Drug Delivery Studies Research Articles

Monitoring of silica colloidal crystal-embedded chitosan hydrogel films swelling and its drug release application

The hydrogels, because of their swelling properties in response to the environmental stimulus, are being widely considered for the design of controlled drug release systems. To meet the need for developing effective drug delivery methods, we developed special silica colloidal crystal (SCC)-embedded chitosan hydrogel films. The SCC films served as an interference substrate and drug storage layer, while the chitosan hydrogel served as a cover to regulate the drug release. The optical interferometry was performed to dynamically monitor the volume phase transition of chitosan hydrogel response to pH stimulation. Furthermore, the effects of crosslinking ratio and hydrogel thickness on the swelling properties of chitosan hydrogel were also evaluated. More importantly, the pH-responsive swelling of chitosan hydrogel was used to slowly release indomethacin. This system may provide support for drug delivery studies, therefore further expected to apply in the enhancement of the treatment efficiency of new drug therapies.

Harnessing Ultrasound for Targeting Drug Delivery to the Brain and Breaching the Blood-Brain Tumour Barrier.

Despite significant advances in developing drugs to treat brain tumours, achieving therapeutic concentrations of the drug at the tumour site remains a major challenge due to the presence of the blood–brain barrier (BBB). Several strategies have evolved to enhance brain delivery of chemotherapeutic agents to treat tumours; however, most approaches have several limitations which hinder their clinical utility. Promising studies indicate that ultrasound can penetrate the skull to target specific brain regions and transiently open the BBB, safely and reversibly, with a high degree of spatial and temporal specificity. In this review, we initially describe the basics of therapeutic ultrasound, then detail ultrasound-based drug delivery strategies to the brain and the mechanisms by which ultrasound can improve brain tumour therapy. We review pre-clinical and clinical findings from ultrasound-mediated BBB opening and drug delivery studies and outline current therapeutic ultrasound devices and technologies designed for this purpose.

Synthesis of albumin nanoparticles in a water-miscible ionic liquid system, and their applications for chlorambucil delivery to cancer cells

Serum albumin has been a preferred protein to generate biodegradable and non-toxic nanoparticles (NPs) for drug delivery applications. Different methods applied for the preparation of serum albumin NPs mostly used organic solvents. Here, we prepared serum albumin NPs in an ionic liquid (IL) system. ILs are considered to be green and designer solvents with unique properties that can replace organic solvents in the synthesis of albumin NPs. Bovine serum albumin (BSA) proteins dissolved in water were transformed into BSA NPs in a water/ Triton™X (TX-100), 1-butanol/1-butyl-3-methylimidazolium trifluoromethanesulfonate (BmimCF3SO3) microemulsion-like system by using a high-speed homogenizer and crosslinker glutaraldehyde. The obtained BSA NPs have been used in drug loading and release studies with a hydrophobic anticancer drug chlorambucil (Chl). Drug loading increased as increasing the ratio of Chl incubated with BSA NPs. Monitoring the drug release by UV–Vis spectroscopy revealed a burst release at first 4 h, but two-thirds of drugs stayed with NPs upon diffusion method. On the other hand, cellular uptake of Chl loaded BSA NPs caused a significant MCF7 breast cancer cell death, whereas free Chl and unloaded BSA NPs did not have a significant effect on the cell viability. Furthermore, in vivo toxicity assessment of BSA NPs obtained in the IL system was conducted in the zebrafish animal model. It showed that zebrafish body is able to eliminate BSA NPs without any toxic side effects and encapsulation of Chl into NPs reduced the toxicity of free Chl. In summary, we showed that BSA NPs with size smaller than 200 nm could be prepared in BmimCF3SO3 mediated system. They can be used for Chl loading (up to 6.9 wt%) with a sustainable release and they induce significant cell death in Chl sensitive cancer cells up to 45% in 24 h. These results indicate that BSA NPs could be prepared alternatively in IL systems and used in drug delivery studies.

In Vitro Permeation Studies on Carvedilol Containing Dissolving Microarray Patches Quantified Using a Rapid and Simple HPLC-UV Analytical Method

Analytical method validation is a vital element of drug formulation and delivery studies. Here, high-performance liquid chromatography in conjunction with UV detection (HPLC-UV) has been used to produce a straightforward, quick, yet sensitive analytical approach to quantify carvedilol (CAR). A C18 column was used to isolate the analyte from the mixture by isocratic elution with a mobile phase comprising a mixture of 0.1% v/v trifluoroacetic acid in water and acetonitrile in a ratio of 65:35 v/v at a flow rate of 0.6 mL min−1. Linearity was observed for CAR concentrations within the range of 1.5–50 μg mL−1 (R2 = 0.999) in phosphate buffer saline and within the range of 0.2–6.2 μg mL−1 (R2 = 0.9999) in methanol. The International Council on Harmonization (ICH) requirements were followed throughout the validation of the isocratic approach, rendering it specific, accurate, and precise. Moreover, robustness tests indicated that the method remained selective and specific despite small deliberate changes to environmental and operational factors. An efficient extraction procedure was also developed to extract and quantify CAR from excised neonatal porcine skin, resulting in recovery rates ranging from 95 to 97%. The methods reported here have been successfully utilised to evaluate CAR permeation, both transdermally and intradermally following application of a dissolving microarray patch (MAP) to excised neonatal porcine skin.Graphical

PH-Responsive Drug Delivery and Imaging Study of Hybrid Mesoporous Silica Nanoparticles.

A system of pH-responsive and imaging nanocarriers was developed using mesoporous silica nanoparticles (MSNs), in which gadolinium (Gd) was doped through in situ doping (Gd2O3@MSN). Sodium alginate (SA) was attached to the surfaces of the amino groups of MSNs (NH2-Gd2O3@MSN) through the electrostatic adsorption between the amino groups and the carboxyl groups with the formation of hybrid SA-Gd2O3@MSN nanoparticles (NPs). The SA-coated NPs were spherical or near-spherical in shape with an average size of nearly 83.2 ± 8.7 nm. The in vitro drug release experiments of a model rhodamine B (RhB) cargo were performed at different pH values. The result confirmed the pH-responsiveness of the nanocarriers. The results of the cytotoxicity studies indicated that the SA-Gd2O3@MSN NPs were not cytotoxic by themselves. The results of the in vivo safety evaluation and the hemolysis assay confirmed that the system is highly biocompatible. It is noteworthy that the T1 contrast of the system was significantly enhanced by the Gd, as indicated by the result of the MR imaging. This study confirms that the synthesized hybrid nanosystem is promising for pH-responsive drug delivery and MR imaging for cancer diagnosis and treatment.

Computational fluid dynamics and machine learning algorithms analysis of striking particle velocity magnitude, particle diameter, and impact time inside an acinar region of the human lung

Complementing computational fluid dynamics (CFD) simulations with machine learning algorithms is becoming increasingly popular as the combination reduces the computational time of the CFD simulations required for classifying, predicting, or optimizing the impact of geometrical and physical variables of a specific study. The main target of drug delivery studies is indicating the optimum particle diameter for targeting particular locations in the lung to achieve a desired therapeutic effect. In addition, the main goal of molecular dynamics studies is to investigate particle–lung interaction through given particle properties. Therefore, this study combines the two by numerically determining the optimum particle diameter required to obtain an ideal striking velocity magnitude (velocity at the time of striking the alveoli, i.e., deposition by sedimentation/diffusion) and impact time (time from release until deposition) inside an acinar part of the lung. At first, the striking velocity magnitudes and time for impact (two independent properties) of three different particle diameters (0.5, 1.5, and 5 μm) are computed using CFD simulations. Then, machine learning classifiers determine the particle diameter corresponding to these two independent properties. In this study, two cases are compared: A healthy acinus where a surfactant layer covers the inner surface of the alveoli providing low air–liquid surface tension values (10 mN/m), and a diseased acinus where only a water layer covers the surface causing high surface tension values (70 mN/m). In this study, the airflow velocity throughout the breathing cycle corresponds to a person with a respiratory rate of 13 breaths per minute and a volume flow rate of 6 l/min. Accurate machine learning results showed that all three particle diameters attain larger velocities and smaller impact times in a diseased acinus compared to a healthy one. In both cases, the 0.5-μm particles acquire the smallest velocities and longest impact times, while the 1.5-μm particles possess the largest velocities and shortest impact times.

A randomized comparative study of fractional carbon dioxide laser-assisted drug delivery with amorolfine versus amorolfine alone for the treatment of onychomycosis

Objective The study was done to compare the clinical efficacy rate, patient satisfaction, and side effects of fractional carbon dioxide (CO2) laser-assisted topical therapy with amorolfine versus amorolfine alone for the treatment of onychomycosis. Patients and methods In all, 100 patients were recruited for the study and were divided based on the lottery system into two groups. Group 1 (50 patients) received a combination of fractional CO2 laser and topical amorolfine (5%) and group 2 (n=50) received 5% amorolfine alone. The overall treatment efficacy was determined using clinical examination, onychoscopic pattern, and mycological clearance by comparing the infected area at baseline and 12 weeks after last treatment. Results Compared with group 2, clinical efficacy rate was significantly more in group 1 (22 vs. 0%, P<0.0001). Patient satisfaction rate was also higher in group 1 (64 vs. 6%, P<0.0001). Among the side-effects, mild pain was noted in group 1 with none in group 2 patients. Conclusion Fractional CO2 laser-assisted delivery of topical amorolfine (5%) therapy of onychomycosis showed a better clinical response than topical amorolfine (5%) alone. Fractional CO2 lasers may be explored further for use by standardizing the parameters and number of sessions to achieve better cure rates and thereby can replace systemic treatment.

Exploring ex vivo peptideolysis of thymopentin and lipid-based nanocarriers towards oral formulations

The oral delivery of medicines is the most popular route of administration for patients. However, thymopentin (TP5) is only available in the market in forms for parenteral administration. In large part, this is because of extensive peptidolytic degradation in the gastrointestinal tract (GIT), which decreases the amount of TP5 available for absorption. This study aims to understand the extent of TP5 peptideolysis and determine effective inhibitors and suitable lipid-based nanocarriers to aid in the development of an effective oral delivery formulation. Enzymatic degradation kinetics of TP5 was investigated in the presence or absence of mucosal and luminal components extracted from various parts of the rat intestine, including the duodenum, jejunum, ileum, and colon. Inhibition of TP5 enzymatic peptidolysis was screened in the presence or absence of EDTA, trypsin and chymotrypsin inhibitors from soybean (SBTCI), and bestatin. TP5 with SBTCI was loaded into lipid-based nanocarriers, including microemulsions, niosomes and solid lipid nanoparticles. These TP5-loaded nanocarriers were investigated through characterization of morphology, particle size, zeta potential, entrapment efficacy (EE%), and ex vivo rat intestinal degradation studies to select a lead formulation for a future oral drug delivery study. The degradation kinetics of TP5 followed pseudo-first-order kinetics, and the biological metabolism of TP5 was displayed in the presence of luminal contents, indicating that TP5 is sensitive to luminal enzymes. Notably, a considerable decrease in TP5 peptidolysis was found in the presence of SBTCI, bestatin, and EDTA. TP5 and SBTCI were loaded into three lipid-based delivery systems, displaying superior protection under ex vivo intestinal luminal contents and mucosal homogenates for 6 h compared with the pure drug solution. These findings suggest that using select inhibitors and lipid-based nanocarriers can decrease peptide degradation and may improve oral bioavailability of TP5 following oral administration.

Multi-Omics Uncover Neonatal Cecal Cell Development Potentials

Although, the cecum plays vital roles in absorption of water, electrolytes, and other small molecules, and harbors trillions of commensal bacteria to shape large intestine immune functions, it is unknown the cecum development potentials at single cell level during the very crucial neonatal developmental period. Using singe cell RNA-seq and proteomics, we have characterized six major types of cecal cells: undifferentiated cells; immune cells (Ims); cecumocytes (CCs); goblet, Paneth like cells (PLCs), and enteroendocrine cells (EECs) with specific markers. CCs mature with a gradual decrease in proportion of cells; however, Ims develop with a continuing increase in proportion of cells. Meanwhile, goblet and EEC cells reduced in proportion of cells from do to d14 or d21; PLCs increased in proportion of cells from d0 to d7 then decreased at d14 and d21. The cells exhibit specific development and maturation trends controlled by transcriptional factors, ligand-receptor pairs, and other factors. As piglets grow, cecal content and mucosal microbial diversity increases dramatically with population of beneficial microbiota, such as lactobacillus. Moreover, cecal mucosal-associated and cecal content microbiota are positively correlated and both show significant correlation with different types of cecal cells and plasma metabolites. This is the first presentation of neonatal cecal cell development and maturation naturally at single cell level with transcript, protein, microbiota and metabolism perspectives. Furthermore, this study provides an important tool for the determination of novel interventions in cecal drug delivery and metabolism studies.

Microfluidic Invasion Chemotaxis Platform for 3D Neurovascular Co-Culture

Advances in microfabrication and biomaterials have enabled the development of microfluidic chips for studying tissue and organ models. While these platforms have been developed primarily for modeling human diseases, they are also used to uncover cellular and molecular mechanisms through in vitro studies, especially in the neurovascular system, where physiological mechanisms and three-dimensional (3D) architecture are difficult to reconstruct via conventional assays. An extracellular matrix (ECM) model with a stable structure possessing the ability to mimic the natural extracellular environment of the cell efficiently is useful for tissue engineering applications. Conventionally used techniques for this purpose, for example, Matrigels, have drawbacks of owning complex fabrication procedures, in some cases not efficient enough in terms of functionality and expenses. Here, we proposed a fabrication protocol for a GelMA hydrogel, which has shown structural stability and the ability to imitate the natural environment of the cell accurately, inside a microfluidic chip utilizing co-culturing of two human cell lines. The chemical composition of the synthesized GelMA was identified by Fourier transform infrared spectrophotometry (FTIR), its surface morphology was observed by field emission electron microscopy (FESEM), and the structural properties were analyzed by atomic force microscopy (AFM). The swelling behavior of the hydrogel in the microfluidic chip was imaged, and its porosity was examined for 72 h by tracking cell localization using immunofluorescence. GelMA exhibited the desired biomechanical properties, and the viability of cells in both platforms was more than 80% for seven days. Furthermore, GelMA was a viable platform for 3D cell culture studies and was structurally stable over long periods, even when prepared by photopolymerization in a microfluidic platform. This work demonstrated a viable strategy to conduct co-culturing experiments as well as modeling invasion and migration events. This microfluidic assay may have application in drug delivery and dosage optimization studies.

Fabrication of Biologically Active Fish Bone Derived Hydroxyapatite and Montmorillonite Blended Sodium Alginate Composite for In-Vitro Drug Delivery Studies

Fishbone comprising hydroxyapatite (bio-ceramic) is regularly viewed as a natural resource for biological and pharmaceutical applications. In this study, hydroxyapatite has been prepared from fishbone waste using thermal calcination method. The composite hydroxyapatite–montmorillonite–sodium alginate was synthesized by co-precipitation method. Various functional groups of biocomposite were characterised using Fourier transform infrared spectroscopy. Thermal stability and crystallinity of biocomposite were analysed through thermal gravimetric analysis and X-ray diffraction studies respectively. The morphological surface of composites was studied using scanning electron microscopy. The synthesized composite was designed to study the enhanced biological potential such as antibacterial, antioxidant, antidiabetic, drug loading and the drug releasing ability. Antioxidant and anti-diabetic analysis of composite were studied using phosphomolybdenum and α-amylase inhibitory method respectively. The drug releasing ability of compounds (Doxorubicin and Curcumin) were investigated by UV–spectrophotometry method at different pH medium (pH = 5.5, 6.8 and 7.4). Additionally, in-vitro kinetic studies were carried out on composite to determine the drug releasing ability of doxorubicin and curcumin.Graphical Abstract

Glycopolymer-Functionalized MOF-808 Nanoparticles as a Cancer-Targeted Dual Drug Delivery System for Carboplatin and Floxuridine

Codelivery of chemotherapeutics via nanomaterials has attracted much attention over the last decades due to improved drug delivery to tumor tissues, decreased systemic effects, and increased therapeutic efficacies. High porosities, large pore volumes and surface areas, and tunable structures have positioned metal-organic frameworks (MOFs) as promising drug delivery systems (DDSs). In particular, nanoscale Zr-linked MOFs such as MOF-808 offer notable advantages for biomedical applications such as high porosity, good stability, and biocompatibility. In this study, we report efficient dual drug delivery of floxuridine (FUDR) and carboplatin (CARB) loaded in MOF-808 nanoparticles to cancer cells. The nanoparticles were further functionalized by a poly(acrylic acid-mannose acrylamide) (PAAMAM) glycopolymer coating to obtain a highly selective DDS in cancer cells and enhance the therapeutic efficacy of chemotherapy. While MOF-808 was found to enhance the individual therapeutic effects of FUDR and CARB toward cancerous cells, combining FUDR and CARB was seen to cause a synergistic effect, further enhancing the cytotoxicity of the free drugs. Enhancement of CARB loading and therefore cytotoxicity of the CARB-loaded MOFs could be induced through a modified activation protocol, while coating of MOF-808 with the PAAMAM glycopolymer increased the uptake of the nanoparticles in cancer cells used in the study and offered a particularly significant selective drug delivery with high cytotoxicity in HepG2 human hepatocellular carcinoma cells. These results show how the enhancement of cytotoxicity is possible through both nanovector delivery and synergistic treatment, and that MOF-808 is a viable candidate for future drug delivery studies.

Count- and mass-based dosimetry of MDI spray droplets with polydisperse and monodisperse size distributions

Most previous numerical studies of inhalation drug delivery used monodisperse aerosols or quantified deposition as the ratio of deposited particle number over the total number of released particles (i.e., count-based). These practices are reasonable when the aerosols have a sufficiently narrow size range. However, spray droplets from metered-dose inhalers (MDIs) are often polydisperse with a wide size range, so using monodisperse aerosols and/or count-based deposition quantification may lead to significant errors. The objective of this study was to develop a mass-based dosimetry method and evaluate its performance in lung delivery in a mouth-lung (G9) geometry with an albuterol-CFC inhaler. The conventional practices (monodisperse and polydisperse-count-based) were also simulated for comparison purposes. The MDI actuation in the open space was studied using both high-speed imaging and LES-Lagrangian simulations. Experimentally measured spray velocities and size distribution were implemented in the computational model as boundary conditions. Good agreement was achieved between recorded and simulated spray plume evolution spatially and temporally. The polydisperse-mass-based predictions of MDI doses compared favorably with the measurements in all three regions considered (device, mouth-throat, and lung). Significant errors in MDI regional deposition were predicted using the monodisperse and count-based methods. The new polydisperse-mass-based method also predicted local deposition hot spots that were one order of magnitude higher in intensity than the two conventional methods. The results of this study highlighted that a presentative polydisperse size distribution and appropriate deposition quantification method should be applied to reliably predict the MDI drug delivery in the human respiratory tract.

A Novel Capsule-Delivered Enteric Drug-Injection Device for Delivery of Systemic Biologics: A Pilot Study in a Porcine Model.

Innovative swallowable capsule technologies such as drug-loaded, dissolvable microneedles, mucoadhesive patches, and various microdevices present unique drug-carrying capabilities to overcome challenges regarding oral delivery of biologics. Here, we report a swallowable capsule for intestinal drug delivery (SCIDD) with the potential of directly injecting biological therapeutics into the insensate small intestine wall. The design, optimization, and validation of the SCIDD's primary subsystems were performed both ex-vivo and in-vivo. The assembled capsule was further tested in vivo to validate the actuation sequence and showed a 70% (n = 17) success rate in an animal model. Additionally, a drug delivery study indicated systemic uptake of adalimumab via SCIDD compared with luminal delivery in the small intestine. The pilot study presented here establishes that the novel platform could be used to orally deliver systemic biologics.

One-Year Clinical, Microbiological and Immunological Results of Local Doxycycline or Antimicrobial Photodynamic Therapy for Recurrent/Persisting Periodontal Pockets: A Randomized Clinical Trial.

We evaluated, in this study, the clinical, microbiological and immunological effects of local drug delivery (LDD) or photodynamic therapy (PDT), adjunctive to subgingival instrumentation (SI) in persistent or recurrent periodontal pockets in patients enrolled in supportive periodontal therapy (SPT) after one year. A total of 105 patients enrolled in SPT with persistent/recurrent pockets were randomly treated with SI +PDT or SI + LDD or SI (control). The number of treated sites with bleeding on probing (n BOP+), probing pocket depths (PPD), clinical attachment level (CAL), full-mouth plaque and bleeding scores (gingival bleeding index, %bleeding on probing-BOP) was evaluated at baseline and after 12 months. Additionally, eight periodontopathogens and the immunomarkers IL-1β (interleukin)and MMP-8 (matrix metalloprotease) were quantitatively determined using real-time PCR and ELISA, respectively. All three treatments resulted in statistically significant clinical improvements (p < 0.05) without statistically significant intergroup differences (p > 0.05), which were maintained up to 12 months. The presence of BOP negatively affected the PPD and CAL. Moreover, statistically significantly fewer bleeding sites at 12 months were observed in the test groups (p = 0.049). Several periodontopathogens were reduced after 12 months. In conclusion, the present data indicate that in periodontal patients enrolled in SPT, treatment of persistent/recurrent pockets with SI alone or combined with either PDT or LDD may lead to comparable clinical, microbiological and immunological improvements, which are maintained up to 12 months. Secondly, the presence of BOP directly impacts the PPD and CAL.

EXPLORING LIPID-BASED DRUG DELIVERY IN CANCER THERAPY VIA LIPOSOMAL FORMULATIONS

In many countries across the world, cancer is a leading cause of death. Cancer is the biggest cause of death worldwide, with approximately 10 million fatalities expected in 2020, accounting for nearly one in every six deaths. Mutations in ~300 human genes can unleash cell division, potentially leading to cancer. The effectiveness of existing conventional therapies for a number of cancers is, however, inefficient in terms of safety and efficacy. Medication systems based on lipid can be configured to treat tumors passively with increasing safety by reducing toxicity and increasing efficacy by target drug delivery. Lipid-based drug dosage form is the new identified technological design to overcome problems such as water-soluble solubility and bioavailability. A wide range of product specifications determined by indication of disease, route of administration, price evaluation, safety, toxicity, and efficiency could be customized to lipid formulations. This analysis explores the current state of lipid drug delivery studies, including the production of cancer liposomes, different cancer-focused strategies, and liposomal formulation of numerous anti-cancer drugs.

Spray characteristics from nasal spray atomization

In addition to topical delivery, nasal sprays offer an alternative drug administration route to the systemic circulation, therefore avoiding the need for painful, invasive delivery techniques. Studies on the efficacy of nasal drug delivery to date have been conflicting despite its potential. In particular computational studies, e.g. Computational Fluid Dynamics (CFD), of nasal spray deposition require realistic initial spray conditions, which are lacking in the literature. This study aims to provide benchmark experimental data for CFD inputs by characterizing four different types of commercially available nasal sprays used in an ENT (Ear Nose Throat) clinic. Spray characteristics were obtained via high-speed videography, while droplet size distribution (DSD) measurements were obtained with laser diffraction. Three actuation forces were evaluated, representing the use-case of an average adult, average child and the maximum force applied to the spray device. The results demonstrated that actuation force influenced spray velocity, spray duration, DSD, and breakup length. Quantitative data of Rosin–Rammler diameter distributions, spray cone angles, dispersion angles and breakup lengths were found, assisting computational models with realistic values, thereby improving future CFD studies of nasal spray drug delivery in the nasal cavity.

Ultrasound-enhanced drug delivery to spinal cord tumors

The blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) are major obstacles to the treatment of CNS diseases and disorders as they prevent the passage of most therapeutic agents from the blood pool to the CNS tissue. Transient, reversible opening of the BBB using ultrasound and microbubbles (MBs) has been extensively studied and has reached clinical investigations. Ultrasound and MBs can similarly modify the BSCB, although applications in the spinal cord have received less attention. We have previously demonstrated ultrasound and MB-mediated opening of the BSCB in rodents, as well as in large animals through the intact spine, using a spine-specific pulse scheme called short-burst phase keying (SBPK). In this talk, we will discuss our work evaluating treatment control approaches for controlling SBPK exposures and will present recent results from drug delivery studies in rodent models of primary and metastatic spinal cord tumors.

Quantifying the role of microstreaming in sonoporation

Cavitation microstreaming has been identified as an important mechanism underpinning sonoporation. The reported evidence includes experimental observation of the permeabilization of non-adherent cells or vesicles in microstreaming and theoretical and experimental estimates of the fluid shear stress required to induce pore formation in cell membranes and/or the activation of membrane components such as ion channels. The aim of this study was to assess the relative contribution of microstreaming to sonoporation observed in vitro with adherent cells, as commonly used in drug delivery studies. Streak velocimetry measurements were performed within a microfluidic cell of the microstreaming around a contrast agent microbubble driven at 0.5 and 1MHz and peak negative pressures up to 1MPa. The results suggest that, for the cell densities and microbubble concentrations typically reported in sonoporation studies, only a very small proportion of cells within a typical culture device would be exposed to sufficiently high shear stresses to be permeabilised. This finding is inconsistent with reported results for drug delivery efficiency and suggests that microstreaming may not be the dominant mechanism of sonoporation in this type of experiment.

Synergistic effect of chemical crosslinking and addition of graphene-oxide in Chitosan—Hydrogels, films, and drug delivery

We investigate the synergistic effect of chemical crosslinking by Glutaraldehyde (GA) and physical crosslinking induced by Graphene Oxide (GO) nanosheets addition on Chitosan (CH) to enhance the mechanical strength of CH hydrogels and their films. An increase in the [GA] and GO loading in CH hydrogels increase the G' (Storage Modulus) and τy(Yield Stress) values. The G' of 0.5 wt% GO incorporated 53 mM [GA] crosslinked CH hydrogel is 7.2 times greater than the 53 mM [GA] crosslinked CH hydrogel. The morphology studies by FESEM indicate that the porosity of CH-GA and CH-GO-GA hydrogels improves with an increase in the [GA] and GO loading. The CH-GO (0.1 wt%)-GA(35.3 mM) nanocomposite hydrogel film displays a higher Young's modulus than the pristine CH film by more than 20 times. Drug delivery studies carried on the tetracycline hydrochloride (TH) loaded films show a pH-responsive behavior where the drug elusion is higher at pH 4 than pH 7.4. Sustained drug delivery is observed in 0.1 wt% GO-loaded CH film crosslinked with [GA] = 35 mM. The GA crosslinking and GO nanosheets incorporation play a prominent role in reducing the burst release from the CH films.