Controlled Release Applications Research Articles

Fabrication of Multiresponsive Magnetic Nanocomposite Double‐Network Hydrogels for Controlled Release Applications (Small 52/2021)

Nanocomposite Double-Network Hydrogels A multi-responsive magnetic nanocomposite double-network hydrogel is developed for controlled protein delivery in article number 2105997 by Cheng-Hsun Lu and Yi-Cheun Yeh. Proteins are rapidly released from the hydrogel network at acidic pH and high temperature. This study provides a new strategy for hydrogel design to present multi-stimuli responsiveness for biomedical applications.

Fabrication of Multiresponsive Magnetic Nanocomposite Double-Network Hydrogels for Controlled Release Applications.

Nanocomposite double-network hydrogels (ncDN hydrogels) have been demonstrated as promising biomaterials to present several desired properties (e.g., high mechanical strength, stimuli-responsiveness, and local therapy) for biomedicine. Here, a new type of ncDN hydrogels featuring definable microstructures and properties as well as multistimuli responsiveness for controlled release applications is developed. Amine-functionalized iron oxide nanoparticles (IOPs_NH2 ) are used as nanoparticle cross-linkers to simultaneously connect the dual networks of gelatin (Gel) and polydextran aldehyde (PDA) through hydrogen bonding, electrostatic interactions, and dynamic imine bonds. The pH- and temperature-responsive Gel/PDA/IOP_NH2 ncDN hydrogels present a fast release profile of proteins at acidic pH and high temperature. Besides, IOP_NH2 also contributes the magnetic-responsiveness to the ncDN hydrogels, allowing the use of magnetic field to generate heat to facilitate the structural change of hydrogels and the subsequent applications. Taken together, a versatile ncDN hydrogel platform capable of multistimuli responsiveness and local heating for controlled release is developed for advanced biomedical applications.

4-Nitrophenol-Loaded Magnetic Mesoporous Silica Hybrid Materials for Spectrometric Aptasensing of Carcinoembryonic Antigen.

Aptamer- or antibody-based sensing protocols have been reported for detecting carcinoembryonic antigen (CEA), but most exhibit complicated procedures or multiple reactions. In this work, we developed a one-step aptasensing protocol for the spectrometric determination of CEA based on 4-nitrophenol (4-NP)-loaded magnetic mesoporous silica nanohybrids (MMSNs) for bioresponsive controlled-release applications. To fabricate such a responsive–controlled sensing system, single-stranded complementary oligonucleotides relative to the CEA-specific aptamer were first modified on the aminated MMSN. Thereafter, 4-NP molecules blocked the pores with the assistance of the aptamers via a hybridization reaction. The introduced target CEA specifically reacted with the hybridized aptamer, thus detaching from the MMSN to open the gate. The loaded 4-NP molecules were released from the pores, as determined using ultraviolet–visible (UV–vis) absorption spectroscopy after magnetic separation. Under optimum conditions, the absorbance increased with an increase in the target CEA in the sample and exhibited a good linear relationship within the dynamic range of 0.1–100 ng mL−1, with a detection limit of 46 pg mL−1. Moreover, this system also displayed high specificity, good reproducibility, and acceptable accuracy for analyzing human serum specimens, in comparison with a commercialized human CEA-enzyme-linked immunosorbent assay (ELISA) kit.

Effect of fabrication parameters on morphology and drug loading of polymer particles for rosiglitazone delivery

For the past several decades, drug-encapsulated polymer particles have been investigated as locally-delivered, long-acting therapies. The most common method of producing such particles is the oil in water solvent extraction technique. Using this technique, we produced poly(lactide-co-glycolide) (PLG) microparticles encapsulating rosiglitazone, a small molecule anti-diabetic drug. We investigated the impact of modulating fabrication parameters, including choice of organic solvent, concentration of polymer, and speed of homogenization and centrifugation on particle morphology and drug loading. Additionally, we studied the ratio of air-water-interface area to the extraction bath volume, a previously unstudied fabrication parameter, and its impact on rosiglitazone loading when using dichloromethane as the organic solvent. Under the conditions tested, drug loading can be increased 5-fold by increasing this ratio, which may be achieved by simply selecting a larger extraction vessel. By changing the organic solvent from dichloromethane to ethyl acetate, we produced particles with 60% higher rosiglitazone loading. Interestingly, the particles made with ethyl acetate appeared phase dark under light microscopy suggesting the presence of internal pores. By increasing the proportion of organic phase in the emulsion we eliminated the aberrant morphology but did not alter drug loading. As a final step in the development of the particles, we established that rosiglitazone remained stable throughout the encapsulation process and its subsequent release from particles by demonstrating that rosiglitazone loaded particles enhanced adipocyte lipid storage and adiponectin secretion. Taken together, for this system, air-water-interface area to volume ratio of the extraction bath and organic solvent both arose as key parameters in maximizing rosiglitazone loading in PLG microparticles. This study of how fabrication parameters impact drug loading and particle morphology may be useful in other investigations to encapsulate small molecules in polymer particles for controlled release applications.

Properties and Applications of Nanoparticles from Plant Proteins.

Nanoparticles from plant proteins are preferred over carbohydrates and synthetic polymeric-based materials for food, medical and other applications. In addition to their large availability and relatively low cost, plant proteins offer higher possibilities for surface modifications and functionalizing various biomolecules for specific applications. Plant proteins also avoid the immunogenic responses associated with the use of animal proteins. However, the sources of plant proteins are very diverse, and proteins from each source have distinct structures, properties and processing requirements. While proteins from corn (zein) and wheat (gliadin) are soluble in aqueous ethanol, most other plant proteins are insoluble in aqueous conditions. Apart from zein and gliadin nanoparticles (which are relatively easy to prepare), soy proteins, wheat glutenin and proteins from several legumes have been made into nanoparticles. The extraction of soluble proteins, hydrolyzing with alkali and acids, conjugation with other biopolymers, and newer techniques such as microfluidization and electrospraying have been adopted to develop plant protein nanoparticles. Solid, hollow, and core-shell nanoparticles with varying sizes and physical and chemical properties have been developed. Most plant protein nanoparticles have been used as carriers for drugs and as biomolecules for controlled release applications and for stabilizing food emulsions. This review provides an overview of the approaches used to prepare nanoparticles from plant proteins, and their properties and potential applications. The review’s specific focus is on the preparation methods and applications, rather than the properties of the proteins, which have been reported in detail in other publications.

The in vitro release features of 5-Fluorouracil from tablets with chitosan, soy protein extract and chitosan-soyprotein extract blend as carriers and their thermal degradation characteristics

Natural polymers are finding widespread applications in drug delivery, scaffold fabrication, bio plastic production, food packaging, wound dressing etc. due to their availability, biodegradability, biocompatibility, renewable nature, ease of modification to achieve the desirable properties etc. In the present study, the commercially available soy protein extract (SPE), chitosan(CSN) and their physical blend(CSN-SPE) have been chosen as drug carrier matrices to campare their in vitro drug release features in simulated intestinal fluid for controlled release applications taking 5-fluorouracil (5-FU) as a typical drug. The percentages of 5-FU released from the SPE, CSN and CSN-SPE tablets as a function of time were quantified by reverse phase High Performance Liquid Chromatography using KH2PO4 solution (pH 6.8) as the mobile phase and C-18 column as the stationery phase. The observed drug release features were found to be different for these polymer carriers. The percentages of drug released during the initial periods upto 60 min were less in the CSN-SPE tablet than those observed for CSN and SPE tablets. This implied that the drug release rate can be modified by the proper choice of natural polymers in the blends as carriers. The thermal degradation characteristics of CSN, SPE and CSN-SPE blend and their 5-FU tablets were also analysed by simultaneous Thermogravimetry (TG) and Differential Thermal Analysis (DTA). Comparative analysis of the TG and DTA traces of these polymers and their 5-FU tablets implied that there may be a drug-matrix interaction. This along with different degrees of swellability and degradability of these polymers might account for the differences in the drug release features. The structures of CSN, SPE and CSN-SPE blend were characterized by FT-IR spectroscopy.

Dual pH responsive via double - layered microencapsulation for controlled release of active ingredients in simulated gastrointestinal tract: A model case of chitosan-alginate microcapsules containing basil oil (Ocimum basilicum Linn.)

Phytogenic feed additives (PFAs) have gained more attention to replace antibiotic growth promoters (AGPs) in poultry industry. However, the efficiency of PEAs might be lost during feed pelleting, storage and gastrointestinal (GI) tract resulting in an insufficient level at the small intestine. The present work demonstrates the use of double-layered polymers with opposite charges leading to a dual pH responsiveness where the encapsulated ingredients are remained active through the acidic gastric stage and ready to be released at the intestine. Anionic sodium alginate (SA) and cationic chitosan (CS) are a good combination to represent double-layered polymer of which an effective incorporation of active ingredient, i.e. basil oil (BO), a model PEA, can be achieved. By simply fabricating SA porous microcapsules followed by the absorption of BO before the surface coating with CS, the double-layered microcapsules, CS-SA, are obtained. The release performances confirm that CS-SA retains the antioxidant and antimicrobial activities of BO under storage in addition to a great tolerance of acids, bile, trypsin, including the thermal conditions. The present work, for the first time, proposes the concept of porous double-layered polymer in microcapsule form which shows the dual pH responsive for controlled release application. The use of ionic polysaccharides is simple, biocompatible and environmentally friendly, whereas the plausible upscaling for wide range of controlled release applications has to be further investigated.

The usage of composite nanomaterials in biomedical engineering applications

Nanotechnology is still developing over the decades and it is commonly used in biomedical applications with the design of nanomaterials due to the several purposes. With the investigation of materials on the molecular level has increased the develop composite nanomaterials with exceptional properties using in different applications and industries. The application of these composite nanomaterials is widely used in the fields of textile, chemical, energy, defense industry, electronics, and biomedical engineering which is growing and developing on human health. Development of biosensors for the diagnosis of diseases, drug targeting and controlled release applications, medical implants and imaging techniques are the research topics of nanobiotechnology. In this review, overview of the development of nanotechnology and applications which is use of composite nanomaterials in biomedical engineering is provided.

Preparation of Monodispersed Nanoporous Eu(III)/Titania Loaded with Ibuprofen: Optimum Loading, Luminescence, and Sustained Release.

Functional nanomaterials are one of the potential carriers for drug delivery, whereas there are many prerequisites for this purpose. The carrier should be monodispersed, be fluorescent, and have a proper nanostructure to keep/release drug molecules to achieve controlled release, although preparing a nanomaterial which fulfills all the demands is still very challenging. In this paper, we show the preparation of monodispersed nanoporous amorphous titania submicron particles with fluorescent property. They adsorb a model drug molecule-ibuprofen-with their surface coverage up to 100%. Such a perfect loading does not decrease the fluorescent intensity because of any quenching effects but even maximize it. We also demonstrate the release behavior of IBU into simulated body fluid. Interestingly, the present carrier releases most of IBU in 6 h, whereas that modified with the polyethylene glycol moiety takes 48 h to finish releasing IBU, indicating its potential for controlled release applications.

Antimicrobial nanofibrous mats with controllable drug release produced from hydrophobized hyaluronan

Due to their large active surface, high loading efficiency, and tunable dissolution profiles, nanofibrous mats are often cited as promising drug carriers or antimicrobial membranes. Hyaluronic acid has outstanding biocompatibility, but it is hydrophilic. Nanofibrous structures made from hyaluronan dissolve immediately, making them unsuitable for controlled drug release and longer applications. We aimed to prepare a hyaluronan-based antimicrobial nanofibrous material, which would retain its integrity in aqueous environments. Self-supporting nanofibrous mats containing octenidine dihydrochloride or triclosan were produced by electrospinning from hydrophobized hyaluronan modified with a symmetric lauric acid anhydride. The nanofibrous mats required no cross-linking to be stable in PBS for 7 days. The encapsulation efficiency of antiseptics was nearly 100%. Minimal release of octenidine was observed, while up to 30% of triclosan was gradually released in 72 h. The nanofibrous materials exhibited antimicrobial activity, the fibroblast viability was directly dependent on the antiseptic content and its release.

Synthesis and Characterisation of Zinc Layered Hydroxide Intercalated with 2-Methyl-4- Chlorophenoxyacetic Acid and its Controlled Release Application

2-methyl-4-chlorophenoxyacetic acid (MCPA) is herbicide in group of phenoxyherbicides. It has been widely used in agriculture industry to control the weeds population especially thistle and dock. The toxicity of MCPA may impact the environment and harmful for living organisms especially human and aquatic life. This research aimed to intercalate MCPA herbicide with zinc layered hydroxide (ZLH) to form a composites (ZMCPA) and its controlled release properties. In this study, ZMCPA was prepared as an advanced delivery system by ion exchange method and further by hydrothermal treatment. The intercalations of zinc oxide were done with various MCPA concentration of 0.1 M, 0.3 M, 0.5 M, 0.7 M and 0.9 M. Intercalation performances were detected using powder X- ray diffraction (PXRD) and supported by Fourier Transform infrared spectroscopy (FTIR). The study for porosity of the composite was performed by BET analyzer. Among all of these concentrations, 0.5M represented the successful intercalation due to the presence of four sharp and intense harmonic peaks at 2θ with basal spacing of 24.6 Å, 12 Å, 8 Å and 6 Å, respectively. Herbicides release study was conducted in three salt solution, sodium chloride, sodium carbonate and sodium phosphate. Sustain release of MCPA was faster in sodium phosphate solution by 85%. This controlled release study was determined by UV-Vis spectrometry.

Fabrication, characterization and controlled release properties of yak casein cold-set gels

The casein cold-set gel was prepared from yak qula and the gel characterizations and embedding features were investigated by means of rheological property analysises, texture profile analysises, laser confocal microscopic observation, and in vitro simulated digestion experiment. The results showed that the hardness and elasticity of the gel were increased with the concentration of glucono-δ-lactone (GDL) and NaCl. Better water holding capacity (WHC) was observed in the gel with a lower concentration of GDL (1%) and NaCl (0.2M) than that with high concentration of GDL (2%) and NaCl (0.2M, 0.4M). GDL significantly affected the energy storage modulus (G’) and loss modulus (G”) values. Confocal laser scanning microscopy (CLSM) observations and fractal analysis further demonstrated that electrostatic interaction was the major force in the gel formation, which was characterized by reactive limited polymerization. The in vitro experiment on casein cold-set gel encapsulation of bioactive ingredient (Que) showed favorable encapsulation and controlled-release performance. In conclusion, Yak casein (YCN) cold-set gel would be an useful matrix for the application of encapsulation, protection, delivery and controlled-release of some bioactive components.

DNA-Scaffolded Disulfide Redox Network for Programming Drug-Delivery Kinetics.

In response to specific stimuli, dynamic covalent materials enable the generation of new structures by reversibly forming/breaking chemical bonds, thus showing great potential for application in controlled drug release. However, using dynamic covalent chemistry to program drug-delivery kinetics remains challenging. Herein, an in situ polymerization-generated DNA-scaffolded disulfide redox network (DdiSRN) is reported in which nucleic acids are used as a scaffold for dynamic disulfide bonds. The constructed DdiSRN allows selective release of loading cargos inside cancer cells in response to redox stimuli. Moreover, the density of disulfide bonds in network can be tuned by precise control over their position and number on DNA scaffolds. As a result, drug-delivery kinetics can be programmed with a half-life, t1/2 , decreasing from 8.3 to 4.4 h, thus facilitating keeping an adequate drug concentration within the therapeutic window. Both in vitro and in vivo studies confirm that co-delivery of DOX and siRNA in combination with fast drug release inside cells using this DdiSRN enhances the therapeutic effect on multidrug-resistant cancer. This nontrivial therapeutic platform enabling kinetic control provides a good paradigm for precision cancer medicine.

Zinc micronutrient-loaded carboxymethyl tamarind kernel gum-based superabsorbent hydrogels: controlled release and kinetics studies for agricultural applications

The novel zinc-loaded superabsorbent hydrogel (ZSAH) was synthesized through in situ incorporation of zinc micronutrient in carboxymethyl tamarind kernel gum cross-linked network. The synthesized ZSAH was characterized by FTIR, SEM, TGA, swelling studies, etc. and found to have good water absorption capacity (410 g/g in distilled water) and with entanglement of zinc with weak physical forces. The ZSAH thus synthesized was assessed for controlled release application in soil as well as water, to test its application in the field of agriculture. The ZSAH exhibited slow and steady release pattern of zinc with 55% release within 72 h in water, and 83% release within 80 days in soil. Under the release kinetics studies, Korsmeyer-Peppas model was found to be best explaining the zinc release pattern through ZSAH. The ZSAH followed Fickian mechanism for release and it was observed that the diffusion was independent of the structure of the polymeric network. The time for zinc release from ZSAH, predicted as per the Olson’s single exponential model, revealed significantly prolonged T99 (time for release of 99% Zn) in water (12.22 days) as also in soil (625 days). Hence, the novel synthesized ZSAH exhibited great potential as a zinc micronutrient delivery system in agriculture.

Fluidized bed spray-coating of enzyme in a cross-linked alginate matrix shell (CLAMshell)

One-step encapsulation of subtilisin by fluidized bed spray-coating in a cross-linked alginate matrix shell (CLAMshell) particle is introduced. The CLAMshell process maximizes process productivity, while simultaneously improving coating quality of spray-coated enzyme. Overall, higher spray rates were achieved with improved mechanical strength of the coating, significantly limiting attrition and suppressing surface damage. Incorporating the CLAMshell formulation improved the overall coating process compared to coatings of cargo-only by achieving a 40% faster spray rate and maintaining coating efficiencies above 90%, with aggregates and fines below 2% of the final product. Process interruptions for removing excessive fines obstructing the outlet filter were eliminated and filter fouling was minimized. Increased alginate content and combination with polyvinyl alcohol in the coating yielded the greatest mechanical strength with low attrition and minor particle damage. CLAMshell particles exhibited high coating integrity through delayed dissolution of the salt core in solution, indicating potential controlled release applications.

Swelling Behaviors of 3D Printed Hydrogel and Hydrogel-Microcarrier Composite Scaffolds.

The present study sought to demonstrate the swelling behavior of hydrogel-microcarrier composite constructs to inform their use in controlled release and tissue engineering applications. In this study, gelatin methacrylate (GelMA) and GelMA-gelatin microparticle (GMP) composite constructs were three-dimensionally printed, and their swelling and degradation behavior was evaluated over time and as a function of the degree of crosslinking of included GMPs. GelMA-only constructs and composite constructs loaded with GMPs crosslinked with 10 mM (GMP-10) or 40 mM (GMP-40) glutaraldehyde were swollen in phosphate-buffered saline for up to 28 days to evaluate changes in swelling and polymer loss. In addition, scaffold reswelling capacity was evaluated under five successive drying-rehydration cycles. All printed materials demonstrated shear thinning behavior, with microparticle additives significantly increasing viscosity relative to the GelMA-only solution. Swelling results demonstrated that for GelMA/GMP-10 and GelMA/GMP-40 scaffolds, fold and volumetric swelling were statistically higher and lower, respectively, than for GelMA-only scaffolds after 28 days, and the volumetric swelling of GelMA and GelMA/GMP-40 scaffolds decreased over time. After 5 drying-rehydration cycles, GelMA scaffolds demonstrated higher fold swelling than both GMP groups while also showing lower volumetric swelling than GMP groups. Although statistical differences were not observed in the swelling of GMP-10 and GMP-40 particles alone, the interaction of GelMA/GMP demonstrated a significant effect on the swelling behaviors of composite scaffolds. These results demonstrate an example hydrogel-microcarrier composite system's swelling behavior and can inform the future use of such a composite system for controlled delivery of bioactive molecules in vitro and in vivo in tissue engineering applications. Impact statement In this study, porous three-dimensional printed (3DP) hydrogel constructs with and without natural polymer microcarriers were fabricated to observe swelling and degradation behavior under continuous swelling and drying-rehydration cycle conditions. Inclusion of microcarriers with different crosslinking densities led to distinct swelling behaviors for each biomaterial ink tested. 3DP hydrogel and hydrogel-microcarrier composite scaffolds have been commonly used in tissue engineering for the delivery of biomolecules. This study demonstrates the swelling behavior of porous hydrogel and hydrogel-microcarrier scaffolds that may inform later use of such materials for controlled release applications in a variety of fields including materials development and tissue regeneration.

A novel anhydrous preparation of PEG hydrogels enables high drug loading with biologics for controlled release applications

Hydrogels are very attractive materials to embed biologics for controlled release over long timescales. However, aqueous preparations pose certain obstacles regarding protein integrity, stability of functional groups, and loading capacity. To overcome these obstacles, the Diels-Alder reaction of furyl- and maleimide-functionalized eight-armed poly(ethylene glycol) (PEG) was used for the polymer preparation in the melt. The water-free reaction was investigated for protein interactions, protein- and maleimide group stability, and protein loading capacity. The melt polymerization was found to be highly protective against protein PEGylation and maleimide hydrolysis. The polymer gels were evaluated as a potential release system for biologics, achieving controlled release of the model protein glucose oxidase over a time period of 100 days. Furthermore, the loading could be increased to 15%(w/w) without influencing the release kinetics. This work represents a promising preparation method for degradable and water-free drug delivery systems that can be used to encapsulate biologics for controlled release.

High-resolution micro-computed tomography reveals cracking in a hydrophobic composite; a new mechanism for mobilisation in controlled release applications

High-resolution micro-computed tomography (μ-CT) provides new insights into the release of water-soluble crystalline materials from hydrophobic polymer matrices. This technique was applied to investigate the complex pathways underpinning the release of the agrichemical dicyandiamide (DCD), a common crystalline, water-soluble nitrification inhibitor, following its encapsulation in a biodegradable poly(3-hydroxybutyrate- co -3-hydroxyvalerate) (PHBV) matrix at a loading of 250 g kg −1 . Such a material allows controlled DCD delivery and improves its stability in tropical cropping systems. The insights gained from the use of this advanced 3-D imaging technique has led to a new understanding of the processes driving release of active agents and will aid the modelling and design of such tailored delivery formulations. These insights are broadly applicable and relevant to various soluble crystalline agrichemicals, drugs and medical implants. The release rate from DCD-PHBV pellets, fabricated through industrially relevant extrusion processing, was initially rapid, exponentially decaying over the first eight weeks. This was followed by a very gradual, linear release over the next 18 weeks. High-resolution μ-CT (0.5 μm) led to two important conclusions: i) the DCD that was rapidly mobilized existed within channels connected to the surface of the pellet, and ii) fine cracks present before and after release may explain the very slow mobilisation from the eighth week onward. Revealing the microstructure of this type of composite improves our current understanding of the mechanisms controlling the release of soluble crystalline materials encapsulated in a hydrophobic biodegradable polymer matrix. • μ-CT reveals cracks that contribute to release of DCD from a biodegradable matrix. • Analysis found 2–4 μm cracks that propagate from pores and vertices of DCD crystals. • The biopolymer, PHBV, is shown to not follow Higuchi's classic moving front theory. • Pore analysis quantifies initial and final porosity and orientation of DCD crystals.

Injectable hydrogels self-assembled from oligopeptide-poly(2-methacryloyloxyethyl phosphorylcholine) hybrid graft copolymers for cell scaffolds and controlled release applications

An injectable hydrogel composed of biocompatible PMPC with PEG-attached self-assembling peptide grafts was newly prepared, and it could be used as 3D cell scaffolds and controlled-release applications.

Engineering bioactive synthetic polymers for biomedical applications: a review with emphasis on tissue engineering and controlled release

We review strategies for engineering synthetic polymers from fabrication to chemical functionalization for biomedical applications. Particular emphasis is devoted to strategies related to tissue engineering and controlled release applications.