Dual Release System Research Articles

Antibiotic-eluting scaffolds with responsive dual-release kinetics facilitate bone healing and eliminate S. aureus infection

Osteomyelitis (OM) is a progressive, inflammatory infection of bone caused predominately by Staphylococcus aureus. Herein, we engineered an antibiotic-eluting collagen-hydroxyapatite scaffold capable of eliminating infection and facilitating bone healing. An iterative freeze-drying and chemical crosslinking approach was leveraged to modify antibiotic release kinetics, resulting in a layered dual-release system whereby an initial rapid release of antibiotic to clear infection was followed by a sustained controlled release to prevent reoccurrence of infection. We observed that the presence of microbial collagenase accelerated antibiotic release from the crosslinked layer of the scaffold, indicating that the material is responsive to microbial activity. As exemplar drugs, vancomycin and gentamicin-eluting scaffolds were demonstrated to be bactericidal, and supported osteogenesis in vitro. In a pilot murine model of OM, vancomycin-eluting scaffolds were observed to reduce S. aureus infection within the tibia. Finally, in a rabbit model of chronic OM, gentamicin-eluting scaffolds both facilitated radial bone defect healing and eliminated S. aureus infection. These results show that antibiotic-eluting collagen-hydroxyapatite scaffolds are a one-stage therapy for OM, which when implanted into infected bone defects simultaneously eradicate infection and facilitate bone tissue healing.

Application effect of a dual release system of androgen and its antagonist in the repair of full-thickness burn wounds in mice

Application effect of a dual release system of androgen and its antagonist in the repair of full-thickness burn wounds in mice

Preparation of Nanoemulgels Containing Lemon Essential Oil and Pectin: Physical Stability and Rheological Properties

Nanoemulgels are novel formulations of great interest for their use as dual-release systems and as fat substitutes in foods. Lemon essential oil, with a large number of benefits due to its antimicrobial, antifungal, and medicinal properties, and low methoxyl pectin, a natural polysaccharide capable of gelling by adding divalent ions such as calcium, are very appropriate ingredients to produce nanoemulgels with potential applications in industries such as cosmetics, agrochemistry, pharmaceuticals, or food. In this work, lemon-essential-oil-in-water nanoemulgels containing low methoxyl pectin derived from citrus peels were prepared following a three-step process that involves the preparation of a nanoemulsion, a pectin gel, and the mixture of both. In the first stage, the stirring time and the rotational rate employed during the mixing step were assessed. Once the preparation protocol was established, the pectin gel/nanoemulsion mass ratio was investigated. Different techniques were combined to evaluate the influence of the processing and the composition variables on the particle size distribution, mean diameters, flow curves, and physical stability of different emulgels obtained. It was found that the processing variables studied, stirring time, and rotational rate, do not influence the mean particle size of the emulgel, with values matching those of the starting nanoemulsion. However, 3 min and 200 rpm were selected for exhibiting the lowest TSI values. Regarding the composition, a higher content of pectin gel caused a higher viscosity, and therefore a higher physical stability, with the 75P/25E emulgel being the most stable. Aggregation of gel particles, because the pectin gel was really a sheared gel, was the main responsible contributor to the results obtained. This work highlights the importance of the preparation and formulation variables to develop stable, innovative formulations based on nanoemulgels.

Development of a Silk Fibroin-Small Intestinal Submucosa Small-Diameter Vascular Graft with Sequential VEGF and TGF-β1 Inhibitor Delivery for In Situ Tissue Engineering.

Proper endothelialization and limited collagen deposition on the luminal surface after graft implantation plays a crucial role to prevent the occurrence of stenosis. To achieve these conditions, a biodegradable graft with adequate mechanical properties and the ability to sequentially deliver therapeutic agents isfabricated. In this study, a dual-release system is constructed through coaxial electrospinning by incorporating recombinant human vascular endothelial growth factor (VEGF) and transforming growth factor β1 (TGF-β1) inhibitor into silk fibroin (SF) nanofibers to form a bioactive membrane. The functionalized SF membrane as the inner layer of the graft is characterized by the release profile, cell proliferation and protein expression. It presents excellent biocompatibility and biodegradation, facilitating cell attachment, proliferation, and infiltration. The core-shell structure enables rapid VEGF release within 10 days and sustained plasmid delivery for 21 days. A 2.0-mm-diameter vascular graft is fabricated by integrating the SF membrane with decellularized porcine small intestinal submucosa (SIS), aiming to facilitate the integration process under a stable extracellular matrix structure. The bioengineered graft is functionalized with the sequential administration of VEGF and TGF-β1, and with the reinforced and compatible mechanical properties, thereby offers an orchestrated solution for stenosis with potential for in situ vascular tissue engineering applications.

Hydrolyzable emulsions as a dual release platform for hydrophobic drugs and DNA.

Several challenges need to be overcome when applying nucleic acids as therapeutic agents. We developed a new way to control the onset of the release of cholesterol-conjugated oligonucleotides with a simple, versatile, and cheap platform. Moreover, we combine the platform into a dual-release system that can release a hydrophobic drug with zero-order kinetics, followed by a rapid release of cholesterol-conjugated DNA.

Emulgel: A dual release system for hydrophobic drug delivery

Emulgel is NDDS that is in recent light for its capacity to deliver hydrophobic drugs. In a topical drug delivery system, the most important task is to pass the drug through the barrier and the proper diffusion of the drug in the skin. Emulgel is made up of emulsion and gel where emulsion helps in the delivery of hydrophobic drugs while gel gives proper diffusion, spread ability and improves the stability of an emulsion. It’s a dual release system in which the emulsion is jellified by gelling agents giving us characteristics of both emulsion and gel along with improved patient compliance. In the following review, we will discuss about the emulgel and its types along with its method of preparation, evaluation and applications in a comprehensive way.

Emulgel: A dual release system for hydrophobic drug delivery

Emulgel: A dual release system for hydrophobic drug delivery

Injectable Composite Systems of Gellan Gum:Alginate Microparticles in Pluronic Hydrogels for Bioactive Cargo Controlled Delivery: Optimization of Hydrogel Composition based on Rheological Behavior

Due to the high complexity of some treatments, there is a need to develop drug-delivery systems that can release multiple drugs/bioactive agents at different stages of treatment. In this study, a thermoresponsive injectable dual-release system was developed with gellan gum/alginate microparticles (GG:Alg) within a thermoresponsive Pluronic hydrogel composed of a mixture of Pluronic F127 and F68. The increase in F68 ratio and decrease in F127 lead to higher transition temperatures. The addition of the GG:Alg microparticles decreased the transition temperatures with a linear tendency. In Pluronic aqueous solutions (20 wt.%), the F127:F68 ratios of 16:4 and 17:3 (wt.%:wt.%) and the addition of microparticles (up to 15 wt.%) maintained the sol–gel transition temperatures within a suitable range (between 25 °C and 37 °C). Microparticles did not hinder the injectability of the system in the sol phase. Methylene blue was used as a model drug to evaluate the release mechanisms from microparticles, hydrogel, and composite system. The hydrogel delayed the release of methylene blue from the microparticles. The hydrogel loaded with methylene blue released at a faster rate than the microparticles within the hydrogel, thus demonstrating a dual-release profile.

Gelatin Methacryloyl Hydrogels for Musculoskeletal Tissue Regeneration.

Musculoskeletal disorders are a significant burden on the global economy and public health. Hydrogels have significant potential for enhancing the repair of damaged and injured musculoskeletal tissues as cell or drug delivery systems. Hydrogels have unique physicochemical properties which make them promising platforms for controlling cell functions. Gelatin methacryloyl (GelMA) hydrogel in particular has been extensively investigated as a promising biomaterial due to its tuneable and beneficial properties and has been widely used in different biomedical applications. In this review, a detailed overview of GelMA synthesis, hydrogel design and applications in regenerative medicine is provided. After summarising recent progress in hydrogels more broadly, we highlight recent advances of GelMA hydrogels in the emerging fields of musculoskeletal drug delivery, involving therapeutic drugs (e.g., growth factors, antimicrobial molecules, immunomodulatory drugs and cells), delivery approaches (e.g., single-, dual-release system), and material design (e.g., addition of organic or inorganic materials, 3D printing). The review concludes with future perspectives and associated challenges for developing local drug delivery for musculoskeletal applications.

Emulgel A Reliable System for Topical Delivery of Lipophilic Drugs in Present Scenario: Review

Topical drug delivery can be defining as good delivery system for drugs, in which drug directly get interact with skin and give its pharmacological effect to desired site to cure and treat variety of disorder. Gel has major disadvantage because it cannot prepare for hydrophobic drugs this type of limitation can be defeated by emulgel. Emulgel have dual property like emulsion and gel and gives dual release system. Primary disadvantage of lipophilic drug that it does not dissolves in aqueous solvent and cause problem in drug delivery. Emulgels gives a good advantage over gel that hydrophobic drugs are easily dissolve in oil phase and then added in aqueous phase to form w/o type emulsion. These emulgel then incorporate into gel to form emulgel. Emulgel are good carrier for topical delivery of lipophilic drugs and have several advantages over different drug delivery system. Emulgel give better patient compliance and promote controlled pattern of drug delivery due to presence of cross linked structure of gelling agent. Emulgels formulations can be used for anti-inflammatory, analgesic, antifungal, acne, skin disorder and also in form of cosmetic products.

A Sweet H2S/H2O2 Dual Release System and Specific Protein S-Persulfidation Mediated by Thioglucose/Glucose Oxidase.

H2S and H2O2 are two redox regulating molecules that play important roles in many physiological and pathological processes. While each of them has distinct biosynthetic pathways and signaling mechanisms, the crosstalk between these two species is also known to cause critical biological responses such as protein S-persulfidation. So far, many chemical tools for the studies of H2S and H2O2 have been developed, such as the donors and sensors for H2S and H2O2. However, these tools are normally targeting single species (e.g., only H2S or only H2O2). As such, the crosstalk and synergetic effects between H2S and H2O2 have hardly been studied with those tools. In this work, we report a unique H2S/H2O2 dual donor system by employing 1-thio-β-d-glucose and glucose oxidase (GOx) as the substrates. This enzymatic system can simultaneously produce H2S and H2O2 in a slow and controllable fashion, without generating any bio-unfriendly byproducts. This system was demonstrated to cause efficient S-persulfidation on proteins. In addition, we expanded the system to thiolactose and thioglucose-disulfide; therefore, additional factors (β-galactosidase and cellular reductants) could be introduced to further control the release of H2S/H2O2. This dual release system should be useful for future research on H2S and H2O2.

Natural polysaccharide based complex drug delivery system from microfluidic electrospray for wound healing

Natural polysaccharides have a demonstrated value in drug encapsulation and delivery. Efforts in this area are focused on improving the performances of these biomaterials. In this study, we present a multicompartment polysaccharide core-shell microparticle to construct a sustainable dual-release system of active molecules for enhancing wound healing. These microparticles were generated utilizing a microfluidic electrospray approach, in which a mixture of cellulose nanocrystals (CNC) and vascular endothelial growth factor (VEGF) were employed as the cores, with doxycycline hydrochloride (DH) mixed alginate as the shells. The resultant multicompartment particles exhibited wonderful antibacterial properties inherited from the alginate shell, and angiogenesis properties from the CNC core after the shell disintegrated. It was demonstrated that these core-shell microparticles performed their outstanding capabilities in inhibiting inflammation, promoting granulation tissue formation, collagen deposition, and angiogenesis, thereby accelerating rodents’ wound healing. These findings support the great potential value of CNC/alginate core-shell microparticles based on the synergistic drug delivery strategy for orchestrating wound healing.

Scaffold-based osteogenic dual delivery system with melatonin and BMP-2 releasing PLGA microparticles

The growing safety problems about the use of bone morphogenetic protein 2 (BMP-2) is one of the recent issues that was improved by using low doses of BMP-2 with the support of other osteoinductive agents and/or using appropriate carriers. The aim of the present study is to investigate the effect of scaffold-based dual release system including melatonin (MEL) and BMP-2 loaded polylactic-co-glycolic acid (PLGA) microparticles on the osteogenic activity of pre-osteoblastic MC3T3-E1 cells. MEL and BMP-2 loaded microparticles were prepared by double emulsion solvent evaporation method in the average diameters of ~2 µm and ~11 µm, respectively and loaded into chitosan/hydroxyapatite (HAp) scaffolds. In vitro MC3T3-E1 culture studies were carried out comparatively with blank scaffolds, single (BMP-2 or MEL) releasing groups and dual (BMP-2 and MEL) releasing group. Microscopic observations and hematoxylin/eosin staining showed enhanced number of cells and dense ECM in dual release group. The expressions of differentiation markers, Runt-related transcription factor 2 (RUNX2) and alkaline phosphatase (ALP) and also mineralization were higher in dual release group than that of the other groups. Our findings showed that BMP-2 at low doses (~20 ng per scaffold) was sufficient in terms of osteogenic activity with controlled release systems where it was used in combination with MEL (~10 µg per scaffold).

A distinctive nanocomposite hydrogel integrated platform for the healing of wound after the resection of melanoma

During the surgical removal of melanoma, that the incompletely eradicated cancer cells enter the circulatory system with blood flow will lead to the risk of distant metastasis and then the recurrence of postoperative residual tumor, which will greatly reduce the cure rate. Additionally, microbial resistance makes the problem of infection more serious during the process of defect repair. Considering these problems, we developed a nanocomposite hydrogel (Gel/PF127) with excellent mechanical properties, hemostasis and broad-spectrum antibacterial activity. It was used for the dual release system based on micelles and hydrogel used for maintaining long-term release of paclitaxel (PTX) at the wound site after melanoma surgery, thereby killing residual tumor cells and repairing tissue defects better. The results showed that PF127 nano micelles could effectively load PTX and release it in tumor environment. Moreover, the quaternary ammonium gel network showed excellent growth inhibition for E. coli and S. aureus (inhibition rate up to 98%). The introduction of Ca2+ endowed the gel with the excellent hemostatic effect. The combination of reversible chemical bonds and electrostatic interaction made Gel/PF127 have good mechanical stability, excellent tissue adhesion and self-healing properties. The experimental results showed that such nanocomposite hydrogel could stop bleeding quickly and avoid wound infection, induce apoptosis of tumor cells and inhibit their recurrence very effectively, thus suggesting that the construction of in situ chemotherapy platform which integrates trauma repair and tumor inhibition will greatly promote the recurrence inhibition and trauma repair of melanoma. At the same time, it provides a simple and efficient strategy for other cancer postoperative wound healing.

Dual-Controlled Release of Icariin/Mg2+ from Biodegradable Microspheres and Their Synergistic Upregulation Effect on Bone Regeneration.

Current scaffolds applied for bone tissue engineering are still lacking sufficient osteogenic capacity to induce efficient bone regeneration. Biodegradable microsphere-type scaffolds are designed to achieve the dual-controlled release of a Chinese medicine (i.e., icariin, ICA) and a bioactive ion (i.e., Mg2+ ), in order to achieve their synergistic effect on inducing osteogenesis. The hydrophobic icariin is preloaded onto MgO/MgCO3 (1:1 in weight ratio) particles at different amounts and then the particles are encapsulated into biodegradable poly(lactide-co-glycolide) (PLGA) microspheres (PMI) at a fixed fraction (20wt%). Continuous releases of Mg2+ ion and icariin from the microspheres are detected, showing dependence on icariin amounts. At an optimized moderate loading amount, the resulting PMI-M microspheres display the strongest activation effect on cell biological behaviors among all the designs. By implanting the PMI-M microspheres into rat calvarial defects for 16 weeks, it is found that they can effectively enhance new bone formation, presenting significantly higher capacity in inducing osteogenesis than PMg (containing MgO/MgCO3 but without icariin) and blank PLGA microspheres. Clearly, the released Mg2+ ions are beneficial to osteogenesis, and the coincorporation of icariin exerts supplemental effects in inducing new bone formation, which suggest a promising strategy to regenerate severe bone injuries by designing a dual-release system.

A Distinctive Nanocomposite Hydrogel Integrated Platform for the Healing of Wound after the Resection of Melanoma

During the surgical removal of melanoma, that the incompletely eradicated cancer cells enter the circulatory system with blood flow will lead to the risk of distant metastasis and then the recurrence of postoperative residual tumor, which will greatly reduce the cure rate. Additionally, microbial resistance makes the problem of infection more serious during defect repair. Considering these problems, we developed a nanocomposite hydrogel (Gel/PF127) with excellent mechanical properties, hemostasis and broad-spectrum antibacterial activity. It was used for the dual release system based on micelles and hydrogel used for maintaining long-term release of paclitaxel (PTX) at the wound site after melanoma surgery, thereby killing residual tumor cells and repairing tissue defects better. The results showed that PF127 nano micelles could effectively load PTX and release it in tumor environment. Moreover, the quaternary ammonium gel network showed excellent growth inhibition for E. coli and S. aureus (more than 98%). The introduction of Ca2+ endowed the gel with excellent hemostatic effect. The combination of reversible chemical bonds and electrostatic interaction made Gel/PF127 have excellent mechanical, tissue adhesion and self-healing properties. The experimental results showed that such nanocomposite hydrogel could stop bleeding quickly and avoid wound infection, induce apoptosis of tumor cells and inhibit their recurrence very effectively, thus suggesting that the construction of in situ chemotherapy platform which integrates trauma repair and tumor inhibition will greatly promote the recurrence inhibition and trauma repair of melanoma. At the same time, it provides a simple and efficient strategy for other cancer postoperative wound healing.

A multifunctional long‐term release system for treatment of hypothyroidism

Hypothyroidism is an autoimmune disease associated with underactive thyroid gland. In this study, a dual effect polymeric system was designed to release Cepharanthine (CEP) to block T cell activation and Selenium (Se) to decrease the anti-thyroid peroxidase (TPOAb) concentration in order to treat hypothyroidism. For this purpose, poly(ethylene-vinyl acetate) (PEVA) and polyethylene glycol (PEG) nanoparticles (NPs) including CEP were synthesized by emulsion solvent evaporation method and they were loaded to polyurethane (PU)/PEG-PUSe-PEG block copolymer blends which were fabricated by particulate leaching technique as porous sponges. Fourier-Transform Infrared (FTIR), Raman, and Nuclear Magnetic Resonance (NMR) analysis showed successful synthesis of PEG-PUSe-PEG block copolymer. A long-term zero-order release profile was obtained for CEP. Se release rate from matrices showed an oxidative stress-mediated release which can be used to adjust Se amount. According to MTS results conducted by NIH 3T3 fibroblasts, both NPs and matrices have no adverse effect on cell viability. Fluorescence microscopy and SEM images confirm the MTS results. The dual release system has potential to be effectively used in long-term treatment of hypothyroidism by addressing both auto-immune response and hormone regulation.

Effect of Dual Releasing of β-glycerophosphate and Dexamethasone from Ti Nanostructured Surface for Using in Orthopedic Applications

Nano-structured surface and its ability to dual release of osteogenic and anti-inflammatory agents have a positive effect on the success of using titanium in orthopedic applications. For this purpose, TiO2 nanotubes (TNTs) were created via anodization method on Ti sheets and loaded by β-glycerophosphate (GP) and dexamethasone (DEX) as osteogenic and anti-inflammatory agents, respectively. They were coated with a polyvinyl alcohol (PVA) layer for controlling their releasing rate. The synthesized dual-release system was characterized by field emission scanning electron microscopy (FE-SEM), Fourier transform infrared spectroscopy (FTIR) analysis, XRD and UV-Vis techniques. The average diameter of TNTs was 84.182 nm. The presence of drugs in the system has been proven in the FTIR analysis. UV-Vis technique’s results show that the coated layer could control the release rate to improve the potential of the structures for supporting mineralization. Releasing of DEX was higher than GP and reached to a constant rate after 9 days. MTT test results confirmed the possibility of the surface designed Ti for bone regeneration purposes.

Preparation and Characterization of Coaxial Electrospinning rhBMP2-Loaded Nanofiber Membranes

DEX and rhBMP2-loaded core-shell nanofiber membranes were synthesized by electrospinning method in one step. Zein/PLLA, Zein-DEX/PLLA, Zein/PLLA-rhBMP2, and Zein-DEX/PLLA-rhBMP2 were fabricated; and morphology, hydrophilicity, mechanics properties, in vitro drug release behavior, cell proliferation, and osteogenic differentiation were investigated. The results showed that the dual-release system containing rhBMP2 and DEX prepared by electrospinning had rough surface, constant drug release behavior, and could also significantly promote cell proliferation and osteogenic differentiation of RMSCs, indicating that the scaffolds we fabricated might be suitable for bone tissue engineering.

Modifications of silk film for dual delivery

Silk biomaterials can be designed to provide an architectural framework comparable to connate extracellular matrix in order to boost cell growth and eventual tissue regeneration. Silk (Bombyx mori) fibroins self-assemble into hydrophobic crystalline β sheets, which provide mechanical strength and tunable degradability. The next generation of tissue engineering scaffolds aim to provide spatially controlled modulation of cell adhesion and differentiation, which can be achieved by spatially controlled surface functionalization of the scaffolds. In this respect, it is even more important to be able to release molecules at timescales ranging from hours to days, as many biological processes require signals early on to initiate processes, and over prolonged periods to sustain them. Unfortunately, achieving spatio-temporal control over multiple release profiles from silk based substrates is challenging due to their intrinsic slow release behaviour. Here, we report a simple strategy that provides spatio-temporal control over the release of drugs from silk films (SFs). We have developed a UV based strategy to modify the SFs with nanogels, which can provide a fast as well as slow release profile from a single platform. We demonstrate that the release profile of encapsulated molecules on the SF substrate can be tuned from fast (within hours) to slow (within days), thus resulting in a dual release system, which can be eventually utilized to deliver bioactive molecules at specific regions with different rates to achieve the desired multiple biological effects.