Spatial repellents transfluthrin and metofluthrin affect the behavior of Dermacentor variabilis, Amblyomma americanum, and Ixodes scapularis in an in vitro vertical climb assay.

Repellents serve an important role in bite protection. Tick repellents largely rely on biomechanisms that induce responses with direct contact, but synthetic pyrethroids used as spatial repellents against insects have received recent attention for potential use in tick protection systems. An in vitro vertical climb assay was designed to assess spatial repellency against Dermacentor variabilis, Amblyomma americanum, and Ixodes scapularis adult, female ticks. Climbing behavior was assessed with and without the presence of two spatial repellents, transfluthrin and metofluthrin. Repellency parameters were defined to simulate the natural questing behavior of ambushing ticks, including measures of detachment, pseudo-questing duration, climbing deterrence, and activity. Significant effects were observed within each parameter. D. variabilis showed the greatest general susceptibility to each repellent, followed by A. americanum, and I. scapularis. The most important and integrative measure of repellency was climbing deterrence-a measure of the spatial repellent's ability to disrupt a tick's natural propensity to climb. Transfluthrin deterred 75% of D. variabilis, 67% of A. americanum, and 50% of I. scapularis. Metofluthrin was slightly more effective, deterring 81% of D. variabilis, 73% of A. americanum, and 72% of I. scapularis. The present study poses a novel paradigm for repellency and reports a preliminary assessment of spatial repellent effect on tick behavior. Further research will assess spatial repellency in a more natural setting, scale exposure conditions, and incorporate host cues.

Field Evaluation of Novel Spatial Repellent Controlled Release Devices (CRDs) against Mosquitoes in an Outdoor Setting in the Northern Peruvian Amazon.

U.S. military troops are exposed to mosquito-borne pathogens when deployed to endemic regions. Personal protective measures such as permethrin-treated uniforms and dermal repellents are the cornerstones of mosquito-borne disease prevention for the U.S. military. These measures have limitations and additional personal protection tools, such as spatial repellent devices to decrease the risk of vector-borne pathogen transmission, are required. Novel spatial repellent controlled-release devices formulated with metofluthrin were evaluated in an outdoor setting in the northern Amazon of Peru to evaluate performance under field conditions. The metofluthrin emitting devices lowered the number of mosquitoes captured in protected human landing collections (HLC) compared to blank devices, although there were effect differences between Anopheles spp. and species in other mosquito genera. A computational-experimental model was developed to correlate HLC and active ingredient (AI) concentrations as a function of time and space. Results show a strong correlation between the released AI and the decrease in HLC. This model represents the first effort to obtain a predictive analytical tool on device performance using HLC as the entomological endpoint.

Correction to: Rapid reconstitution packages (RRPs) for stable storage and delivery of glucagon.

Following are updated Figs. 1, 3, 5, and 7. The original article has also been updated: Fig. 1 a RRP. b RRP dimensions. c RRP inside of syringe. Fig. 3 RRP activation and fluid flow.

A combined experimental-computational approach for spatial protection efficacy assessment of controlled release devices against mosquitoes (Anopheles).

This work describes the use of entomological studies combined with in silico models (computer simulations derived from numerical models) to assess the efficacy of a novel device for controlled release of spatial repellents. Controlled Release Devices (CRDs) were tested with different concentrations of metofluthrin and tested against An. quadrimaculatus mosquitoes using arm-in cage, semi-field, and outdoor studies. Arm-in-cage trials showed an approximate mean values for mosquito knockdown of 40% and mosquito bite reduction of 80% for the optimal metofluthrin formulation for a 15-minute trial. Semi-field outdoor studies showed a mean mortality of a 50% for 24 hour trial and 75% for a 48 hour trial for optimal concentrations. Outdoors studies showed an approximate mean mortality rate of 50% for a 24 hour trial for optimal concentrations. Numerical simulations based on Computational Fluid Dynamics (CFD) were performed in order to obtain spatial concentration profiles for 24 hour and 48 hour periods. Experimental results were correlated with simulation results in order to obtain a functional model that linked mosquito mortality with the estimated spatial concentration for a given period of time. Such correlation provides a powerful insight in predicting the effectiveness of the CRDs as a vector-control tool. While CRDs represent an alternative to current spatial repellent delivery methods, such as coils, candles, electric repellents, and passive emanators based on impregnated strips, the presented method can be applied to any spatial vector control treatment by correlating entomological endpoints, i.e. mortality, with in-silico simulations to predict overall efficacy. The presented work therefore presents a new methodology for improving design, development and deployment of vector-control tools to reduce transmission of vector-borne diseases, including malaria and dengue.

Rapid reconstitution packages (RRPs) for stable storage and delivery of glucagon.

Current emergency injectors of glucagon require manual reconstitution, which involves several steps that may lead to dosage errors. Rapid reconstitution packages (RRPs) are new devices, designed using computational fluid dynamics (CFD) to optimize fluid mixing, integrating physical properties of active pharmaceutical ingredients (APIs), excipients and diluents. RRPs improve drug stability for long-term storage and ease of delivery. Device prototypes were manufactured using advanced stereolithography apparatus (SLA) 3D printing technology. Reconstitution of glucagon with RRPs was evaluated by high-performance liquid chromatography (HPLC) and optical spectroscopy methods. Enzyme-linked immunosorbent assays were performed to test in vitro activity. Experimental results showed that RRPs effectively reconstituted glucagon even after exposure to 60 °C for a 24-h period. RRPs exhibited improved performance at maintaining drug stability compared to lyophilized glucagon stored in a standard glass vial under the same temperature conditions. RRPs represent a portable platform for rapid reconstitution of lyophilized drugs, compatible with standard syringes available in any clinical setting. The RRP provides an alternative to manual reconstitution process, especially designed for medical emergencies.

Controlled release spatial repellent devices (CRDs) as novel tools against malaria transmission: a semi-field study in Macha, Zambia.

BACKGROUND: The emergence of mosquitoes that can avoid indoor-deployed interventions, such as treated bed nets and indoor residual spraying, threatens the mainstay of malaria control in Zambia. Furthermore, the requirement for high coverage of these tools poses operational challenges. Spatial repellents are being assessed to supplement these vector control tools, but limitations exist in the residual effect of the repellent and the need for external power or heat for diffusion of the volatiles. METHODS: A semi-field evaluation of a novel controlled release spatial repellent device (CRD) was conducted in Macha, Zambia. These devices emanate metofluthrin with no need for external power. Devices were deployed in huts within the semi-field system (SFS). Female Anopheles gambiae sensu stricto released within the SFS were trapped overnight by light traps and collected by aspiration the next morning inside and outside of huts to determine the extent of mosquito repellency and the impact on host-seeking and survival. Experiments studied the impact of number of devices as well as the presence of hut occupants. The study was complemented with numerical methods based on computational fluid dynamics to simulate spatial distribution of metofluthrin. RESULTS: Presence of CRDs was associated with significant reductions in indoor counts of mosquitoes, regardless of whether huts were occupied or not. Repellency ranged from 15 to 60% compared to huts with no devices. Reducing the number of devices from 16 to 4 had little impact on repellency. When huts were occupied, indoor mosquito host-seeking was higher in the presence of CRDs, whilst survival was significantly reduced. CONCLUSIONS: This study demonstrated that deployment of as few as four CRDs within a hut was associated with reduced indoor mosquito densities. As would be expected, presence of occupants within huts, resulted in greater indoor catches (both with and without devices). The increased indoor mosquito host-seeking and mortality in huts when devices were present may be explained by the excito-repellency activity of metofluthrin. These semi-field experiments provide preliminary data on the utility of CRD spatial repellents to reduce indoor densities of An. gambiae mosquitoes. Studies will further investigate the impact of CRDs on mosquito behaviour as well as epidemiological protective efficacy.

The Use of Microdispensers with Spatial Repellents for Personal Protection Against Mosquito Biting.

Mosquito-borne pathogens affect millions of people worldwide. This work describes a new method to deliver spatial repellents. Functional microdispensers (FMDs) were designed to deliver spatial repellents against mosquitoes. In vivo trials showed that FMDs protect human subjects against mosquitoes by reducing 70­90% of bites received, with a protection that lasted up to 4 weeks. FMDs can be cost-effectively implemented as wearable or field-dispensed devices for local area protection, defined as a confined geographical region.

Clinical applications of biomedical microdevices for controlled drug delivery.

Miniaturization of devices to micrometer and nanometer scales, combined with the use of biocompatible and functional materials, has created new opportunities for the implementation of drug delivery systems. Advances in biomedical microdevices for controlled drug delivery platforms promise a new generation of capabilities for the treatment of acute conditions and chronic illnesses, which require high adherence to treatment, in which temporal control over the pharmacokinetic profiles is critical. In addition, clinical conditions that require a combination of drugs with specific pharmacodynamic profiles and local delivery will benefit from drug delivery microdevices. This review provides a summary of various clinical applications for state-of-the-art controlled drug delivery microdevices, including cancer, endocrine and ocular disorders, and acute conditions such as hemorrhagic shock. Regulatory considerations for clinical translation of drug delivery microdevices are also discussed. Drug delivery microdevices promise a remarkable gain in clinical outcomes and a substantial social impact. A review of articles covering the field of microdevices for drug delivery was performed between January 1, 1990, and January 1, 2014, using PubMed as a search engine.

Rapid Reconstitution Packages (RRPs) implemented by integration of computational fluid dynamics (CFD) and 3D printed microfluidics.

Rapid Reconstitution Packages (RRPs) are portable platforms that integrate microfluidics for rapid reconstitution of lyophilized drugs. Rapid reconstitution of lyophilized drugs using standard vials and syringes is an error-prone process. RRPs were designed using computational fluid dynamics (CFD) techniques to optimize fluidic structures for rapid mixing and integrating physical properties of targeted drugs and diluents. Devices were manufactured using stereo lithography 3D printing for micrometer structural precision and rapid prototyping. Tissue plasminogen activator (tPA) was selected as the initial model drug to test the RRPs as it is unstable in solution. tPA is a thrombolytic drug, stored in lyophilized form, required in emergency settings for which rapid reconstitution is of critical importance. RRP performance and drug stability were evaluated by high-performance liquid chromatography (HPLC) to characterize release kinetics. In addition, enzyme-linked immunosorbent assays (ELISAs) were performed to test for drug activity after the RRPs were exposed to various controlled temperature conditions. Experimental results showed that RRPs provided effective reconstitution of tPA that strongly correlated with CFD results. Simulation and experimental results show that release kinetics can be adjusted by tuning the device structural dimensions and diluent drug physical parameters. The design of RRPs can be tailored for a number of applications by taking into account physical parameters of the active pharmaceutical ingredients (APIs), excipients, and diluents. RRPs are portable platforms that can be utilized for reconstitution of emergency drugs in time-critical therapies.

Pharmacogenomics-based RNA interference nanodelivery: focus on solid malignant tumors.

INTRODUCTION: RNA interference represents one of the most promising strategies in fighting disease. However, small RNA interference faces substantial challenges for in vivo application due to the inherent instability of the RNA interference molecule. Among the nonviral gene delivery carriers, nanoparticles have attracted interest due to their success in various model systems. Nanomaterials have unique properties compared to conventional bulk materials that may be applicable in this setting. The nanoparticle complex carrying small interference RNA can undergo surface modification to achieve targeted modification for tissue-specific delivery. However, toxicity issues of the delivery systems need to be addressed and they require a pharmacogenomic profile of their own. AREAS COVERED: The authors review pharmacogenomics, toxicogenomics, nanoparticle-based drug delivery, and small interference RNA, with a focus on how logically engineered nanoparticle delivery systems can be used for personalized medicine in malignant tumors. EXPERT OPINION: Pharmacogenomics may be helpful in addressing possible individualized drug response for both the gene silencing capability of the delivered siRNA and the nanoparticle drug delivery system as both complete and distinct units. This may be done by assessing variations in gene expressions and single nucleotide polymorphisms. Patient profiling may be key as patient noncompliance due to toxicity plays a major role in treatment failure.

Carbon nanotubes in drug delivery: focus on infectious diseases.

Carbon nanotubes have the potential to address the challenges of combating infectious agents by both minimizing toxicity by dose reduction of standard therapeutics and allowing a multiple payload capacity to achieve both targeted activity and combating infectious strains, resistant strains in particular. One of their unique characteristics is the network of carbon atoms in the nanometer scale, allowing the creation of nano-channels via cellular membranes. This review focuses on the characterization, development, integration and application of carbon nanotubes as nanocarrier-based delivery systems and their appropriate design for achieving the desired drug delivery results in the different areas of infectious diseases. While a more extensive toxicological and pharmacological profile must be obtained, this review will focus on existing research and pre-clinical data concerning the potential use of carbon nanotubes.

Towards toxicity detection using a lab-on-chip based on the integration of MOEMS and whole-cell sensors.

A lab-on-chip consisting of a unique integration of whole-cell sensors, a MOEMS (Micro-Opto-Electro-Mechanical-System) modulator, and solid-state photo-detectors was implemented for the first time. Whole-cell sensors were genetically engineered to express a bioluminescent reporter (lux) as a function of the lac promoter. The MOEMS modulator was designed to overcome the inherent low frequency noise of solid-state photo-detectors by means of a previously reported modulation technique, named IHOS (Integrated Heterodyne Optical System). The bio-reporter signals were modulated prior to photo-detection, increasing the SNR of solid-state photo-detectors at least by three orders of magnitude. Experiments were performed using isopropyl-beta-d-thiogalactopyranoside (IPTG) as a preliminary step towards testing environmental toxicity. The inducer was used to trigger the expression response of the whole-cell sensors testing the sensitivity of the lab-on-chip. Low intensity bio-reporter optical signals were measured after the whole-cell sensors were exposed to IPTG concentrations of 0.1, 0.05, and 0.02mM. The experimental results reveal the potential of this technology for future implementation as an inexpensive massive method for rapid environmental toxicity detection.