Temporal Delivery Research Articles

Facile preparation of acrylamide grafted locust bean gum-poly(vinyl alcohol) interpenetrating polymer network microspheres for controlled oral drug delivery

Hybridization of natural and synthetic polymers is used to improve the physicochemical stability, swelling and drug release pattern of the respective materials in biological condition. In present study, a biodegradable, biocompatible and stable interpenetrating polymer network (IPN) of acrylamide grafted locust bean gum (Am-g-LBG) and poly(vinyl alcohol) (PVA) was developed by emulsion crosslinking method for spatial and temporal drug delivery. The IPN microspheres were prepared with the help of glutaraldehyde as a crosslinker for controlled oral delivery of buflomedil hydrochloride. The formulation parameters were optimized in terms of different gum:PVA ratio, crosslinker amount and drug loading. The microspheres were evaluated for their drug entrapment efficiency, particle size, swelling, SEM, FTIR, NMR, DSC, XRD and in vitro drug release profile. The particles showed well controlled release characteristics and continued to drug release following diffusion controlled release pattern. The drug release was for prolong time without collapsing the particle matrix. Thus, IPN microspheres based delivery system can be a better approach for controlled delivery of highly water soluble drugs like buflomedil hydrochloride.

Germicide wound pad with active, in situ, electrolytically produced hypochlorous acid.

We describe a new wound dressing technology that can actively generate an inorganic germicide agent, in situ, within the wound pad. The technology provides real time control over the quantitative, spatial and temporal delivery of the germicide. The identity of the germicide is hypochlorous acid (HClO). The HClO is produced in a flexible wound pad, made of a composite of thin (micrometer scale) layers of various materials, with different electrochemical propertiesthat enhance HClO production. Active control over the production of HClO is achieved by control of the pH and of the electric potential across the layers. The effectiveness of the Active HClO Pad (AHClOP) concept is demonstrated in a study on sterilization of E. coli in a deep wound contamination simulating gel. The performance of the AHClOP is compared with that of four commercial wound dressings. Results show that the AHClOP can sterilize throughout the gel, while the commercial dressings cannot.

Preparation and Characterization of Vancomycin-Loaded ElectrospunRana chensinensisSkin Collagen/Poly(L-lactide) Nanofibers for Drug Delivery

Collagen was extracted from abandonedRana chensinensisskin in northeastern China via an acid enzymatic extraction method for the use of drug carriers. In this paper we demonstrated two different nanofiber-vancomycin (VCM) systems, that is, VCM blended nanofibers and core-shell nanofibers with VCM in the core.Rana chensinensisskin collagen (RCSC) and poly(L-lactide) (PLLA) (3 : 7) were blended in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) at a concentration of 10% (g/mL) to fabricate coaxial and blend nanofibers, respectively. Coaxial and blend electrospun RCSC/PLLA nanofibers containing VCM (5 wt%) were evaluated for the local and temporal delivery of VCM. The nanofiber scaffolds were characterized by environmental scanning electron microscope (ESEM), transmission electron microscopy (TEM), Fourier transform infrared spectra (FTIR), differential scanning calorimeter (DSC), water contact angle (WCA), and mechanical tests. The drug release of VCM in these two systems was compared by using UV spectrophotometer. The empirical result indicated that both the blend and coaxial RCSC/PLLA scaffolds followed sustained control release for a period of 80 hours, but the coaxial nanofiber might be a potential drug delivery material for its better mechanical properties and sustained release effect.

Optogenetic strategies for the treatment of neurodegenerative diseases

Optogenetic tools and strategies, as an innovative approach to control neurodegenerative diseases, have been developed in recent years with the application of a combination of optical and genetic techniques on a certain group of cells of living tissue. With this technique, a particular cell type and their predefined pathway can be controlled precisely. The basic steps of this optogenetics include discovery and placing of light-sensitive molecules into cells to provide optical control and applications in animal experiments. Strategies for suppressing neurons are based on activation of light-sensitive prokaryotic membrane proteins that act as ion channels and transporters. Optogenetic strategies that are adapted clinically have the capacity to provide temporal, regional and cellular specific delivery in ways that no other treatment may suggest. Engineering channelrhodopsin(CR) molecule and its expression are very important in terms of optogenetic experiments. Because experiments conducted with conventional CR are not suitable for testing chronic long-term studies, there is a certain need for a controlled medium for optogenetic neurodegenerative disease experiments. Keywords: Alzheimer’s disease; neurodegenerative diseases; optogenetics; Parkinson disease

Finely Tuned Temporal and Spatial Delivery of GDNF Promotes Enhanced Nerve Regeneration in a Long Nerve Defect Model

The use of growth factors, such as glial cell line-derived neurotrophic factor (GDNF), for the treatment of peripheral nerve injury has been useful in promoting axon survival and regeneration. Unfortunately, finding a method that delivers the appropriate spatial and temporal release profile to promote functional recovery has proven difficult. Some release methods result in burst release profiles too short to remain effective over the regeneration period; however, prolonged exposure to GDNF can result in axonal entrapment at the site of release. Thus, GDNF was delivered in both a spatially and temporally controlled manner using a two-phase system comprised of an affinity-based release system and conditional lentiviral GDNF overexpression from Schwann cells (SCs). Briefly, SCs were transduced with a tetracycline-inducible (Tet-On) GDNF overexpressing lentivirus before transplantation. Three-centimeter acellular nerve allografts (ANAs) were modified by injection of a GDNF-releasing fibrin scaffold under the epineurium and then used to bridge a 3 cm sciatic nerve defect. To encourage growth past the ANA, GDNF-SCs were transplanted into the distal nerve and doxycycline was administered for 4, 6, or 8 weeks to determine the optimal duration of GDNF expression in the distal nerve. Live imaging and histomorphometric analysis determined that 6 weeks of doxycycline treatment resulted in enhanced regeneration compared to 4 or 8 weeks. This enhanced regeneration resulted in increased gastrocnemius and tibialis anterior muscle mass for animals receiving doxycycline for 6 weeks. The results of this study demonstrate that strategies providing spatial and temporal control of delivery can improve axonal regeneration and functional muscle reinnervation.

Reconstructing dynamical models from optogenetic data

Optogenetics allows optical control of neuronal activity by using genetically altered neural cells and optical tools. Briefly, optogenetics uses a photosensitive element that, upon absorption of light, produces some change in the activity of the cells. Although the technique evolved, it involves inserting a light-sensitive channel from green algae, called channelrhodopsin-2 (ChR2), into neurons [1]. By precise spatial and temporal delivery of light pulses we can identify the local interconnections among neurons and investigate their dynamical response under different conditions. Data were recorded with a custom made optrode made of a recording pipette glued to optic fiber inserted in the medial prefrontal cortex (PFC) of male PV-Cre mice injected with virus suspension AV2/5.EF1a.DIO.hChR2(H134R)-EYFP.WPRE.hGH [2]. A 473 nm laser generated light stimulation and stable single unit recordings were monitored before filtering to record field potentials (0.1-100 Hz). Optical stimulation consisted of 10 ms pulses followed by 15 ms pause (40 Hz). A train of 10 pulses that lasted 250 ms was applied every 4 seconds and local filed potentials were recorded with a sampling rate of 10 KHz (Figure ​(Figure1A).1A). We used delay-embedding method to reconstruct the phase space attractor [3]. We found that the minimum dimension that unfolds the attractors is three and the delay time is about 3600 data points (Figure ​(Figure1B).1B). Based on the phase space reconstruction, we were able to extract a low-dimensional mathematical model that describes the dynamics of the system. Although every single neuron in the mPFC is described by a large number of independent variables such as ionic channel activation/inactivation variables, the local neural network activated by light pulses can be modeled with only three variables. We hypothesize these three global variables could be the activity of excitatory, inhibitory interneurons, and light-sensitive neurons. Figure 1 A. Average local filed potential (LFP) recordings that show the response of mPFC to 250 ms light stimuli. B. Phase space reconstruction of LFP using delayed embedding method in a three dimensional space and a delay time of 3600 data points (360 ms).

Predicting uncertainty in sediment transport and landscape evolution – the influence of initial surface conditions

Numerical landscape evolution models were initially developed to examine natural catchment hydrology and geomorphology and have become a common tool to examine geomorphic behaviour over a range of time and space scales. These models all use a digital elevation model (DEM) as a representation of the landscape surface and a significant issue is the quality and resolution of this surface. Here we focus on how subtle perturbations or roughness on the DEM surface can produce alternative model results. This study is carried out by randomly varying the elevations of the DEM surface and examining the effect on sediment transport rates and geomorphology for a proposed rehabilitation design for a post-mining landscape using multiple landscape realisations with increasing magnitudes of random changes. We show that an increasing magnitude of random surface variability does not appear to have any significant effect on sediment transport over millennial time scales. However, the random surface variability greatly changes the temporal pattern or delivery of sediment output. A significant finding is that all simulations at the end of the 10,000 year modelled period are geomorphologically similar and present a geomorphological equifinality. However, the individual patterns of erosion and deposition were different for repeat simulations with a different sequence of random perturbations. The alternative positions of random perturbations strongly influence local patterns of hillslope erosion and evolution together with the pattern and behaviour of deposition. The findings demonstrate the complex feedbacks that occur even within a simple modelled system.

Impact of aeolian processes on peat accumulation: Late Glacial–Holocene history of the Hamernia peat bog (Roztocze region, south-eastern Poland)

The Hamernia peat bog in the Roztocze region started to develop in the Allerød within the deflation basin divided into two sub-basins by a parabolic dune formed in the Older or the Oldest Dryas. Lithological and palynological analyses as well as radiocarbon dating of samples from three logs cored in different parts of the peat-bog indicate that up to the Subatlantic, when the top of the dune bar was inundated, the evolution of both sub-basins was different in hydrological and sedimentological aspects. Aeolian processes were active in the Younger Dryas, generating delivery of mineral material to both sub-basins. However, the intensiveness of this process was much lower than in earlier cold phases, as indicated by the limited spatial and temporal delivery of this material (restricted mainly to the wind-ward sub-basin). The nature of the next short episode of mineral material delivery to one sub-basin, recorded during the climate cooling at the turn of the Boreal and the Atlantic Phases, is not clear. Local aeolian or slope processes (water erosion accompanied by mass movements) are suspected to be responsible for this episode. The youngest stage of slight but continuous mineral material delivery, caused by aeolian processes, started in the climate cooling at the beginning of the Subatlantic, and was contemporary with the intensification of human activity in this area. The geological history in the Late Vistulian and the Holocene suggests that the last dune-forming stage in this area occurred during the Older Dryas.

601. Gene Therapy for Cockayne Syndrome

Cockayne Syndrome (CS) is a rare autosomal recessive genetic disorder. The majority of CS cases involve mutations in either the CSA (25%) or CSB (75%) gene, leading to defective transcription-coupled nucleotide excision repair and RNA polymerase II mediated transcription. Clinically this presents as progressive degeneration of the central nervous system, retina, cardiovascular system, and cochlea, causing mental retardation, post-natal growth defects, pigmented retinopathy, cataracts, dermal UV sensitivity, organ dysfunction and shortened life expectancy.CSA and CSB single mutant mice display retinal degeneration with age and ocular sensitivity to ionizing radiation. Because limited publications on these mouse models exist we began by characterizing the retinal dysfunction through histology and electroretinography (ERG). We found that the retinal degeneration in CSA and CSB mutant mice (C57Bl6 background) was occurring over a slower time course (over 1 year) than previously reported. Therefore we aimed to increase the rate of retinal degeneration in these animals using UV light exposure, whole body radiation, or high intensity light exposure. Our goal was to increase the speed of retinal degeneration to a timeframe that is more readily studied for the purposes of gene therapy correction. Preliminary data indicates that we can cause a decrease in the scotopic ERG (b-wave) 2 weeks after high-dose ultraviolet light exposure (100000J/m^2), a change not seen in C57Bl6 mice at the same UV dose. There was also a decrease in b-wave amplitude following radiation exposure (2-3 gray) in the CSB mouse model that was not seen in C57Bl6 mice. Histology on these mice is currently pending. Improving the rate of photoreceptor loss will allow us to perform rAAV based gene therapy to deliver the CSB gene back to the retina and ascertain whether UV and radiation resistance can be restored.While single mutant CSA and CSB mice do not have significant neurological deficits, when crossed with XPA deficient mice they develop clinical signs similar to severely affected human patients. Signs in these mice include neurologic deficits, poor weight gain and death around postnatal day 21. These mice could be ideal candidates to show that correction of both the central nervous system disease as well as the retinal degeneration is possible in a single model. To determine if both the brain and retina could be targeted in the same animal (and therefore model what may be necessary in the human patients) we have looked at targeting both organs simultaneously using either a single IV injection in neonatal mice or a combined intra-cerebral ventricular (ICV) injection and IV injection in the same animal. We found that delivery of the rAAV vector (regardless of serotype tested) into the retro-orbital sinus at postnatal day 1-3 leads to widespread transduction of the retina. Temporal vein delivery postnatal day 1-3 only resulted in transduction of the inner layer of the retina, not the photoreceptors. When ICV and IV injections were combined in neonates widespread brain and retinal transduction was achieved.These preliminary data indicate that a murine model for retinal gene therapy of CS is feasible and that potentially both the retina and brain could be targeted in a single model.

N-Heterocyclic carbene ligands bearing a naphthoquinone appendage: Synthesis and coordination chemistry

Many biochemical transformations for small molecule functionalisation depend on the temporal delivery of multiple protons and electrons. For this purpose, Nature elegantly combines transition metals with redox-active cofactors. In a biomimetic spirit, we report on the synthesis and coordination chemistry of an N-heterocyclic carbene ligand bearing a naphthoquinone moiety NHC 1. Both the silver and palladium complexes [Ag(μ-Cl)(NHC 1)]22 and [Pd(η3-allyl)(NHC 1)Cl] 5 were characterized by X-ray crystallography. Cyclic voltammetry of the metal complexes suggest that redox events occur both on the naphthoquinone and on the metal for the iridium and ruthenium complexes.

English

Oral administration has only limited use for important drugs from various pharmacological categories, that have poor oral bio-availability due to incomplete absorption and/or degradation in the gastrointestinal tract (GIT). Drugs that are easily absorbed from the gastrointestinal tract (GIT) and have a short half-life are eliminated quickly from the blood circulation, so they require frequent dosing. To avoid this drawback, the oral sustained-controlled release formulations have been developed in an attempt to release the drug slowly into the gastrointestinal tract (GIT) and maintain an effective drug concentration in the serum for longer period of time. However, such oral drug delivery devices have a physiological limitation of gastric retention time (GRT), variable and short gastric emptying time can result in incomplete drug release from the drug delivery system (DDS) in the absorption zone (stomach or upper part of small intestine), leading to diminished efficacy of the administered dose. The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body to achieve promptly and then maintain the desired drug concentration. This idealized objective points to the two aspects most important to the drug delivery; namely spatial placement and temporal delivery of a drug. Spatialplacement relates to targeting a drug to a specific organ or a tissue while temporal delivery refers to controlling the rate of drug delivery to that specific organ or a Tissue. Key words: Gastroretentive, drugdelivery, controlled.

Spontaneous gene transfection of human bone cells using 3D mineralized alginate-chitosan macrocapsules.

The effectiveness of nonviral gene therapy remains uncertain because of low transfection efficiencies and high toxicities compared with viral-based strategies. We describe a simple system for transient transfection of continuous human cell lines, with low toxicity, using mineral-coated chitosan and alginate capsules. As proof-of-concept, we demonstrate transfection of Saos-2 and MG63 human osteosarcoma continuous cell lines with gfp, LacZ reporter genes, and a Sox-9 carrying plasmid, to illustrate expression of a functional gene with therapeutic relevance. We show that continuous cell lines transfect with significant efficiency of up to 65% possibly through the interplay between chitosan and DNA complexation and calcium/phosphate-induced translocation into cells entrapped within the 3D polysaccharide based environment, as evidenced by an absence of transfection in unmineralized and chitosan-free capsules. We demonstrated that our transfection system was equally effective at transfection of primary human bone marrow stromal cells. To illustrate, the Sox-9, DNA plasmid was spontaneously expressed in primary human bone marrow stromal cells at 7 days with up to 90% efficiency in two repeats. Mineralized polysaccharide macrocapsules are gene delivery vehicles with a number of biological and practical advantages. They are highly efficient at self-transfecting primary bone cells, with programmable spatial and temporal delivery prospects, premineralized bone-like environments, and have no cytotoxic effects, as compared with many other nonviral systems.

SITE SPECIFIC DRUG DELIVERY THROUGH NASAL ROUTE USING BIOADHESIVE POLYMERS

This review explains some aspects of mucoadhesion related to the nasal drug delivery system. On the first count, the theories of the adhesion of mucoadhesive polymers to the mucosa epithelium are described. Secondly, the characteristics and application of several widely used mucoadhesive polymers in nasal drug delivery are presented. The nasal mucosa provides a potentially good route for systemic drug delivery. One of the most important features of the nasal route is that it avoids first-pass hepatic metabolism, thereby reducing metabolism. The application of mucoadhesive polymers in nasal drug delivery systems has gained to promote dosage form residence time in the nasal cavity as well as improving intimacy of contact with absorptive membranes of the biological system. The aspiration of any drug delivery system is to endow with a therapeutic amount of drug to the proper site in the body to achieve promptly & then uphold the desired drug concentration. That is why the drug delivery system should deliver drug at a state dictated by the needs of the body over a specified period of treatment. This idealized objective points to the two aspects most important to drug delivery, namely, spatial placement relates to targeting a drug to a specific organ or tissue while temporal delivery refers to the control of rate of drug delivery to the target tissue. Over the last few decades, the relevance of mucoadhesive polymers in nasal drug delivery systems has gained significance among pharmaceutical scientists as a means of promoting dosage form residence time in the nasal cavity as well as for improving intimacy of contact with absorptive membranes of the biological system. In addition, the improved paracellular absorption subsequent the swelling of the mucoadhesive polymers on the nasal membranes provides an important way for the absorption of the macromolecules through the nasal cavity. Keywords: Nasal route, Mucoadhesive polymers, Paracellular absorption,

Wireless implantable chip with integrated nitinol-based pump for radio-controlled local drug delivery.

We demonstrate an active, implantable drug delivery device embedded with a microfluidic pump that is driven by a radio-controlled actuator for temporal drug delivery. The polyimide-packaged 10 × 10 × 2 mm(3) chip contains a micromachined pump chamber and check valves of Parylene C to force the release of the drug from a 76 μL reservoir by wirelessly activating the actuator using external radio-frequency (RF) electromagnetic fields. The rectangular-shaped spiral-coil actuator based on nitinol, a biocompatible shape-memory alloy, is developed to perform cantilever-like actuation for pumping operation. The nitinol-coil actuator itself forms a passive 185 MHz resonant circuit that serves as a self-heat source activated via RF power transfer to enable frequency-selective actuation and pumping. Experimental wireless operation of fabricated prototypes shows successful release of test agents from the devices placed in liquid and excited by radiating tuned RF fields with an output power of 1.1 W. These tests reveal a single release volume of 219 nL, suggesting a device's capacity of ~350 individual ejections of drug from its reservoir. The thermal behavior of the activated device is also reported in detail. This proof-of-concept prototype validates the effectiveness of wireless RF pumping for fully controlled, long-lasting drug delivery, a key step towards enabling patient-tailored, targeted local drug delivery through highly miniaturized implants.

Electrospun PCL/PEO coaxial fibers for basic fibroblast growth factor delivery

The poor innate healing capacity of fibroblastic tissues, such as pelvic floor fascia, is attributed to the scarcity of fibroblasts to produce collagen, as the main collagen producing cells. Coaxial electrospun PCL/PEO fibers containing basic fibroblast growth factor (FGF-2) were evaluated for the local and temporal delivery of FGF-2 for promoting fibroblast proliferation. PCL/PEO coaxial fibers with a highly porous surface were successfully developed using coaxial electrospinning. The diameter of the PCL/PEO microfibers produced by coaxial electrospinning could be tuned by the electrospinning parameters. XPS surface chemistry probing and CA wettability analysis confirmed that the outer surface of the coaxial fibers is PCL. The protein was successfully encapsulated and a sustained release was observed over more than 9 days. In vitro, PCL/PEO coaxial fibers supported fibroblast cell adhesion. In addition, PCL/PEO coaxial fibers containing FGF-2 significantly enhanced fibroblast cell viability and proliferation. Further, Coll-I expression was significantly expressed after day 1 while down-regulated after day 9 compared to the control group. These results indicate that coaxial polymeric fibers allow local and sustained growth factor delivery with prolonged efficacy and longevity for connective tissue regeneration.

Comparative bio-safety and in vivo evaluation of native or modified locust bean gum-PVA IPN microspheres

Strategically developed natural polymer-based controlled release multiparticulate drug delivery systems have gained special interest for “spatial placement” and “temporal delivery” of drug molecules. In our earlier study, locust bean gum-poly(vinyl alcohol) interpenetrating polymer network (LBG-PVA IPN), carboxymethylated locust bean gum-poly(vinyl alcohol) interpenetrating polymer network (CMLBG-PVA IPN) and acrylamide grafted locust bean gum-poly(vinyl alcohol) interpenetrating polymer network (Am-g-LBG-PVA IPN) were prepared and characterized. The present study deals with accelerating stability testing, comparative bio-safety and single dose in vivo pharmacokinetic study of all three IPN microspheres for controlled oral delivery of buflomedil hydrochloride (BH). From the stability study, it was observed that the particles were stable throughout the study period. From toxicity and biodegradability study it was proved that the microspheres were safe for internal use and complied with bio-safety criterion. From the in vivo pharmacokinetic study in rabbits, it was observed that the CMLBG-PVA IPN microspheres possessed almost similar Tmax value with BH oral suspension. However, in comparison between the LBG-PVA and Am-g-LBG-PVA IPN microspheres, the later showed well controlled release property than the first in biological condition. Thus, this type of delivery system might be useful to achieve the lofty goals of the controlled release drug delivery.

Sustained delivery of biomolecules from gelatin carriers for applications in bone regeneration.

Local delivery of therapeutic biomolecules to stimulate bone regeneration has matured considerably during the past decades, but control over the release of these biomolecules still remains a major challenge. To this end, suitable carriers that allow for tunable spatial and temporal delivery of biomolecules need to be developed. Gelatin is one of the most widely used natural polymers for the controlled and sustained delivery of biomolecules because of its biodegradability, biocompatibility, biosafety and cost-effectiveness. The current study reviews the applications of gelatin as carriers in form of bulk hydrogels, microspheres, nanospheres, colloidal gels and composites for the programmed delivery of commonly used biomolecules for applications in bone regeneration with a specific focus on the relationship between carrier properties and delivery characteristics.

Multiple proxy estimates of source and spatial variation in organic matter in surface sediments from the southern Yellow Sea

Marginal seas play an important role in the global carbon cycle as organic matter (OM) buried in shelf seas accounts for ca. 80% of marine sedimentary OM. The Yellow Sea (YS) is a significant sink for both terrestrial OM (TOM) and marine OM (MOM), so the source and spatial variation of sedimentary OM in the southern YS were investigated by analyzing several parameters for 54 surface sediment samples. Spatial ranges were 5.4–12.8 for total organic carbon/total organic nitrogen (TOC/TON), −22.8‰ to −19.9‰ for TOC δ13C, 421–4515ng/g TOC for ∑(C27+C29+C31) n-alkanes, 33–152ng/g TOC for branched glycerol dialkyl glycerol tetraethers, 316–8550ng/g TOC for total marine biomarkers. TOC/TON displayed no distinct spatial pattern, but the BIT (branched isoprenoid tetratether index) proxy, TMBR [terrestrial and marine biomarker ratio: (C27+C29+C31n-alkanes)/(C27+C29+C31) n-alkanes+(brassicasterol+dinosterol+alkenones)] and δ13C values revealed similar spatial distribution patterns, indicating higher TOM near coastal regions and especially near the old Huanghe Estuary. Quantitative estimates using a binary model revealed higher %TOM (avg. 34%) from TMBR than from δ13C (avg. 26%) and BIT (avg. 12%). TMBR is a proxy incorporating both soil OM (OMsoil) and plant OM (OMplant) while BIT is a proxy for OMsoil, so quantitative estimates using a three end member model indicated higher OMplant and OMsoil values near the old Huanghe Estuary, but %OMplant (avg. 23%) was higher than %OMsoil (avg. 13%). Our study suggests that these proxies can be used to study the spatial and temporal variation and delivery mechanisms for both OMsoil and OMplant in marginal seas.

Biomimetic protein nanoparticles facilitate enhanced dendritic cell activation and cross-presentation.

Many current cancer vaccine strategies suffer from the inability to mount a CD8 T cell response that is strong enough to overcome the low immunogenicity of tumors. Viruses naturally possess the sizes, geometries, and physical properties for which the immune system has evolved to recognize, and mimicking those properties with nanoparticles can produce robust platforms for vaccine design. Using the nonviral E2 core of pyruvate dehydrogenase, we have engineered a viral-mimicking vaccine platform capable of encapsulating dendritic cell (DC)-activating CpG molecules in an acid-releasable manner and displaying MHC I-restricted SIINFEKL peptide epitopes. Encapsulated CpG activated bone marrow-derived DCs at a 25-fold lower concentration in vitro when delivered with the E2 nanoparticle than with unbound CpG alone. Combining CpG and SIINFEKL within a single multifunctional particle induced ∼3-fold greater SIINFEKL display on MHC I by DCs over unbound peptide. Importantly, combining CpG and SIINFEKL to the E2 nanoparticle for simultaneous temporal and spatial delivery to DCs showed increased and prolonged CD8 T cell activation, relative to free peptide or peptide-bound E2. By codelivering peptide epitopes and CpG activator in a particle of optimal DC-uptake size, we demonstrate the ability of a noninfectious protein nanoparticle to mimic viral properties and facilitate enhanced DC activation and cross-presentation.

Digital Metronomes and Metric Devices for Venous Ablation Procedures

Ultrasound-guided endovenous ablation procedures have revolutionized the care of patients with venous reflux disease for more than a decade. Precise application of energy forms and substances that occlude superficial truncal veins is pivotal for technical success. Exact spatial and temporal delivery of ablative vectors to the vein is operator dependent, readily measurable, and hinges on precise timing of pullback of the various catheters and fibers that effect vein ablation. Several physical and online electronic pullback timing aids, including metronomes and other metric devices, are available to ensure precise ablation, although operators are often left to discover them. Although these are not ultrasound devices per se, they are essential adjuncts for the effective delivery of a key ultrasound-guided intervention and are used in direct proximity to ultrasound. To the authors’ knowledge, there are no publications regarding this key ablation step, which is typically dependent on operator resourcefulness.