enhanced chemical vapor deposition process using trimethylborazine as precursor and with H2, He, N2, and NH3, respectively, as auxiliary gas. These films deposited on Si(100) wafers or fused quartz glass substrates were characterized chemically by X-ray photoelectron spectroscopy and by synchrotron radiation-based total-reflection X-ray fluorescence combined with near-edge X-ray absorption fine structure. Independent of the auxiliary gas, the B-N bonds are dominating. Furthermore, B-C and N-C bonds were identified. Oxygen, present in the bulk (in contrast to the surface layer of some nanometers, where molecular oxygen and/or water are absorbed) as an impurity, is bonded to boron or to carbon, respectively. The relation of boron and nitrogen changes with the character of the auxiliary gas: cB/cN approximately = 4:3 (for H2 and He) and cB/cN approximately = 1 (for N2 or NH3). Furthermore, physical properties such as the refractive index and the optical band-gap energy were determined.