Tunable Release Rates Research Articles

Synergistic effects of graphene nanoparticles on the thermomechanical properties of PEEK-HNTs nanocomposites

In our previous study, we selected a 3% concentration (PH3) from various prepared PEEK-HNTs nanocomposites. Poly (ether ether ketone) (PEEK) is characterized by non-perfluorinated aromatic compounds with 1,4-disubstituted phenyl groups linked by carbonyl (––CO––) and ether (––O––) groups, offering exceptional thermal stability, mechanical strength, tribological properties, and chemical resistance at high temperatures. Halloysite nanotubes (HNTs) are known for their non-toxic, environmentally friendly, cost-effective properties, with tunable release and rapid adsorption rates. In this study, we prepared graphene nanoparticle (GNP) composites at three different concentrations while maintaining constant PH3 levels. The composites underwent comprehensive characterization using FTIR, TGA, DSC, SEM, and DMA techniques. Thermomechanical properties were evaluated using a universal testing machine. Results demonstrate significant enhancements in hardness, impact strength, elongation at break, tensile modulus, and flexural modulus, with the highest performance observed in the GNP-loaded 0.3% (PHG3) concentration. The synergistic effects of GNP fillers in PH3 are attributed to enhanced interfacial adhesion and favorable interactions with the polymer matrix.

3D printed O2-generating scaffolds enhance osteoprogenitor- and type H vessel recruitment during bone healing

Oxygen (O2)-delivering tissue substitutes have shown tremendous potential for enhancing tissue regeneration, maturation, and healing. As O2 is both a metabolite and powerful signaling molecule, providing controlled delivery is crucial for optimizing its beneficial effects in the treatment of critical-sized injuries. Here, we report the design and fabrication of 3D-printed, biodegradable, O2-generating bone scaffold comprising calcium peroxide (CPO) that once hydrolytically activated, provides long-term generation of oxygen at a controlled, concentration-dependent manner, and polycaprolactone (PCL), a hydrophobic polymer that regulate the interaction of CPO with water, preventing burst release of O2 at early time points. When anoxic conditions were simulated in vitro, CPO-PCL scaffolds maintained the survival and proliferation of human adipose-derived stem/stromal cells (hASCs) relative to PCL-only controls. We assessed the in vivo osteogenic efficacy of hASC-seeded CPO-PCL scaffolds implanted in a non-healing critical-sized 4-mm calvarial defects in nude mice for 8 weeks. Even without exogenous osteoinductive factors, CPO-PCL scaffolds demonstrated increased new bone volume compared to PCL-only scaffolds as verified by both microcomputed tomography analysis and histological assessments. Lastly, we employed a quantitative 3D lightsheet microscopy platform to determine that O2-generating scaffolds had similar vascular volumes with slightly higher presence of CD31hiEmcnhi pro-osteogenic, type H vessels and increased number of Osterix+ skeletal progenitor cells relative to PCL-only scaffolds. In summary, 3D-printed O2 generating CPO-PCL scaffolds with tunable O2 release rates provide a facile, customizable strategy for effectively treating, craniofacial bone defects. Statement of significanceOxygen(O2)-delivering bone substitutes show promise in defect repair applications by supplying O2 to the cells within or around the graft, improving cell survivability and enhancing bone matrix mineralization. A novel O2-generating bone scaffold has been 3D printed for the first-time which ensures patient and defect specificity. 3D printed calcium peroxide-polycaprolactone (CPO-PCL) bone scaffold provides uninterrupted O2 supply for 22 days allowing cell survival in deprived O2 and nutrient conditions. For the first time, O2-driven bone regenerative environment in mice calvaria has been captured by light-sheet imaging which illuminates abundance of Osterix+ cells, angiogenesis at a single cell resolution indicating active site of bone remodeling and growth in the presence of O2.

High-yield fabrication of monodisperse multilayer nanofibrous microparticles for advanced oral drug delivery applications

Recent advances in the use of nano- and microparticles in drug delivery, cell therapy, and tissue engineering have led to increasing attention towards nanostructured microparticulate formulations for maximum benefit from both nano- and micron sized features. Scalable manufacturing of monodisperse nanostructured microparticles with tunable size, shape, content, and release rate remains a big challenge. Current technology, mainly comprises complex multi-step chemical procedures with limited control over these aspects. Here, we demonstrate a novel technique for high-yield fabrication of monodisperse monolayer and multilayer nanofibrous microparticles (MoNami and MuNaMi respectively). The fabrication procedure includes sequential electrospinning followed by micro-cutting at room temperature and transfer of particles for collection. The big advantage of the introduced technique is the potential to apply several polymer-drug combinations forming multilayer microparticles enjoying extracellular matrix (ECM)-mimicking architecture with tunable release profile. We demonstrate the fabrication and study the factors affecting the final three-dimensional structure. A model drug is encapsulated into a three-layer sheet (PLGA-pullulan-PLGA), and we demonstrate how the release profile changes from burst to sustain by simply cutting particles out of the electrospun sheet. We believe our fabrication method offers a unique and facile platform for realizing advanced microparticles for oral drug delivery applications.

Activatable theranostic prodrug scaffold with tunable drug release rate for sequential photodynamic and chemotherapy

AbstractGlutathione (GSH)‐activated prodrugs are promising for overcoming the limitations of conventional anti‐tumor drugs. However, current GSH‐responsive disulfide groups exhibit unregulated reactivity, making it impossible to precisely control the drug release rate. We herein report a series of GSH‐responsive prodrugs with a “three‐in‐one” molecular design by integrating a fluorescence report unit, stimuli‐responsive unit and chemodrug into one scaffold with tunable aromatic nucleophilic substitution (SNAr) reactivity. The drug release rate of these prodrugs is tailored by modification of substituent groups with different electron‐withdrawing or ‐donating abilities on the BODIPY core. Furthermore, the prodrugs self‐assemble in water to form nanoparticles that serve as photosensitizers to produce reactive oxygen species upon irradiation for photodynamic therapy (PDT). The PDT process also increases the concentration of GSH in cells, further promoting the release of drugs for chemotherapy. This strategy provides a powerful platform for sequential photodynamic and chemotherapy with tunable drug release rates and synergistic therapeutic effects.

Controlled Release of Mahaad Extract Using Span 80 Co-Loaded on a Dendritic Fibrous Silica

Mahaad (Artocarpus lakoocha Roxb.) is a plant variety that can be found in Southern and Eastern Asia. Its extract contains a major component, oxyresveratrol (ORES), and a minority component, resveratrol (RES), both of which are important cosmetic compounds with antioxidant and skin-brightening properties. However, both ORES and RES are easily degraded by light, heat, and oxygen, making proper storage necessary for effective use in cosmetics. In this study, dendritic fibrous silica was selected as the carrier to protect the active compounds due to its high porosity and surface area with a unique open pore structure, as well as its low toxicity. The synthesized silica was characterized using various techniques, including SEM, FE-SEM, XRD, N2 adsorption-desorption, and FTIR. The synthesized silica had a particle size, specific surface area, pore size, and pore volume of 500-600 nm, 703 m2/g, 6.21 nm, and 1.09 cm3/g, respectively. The Mahaad extract was co-loaded with Span 80, a non-ionic surfactant widely used in cosmetics in different ratios on KCC-1. The FTIR results confirmed successful loading of Mahaad and surfactant onto the KCC-1 carrier, and we observed that the release rate of Mahaad decreased with an increase in the Span 80-to-drug ratio. These findings suggest that co-loading Span 80 with the drug on a silica surface can provide a controlled and tunable drug release rate that is desirable for cosmetic applications.

Tunable Drug Release Rate Using Modular Oral Dosage Forms.

Oral dosage forms with adjustable drug release profiles were prepared using progesterone (PGR) as a poorly-soluble model drug. The dosage forms were made as stack assemblies of functional modules. The modules were made as PGR-carrying HPMC films cut into wafer-like circular pieces. Two types of modules were used in the study; one exhibited comparatively fast drug release and the other slow release. The fast vs. slow release of each type of film utilized resulted from the grade of HPMC used in each case. Drug loading in the assembly was controlled through the total number of modules. By adjusting the proportions of the two types of modules, it is possible to fine-tune the drug release rate of the multi-layer assemblies to a wide range of profiles, bracketed between a high and low end, corresponding to the inherently fastest or slowest release obtainable with the specific materials and procedures employed. This procedure is suitable for adjusting the spring-and-parachute parameters for enhancing/optimizing the bioavailability of poorly-soluble drugs, and for developing patient-centric formulations.

Real-time evaluation of a hydrogel delivery vehicle for cancer immunotherapeutics within embedded spheroid cultures.

Many protein immunotherapeutics are hindered by transport barriers that prevent the obtainment of minimum effective concentrations (MECs) in solid tumors. Local delivery vehicles with tunable release (infusion) rates for immunotherapeutics are being developed to achieve local and sustained release. To expedite their discovery and translation, in vitro models can identify promising delivery vehicles and immunotherapies that benefit from sustained release by evaluating cancer spheroid killing in real-time. Using displacement affinity release (DAR) within a hydrogel, we tuned the release of a CD133 targeting dual antigen T cell engager (DATE) without the need for further DATE or hydrogel modifications, yielding an injectable vehicle that acts as a tunable infusion pump. To quantify bioactivity benefits, a 3D embedded cancer spheroid model was developed for the evaluation of sustained protein release and combination therapies on T cell mediated spheroid killing. Using automated brightfield and fluorescent microscopy, the size of red fluorescent protein (iRFP670) expressing spheroids were tracked to quantify spheroid growth or killing over time as a function of controlled delivery. We demonstrate that sustained DATE release enhanced T cell mediated killing of embedded glioblastoma spheroids at longer timepoints, killing was further enhanced with the addition of anti-PD1 antibody (αPD1). The multi-cellular embedded spheroid model with automated microscopy demonstrated the benefit of extended bispecific release on T cell mediated killing, which will expedite the identification and translation of delivery vehicles such as DAR for immunotherapeutics.

Self-Immolative Hydroxybenzylamine Linkers for Traceless Protein Modification

Traceless self-immolative linkers are widely used for the reversible modification of proteins and peptides. This article describes a new class of traceless linkers based on ortho- or para-hydroxybenzylamines. The introduction of electron-donating substituents on the aromatic core stabilizes the quinone methide intermediate, thus providing a platform for payload release that can be modulated. To determine the extent to which the electronics affect the rate of release, we prepared a small library of hydroxybenzylamine linkers with varied electronics in the aromatic core, resulting in half-lives ranging from 20 to 144 h. Optimization of the linker design was carried out with mechanistic insights from density functional theory (DFT) and the in silico design of an intramolecular trapping agent through the use of DFT and intramolecular distortion energy calculations. This resulted in the development of a faster self-immolative linker with a half-life of 4.6 h. To demonstrate their effectiveness as traceless linkers for bioconjugation, reversible protein-polyethylene glycol conjugates with a model protein lysozyme were prepared, which had reduced protein activity but recovered ≥94% activity upon traceless release of the polymer. This new class of linkers with tunable release rates expands the traceless linkers toolbox for a variety of bioconjugation applications.

Redox-Responsive Hydrogels with Decoupled Initial Stiffness and Degradation.

Disulfide-cross-linked hydrogels have been widely used for biological applications because of their degradability in response to redox stimuli. However, degradability often depends on polymer concentration, which also influences the hydrogel mechanical properties such as the initial stiffness. Here, we describe a one-pot cross-linking approach utilizing both a thiol-ene reaction through a Michael pathway with divinyl sulfone (DVS) to form non-reducible thioether bonds and thiol oxidation promoted by ferric ethylenediaminetetraacetic acid (Fe-EDTA) to form reducible disulfide bonds. The ratio between these two bonds was modulated by varying the DVS concentration used, and the initial shear or elastic modulus and degradation rate of the hydrogels were decoupled. These gels had tunable release rates of encapsulated dextran when exposed to 10 μM glutathione. Fibroblast encapsulation results suggested good cytocompatibility of the cross-linking reactions. This work shows the potential of combining DVS and Fe-EDTA to create thiol-cross-linked hydrogels as redox-responsive drug delivery vehicles and tissue engineering scaffolds with variable degradability.

Effect of Process Parameters on the Properties of Direct Written Gas-Generating Reactive Layers

A mixture of copper complex and Al/CuO nanothermite, Al/CuO/CuC, represents one of the state-of-the-art gas-generating thermite systems with various pyrotechnic applications due to its tunable gas release rates. The reactivity of reactive inks with various loadings of the poly(vinylpyrrolidone) (PVP) binder mixed with Al/CuO/CuC is characterized using high-speed imaging diagnostics and pressure measurements. For a PVP mass fraction of <7 wt %, the printed materials remain highly reactive and burn at a high velocity (10–54 m/s), which was one of the important goals of this study. At higher PVP contents, the polymer inhibits the reaction. Printing (dropwise and continuously writing) of inks containing 5 wt % PVP and 95 wt % reactive Al/CuO/CuC powder was demonstrated using a volumetrically controlled dispenser and a pneumatically actuated syringe. The pressure development and burning rate of the printed materials are 0.37 MPa (at 46.3% theoretical maximum density (TMD)) and 17 m/s (at 0.24% TMD), respectively, more than 10 times faster than the majority of works dealing with printed energetic formulations.

Molecular design of peptide amphiphiles for controlled self-assembly and drug release.

Peptide amphiphile-based supramolecular hydrogels hold great promise in drug delivery applications. To cater for a specific drug dose in a demanding biomedical scenario, sophisticated design of peptide amphiphile (PA) molecules is required to tune their self-assembling behaviours as well as drug releasing profiles. Herein, we designed a series of PAs with various capping groups and C-terminal amino acids to systematically optimize their self-assembling capabilities for controlled drug release. First, we evaluated the influence of N-terminal capping groups to find that the 2-naphthylacetyl moiety (Nap) greatly assisted hydrogelation of PAs. Next, self-assembling behaviours of Nap-capped PAs were compared among three candidates that bore varying hydrophilic moieties at the C-terminus (Nap-C12-VVAAG, Nap-C12-VVAAD and Nap-C12-VVAADD, denoted as 1-G, 1-D, and 1-DD). It was found that 1-G and 1-D co-assembled with doxorubicin (DOX) and calcium ions (Ca2+) at a higher efficiency than 1-DD, for 1-G/Ca2+/DOX and 1-D/Ca2+/DOX hydrogels displayed a dense nanofibrillar network, with lower minimal gelation concentrations and greater storage modulus values. Interestingly, these PA/Ca2+/DOX hydrogels exhibited tunable release rates of DOX in vitro, with fast release of DOX found in 1-DD/Ca2+/DOX and slow release in 1-G/Ca2+/DOX and 1-D/Ca2+/DOX. Further cell experiments demonstrated that 1-G/Ca2+/DOX and 1-D/Ca2+/DOX exhibited higher inhibitory efficacy against HeLa cells, as compared to DOX solution and 1-DD/Ca2+/DOX. Finally, PA/Ca2+/DOX hydrogels displayed a longer retention time of DOX than aqueous DOX solution in animal experiments, and sustained release of DOX from hydrogels was also evidenced by slow and persisting accumulation of DOX in the major organs of hydrogel-treated mice.

A novel diclofenac-hydrogel conjugate system for intraarticular sustained release: Development of 2-pyridylamino-substituted 1-phenylethanol (PAPE) and its derivatives as tunable traceless linkers.

A local sustained-release drug delivery system, or depot, for intra-articular injection offers the opportunity to release a therapeutic agent directly to the joint with limited need for reinjection. A successful system would provide more consistent efficacy and minimize systemic side effects. In this paper, we explore the potential use of diclofenac, a non-steroidal anti-inflammatory drug, for use in a polymer-conjugate depot system. During the course of our exploration it was determined that "conventional ester" conjugates of diclofenac were not appropriate as upon incubation in buffer (pH 7.4) or in bovine synovial fluid, a considerable amount of undesired diclofenac-lactam was released. Thus we developed a novel linker system for diclofenac in order to minimize the production of the lactam. This new linker enables a diclofenac conjugate system with tunable release rates and minimizes the production of undesired lactam side-products.

Designer Direct Ink Write 3D‐Printed Thermites with Tunable Energy Release Rates

Designer Direct Ink Write 3D‐Printed Thermites with Tunable Energy Release Rates

Probing the Reaction Zone of Nanolaminates at ∼μs Time and ∼μm Spatial Resolution

Reactive nanolaminates are a high-energy-density configuration for energetics that have been widely studied for their tunable energy release rates. In this study, we characterized Al/CuO nanolamina...

Design of polyester structure in amphiphilic copolymer coated on magnetite nanoparticle: Effect on loading and sustaining release of indomethacin

This works presented the surface modification of magnetite nanoparticles (MNPs) with the copolymers containing hydrophilic mPEG and hydrophobic polyester for use in drug controlled release applications. Polyester moieties in the copolymers were adsorbed on MNPs to form hydrophobic layer for entrapment of a hydrophobic indomethacin model drug, while hydrophilic mPEG provided their good water dispersibity. Three different polyester structures in the copolymer for MNP coating were; 1) saturated, 2) unsaturated and 3) crosslinked polyesters. The copolymer structures were characterized via1H NMR and their coatings were confirmed by FTIR. These water dispersible MNPs contained 53–61% copolymer in the complexes with the size ranging between 8 and 14 nm. The MNPs containing saturated polyester showed higher drug entrapment and loading efficiencies than the other two samples. Interestingly, those containing crosslinked polyester exhibited a potential to sustain the release of the entrapped drug. These complexes might be suitable for use as vehicles for entrapment of hydrophobic drugs with tunable and controllable release rate.

Designer Direct Ink Write 3D‐Printed Thermites with Tunable Energy Release Rates

Breakthroughs in additive manufacturing (AM), particularly direct ink write 3D printing, have allowed for greater control of material performance by manipulation of architecture and/or spatial composition. Herein, the range of control over the dynamic energy release rate in 3D‐printed Al/CuO thermite is quantified by substituting random porous pathways present in powder beds or compacts with printed void channels to modulate the energy transport during a reaction. The thermite is produced via on‐the‐fly static mixing of constituent Al and CuO inks, which offers a safe way to handle these materials. By reducing the fundamental burn unit size (i.e., filament size) and introducing small amounts of engineered porosity for gas flow, it is shown that energy release rates can be increased by more than 100 times that of maximum print density strips. Unique channel structures, which display propagation velocities of over 100 m s−1 due to confinement of gas flow, are reported. Ashby plots that show the reactivity design space for 3D‐printed thermites are presented as a function of the effective print/energy density. Architecting with AM tailors an object to release its energy in a prescribed way, and this control adds much‐needed versatility by allowing a single formulation to satisfy multiple applications.

Self-powered, on-demand transdermal drug delivery system driven by triboelectric nanogenerator

In this work, we present a self-powered and on-demand transdermal drug delivery system driven by triboelectric nanogenerator (TENG). A miniaturized TENG and a home-built power management circuit were designed to trigger the electric-responsive drug carrier for controlled drug release, as well as to activate the iontophoresis treatment for enhanced drug delivery efficiency. In the system, the TENG can harvest electricity from bio-mechanical energy, and the power management circuit is able to store, adjust, and stabilize the electricity for on-demand drug release actions. Our results demonstrate that the on-demand drug release can be simply realized by operating the TENG. Manually rotating the TENG (30–40 rpm) for 1.5 min can release a drug dosage of 3 μg/cm2. Furthermore, the system has achieved tunable drug release rate for the transdermal drug delivery: the rate can be tuned from 0.05 to 0.25 μg/cm2 per minute by changing the duration of TENG charging or the resistance of the power management circuit. In addition, ex vivo experiments on porcine skin validate the performance of such TENG-based drug delivery system with ∼50% enhancement over conventional transdermal patches. The proposed system is intended to provide patients with an easy approach to achieve customized rate and dosage of drug release.

A 3D bioprinted hydrogel mesh loaded with all-trans retinoic acid for treatment of glioblastoma

Treatment of glioblastoma (GBM), as the most lethal type of brain tumor, still remains a major challenge despite the various therapeutic approaches developed over the recent decades. GBM is considered as one of the most therapy-resistant human tumors. Treatment with temozolomide (TMZ) chemotherapy and radiotherapy in GBM patients has led to 30% of two-year survival rate (American Brain Tumor Association), representing a demanding field to develop more effective therapeutic strategies. This study presents a novel method for local delivery of all-trans retinoic acid (ATRA) for targeting GBM cells as a possible adjuvant therapeutic strategy for this disease. We have used 3D bioprinting to fabricate hydrogel meshes laden with ATRA-loaded polymeric particles. The ATRA-loaded meshes have been shown to facilitate a sustained release of ATRA with tunable release rate. Cell viability assay was used to demonstrate the ability of fabricated meshes in reducing cell growth in U-87 MG cell line. We later showed that the developed meshes induced apoptotic cell death in U-87 MG. Furthermore, the use of hydrogel for embedding the ATRA-loaded particles can facilitate the immobilization of the drug next to the tumor site. Our current innovative approach has shown the potential to open up new avenues for treatment of GBM, benefiting patients who suffer from this debilitating disease.

Postfunctionalization of Noncationic RNA–Polymer Complexes for RNA Delivery

We present a postfunctionalization strategy to formulate noncationic RNA–polymer complexes for RNA delivery. Utilizing the methylated pyridinium moieties on the polymer, RNA–polymer polyelectrolytes were first formed via electrostatic interaction. Next, the polyelectrolytes were partially cross-linked with dithiothreitol, “locking” the RNA inside the complex and leaving the rest of the N-methylated pyridyl disulfide groups to subsequently react with thiols. We carried out the postfunctionalization using thiolated oligoethylene glycol and removed a majority of the cationic moieties among the RNA–polymer complexes. The strategy facilitates the noncationic RNA–polymer complexes with tunable RNA release rates in the presence of intracellularly abundant glutathione. With significantly reduced cytotoxicity, the resultant complexes protect RNA against the enzymatic degradation by ribonuclease A and fetal bovine serum. Moreover, the RNA–polymer complexes demonstrated successful siRNA delivery and gene specific kn...

Potential core-shell designed scaffolds with a gelatin-based shell in achieving controllable release rates of proteins for tissue engineering approaches.

The biomaterials design as core-shell structures opens a new door to the release of susceptible biomolecules in a controllable manner and enables to place natural biomaterials as shell layers to impart the effective biofunctional features at surfaces. In this study, core-shell designed scaffolds were prepared using coaxial electrospinning with hybrid of gelatin (GT)/polycaprolactone (PCL) at different weight ratios as their shell and protein solution as their core, followed by cross-linking to impart controllable release rates, tunable mechanical properties, and enhanced cytocompatibility. SEM, FM, and TEM confirmed the successful production of uniform core-shell nanofibers and homogeneous protein distribution. Results showed that an increase in GT proportion in the shell resulted in a decrease in fiber diameter, an increase of Young's modulus, and an intense burst release of BSA 0.2% which could be controlled through cross-linking. The mechanical tests revealed that the GT/PCL combining and cross-linking improved mechanical properties which correlated with an increase in spreading and proliferation of HUVECs. A slight burst release was also detected from BSA 0.05% and EGF encapsulated GT73P-cross-linked scaffold which demonstrated their applicability for a controlled release of dilute proteins. We were able to successfully incorporate two types of protein with different concentrations without supporting polymer into the GT shell to provide scaffolds possessing tunable mechanical properties and controllable release rates through blending with PCL at different ratios and/or cross-linking. These findings are promising to promote delivery systems of angiogenic growth factors that are needed a sustained release with different rates at each angiogenesis stage. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2019.