Real-time multimode dynamics of terahertz quantum cascade lasers via intracavity self-detection: observation of self mode-locked population pulsations.

Mode-locking operation and multimode instabilities in Terahertz (THz) quantum cascade lasers (QCLs) have been intensively investigated during the last decade. These studies have unveiled a rich phenomenology, owing to the unique properties of these lasers, in particular their ultrafast gain medium. Thanks to this, in QCLs a modulation of the intracavity field intensity gives rise to a strong modulation of the population inversion, directly affecting the laser current. In this work we show that this property can be used to study in real-time the dynamics of multimode THz QCLs, using a self-detection technique combined with a 60GHz real-time oscilloscope. To demonstrate the potential of this technique we investigate a 4.2THz QCL operating in free-running, and observe a self-starting periodic modulation of the laser current, producing trains of regularly spaced, ∼100ps-long pulses. Depending on the drive current we find two distinct regimes of oscillation with dramatically different properties: a first regime at the fundamental cavity repetition rate, characterised by large amplitude and phase noise, with coherence times of a few tens of periods; a much more regular second-harmonic-comb regime, with typical coherence times of ∼105 oscillation periods. We interpret these measurements using a set of effective semiconductor Maxwell-Bloch equations that qualitatively reproduce the fundamental features of the laser dynamics, indicating that the observed carrier-density and optical pulses are in antiphase, and appear as a rather shallow modulation on top of a continuous wave background. Thanks to its simple implementation and versatility, the demonstrated broadband self-detection technique is a powerful tool for the study of ultrafast dynamics in THz QCLs.

Quantum cascade laser-pumped terahertz molecular lasers: frequency noise and phase-locking using a 1560†nm frequency comb.

We report the measurement of the frequency noise power spectral density (PSD) of a Terahertz (THz) molecular laser (ML) pumped by a mid-infrared (MIR) quantum cascade laser (QCL), and emitting 1 mW at 1.1THz in continuous wave. This is achieved by beating the ML frequency with the 1080th harmonic of the repetition rate of a 1560 nm frequency comb (FC). We find a frequency noise PSD < 10Hz2/Hz (-95dBc/Hz) at 100kHz from the carrier. To demonstrate the effect of the stability of the pump laser on the spectral purity of the THz emission we also measure the frequency noise PSD of a CO2-laser-pumped 2.5THz ML, reaching 0.1Hz2/Hz (-105dBc/Hz) at 40kHz from the carrier, limited by the frequency noise of the FC harmonic. Finally, we show that it is possible to actively phase-lock the QCL-pumped molecular laser to the FC repetition rate harmonic by controlling the QCL current, demonstrating a sub-Hz linewidth.

Dynamics of ultra-broadband terahertz quantum cascade lasers for comb operation.

We present an experimental investigation of the multimode dynamics and the coherence of terahertz quantum cascade lasers emitting over a spectral bandwidth of ~1THz. The devices are studied in free-running and under direct RF modulation. Depending on the pump current we observe different regimes of operation, where RF spectra displaying single and multiple narrow beat-note signals alternate with spectra showing a single beat-note characterized by an intense phase-noise, extending over a bandwidth up to a few GHz. We investigate the relation between this phase-noise and the dynamics of the THz modes through the electro-optic sampling of the laser emission. We find that when the phase-noise is large, the laser operates in an unstable regime where the lasing modes are incoherent. Under RF modulation of the laser current such instability can be suppressed and the modes coherence recovered, while, simultaneously, generating a strong broadening of the THz emission spectrum.

Liposome sensing and monitoring by organic electrochemical transistors integrated in microfluidics.

BACKGROUND: Organic electrochemical transistors (OECTs), which are becoming more and more promising devices for applications in bioelectronics and nanomedicine, are proposed here as ideally suitable for sensing and real time monitoring of liposome-based structures. This is quite relevant since, currently, the techniques used to investigate liposomal structures, their stability in different environments as well as drug loading and delivery mechanisms, operate basically off-line and/or with pre-prepared sampling. METHODS: OECTs, based on the PEDOT:PSS conductive polymer, have been employed as sensors of liposome-based nanoparticles in electrolyte solutions to assess sensitivity and monitoring capabilities based on ion-to-electron amplified transduction. RESULTS: We demonstrate that OECTs are very efficient, reliable and sensitive devices for detecting liposome-based nanoparticles on a wide dynamic range down to 10(-5)mg/ml (with a lowest detection limit, assessed in real-time monitoring, of 10(-7)mg/ml), thus matching the needs of typical drug loading/drug delivery conditions. They are hence particularly well suited for real-time monitoring of liposomes in solution. Furthermore, OECTs are shown to sense and discriminate successive injection of different liposomes, so that they could be good candidates in quality-control assays or in the pharmaceutical industry. GENERAL SIGNIFICANCE: Drug loading and delivery by liposome-based structures is a fast growing and very promising field that will strongly benefit from real-time, highly sensitive and low cost monitoring of their dynamics in different pharma and biomedical environments, with a particular reference to the pharmaceutical and production processes, where a major issue is monitoring and measuring the formation and concentration of liposomes and the relative drug load. The demonstrated ability to sense and monitor complex bio-structures, such as liposomes, paves the way for very promising developments in biosensing and nanomedicine. This article is part of a Special Issue entitled Organic Bioelectronics-Novel Applications in Biomedicine.

Laparoscopic Splenectomy of a Wandering Pelvic Splenomegaly in a Young Woman Treated in Childhood with Surgery for Diaphragmatic Hernia and Adhesiolysis for Intestinal Obstruction.

BACKGROUND Wandering spleen (WS) is a rare medical condition in which the spleen migrates from its usual position commonly to the pelvis or lower abdomen assuming an ever-wandering state. The incidence of ectopic spleen is 0.2%, with variable clinical manifestations from asymptomatic to abdominal emergency. Symptoms are most attributed to complications related to torsion, so that a nonoperative management of a WS is not advised. According to the literature, 69.5% of patients with WS need splenectomy and 78.6% need laparotomy. CASE REPORT The patient exhibited vague intermittent lower abdominal pain for 6 months due to progressive torsion of the spleen, which resulted in venous congestion. Abdominal investigation revealed a mobile intra-abdominal mass and parenchymatous consistency in the pelvis. Diagnosis by computed tomography outlined abdominal splenomegaly with abnormal position both of pancreas and stomach. Laparoscopy established a giant spleen, with a lengthened pelvic and twisty vascular pedicle. In its ectopic location, the spleen had dragged the pancreas with it, which had taken a vertical position. The classic splenic ligaments were not recognizable. Spleen was removed with median laparotomic incision. Splenectomy was performed to prevent any traumatic fractures of the spleen, a complete twist of the splenic hilum, and the onset of recurrent acute pancreatitis. CONCLUSIONS Wandering spleen is rare in patients presenting with acute abdominal pain. An approach supported by clinical findings and investigation, even considering splenectomy over splenopexy, and laparoscopy over open surgery, may solve and prevent complications and health risks.

Effects of magnesium supplementation on post-thyroidectomy hypocalcemia: a prospective single-center study.

BACKGROUND: Severe and/or symptomatic hypocalcemia due to hypoparathyroidism is the main contraindication for discharge in patients who have undergone thyroid surgery. Hypomagnesemia may contribute to the onset of hypoparathyroidism and is frequently observed after thyroid surgery in hypocalcemic patients. The impact of prophylactic and postoperative Magnesium supplementation on postoperative hypocalcemia and hypomagnesemia was prospectively evaluated by comparing patients undergoing prophylactic supplementation to a control group of patients who had only received Magnesium after evidence of postoperative hypoMg. METHODS: One hundred and twenty patients who underwent a total thyroidectomy participated in the study. Seventy-three patients were included in the study group, 47 in the control group. Prior to surgery, patients in the study group were given Magnesium orally for 5 days; postoperatively, Calcium and Magnesium was administered to all patients who displayed hypocalcemia and hypomagnesemia. RESULTS: Postoperative biochemical hypocalcemia (serum Calcium<8.5 mg/dL, regardless of its clinical severity) was found in 60 patients (50%) on D1 and in 58 patients (48.4%) on D2. Among hypocalcemic patients, hypomagnesemia was recorded in 29 at D1 (48%), and in 46 at D2 (79%). A significant positive correlation was found between Magnesium, Calcium, and parathyroid hormone in the first two postoperative days, while a significant inverse correlation occurred for these same parameters and length of hospital stay (p<0.001). One hundred and five patients (87.5%) were discharged as expected on the second postoperative day (Study group = 65, Control group = 40, p = 0.724), whereas 15 patients (12.5%) required prolonged hospitalization (Study group = 8, Control group = 7, p = 0.721). The Study group only showed significantly higher Magnesium levels on the first postoperative day (p=0.03). CONCLUSIONS: Although Magnesium and Calcium levels showed the same trend after thyroidectomy, neither Magnesium prophylaxis nor Magnesium treatment influenced the clinical course of postoperative hypocalcemia.

Injection-locking of terahertz quantum cascade lasers up to 35GHz using RF amplitude modulation.

We demonstrate that the cavity resonance frequency - the round-trip frequency - of Terahertz quantum cascade lasers can be injection-locked by direct modulation of the bias current using an RF source. Metal-metal and single-plasmon waveguide devices with roundtrip frequencies up to 35GHz have been studied, and show locking ranges above 200MHz. Inside this locking range the laser round-trip frequency is phase-locked, with a phase noise determined by the RF-synthesizer. We find a square-root dependence of the locking range with RF-power in agreement with classical injection-locking theory. These results are discussed in the context of mode-locking operation.

Polymeric films loaded with cisplatin for malignant pleural mesothelioma: a pharmacokinetic study in an ovine model.

BACKGROUND: Malignant pleural mesothelioma (MPM) continues to be a distressing tumor due to its aggressive biologic behavior and scanty prognosis. Several therapeutic approaches have been tested both in clinical and preclinical settings, being intrapleural chemotherapy one of the most promising. Some years ago, our interest focused on polymeric films loaded with cisplatin for the adjuvant intrapleural treatment of surgical patients. After in vitro and in vivo studies in a rat recurrence model of MPM, the aim of this study was to evaluate the pharmacokinetics of the polymeric films in a sheep model in view of further studies in a clinical setting. METHODS: An ovine model was used. Animals were divided into four groups according to pharmacologic treatment: control group (three animals undergoing left pneumonectomy and saline-NaCl solution); intrapleural hyaluronate cisplatin films (HYALCIS) group (six animals undergoing left pneumonectomy and intrapleural application of polymeric films loaded with cisplatin); intrapleural cisplatin solution (six animals undergoing left pneumonectomy and intrapleural application of cisplatin solution); intravenous cisplatin (five animals undergoing left pneumonectomy and intravenous administration of cisplatin solution). The primary objective was the plasmatic and pleural concentration of cisplatin in the treatment groups. The secondary objective was the treatment-related toxicity evaluated by plasmatic analysis performed at prearranged time intervals and histological examinations of tissue samples collected during animal autopsy. Analysis of variance (ANOVA) was used for statistical analysis. Bonferroni correction was applied for comparison between all groups. RESULTS: Twenty female Sardinian sheep with a mean weight of 45.1 kg were studied. All animals survived the surgical procedures. The whole surgical procedure had a mean duration of 113 minutes. Cisplatin blood levels obtained from polymeric films application were low during the first 24 hours after the application; then, the cisplatin blood level increased gradually and progressively until it reached significantly higher plasmatic concentrations after 120 hours compared to intrapleural cisplatin solution (P=0.004) and intravenous administration (P=0.001), respectively. Considering cisplatin concentration at 168 hours after the application, animals treated with polymeric films had higher plasmatic values than animals treated with intrapleural cisplatin solution and intravenous cisplatin (P=0.001). Despite the high cisplatin plasmatic concentrations, treatment related-toxicity towards kidneys and liver was comparatively lower compared to the intravenous and intrapleural cisplatin administration and closer to the control levels. CONCLUSIONS: Polymeric films loaded with cisplatin allowed to reach significantly higher intrapleural and plasmatic cisplatin concentrations compared to intrapleural and intravenous cisplatin solution, providing at the same time, a significant reduction of treatment related toxicity.

Physicochemical and pharmacokinetic properties of polymeric films loaded with cisplatin for the treatment of malignant pleural mesothelioma.

BACKGROUND: Malignant mesothelioma is an invasive neoplasm arising from mesothelial surfaces of the pleural and peritoneal cavities. Mesothelioma treatment is unsatisfactory and recurrence is common. Here an innovative locoregional treatment for malignant pleural mesothelioma is presented. METHODS: Chitosan- and hyaluronate-based films were loaded with 0.5% and 4% w/w cisplatin and were studied for their physicochemical, mechanical and drug release characteristics. The performance of the drug delivery systems was assessed in vitro on A549 cells and on an orthotopic model of MPM recurrence in rats. RESULTS: Polysaccharide films produced were thin, flexible and resistant. Cisplatin was completely released from hyaluronic acid films within 96 hours, while drug release was found to be much more prolonged with chitosan films. The drug released from hyaluronate films was effective against A549 cell line, while for chitosan films the release was too slow to produce cytotoxicity. Similarly, cisplatin-loaded chitosan films in vivo released minimal quantities of cisplatin and induced inflammation and foreign body reaction. Cisplatin-loaded hyaluronate acid films on the contrary were able to prevent tumor recurrence. The cisplatin-loaded hyaluronate films provided higher Cmax and AUC compared to a solution of cisplatin administered intrapleurally, but did not show any sign of treatment related toxicity. CONCLUSIONS: Hyaluronate-based films appear as an optimal platform for the development of drug delivery systems suitable for the loco-regional post-surgical treatment of lung malignancies.

Combined hyaluronate-based films loaded with pemetrexed and cisplatin for the treatment of malignant pleural mesothelioma: Preliminary evaluation in an orthotopic tumor recurrence model.

Malignant pleural mesothelioma (MPM) is a rare malignancy characterized by a long latency period of 20-50 years after exposure to the main aetiology agent that is asbestos. MPM treatments include surgery, chemotherapy, and radiation therapy, with the combination pemetrexed and cisplatin being the standard chemotherapy approach. Despite this multimodality therapy one of the major issues after surgery is the high rate of local recurrence of the tumor. One possible approach would be the intrapleural application of implants loaded with anticancer drug to be applied during surgery to prevent local tumor recurrence. The implant proposed in the present work is a polymeric film of hyaluronic acid loaded with pemetrexed. The film developed is a hydrophilic, thin and flexible film sufficiently resistant to be applied intrapleurally adhering to the mesothelial surface. The release of pemetrexed from the film was found to be complete within2 h in phosphate buffered saline. In an orthotopic model of mesothelioma recurrence in rats, pemetrexed loaded films showed the same antitumor efficacy of pemetrexed disodium solutions administered intravenously or intrapleurally, while when administered in combination with cisplatin-loaded hyaluronate film, the implants almost completely prevented tumor recurrence. The local administration of drug-loaded polymer implants appears an ideal chemotherapy strategy especially for patients in which surgery is already selected as a viable therapeutic option.

Optomechanical terahertz detection with single meta-atom resonator.

Most of the common technologies for detecting terahertz photons (>1 THz) at room temperature rely on slow thermal devices. The realization of fast and sensitive detectors in this frequency range is indeed a notoriously difficult task. Here we propose a novel device consisting of a subwavelength terahertz meta-atom resonator, which integrates a nanomechanical element and allows energy exchange between the mechanical motion and the electromagnetic degrees of freedom. An incident terahertz wave thus produces a nanomechanical signal that can be read out optically with high precision. We exploit this concept to demonstrate a terahertz detector that operates at room temperature with high sensitivity and a much higher frequency response compared to standard detectors. Beyond the technological issue of terahertz detection, our architecture opens up new perspectives for fundamental science of light-matter interaction at terahertz frequencies, combining optomechanical approaches with semiconductor quantum heterostructures.

Continuous wave operation of a superlattice quantum cascade laser emitting at 2 THz.

We report the operation of a 2 THz quantum cascade laser based on a GaAs/Al(0.1)Ga(0.9)As heterostructure. The laser transition is between an isolated subband and the upper state of a 14 meV wide miniband. Lasing action takes place on a high order vertical mode of a 200 microm thick double-metallic waveguide. In pulsed mode operation, with a 3.16mm long device, we report a threshold current density of 115 A/cm(2) at T = 4K, with a maximum measured peak power of 50 mW. The device shows lasing action in continuous wave up to 47K, with a maximum power in excess of 15 mW at T = 4K.

Three-dimensional imaging with a terahertz quantum cascade laser.

Results are presented for the first imaging system that combines the high power of terahertz quantum cascade lasers with three-dimensional image reconstruction based on filtered back-projection. Images of various phantoms have been successfully reconstructed revealing both their external and internal structures.

Imaging with THz quantum cascade lasers using a Schottky diode mixer.

An imaging system in reflection geometry based on a multimode 2.9 THz quantum cascade laser as radiation source is reported. The beating between neighbouring longitudinal modes is detected using a room temperature point-contact Schottky diode as mixing element. We show that the technique can, in principle, give a dynamic range of 60 dB with a time constant of ~ 10 mus.

Lecithin/chitosan controlled release nanopreparations of tamoxifen citrate: loading, enzyme-trigger release and cell uptake.

Tamoxifen citrate (TAM), an anticancer drug with amphiphilic properties, was loaded in lecithin/chitosan nanoparticles (LCN) with a view to oral administration. The influence of tamoxifen loading on the physico-chemical properties of nanoparticles was studied. Size, surface charge and morphological properties of tamoxifen-loaded nanoparticles (LCN-TAM) were assessed. The increase in the tamoxifen amount in the LCN-TAM preparation up to 60 mg/100 ml maintained the positive zeta potential value of about +45 mV. A statistically significant decrease in particle size was observed for TAM amounts between 5 and 20mg. A strong influence of loaded tamoxifen on the structure of lecithin/chitosan nanoparticles was observed, supported by the quantification of free chitosan and morphological analysis. A loading of tamoxifen in nanoparticles of around 19% was obtained. The release of the drug from the LCN-TAM colloidal dispersion was measured, showing that tamoxifen citrate was released very slowly in simulated gastro-intestinal fluids without enzymes. When enzymes able to dismantle the nanoparticle structure were added to the dissolution medium, drug release was triggered and continued in a prolonged manner. Tamoxifen-loaded nanoparticles showed cytotoxicity towards MCF-7 cells comparable to that obtained with tamoxifen citrate solution, but the rate of this toxic effect was dependent on drug release. Caco-2 cells, used as a model of the intestinal epithelium, were shown to take up the TAM loaded nanoparticles extensively.

Lecithin/chitosan nanoparticles of clobetasol-17-propionate capable of accumulation in pig skin.

In this study, clobetasol-17-propionate (CP) loaded lecithin/chitosan nanoparticles were studied with special attention to the transport of the active agent across the skin in vitro. Nanoparticles were characterized by measuring particle size, zeta potential, polydispersity index and encapsulation efficiency. The morphology of nanoparticles was evaluated by transmission electron microscopy. Encapsulation experiments with CP showed high encapsulation efficiency (92.2%). To assess the advantages of this carrier-based formulation in topical administration, the accumulation in and permeation across pig ear skin were compared with chitosan gel and commercially available cream of CP. The results obtained indicate that the incorporation of drug into nanoparticles induced an accumulation of CP especially in the epidermis without any significant permeation across the skin. Dilution of CP loaded nanoparticles with chitosan gel (1:9) produced the same amount of CP in the skin compared with commercial cream, although the former contained ten times less CP. This is a remarkable point for the reduction of the side effects of CP. These results demonstrated the suitability of lecithin/chitosan nanoparticles to induce epidermal targeting and to improve the risk-benefit ratio for topically applied CP.

Phase seeding of a terahertz quantum cascade laser.

The amplification of spontaneous emission is used to initiate laser action. As the phase of spontaneous emission is random, the phase of the coherent laser emission (the carrier phase) will also be random each time laser action begins. This prevents phase-resolved detection of the laser field. Here, we demonstrate how the carrier phase can be fixed in a semiconductor laser: a quantum cascade laser (QCL). This is performed by injection seeding a QCL with coherent terahertz pulses, which forces laser action to start on a fixed phase. This permits the emitted laser field to be synchronously sampled with a femtosecond laser beam, and measured in the time domain. We observe the phase-resolved buildup of the laser field, which can give insights into the laser dynamics. In addition, as the electric field oscillations are directly measured in the time domain, QCLs can now be used as sources for time-domain spectroscopy.