Preparation of Porous Hydroxyethyl Cellulose Materials to Utilize Lactic Acid with Vacuum-Assisted Process.

For the first time, we succeeded in manufacturing a 2-hydroxyethyl cellulose (HEC)-based composite membrane with improved thermal stability, for use as a battery separator, coating a HEC polymer solution to a polypropylene (PP) support and using a vacuum-assisted process. A HEC polymer solution was prepared by utilizing HEC and lactic acid (LA) as a plasticizer. A vacuum-assisted process was used to move ethanol, which a mobile phase to permeate a plasticized region in the HEC polymer side for pore formation. The pores formed with uniform nano sizes, and areas in which some large pores formed were observed. The thermal stability of the composites was measured using TGA. The thermal decomposition temperatures were measured at about 250 °C for the neat HEC, about 210 °C for the HEC/LA film, and about 335 °C for the HEC/LA/PP membrane before the process. After the vacuum-assisted process, the first and second thermal decomposition were observed at about 360 °C and 450 °C, respectively. The HEC/LA/PP membrane after the process showed greater thermal stability than before the process. This means that the adhesion between the HEC polymer and the PP support was created through the rearrangement of the HEC chain, as LA escaped after the process, and it was seen indirectly that the mechanical strength was enhanced. In particular, the surface of the membrane was observed by SEM to investigate whether the HEC penetrated into the PP to block its pores, and whether the HEC region collapsed. Furthermore, the interaction of the HEC chain with the additives and the rearrangement of the HEC was confirmed using FT-IR. As a result, we demonstrated that the mechanical strength and thermal stability of the manufactured HEC/LA/PP membrane were enhanced.

Towards Formulation of Highly Acidic Active Ingredients: Development of Clinically Effective Concentrated Trichloroacetic Acid Gel for Wart Management.

Common warts are benign skin lesions caused by the human papillomavirus. Although they are usually not harmful, they can cause pain, depending on their location. While many modalities are available for treatment of warts, none is a gold standard, and many are not affordable and/or have suboptimal outcomes. Trichloroacetic acid (TCA) is a chemical tissue-destroying agent used as a highly concentrated solution for wart management. While available and efficient, it is difficult to handle as the solution spreads to tissue surrounding the wart causing pain and burning. Hence, we developed a new polymer-based gel of high TCA content (100% w/v). Gels were formed successfully as hydroxyethyl cellulose (HEC) and chitosan were used to impart viscosity and bioadhesion. Formulae of different concentrations were tested for their physical properties, and the optimal formulation was selected for clinical evaluation. A combination of 3% HEC and 2% chitosan provided optimal viscosity and limited water content and have acceptable stability. The efficacy and safety of the biweekly application of TCA gel were evaluated in 30 patients. The clinical study revealed gel's efficacy and tolerability; half of the patients showed a complete cure, and 90% showed improvement within 6 weeks. Only 10-12% of the patients reported side effects. In summary, transforming TCA solution into a gel enabled its application and handling in a practical manner by physicians and patients alike, while maintaining its efficacy as a tissue-destroying agent. Moreover, it is economic and easy to apply, rendering it a promising formulation for similar conditions requiring controlled tissue ablation.

Ethyl Hydroxyethyl Cellulose-A Biocompatible Polymer Carrier in Blood.

The biocompatibility of carrier nanomaterials in blood is largely hampered by their activating or inhibiting role on the clotting system, which in many cases prevents safe intravascular application. Here, we characterized an aqueous colloidal ethyl hydroxyethyl cellulose (EHEC) solution and tested its effect on ex vivo clot formation, platelet aggregation, and activation by thromboelastometry, aggregometry, and flow cytometry. We compared the impact of EHEC solution on platelet aggregation with biocompatible materials used in transfusion medicine (the plasma expanders gelatin polysuccinate and hydroxyethyl starch). We demonstrate that the EHEC solution, in contrast to commercial products exhibiting Newtonian flow behavior, resembles the shear-thinning behavior of human blood. Similar to established nanomaterials that are considered biocompatible when added to blood, the EHEC exposure of resting platelets in platelet-rich plasma does not enhance tissue thromboplastin- or ellagic acid-induced blood clotting, or platelet aggregation or activation, as measured by integrin αIIbß3 activation and P-selectin exposure. Furthermore, the addition of EHEC solution to adenosine diphosphate (ADP)-stimulated platelet-rich plasma does not affect the platelet aggregation induced by this agonist. Overall, our results suggest that EHEC may be suitable as a biocompatible carrier material in blood circulation and for applications in flow-dependent diagnostics.

Exploring the gelation of aqueous cellulose nanocrystals (CNCs)-hydroxyethyl cellulose (HEC) mixtures.

We investigated the gelation and microstructure of cellulose nanocrystals (CNCs) in nonionic hydroxyethyl cellulose (HEC) solutions. Cellulose nanocrystals (CNCs) with a particle length of 90 nm and width of 8 nm currently produced by acid hydrolysis of wood pulp were used in this study. The microstructures of CNCs/polymer suspensions were investigated by performing linear small amplitude oscillatory shear (SAOS) and nonlinear large amplitude oscillatory shear (LAOS), in addition to constructing CNCs phase diagrams and measuring steady-state shear viscosities. Significant viscosity increases at low shear rates coupled with high shear thinning behaviors were observed in CNCs in HEC solutions above the overlapping concentration of HEC. The physical strength of CNCs/HEC solution gels increased with the increase in CNCs concentration and resembled the weakly crosslinked gels according to the scaling of linear dynamic mechanical experiments. According to LAOS analysis, CNCs/HEC mixtures showed type III behavior with intercycle stress softening, while the samples showed stress stiffening in single cycles.

Separation of subcellular fluorescent microspheres by capillary electrophoresis.

Fluorescent microspheres (FMs) are widely employed in diagnostics and life sciences research; here, we investigated the effect of capillary coating, polymer concentration, electric field strength, and sample concentration on the separation performance of 1.0 µm FMs in hydroxyethyl cellulose (HEC) by capillary electrophoresis (CE). Results showed that (1) capillary coating could enhance the fluorescence signal. (2) For HEC with the same molecular weight, the higher HEC concentration is, the later the first peak appears in the electropherogram. (3) When FMs are diluted, increasing the electric field strength can enhance the migration speed and reduce the aggregation of FMs. (4) The number of FMs calculated is close to the theoretical value when it is diluted 10,000 times. The optimum conditions for CE were as follows: 6 cm/8 cm of effective length and total length of the coated capillary, 0.3% HEC (1300 k), and 300 V/cm of electric field strength. Such a study is helpful for the development of a FM counting system. Graphical abstract.

Hydration/Dehydration Behavior of Hydroxyethyl Cellulose Ether in Aqueous Solution.

Hydroxyethyl cellulose (HeC) maintains high water solubility over a wide temperature range even in a high temperature region where other nonionic chemically modified cellulose ethers, such as methyl cellulose (MC) and hydroxypropylmethyl cellulose (HpMC), demonstrate cloud points. In order to clarify the reason for the high solubility of HeC, the temperature dependence of the hydration number per glucopyranose unit, nH, for the HeC samples was examined by using extremely high frequency dielectric spectrum measuring techniques up to 50 GHz over a temperature range from 10 to 70 °C. HeC samples with a molar substitution number (MS) per glucopyranose unit by hydroxyethyl groups ranging from 1.3 to 3.6 were examined in this study. All HeC samples dissolve into water over the examined temperature range and did not show their cloud points. The value of nH for the HeC sample possessing the MS of 1.3 was 14 at 20 °C and decreased gently with increasing temperature and declined to 10 at 70 °C. The nH values of the HeC samples are substantially larger than the minimum critical nH value of ca. 5 necessary to be dissolved into water for cellulose ethers such as MC and HpMC, even in a high temperature range. Then, the HeC molecules possess water solubility over the wide temperature range. The temperature dependence of nH for the HeC samples and triethyleneglycol, which is a model compound for substitution groups of HeC, is gentle and they are similar to each other. This observation strongly suggests that the hydration/dehydration behavior of the HeC samples was essentially controlled by that of their substitution groups.

The use of design of experiments to develop hot melt extrudates for extended release of diclofenac sodium.

The effect of formulation and processing parameters on processability and release from hot-melt extrusion (HME)-based matrices appears to be API and polymer dependent. Accordingly, the aim of this work was to design an extended-release formulation of diclofenac sodium by using HME technique and design of experiment (DoE). The extrudates were prepared using a vertical lab-scale single screw extruder. A D-optimal design with 16 formulations was employed to evaluate and model the effect of diclofenac sodium, ethyl cellulose and Natrosol L levels on the release profile. The percentage of drug release at 2, 4, 8 and 16 h were the dependent variables. The formulation factors that affect drug release were identified and satisfactorily modeled. The goodness of fit (R2) and goodness of prediction (Q2) parameters obtained for release responses were 0.913 and 0.682 at 2 h, 0.946 and 0.67 at 4 h, 0.942 and 0.658 at 8 h, and 0.892 and 0.673 at 16 h, respectively. The design space of optimal fractions of ethyl cellulose and Natrosol L at various drug levels was successfully constructed by response surface methodology. In conclusion, the DoE approach helped to identify and quantify formulation variables that affect the release of diclofenac sodium from HME-based formulation.

Vaginal Gel Component Hydroxyethyl Cellulose Significantly Enhances the Infectivity of Chlamydia trachomatis Serovars D and E.

The transmission of the urogenital serovars of Chlamydia trachomatis can be significantly influenced by vaginal gels. Hydroxyethyl cellulose is a commonly used gelling agent that can be found in vaginal gels. Hydroxyethyl cellulose showed a concentration-dependent growth-enhancing effect on C. trachomatis serovars D and E, with a 26.1-fold maximal increase in vitro and a 2.57-fold increase in vivo.

Cutaneous small-vessel vasculitis following hysterosalpingo-foam sonography (HyFoSy).

We present a case of diffuse skin immune reaction, diagnosed as cutaneous small-vessel vasculitis, following assessment of tubal patency by contrast ultrasound, which appears to be the first reported case of hypersensitivity reaction to sonographic tubal patency testing, based on a literature search. A 32-year-old woman presented with non-thrombocytopenic palpable purpura the day after assessment of tubal patency by two-/three-dimensional hysterosalpingo-foam sonography (HyFoSy) using ExEm® Foam. During real-time ultrasound, the observer identified flow in only the right tube when using saline with air as contrast medium; however, the same observer identified flow in both tubes after injecting ExEm Foam and the woman left the clinic without any complications. The next day, the patient was admitted with a complaint of a red-purple skin rash noticed the same morning, associated with moderate leg pain. Slow-motion analysis of the recorded videos and three-dimensional ultrasound datasets showed previously unnoticed venous intravasation of ExEm Foam into the myometrial vessels. Palpable purpura is typically found in vasculitis as a result of extravasation of red cells outside the inflamed blood vessel. This previously unreported side effect of tubal patency testing by HyFoSy, its potential rare organ consequences, as well as unknown consequences of venous intravasation by foam, should be included in the informed consent prior to the examination. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Development of Dermal Films Containing Miconazole Nitrate.

This study aims to develop new antifungal dermal films based on their mechanical properties (elongation, adhesion, behaviour towards vapour moisture) and the in vitro availability of miconazole nitrate, used as a pharmaceutical active ingredient in various concentrations. The three polymeric films prepared were translucent or shiny, with the surface of 63.585 cm², 0.20⁻0.30 mm thickness, and content of miconazole nitrate of 3.931 or 15.726 mg·cm². The mechanical resistance and elongation tests demonstrated that the two films based on hydroxyethyl cellulose (HEC) polymer were more elastic than the one prepared with hydroxypropyl methylcellulose (HPMC). The vapour water absorption and vapour water loss capacity of the films revealed that the HPMC film did not dry very well in the process of preparation by the evaporation of the solvent technique, unlike the HEC films that jellified more evenly in water and had higher drying capacity at 40 °C. The in vitro availability of miconazole nitrate from dermal films was evaluated using the Franz diffusion cell method, through a synthetic membrane (Ø 25 mm × 0.45 µm) and acceptor media with pH 7.4 (phosphate buffer and sodium lauryl sulphate 0.045%), resulting a release rate of up to 70%.

Investigation of the stabilizing effects of hydroxyethyl cellulose on LDH during freeze drying and freeze thawing cycles.

The objective of this study was to investigate both the cryoprotective and lyoprotective effects of the polymer hydroxyethyl cellulose (HEC) on the model protein lactate dehydrogenase (LDH) during freeze thawing and freeze drying cycles. The effect of annealing on both protein stability and the physical state of HEC was evaluated. HEC was used as a sole excipient in the protein formulations, and its stabilizing was compared to that of other excipients which are commonly used in freeze dried protein formulations. Furthermore, other quality aspects of the freeze dried samples containing solely HEC were investigated, such as, reconstitution time and product elegance. Protein stability was evaluated functionally by measuring the activity recovery of the model protein LDH. The physical state of HEC after freeze drying was investigated and compared to this of other studied solutes using differential scanning calorimetry and X-ray powder diffractometry. HEC showed superior cryoprotective effects on LDH during freeze thawing, and considerable lyoprotective effects during the freeze drying process. Annealing had limited influence on the stabilizing effect of HEC. The extensive reconstitution times of the HEC lyophilisates could be greatly improved by incorporation of the surfactant Tween 80 into the formulations prior to freeze drying.

Safety aspects and side-effects of ExEm-gel and foam for uterine cavity distension and tubal patency testing.

A state-of-the-art overview of the safety and side-effects of ExEm-gel for uterine cavity distension and ExEm-foam for tubal patency testing is presented. A literature search was carried out using PubMed, textbooks, pharmaceutical databases and reports of toxicity tests. Information on clinical use in humans and experiments in animal models was collected and grouped according to the following components: glycerol, hydroxyethyl cellulose and purified water; subjects included toxicity test, influence on sperm cells, oocytes, blastocyst development, uterine cavity distension, tubal patency testing, pain and obstetric applications. No unknown side-effects of gel or foam, or unexpected concerns about safety, were reported. More information than expected was available on the absence of effects of the components on various human tissues. Although it is difficult to prove that the search is complete, and it is possible that side-effects remain unreported, the combination of glycerol, hydroxyethyl cellulose and purified water is considered to be safe for intrauterine application and tubal patency testing, indicating an optimal risk-benefit ratio in clinical use. The safest strategy, however, is to restrict clinical examinations with gel and foam to the pre-ovulatory phase of the menstrual cycle.

Measuring the Salt Content of Sweat inside a Sweat-Absorbing Skin Adhesive.

Biofluids contain a wealth of different biomarkers, and their concentrations are indicative of the state of the body. As one of those biofluids, sweat is easily accessible, and its composition can, for example, be related to particular diseases or sports performance. Due to the relatively low sweat flow rates, however, adequate sampling is paramount. Here, we aim to explore the potential use of sweat-absorbing skin adhesives as a sweat sampling system for wearable sensors with a simple construction. Upon absorption of sweat, the electrochemical properties of the skin adhesive are determined by the composition of sweat and the amount of sweat within the skin adhesive (i.e., hydration). Through the incorporation of two polarizable electrodes within the skin adhesive, its electrical properties can be monitored using impedance spectroscopy. Here, the double layer capacitance is used as an indicator of hydration, while the conductance depends on both the ion concentration and hydration (the mobility of ions). By evaluating the conductance as a function of hydration, the ion concentration within an electrolyte solution can be estimated. We demonstrate the concept based on a simple model sensor patch, which is exposed to electrolyte solutions containing various concentrations of NaCl and an artificial sweat solution. Finally, we show that ion concentrations in human sweat can be estimated when the model sensor patch is worn during exercise.

Oral Viscous Budesonide Solution for Enhanced Localized Treatment of Eosinophilic Esophagitis through Improved Mucoadhesion and Permeation.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus that is immune/antigen-mediated and often requires targeted treatment. In clinical practice, an oral viscous budesonide suspension prepared by adding sucralose to a budesonide suspension for inhalation (Pulmicort®) is used to treat adult EoE and enhance retention in the esophageal mucosa. Inspired by this off-label drug use, oral viscous budesonide solutions (OVBSs) were developed in this study, and their capacities for adhesion, permeation, and stability were explored. Given the insolubility of budesonide as a BCS II drug, we first evaluated its equilibrium solubility and found that Transcutol® HP was an excellent choice for creating an OVBS at a concentration of 0.2 mg/g. The rheological properties of the OVBSs were evaluated with a rheometer, and shear-thinning, which aids in swallowing, was observed. The addition of hydroxyethyl cellulose (HEC) increased the adhesion strength of the preparation, which was associated with the hydration and thickening mechanism. This result was confirmed in a dynamic gelation study and in vitro elution experiment conducted with porcine esophagus tissue. Furthermore, the permeabilities of the OVBSs in the porcine esophagus were evaluated with a Franz diffusion cell device. More than 80% of the budesonide was released after 24 hours, and the release profile was similar to that of the solution. To explore the storage conditions of OVBSs, critical factors such as pH, content, and impurities were determined. It was found that OVBSs exhibited different behaviors at different pH values and temperatures. Notably, the OVBSs containing 1.7% HEC could be stored for more than 6 months at a temperature of 5°C ± 3°C and a pH of 4.5 without significant degradation. Overall, this study demonstrated that OVBSs have the potential to adhere to the esophageal mucosa, permeate the tissue, and remain stable during storage. Moreover, OVBSs exhibit a distinct advantage over traditional converted inhalation-to-oral budesonide therapies by enabling flexible dose adjustment in clinical applications, thereby potentially minimizing systemic side effects commonly associated with oral glucocorticoid administration.

Time-temperature indicator of hydroxyethyl cellulose ink labels for assessing pork freshness.

Pork is widely consumed worldwide, and many consumers now utilize sensory evaluation techniques to determine the freshness of pork when buying it. A color-changing ink label utilizing bromocresol purple (BCP) and N-hydroxyphthalimide (NHPI) had been created to help consumers better and more rapidly determine the freshness of pork while it is stored. The ink was easy to prepare and could be readily transferred to A4 paper using screen printing technology. This study delved deeper into the impact of hydroxyethyl cellulose (HEC) on the functional properties of inks to enhance printing performance. The experiment demonstrated that a 1 % mass fraction of HEC improved thixotropy and facilitated the even distribution of ink on A4 paper, as confirmed by scanning electron microscopy. Screen-printed labels with varying concentrations displayed distinct color change rates when stored at different temperatures, indicating their capability to assess pork freshness. FT-IR, laboratory, and stability tests verified the ink's exceptional color change capabilities and printing attributes. An analysis using the Arrhenius equation revealed a substantial synergistic effect between BCP and NHPI, resulting in improved sensitivity and accuracy of the ink. This study offers a practical and feasible method to monitor the storage quality of pork effectively.

Reduction in Olfactory Discomfort in Inhabited Premises from Areas with Mofettas through Cellulosic Derivative-Polypropylene Hollow Fiber Composite Membranes.

Hydrogen sulfide is present in active or extinct volcanic areas (mofettas). The habitable premises in these areas are affected by the presence of hydrogen sulfide, which, even in low concentrations, gives off a bad to unbearable smell. If the living spaces considered are closed enclosures, then a system can be designed to reduce the concentration of hydrogen sulfide. This paper presents a membrane-based way to reduce the hydrogen sulfide concentration to acceptable limits using a cellulosic derivative-propylene hollow fiber-based composite membrane module. The cellulosic derivatives considered were: carboxymethyl-cellulose (NaCMC), P1; cellulose acetate (CA), P2; methyl 2-hydroxyethyl-cellulose (MHEC), P3; and hydroxyethyl-cellulose (HEC), P4. In the permeation module, hydrogen sulfide is captured with a solution of cadmium that forms cadmium sulfide, usable as a luminescent substance. The composite membranes were characterized by SEM, EDAX, FTIR, FTIR 2D maps, thermal analysis (TG and DSC), and from the perspective of hydrogen sulfide air removal performance. To determine the process performances, the variables were as follows: the nature of the cellulosic derivative-polypropylene hollow fiber composite membrane, the concentration of hydrogen sulfide in the polluted air, the flow rate of polluted air, and the pH of the cadmium nitrate solution. The pertraction efficiency was highest for the sodium carboxymethyl-cellulose (NaCMC)-polypropylene hollow fiber membrane, with a hydrogen sulfide concentration in the polluted air of 20 ppm, a polluted air flow rate (QH2S) of 50 L/min, and a pH of 2 and 4. The hydrogen sulfide flux rates, for membrane P1, fall between 0.25 × 10-7 mol·m2·s-1 for the values of QH2S = 150 L/min, CH2S = 20 ppm, and pH = 2 and 0.67 × 10-7 mol·m-2·s-1 for the values of QH2S = 50 L/min, CH2S = 60 ppm, and pH = 2. The paper proposes a simple air purification system containing hydrogen sulfide, using a module with composite cellulosic derivative-polypropylene hollow fiber membranes.

Antimicrobial Hydroxyethyl-Cellulose-Based Composite Films with Zinc Oxide and Mesoporous Silica Loaded with Cinnamon Essential Oil.

Background: Cellulose derivatives are gaining much attention in medical research due to their excellent properties such as biocompatibility, hydrophilicity, non-toxicity, sustainability, and low cost. Unfortunately, cellulose does not exhibit antimicrobial activity. However, derivatives like hydroxyethyl cellulose represent a proper matrix to incorporate antimicrobial agents with beneficial therapeutic effects. Methods: Combining more antimicrobial agents into a single composite material can induce stronger antibacterial activity by synergism. Results: Therefore, we have obtained a hydroxyethyl-cellulose-based material loaded with zinc oxide nanoparticles and cinnamon essential oil as the antimicrobial agents. The cinnamon essential oil was loaded in mesoporous silica particles to control its release. Conclusions: The composite films demonstrated high antibacterial activity against Staphylococcus aureus and Escherichia coli strains, impairing the bacterial cells' viability and biofilm development. Such antimicrobial films can be used in various biomedical applications such as topical dressings or as packaging for the food industry.

Preparation and optimization of grafted hydroxyethyl cellulose, polypyrrole, and nitrogen-doped carbon quantum dots bionanocomposites for electrical, optical, and photoluminescence multicoloring applications.

The major objective of this research revolves around the integration of polypyrrole (PPy) and various concentrations of nitrogen-doped carbon quantum dots (N-CQDs) into a polyacrylamide (PAm)-grafted hydroxyethyl cellulose (gHEC) to produce gHEC@PPy@N-CQDs bionanocomposites that possess environmentally sustainable properties. The intercalation and uniform distribution of N-CQDs inside the gHEC@PPy matrix have been demonstrated through the analysis of data obtained from X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). The samples underwent analysis using thermogravimetric analysis (TGA and DTG) as well as scanning and transmission electron microscopy. The improved dispersion of PPy and 4 % N-CQDs inside the matrix led to enhanced electrical characteristics of the graphene-hybridized metal bionanocomposite. The peculiar optical and photoluminescence emission observed in the gHEC@PPy@N-CQDs bionanocomposites can be attributed to the surface groups of N-CQDs and the transition between CN and CN. This hypothesis suggests that these factors play a significant role in determining the observed optical properties. The main goal is to identify distinctive and captivating applications for these bionanocomposites across several domains, including electronics, optical and light-emitting devices with a broad spectrum of colors, and bioimaging applications.

Electric-field-sensitive hydrogel based on pineapple peel oxidized hydroxyethyl cellulose/gelatin/Hericium erinaceus residues chitosan and its study in curcumin delivery.

This study focused on synthesis of innovative hydrogels with electric field response from modified pineapple peel cellulose and hericium erinaceus chitosan and gelatin based on Schiff base reaction. A series of hydrogels were prepared by oxidized hydroxyethyl cellulose, gelatin and chitosan at different deacetylation degree via mild Schiff base reaction. Subsequently experiments towards the characterization of oxidized hydroxyethyl cellulose/gelatin/chitosan (OHGCS) hydrogel polymers were carried out by FTIR/XRD/XPS, swelling performances and electric response properties. The prepared hydrogels exhibited stable and reversible bending behaviors under repeated on-off switching of electric fields, affected by ionic strength, electric voltage and pH changes. The swelling ratio of OHGCS hydrogels was found reduced as deacetylation degree increasing and reached the maximum ratio âˆ¼ 2250 % for OHGCS-1. In vitro drug releasing study showed the both curcumin loading capacity and release amount of Cur-OHGCS hydrogels arrived about 90 % during 6 h. Antioxidation assessments showed that the curcumin-loaded hydrogels had good antioxidation activities, in which, 10 mg Cur-OHGCS-1 hydrogel could reach to the maximum of about 90 % DPPH scavenging ratio. These results indicate the OHGCS hydrogels have potentials in sensor and drug delivery system.