Passive Delivery Research Articles

Iontosomes: Electroresponsive Liposomes for Topical Iontophoretic Delivery of Chemotherapeutics to the Buccal Mucosa

The targeted local delivery of anticancer therapeutics offers an alternative to systemic chemotherapy for oral cancers not amenable to surgical excision. However, epithelial barrier function can pose a challenge to their passive topical delivery. The charged, deformable liposomes—“iontosomes”—described here are able to overcome the buccal mucosal barrier via a combination of the electrical potential gradient imposed by iontophoresis and their shape-deforming characteristics. Two chemotherapeutic agents with very different physicochemical properties, cisplatin (CDDP) and docetaxel (DTX), were co-encapsulated in cationic iontosomes comprising 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and Lipoid-S75. The entrapment of CDDP was improved by formulating it in anionic reverse micelles of dipalmitoyl-sn-glycero-3-phospho-rac-glycerol sodium (DPPG) prior to loading in the iontosomes. Cryo-TEM imaging clearly demonstrated the iontosomes’ electroresponsive shape-deformable properties. The in vitro transport study using porcine mucosa indicated that iontosomes did not enter the mucosa without an external driving force. However, anodal iontophoresis resulted in significant amounts of co-encapsulated CDDP and DTX being deposited in the buccal mucosa; e.g., after current application for 10 min, the deposition of CDDP and DTX was 13.54 ± 1.78 and 10.75 ± 1.75 μg/cm2 cf. 0.20 ± 0.07 and 0.19 ± 0.09 μg/cm2 for the passive controls—i.e., 67.7- and 56.6-fold increases—without any noticeable increase in their transmucosal permeation. Confocal microscopy confirmed that the iontosomes penetrated the mucosa through the intercellular spaces and that the penetration depth could be controlled by varying the duration of current application. Overall, the results suggest that the combination of topical iontophoresis with a suitable nanocarrier system can be used to deliver multiple “physicochemically incompatible” chemotherapeutics selectively to oral cancers while decreasing the extent of systemic absorption and the associated risk of side effects.

Topical and transdermal delivery with diseased human skin: passive and iontophoretic delivery of hydrocortisone into psoriatic and eczematous skin.

Psoriasis and atopic dermatitis (eczema) are both common immune-mediated inflammatory skin diseases associated with changes in skin's stratum corneum lipid structure and barrier functionality. The present study aimed to investigate healthy, eczematous, and psoriatic excised human tissue for the effect of non-infectious skin diseases on skin characteristics (surface color, pH, transepidermal water loss, electrical resistance, and histology), as well as on permeation and retention profile of hydrocortisone. Further, differences in percutaneous absorption on application of iontophoresis on healthy and diseased skin were also investigated. Measurements of transepidermal water loss and electrical resistance showed a significant difference in psoriasis skin samples indicating a damaged barrier function. In vitro permeation studies on full-thickness human skin using vertical diffusion cells further confirmed these results as the drug amount retained in the psoriatic tissue was significantly higher when compared with the other groups. Despite no significant difference, the presence of the drug in the receptor chamber in both diseased groups can be concerning as it suggests the increased possibility of systemic absorption and adverse reactions associated with it in the use of topical corticosteroids. Application of anodal iontophoresis resulted in greater distribution of hydrocortisone into deeper layers of skin and the receptor chamber, in comparison to passive permeation. However, no significant differences were observed due to the healthy or diseased condition of skin.

Layer-by-Layer assembled nano-drug delivery systems for cancer treatment

Nano-drug delivery systems (NDDS) are functional drug-loaded nanocarriers widely applied in cancer therapy. Recently, layer-by-layer (LbL) assembled NDDS have been demonstrated as one of the most promising platforms in delivery of anticancer therapeutics. Here, a brief review of the LbL assembled NDDS for cancer treatment is presented. The fundamentals of the LbL assembled NDDS are first interpreted with an emphasis on the formation mechanisms. Afterwards, the tailored encapsulation of anticancer therapeutics in LbL assembled NDDS are summarized. The state-of-art targeted delivery of LbL assembled NDDS, with special attention to the elaborately control over the passive and active targeting delivery, are represented. Then the controlled release of LbL assembled NDDS with various stimulus responsiveness are systematically reviewed. Finally, conclusions and perspectives on further advancing the LbL assembled NDDS toward more powerful and versatile platforms for cancer therapy are discussed.

A nano-biomimetic transformation system enables in planta expression of a reporter gene in mature plants and seeds.

Plant genetic engineering will be essential to decipher the genomic basis of complex traits, optimize crop genomics, and enable plant-based production of recombinant proteins. However, established plant transformation approaches for bioengineering are fraught with limitations. Although nanoparticle-mediated methods show great promise for advancing plant biotechnology, many engineered nanomaterials can have cytotoxic and ecological effects. Here, we demonstrate the efficient uptake of a nano-biomimetic carrier of plasmid DNA and transient expression of a reporter gene in leaves of Arabidopsis, common ice plant and tobacco, as well as in the developing seed tissues of Arabidopsis, field mustard, barley, and wheat. The nano-biomimetic transformation system described here has all the advantages of other nanoparticle-mediated approaches for passive delivery of genetic cargo into a variety of plant species and is also nontoxic to cells and to the environment for diverse biotechnological applications in plant biology and crop science.

Microwave-triggered/HSP-targeted gold nano-system for triple-negative breast cancer photothermal therapy.

Due to the lack of effective therapeutic targets and the passive delivery of a limited quantity of nanoparticles to the tumors, the photothermal conversion agents used in photothermal therapy (PTT) have not been effective in treating triple-negative breast cancer (TNBC). As a result, there is a need to improve the tumor-targeting ability of these photothermal conversion agents. To address this, a microwave-triggered heat shock protein (HSP)-targeted gold nano-system (cmHSP-AuNC), with a gold nanocage (AuNC) as a photothermal conversion agent and anti-HSP monoclonal antibody (cmHSP) as a targeting ligand, was fabricated. cmHSP-AuNC was characterized based on morphology, particle size, zeta potentials, absorption spectrum, and photothermal conversion ability. The expression of HSP70 in 4T1 cells after microwave irradiation was verified by western blotting, and the optimal treatment conditions to achieve the highest expression were determined. Both in vitro and in vivo results indicated that the induction through microwave irradiation could effectively activate the HSP70 overexpression in TNBC, thereby significantly improving the targeting ability, tumor accumulation and anti-tumor efficacy of cmHSP-AuNC. This study proposes a promising strategy for improving the targeting ability and therapeutic efficacy of PTT.

Light/gas cascade-propelled Janus micromotors that actively overcome sequential and multi-staged biological barriers for precise drug delivery

Passive diffusion-based drug delivery systems have indeed shown impressive performance to overcome a cascade of biological barriers, but the delivery efficiency is still modest. Although artificial micro/nanomotors are capable of autonomous movement, oriented navigation and seeking target actively represent an alternative and attractive strategy to revolutionize drug delivery patterns potentially, the separated and single propulsion mode of motors still hampers their further biomedical application that needs to overcome successive biological barriers. Herein, we demonstrated a cascaded NIR-light/gas-driven Janus calcium carbonate particle micromotors (JCPMs) to overcome multi-staged biological barriers and achieved active drug delivery. These JCPMs exhibited NIR light-driven thermophoretic motion with precisely steered start/stop switch, speed, and motion trajectory in biological media and displayed CO2-bubbles-powered autonomous propulsion in an acidic environment. With the collaborative use of cascaded light/gas double-mode driving, JCPMs displayed a multistage self-adapted strategy to overcome sequential biological barriers during tumor-targeted drug delivery in a cascaded manner, involving of light-driven active tumor cells seeking, facilitated tumor penetration and cellular membranes traversal by virtue of photo-thermomechanical force and self-thermophoretic propulsion, gas-driven lysosomes escape and intracellular drug release successively. Such a strategy guaranteed trajectory-controllable active drug delivery to exert the selective tumor therapeutic effect as well as avoided side effects. We envisioned that the proposed cascaded driving mode of micromotors for traversing biological barriers would boost the delivery efficiency for tumor treatment, which may pave a convenient and versatile way to develop next generation active vehicles in the biomedical field.

Besifloxacin liposomes with positively charged additives for an improved topical ocular delivery

Topical ophthalmic antibiotics show low efficacy due to the well-known physiological defense mechanisms of the eye, which prevents the penetration of exogenous substances. Here, we aimed to incorporate besifloxacin into liposomes containing amines as positively charged additives and to evaluate the influence of this charge on drug delivery in two situations: (i) iontophoretic and (ii) passive treatments. Hypothesis are (i) charge might enhance the electromigration component upon current application improving penetration efficiency for a burst drug delivery, and (ii) positive charge might prolong formulation residence time, hence drug penetration. Liposomes elaborated with phosphatidylcholine (LP PC) or phosphatidylcholine and spermine (LP PC: SPM) were stable under storage at 6 ºC for 30 days, showed mucoadhesive characteristics, and were non-irritant, according to HET-CAM tests. Electron paramagnetic resonance spectroscopy measurements showed that neither the drug nor spermine incorporations produced evident alterations in the fluidity of the liposome's membranes, which retained their structural stability even under iontophoretic conditions. Mean diameter and zeta potential were 177.2 ± 2.7 nm and − 5.7 ± 0.3 mV, respectively, for LP PC; and 175.4 ± 1.9 nm and + 19.5 ± 1.0 mV, respectively, for LP PC:SPM. The minimal inhibitory concentration (MIC) and the minimal bactericide concentration (MBC) of the liposomes for P. aeruginosa showed values lower than the commercial formulation (Besivance). Nevertheless, both formulations presented a similar increase in permeability upon the electric current application. Hence, liposome charge incorporation did not prove to be additionally advantageous for iontophoretic therapy. Passive drug penetration was evaluated through a novel in vitro ocular model that simulates the lacrimal flow and challenges the formulation resistance in the passive delivery situation. As expected, LP PC: SPM showed higher permeation than the control (Besivance). In conclusion, besifloxacin incorporation into positively charged liposomes improved passive topical delivery and can be a good strategy to improve topical ophthalmic treatments.

Transcending the Cutaneous Barrier Through Nanocarrier Exploration for Passive Delivery of Anti-hypertensive Drugs: A Critical Review.

Hypertension comes under the category of chronic disease, which requires long term treatment. Hypertension is usually treated by oral administration of various therapeutic agents. There are several limitations of the oral route, making pharmaceutical scientists to discover an alternative route for drug delivery. The transdermal route may be a better alternative as it shows various advantages like lack of first-pass effect and high patient compliance. The skin may act as a primary barrier for the transdermal delivery of anti-hypertensive drugs; therefore, new approaches are required to cross this barrier. Nanocarrier systems come under these new approaches to cross the skin barrier. Various nanocarrier systems explored for transdermal delivery of antihypertensive drugs are liposomes, elastic liposomes, ethosomes, transethosomes, oleic acid vesicles, niosomes, solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions/microemulsions, and carbon nanotubes. This review summarizes the potential of advanced nanocarrier systems for effective management of hypertension following the transdermal route. The entire literature search regarding the utility of nanocarrier systems in transdermal delivery of antihypertensive drugs was done by using Pubmed and Google Scholar. Nanocarrier systems are capable of reducing various drawbacks of conventional formulations of antihypertensive drugs like excessive first-pass effects, high dosing frequency, and toxicity promoting high patient compliance. However, the clinical efficacy determination of such nanocarrier systems is still a challenge and it will govern their presence in the global pharmaceutical market.

Raman suppression within the gain fiber of high-power fiber lasers.

We report the effective suppression of Raman emission in a monolithic ytterbium-doped fiber laser by the insertion of a chirped and tilted fiber Bragg grating (CTFBG) directly within the gain fiber of the laser. In comparison with a non-compensated filtered laser cavity for which the Raman threshold occurs at an output power of 1.54 kW, the insertion of a CTFBG within the gain medium leads to an increase in the Raman threshold by 260 W. We also demonstrate that the insertion of a CTFBG in between a laser cavity and a passive beam delivery fiber leads to an increase in the Raman threshold by 100 W with respect to the non-compensated case.

Field Evaluation of a Spatial Repellent Emanation Vest for Personal Protection Against Outdoor Biting Mosquitoes.

Exophilic vectors are an important contributor to residual malaria transmission. Wearable spatial repellents (SR) can potentially provide personal protection in early evening hours before people retire indoors. An SR prototype for passive delivery of transfluthrin (TFT) for protecting humans against nocturnal mosquitoes in Kanchanaburi, western Thailand, is evaluated. A plastic polyethylene terephthalate (PET) sheet (676 cm2) treated with 55-mg TFT (TFT-PET), attached to the back of short-sleeve vest worn by human collector, was evaluated under semifield and outdoor conditions. Field-caught, nonblood-fed female Anopheles minimus s.l. were released in a 40 m length, semifield screened enclosure. Two collectors positioned at opposite ends conducted 12-h human-landing collections (HLC). The outdoor experiment was conducted between treatments among four collectors at four equidistant positions who performed HLC. Both trials were conducted for 30 consecutive nights. TFT-PET provided 67% greater protection (P < 0.001) for 12 h compared with unprotected control, a threefold reduction in the attack. In outdoor trials, TFT-PET provided only 16% protection against An. harrisoni Harbach & Manguin (Diptera: Culicidae) compared with unprotected collector (P = 0.0213). The TFT-PET vest reduced nonanophelines landing by 1.4-fold compared with the PET control with a 29% protective efficacy. These findings suggest that TFT-PET had diminished protective efficacy in an open field environment. Nonetheless, the concept of a wearable TFT emanatory device has the potential for protecting against outdoor biting mosquitoes. Further development of portable SR tools is required, active ingredient selection and dose optimization, and more suitable device design and materials for advancing product feasibility.

Generation of a cost-effective cell line for support of high-throughput isolation of primary human B cells and monoclonal neutralizing antibodies

The isolation of human monoclonal antibodies (mAbs) arising from natural infection with human pathogens has proven to be a powerful technology, facilitating the understanding of the host response to infection at a molecular level. mAbs can reveal sites of vulnerability on pathogens and illuminate the biological function of the antigenic targets. Moreover, mAbs have the potential to be used directly for therapeutic applications such as passive delivery to prevent infection in susceptible target populations, and as treatment of established infection. The isolation of antigen-specific B cells from vaccine trials can also assist in deciphering whether the desired B cells are being targeted by a given vaccine. Several different processes have been developed to isolate mAbs, but all are generally labor-intensive and result in varying degrees of efficiency. Here, we describe the development of a cost-effective feeder cell line that stably expresses CD40-ligand, interleukin-2 and interleukin-21. Sorting of single B cells onto a layer of irradiated feeder cells sustained antibody production that permits functional screening of secreted antibodies in a manner that enables subsequent recovery of B cells for recombinant antibody cloning. As a proof of concept, we show that this approach can be used to isolate B cells that secrete antibodies that neutralize human papilloma virus (HPV) from participants of an HPV vaccine study.

Iontophoretic Mediated Intraarticular Delivery of Deformable Liposomes of Diclofenac Sodium.

Topical therapy is ineffective in the case of Musculoskeletal Disorders (MSD) as it is not able to maintain therapeutic levels of the drug in the affected joint due to its inability to surpass the dermal circulation and penetrate into deeper tissues. One of the approaches to enhance deep tissue penetration of drugs is to increase drug delivery much above the dermal clearance. The objective of the present work was to formulate negatively charged Deformable Liposomes (DL) of Diclofenac Sodium (DS) using biosurfactants and target the same to the synovial fluid by application of iontophoresis. Deformable liposomes loaded with diclofenac sodium were formulated and characterized for surface morphology, particle size distribution, zeta potential and entrapment efficiency. In vitro permeation of the diclofenac from aqueous solution, conventional liposomes, and deformable liposomes under iontophoresis was performed using Franz diffusion cells and compared to passive control. Intraarticular microdialysis was carried out to determine the time course of drug concentration in the synovial fluid at the knee-joint region of the hind limb in Sprague Dawley rats. The vesicles were found to display a high entrapment (> 60%) and possess a negative zeta potential lower than -30 mV. The size of the vesicles was varied from 112.41 ± 1.42 nm and 154.6 ± 3.22 nm, demonstrated good stability on the application of iontophoresis. The iontophoretic flux values for the DS aqueous solution, conventional liposomes and deformable liposomal formulation were found to be 7.55 ± 0.42, 16.75±1.77and 44.01 ± 3.47 μg/ cm2 h-1, respectively. Deformable liposomes were found to display an enhancement of 5.83 fold compared to passive control. Iontophoresis was found to enhance the availability of DS deformable liposomes (0.56 ± 0.08 μg.h/ml) in the synovial fluid by nearly 2-fold over passive delivery (0.29 ± 0.05 μg.h/ml). Results obtained indicate that iontophoretic mediated transport of deformable liposomes could improve the regional bioavailability of diclofenac sodium to the synovial joints, an efficient mode for treating MSD in the elderly.

Modulated delivery of donepezil using a combination of skin microporation and iontophoresis.

The present study investigated the transdermal delivery of donepezil hydrochloride across dermatomed porcine ear skin using passive and physical enhancement techniques. In vitro permeation studies were performed on Franz diffusion cells. Microneedles were fabricated in the lab using a polymeric blend of polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP). The fabricated microneedles were characterized using SEM. Effect of PVA-PVP microneedles and ablative laser (P.L.E.A.S.E) alone, and in combination with anodal iontophoresis on the delivery of donepezil hydrochloride was investigated. Scanning electron microscopy, histology, methylene blue staining, and confocal laser microscopy were used to characterize the microchannels created in the skin. Permeation of donepezil after passive delivery was found to be 26.87±3.97µg/sq.cm. Microneedles, laser, and iontophoresis significantly increased the permeation to 282.23±8.28µg/sq.cm, 1562±231.8µg/sq.cm and 623.4±21.3µg/sq.cm. Also, a significantly higher permeation was achieved with microneedles and laser in combination with iontophoresis (1000±160.9µg/sq.cm and 1700.4±189.43µg/sq.cm respectively). A sharp increase in flux was observed with a combination of skin microporation and iontophoresis, however, the same was not observed for iontophoretic delivery alone. Thus, flux can be successfully tailored with a combination of skin microporation and iontophoresis to suit patient needs.

Stealth cross-linked polymeric nanoparticles for passive drug targeting: a combination of molecular docking and comprehensive in vitro assay

Till date, several studies have reported magnetic drug targeting as well as passive drug delivery. In this study, the passive characteristic of PEGylated carriers with a neutral surface charge rather than chitosan (CS)-based nanoparticles (NPs) with a positive charge was proved using molecular docking. The complete and without flaw stealth CS-coated magnetic NPs (mNPs) loaded with an anticancer drug for intravenous drug delivery were prepared using a modified ionic-crosslinking method. The physicochemical properties of the prepared magnetic-CS NPs were characterized in detail. The transmission electron micrographs of NPs showed an uniform particle morphology with an average diameter of smaller than 10 nm. The average IC50 values of the drug in PEGylated NPs for MCF-7 and PC-12 cells were 44 and 72 µM, respectively. The fabricated stealth NPs can increase the cytotoxicity and cell permeability of formulation that may release the entire drug in targeted shape to objective tissues that were firstly proved by molecular docking. This strategy showed a reduction in uptaking of mNPs by the reticuloendothelial system, which indeed increases the concentration of therapeutic agent(s) in the target site.

Beam characterisation studies of the 62MeV proton therapy beamline at the Clatterbridge Cancer Centre.

The Clatterbridge Cancer Centre (CCC) in the United Kingdom is the world's first hospital proton beam therapy facility, providing treatment for ocular cancers since 1989. A 62MeV beam of protons is produced by a Scanditronix cyclotron and transported through a passive delivery system. In addition to the long history of clinical use, the facility supports a wide programme of experimental work and as such, an accurate and reliable simulation model of the treatment beamline is highly valuable. However, as the facility has seen several changes to the accelerator and beamline over the years, a comprehensive study of the CCC beam dynamics is needed to firstly examine the beam optics. An extensive analysis was required to overcome facility related constraints to determine fundamental beamline parameters and define an optical lattice written with the Methodical Accelerator Design (MAD-X) and the particle tracking Beam Delivery Simulation (BDSIM) code. An optimised case is presented and simulated results of the optical functions, beam distribution, losses and the transverse rms beam sizes along the beamline are discussed. Corresponding optical and beam information was used in TOPAS to simulate transverse beam profiles and compared to EBT3 film measurements. We provide an overview of the magnetic components, beam transport, cyclotron, beam and treatment related parameters necessary for the development of a present day optical model of the facility. This work represents the first comprehensive study of the CCC facility to date, as a basis to determine input beam parameters to accurately simulate and completely characterise the beamline.

Nafion-Based Nanocarriers for Fluorine Magnetic Resonance Imaging.

The aim of our study was to develop a novel method for nanocarriers’ preparation as a fluorine magnetic resonance imaging (19F MRI)-detectable drug delivery system. The novelty of the proposed approach is based on the application of fluorinated polyelectrolyte Nafion as a contrast agent since typical MRI contrast agents are based on paramagnetic gadolinium or ferro/superparamagnetic iron oxide compounds. An advantage of using an 19F-based tracer comes from the fact that the 19F image is detected at a different resonance frequency than the 1H image. In addition, the close to zero natural concentration of 19F nuclei in the human body makes fluorine atoms a promising MRI marker without any natural background signal. That creates the opportunity to localize and identify only exogenous fluorinated compounds with 100% specificity. The nanocarriers were formed by the deposition of polyelectrolytes on nanoemulsion droplets via the layer-by-layer technique with the saturation approach. The polyelectrolyte multilayer shell was composed of Nafion, the fluorinated ionic polymer used for labeling by 19F nuclei, and poly-l-lysine (PLL). The surface of such prepared nanocarriers was further pegylated by adsorption of pegylated polyanion, poly-l-glutamic acid (PGA). The 19F MRI-detectable hydrophobic nanocarriers with an average size of 170 nm and a sufficient signal-to-noise ratio have been developed and optimized to be used for passive tumor targeting and drug delivery.

A thermosensitive textile-based drug delivery system for treating UVB-induced damage

Ultraviolet radiation is one of the most dangerous sources of damage to skin and causes sunburn, erythema, photoaging, and photocarcinogenesis. Some passive drug delivery systems (DDSs) have been developed to treat skin damage. Nevertheless, there have been few studies on the application of intelligent DDSs to enhance the treatment of sunburn. In this paper, thermosensitive microgels were prepared by porous CaCO3 infiltrated by a thermoresponsive polymer, which was synthesized by grafting carboxyl-terminated poly (N-vinylcaprolactam) (PVCL-COOH) onto hydrolyzed chitosan. By means of the pad-dry-cure method, microgels were attached to cotton fabrics to develop a medical textile for drug delivery. The results indicated that the microgels were deposited both on the fiber surface and in the space between the fibers. The loaded drug presented a thermoresponsive release profile, and the release mechanism also varied with temperature. After being treated with the medical textile, human keratinocyte HaCaT cells could be protected by inhibiting UVB-induced lactate dehydrogenase leakage and increasing the levels of superoxide dismutase and glutathione peroxidase (GSH-Px). Our study suggested that this thermosensitive microgel-finished cotton fabric can be used as an effective device for the treatment of UVB-induced damage.

Combinational Chemotherapy and Photothermal Therapy Using a Gold Nanorod Platform for Cancer Treatment

AbstractMultimodal approaches combined with various nanomaterials and advanced techniques have been developed for synergistic cancer treatment. Among various therapies, conventional chemotherapy (CHT) is a direct cancer treatment that can produce unintended side effects due to nonspecific action on both the tumor and normal cells; patient‐friendly photothermal therapy (PTT) may be able to treat embedded tumors in vital regions with minimal invasion but does not guarantee complete removal of cancers. However, the combination of CHT‐PTT may provide a promising tool for direct cancer treatment with minimal side effects. In this regard, nanostructured materials, such as gold nanorods with tuned size and surface characteristics, are key components designed to enhance the heating capacity and active or passive delivery of drugs to the tumor site. In this review, the pioneering work synergizing CHT and PTT is summarized, and the current state‐of‐the‐art in the development of inorganic and organic nanocomposites for combinational therapy is described.

Tissue Levels of Flurbiprofen in the Rat Plantar Heel after Short-Duration Topical Iontophoresis are Sufficient to Induce Pharmacodynamic Responses to Local Pain Stimuli.

The objective of this study was to investigate the topical iontophoresis of flurbiprofen (FBF) as a means to enhance its local bioavailability and thereby provide an improved and targeted treatment of plantar heel pain. Initial in vitro experiments using porcine ear skin investigated iontophoretic transport of FBF under different conditions. Local FBF biodistribution in the rat paw in vivo was compared after topical or oral administration. Efficacy of pain management was investigated using a plantar incisional model by evaluating pharmacodynamic responses to local pain stimuli. The results demonstrated that iontophoresis of FBF significantly increased cutaneous deposition and transdermal permeation of FBF as compared to passive delivery—it also enabled drug input to be controlled by modulation of current density and drug concentration (r2 > 0.99). Topical iontophoresis of FBF in vivo enabled higher drug levels in skin and muscle in rat plantar aspect and superior pharmacodynamic responses to local pain stimuli, in comparison to oral and passive delivery. In conclusion, short-duration topical iontophoresis of FBF may better help to relieve plantar heel pain than oral or passive administration, which should be of clinical interest.

Characterizing a novel in-situ oxygen delivery device for establishing controlled redox zonation within a high infiltration rate sequential biofilter

By applying favorable oxic and oligotrophic conditions through subsequent aeration and an additional infiltration step, the sequential managed aquifer recharge technology (SMART) was proven to better remove trace organic chemicals (TOrCs) than conventional MAR systems. To minimize the physical footprint, pumping costs and hydraulic retention times, as well as to overcome limitations of site-specific heterogeneities of such systems, the SMART concept was further upgraded by two main engineered technologies. This SMARTplus bioreactor is comprised of an infiltration trench and highly homogenous porous media to provide high infiltration rates and plug-flow conditions. Additionally, an in-situ oxygen delivery device, in particular a self-designed PDMS gas-liquid membrane contactor, was designed to establish favorable subsurface oxic conditions. This novel SMARTplus technology was investigated at pilot scale and is designed for advanced water treatment either in the context of water reuse or treatment of impaired surface water. To determine the design specifications and to construct a pilot-scale membrane contactor, the mass transfer coefficients of the PDMS membrane were investigated at lab-scale for varying Reynold numbers (0.2–2). With the help of the customized membrane contactor, homogenous, bubble-free and passive oxygen delivery could be successfully demonstrated at pilot-scale under laminar flow conditions and short contact times. Oxygen concentrations downstream of the membrane contactors met the design specifications (>1 mg/L) as long as the required feed water quality was provided. However, high NH4+ concentrations in the secondary effluent resulted in higher and unsteady oxygen demand than the target oxygen transfer rates could meet and suboxic conditions prevailed. Although a 20–50% enhancement in the removal of certain compounds (4-FAA, antipyrine, sulfamethoxazole, and citalopram) was achieved, demonstration of the full potential of enhanced TOrC removal by SMARTplus was hindered due to unsteady feed water quality.