Sequential Release Research Articles

A dual-responsive doxorubicin-indoximod conjugate for programmed chemoimmunotherapy.

Herein we report a dual-responsive doxorubicin–indoximod conjugate (DOXIND) for programmed chemoimmunotherapy. This conjugate is able to release doxorubicin and indoximod upon exposure to appropriate stimuli for synergistic chemotherapy and immunotherapy, respectively. We demonstrate its promoting effects on immune response and inhibiting effects on tumor growth through a series of in vitro and in vivo experiments.

Coprecipitation of actinide peroxide salts in the U-Th and U-Pu systems and their thermal decomposition.

The uranium and plutonium co-conversion process constitutes a continuous subject of interest for MOx fuel fabrication. Among the various routes considered, chemical coprecipitation by the salt effect has been widely investigated regarding its simplicity of integration between the partitioning and purification steps of the PUREX process, and the straightforward recovery of precursors that are easily converted into oxide phases by thermal decomposition. The present study focuses on the coprecipitation behavior of U-Th and U-Pu actinide peroxide mixed systems by examining the precipitation yields and settling properties for nitric acidity in the range of 1 to 3 M and hydrogen peroxide concentration in the range of 4.5 to 7 M. The precipitated solids have been characterized by powder XRD, IR and Raman spectroscopy, laser granulometry and SEM-EDS analyses revealing the synthesis of studtite and actinide(IV) peroxo-nitrates as aggregated particles. The actinide solid phases are uniformly distributed within the filtered cakes. The precursor thermal decomposition results in the formation of oxide phases at low temperature according to a sequential release of water molecules, peroxide ligands and nitrate ions. The calcination step has a limited effect on the morphology of the powders which remain highly divided. The high precipitation rate of actinides makes this chemical route potentially interesting as a co-precipitation process.

PH/Thermosensitive dual-responsive hydrogel based sequential delivery for site-specific acute limb ischemia treatment.

Acute limb ischemia (ALI) is the most severe manifestation of peripheral artery disease, accompanied by pH/temperature-microenvironment changes in two different phases. In the acute phase, temperature and pH are significantly decreased, and reactive oxygen species (ROS) are excessively generated owing to the sharp reduction of blood perfusion. Afterwards, in the chronic phase, although the temperature gradually recovers, angiogenesis is delayed due to chronic vascular injury, skeletal muscle cell apoptosis and endothelial cell dysfunction. Current therapeutic strategies mainly focus on recanalization; however, their effects on scavenging ROS in the acute phase and promoting angiogenesis in the chronic phase are quite limited. Herein, an injectable pH and temperature dual-responsive poloxamer 407 (PF127)/hydroxymethyl cellulose (HPMC)/sodium alginate (SA)-derived hydrogel (FHSgel), encapsulating melatonin and diallyl trisulfide-loaded biodegradable hollow mesoporous silica nanoparticles (DATS@dHMSNs), is developed, which can intelligently respond to the different phases of ALI. In the acute phase of ischemia, the decreased pH results in the rapid release of melatonin to scavenge excessive ischemia-induced ROS. On the other hand, in the chronic repair phase, the recovered temperature triggers the sustained release of DATS@dHMSNs from the FHSgel, thus generating hydrogen sulfide (H2S) to enhance the angiogenesis and microcirculation reconstruction of ischemic limbs.

Anion-responsive self-assembled hydrogels of a phenylalanine-TREN conjugate allow sequential release of propranolol and doxorubicin.

Stimuli-responsive self-assembled and supramolecular hydrogels derived from peptide amphiphiles have opened exciting new avenues in biomedicine and drug delivery. Herein, we screened a series of phenylalanine-amphiphiles possessing polyamine and oxyethylene appendages for their self-assembly and anion-responsiveness and found that the tris(aminoethyl)amine (TREN) containing amphiphile NapF-TREN formed injectable hydrogels that could be disrupted upon the addition of stoichiometric amounts of tetrahedral monovalent anions such as H2PO4- and HSO4-, while the addition of other anions such as Cl-, HPO42-, CO32-, HCO3- or SO42- did not affect the gel stability. The anion-gelator interaction was investigated by 1H and 31P NMR spectroscopy as well as by Isothermal Titration Calorimetry (ITC). These studies confirmed a 1 : 1 stoichiometry and revealed negative enthalpy and negative entropy for the binding of H2PO4- with NapF-TREN. Microscopic investigations by TEM, AFM, and SAXS revealed that H2PO4- anions induced a nanofiber-to-nanoglobule morphological change in the aqueous self-assemblies of NapF-TREN. However, upon ageing the samples, slow reformation of the nanofibers was also observed, reflecting the reversibility of the anion-gelator interaction. The anion- and pH-responsive nature of the NapF-TREN hydrogels was exploited to program sequential release of entrapped drugs propranolol and doxorubicin.

Controlled composite processing based on off‐stoichiometric thiol‐epoxy dual‐curing systems with sequential heat release (SHR)

AbstractControl of curing rate and exothermicity during processing of thermosetting composite materials is essential in order to minimize the formation of internal stresses leading to mechanical and dimensional defects in the samples, especially in thick composite samples. It was recently proposed that sequential heat release, an approach based on the kinetic control of the curing sequence of dual‐curing thermosets, would enable a step‐wise release of the reaction heat and therefore a better control of conversion and temperature profiles during the crosslinking stage. In this article, it is shown experimental proof of this concept obtained by means of an instrumented mold that can be used for the processing of small samples with and without carbon fiber reinforcement. Safe processing scenarios have been defined by numerical simulation using a simplified two‐dimensional heat transfer model and validated experimentally.

Selective attention involves a feature-specific sequential release from inhibitory gating

Selective attention is a fundamental cognitive mechanism that allows our brain to preferentially process relevant sensory information, while filtering out distracting information. Attention is thought to flexibly gate the communication of irrelevant information through top-down alpha-rhythmic (8–12 Hz) functional connections, which influence early visual processing. However, the dynamic effects of top-down influence on downstream visual processing remain unknown. Here, we used electroencephalography to investigate local and network effects of selective attention while subjects attended to distinct features of identical stimuli. We found that attention-related changes in the functional brain network organization emerge shortly after stimulus onset, accompanied by an overall decrease of functional connectivity. Signatures of attentional selection were evident from a sequential release from alpha-band parietal gating in feature-selective areas. The directed connectivity paths and temporal evolution of this release from gating were consistent with the sensory effect of each feature, providing a neural basis for how visual processing quickly prioritizes relevant information in functionally specialized areas.

Valorizing okara waste into nutritionally rich polysaccharide/protein-extracts for co-encapsulation of β-carotene and ferrous sulphate as a potential approach to tackle micronutrient malnutrition

Colossal amounts of food waste are generated and discarded daily at the expense of financial resources and at a detriment to the environment. One such food waste, okara - a soybean by-product, is valorized in this study by upcycling it into nutritional extracts for micronutrients encapsulation. Micronutrient malnutrition, particularly in the developing world, is a major public health challenge. Herein, okara extracts were obtained through a low-cost extraction process and was subsequently developed as an encapsulant material for micronutrients β-carotene, and ferrous sulphate encapsulation, using zein as an excipient. Spray-drying, as a scalable technique, was employed to produce variousformulations which were assessed forrelease profiles, shelf-life, β-carotene antioxidant activity and cell cytotoxicity. Finally, an optimized dual-micronutrient formulation displayed a sequential releasewith ferrous sulphate releasing in simulated gastric fluid, and β-carotene releasing predominantly in simulated intestinal fluid. This sequential release profile favors the absorption of both the micronutrients and could potentially enhance their bioavailability.

A Sequential Dual‐Model Strategy Based on Photoactivatable Metallopolymer for On‐Demand Release of Photosensitizers and Anticancer Drugs (Adv. Sci. 23/2021)

Photoactivatable Metallopolymer In article number 2103334, Zhiyong Wei, Yang Li, Wen Sun, and co-workers demonstrate the on-demand release of photosensitizers and anticancer drugs based on photoactivatable metallopolymer Poly(Ru/PTX). Red light irradiation of polymer nanoparticles directly cleaves the Ru complex and produces 1O2 for photodynamic therapy, and sequentially, the generated 1O2 triggers the release of drugs for chemotherapy. This novel sequential dual-model release strategy creates a synergistic chemo-photodynamic therapy while minimizing the drug leakage.

Adhesive, Stretchable, and Spatiotemporal Delivery Fibrous Hydrogels Harness Endogenous Neural Stem/Progenitor Cells for Spinal Cord Injury Repair.

Aligned fibrous hydrogels capable of recruiting endogenous neural stem/progenitor cells (NSPCs) show great promise in spinal cord injury (SCI) repair. However, the hydrogels suffer from severe issues in close contact with the transected nerve stumps and harnessing the NSPC fate in the lesion microenvironment. Herein, we report aligned collagen-fibrin (Col-FB) fibrous hydrogels with stretchable property, adhesive behavior, and stromal cell-derived factor-1α (SDF1α)/paclitaxel (PTX) spatiotemporal delivery capability. The resultant Col-FB fibrous hydrogels exhibited 1.98 times longer elongation at break (230%), 2.55 times lower Young's modulus (17.93 ± 1.16 KPa), and 2.21 times greater adhesive strength (3.45 ± 0.48 KPa) than collagen (Col) fibrous hydrogels. The soft aligned fibrous hydrogels simulate the oriented microstructure and soft tissue feature of a natural spinal cord and provide elasticity and adhesivity to ensure a persistent close contact with host stumps. The repair of complete transection SCI in rats demonstrates that "middle-to-bilateral" SDF1α gradient release induced endogenous NSPC migration to the lesion site in 10 days, and SDF1α/PTX sequential release promoted neuronal differentiation of the recruited NSPCs over 8 weeks, leading to hind limb locomotion recovery. The presented strategy was proved to be efficient for harnessing endogenous NSPCs, which facilitate SCI repair significantly.

On Demand Sequential Release of (Sub)Micron Particles Controlled by Size and Temperature.

Polymeric devices capable of releasing submicron particles (subMP) on demand are highly desirable for controlled release systems, sensors, and smart surfaces. Here, a temperature-memory polymer sheet with a programmable smooth surface served as matrix to embed and release polystyrene subMP controlled by particle size and temperature. subMPs embedding at 80 °C can be released sequentially according to their size (diameter D of 200nm, 500nm, 1µm) when heated. The differences in their embedding extent are determined by the various subMPs sizes and result in their distinct release temperatures. Microparticles of the same size (D≈ 1µm) incorporated in films at different programming temperatures Tp (50, 65, and 80 °C) lead to a sequential release based on the temperature-memory effect. The change of apparent height over the film surface is quantified using atomic force microscopy and the realization of sequential release is proven by confocal laser scanning microscopy. The demonstration and quantification of on demand subMP release are of technological impact for assembly, particle sorting, and release technologies in microtechnology, catalysis, and controlled release.

Spatiotemporal regulation of endogenous MSCs using a functional injectable hydrogel system for cartilage regeneration

Hydrogels have been extensively favored as drug and cell carriers for the repair of knee cartilage defects. Recruiting mesenchymal stem cells (MSCs) in situ to the defect region could reduce the risk of contamination during cell delivery, which is a highly promising strategy to enhance cartilage repair. Here, a cell-free cartilage tissue engineering (TE) system was developed by applying an injectable chitosan/silk fibroin hydrogel. The hydrogel system could release first stromal cell-derived factor-1 (SDF-1) and then kartogenin (KGN) in a unique sequential drug release mode, which could spatiotemporally promote the recruitment and chondrogenic differentiation of MSCs. This system showed good performance when formulated with SDF-1 (200 ng/mL) and PLGA microspheres loaded with KGN (10 μΜ). The results showed that the hydrogel had good injectability and a reticular porous structure. The microspheres were distributed uniformly in the hydrogel and permitted the sequential release of SDF-1 and KGN. The results of in vitro experiments showed that the hydrogel system had good cytocompatibility and promoted the migration and differentiation of MSCs into chondrocytes. In vivo experiments on articular cartilage defects in rabbits showed that the cell-free hydrogel system was beneficial for cartilage regeneration. Therefore, the composite hydrogel system shows potential for application in cell-free cartilage TE.

General Synthesis of Multiple-Cores@Multiple-Shells Hollow Composites and Their Application to Lithium-Ion Batteries.

Rational nanostructure design has proved fruitful in addressing the bottlenecks of diverse fields. Especially hollow multi-shelled structures (HoMS) have stood out due to their temporal-spatial ordering mass transfer and buffering effect. Localizing multiple cores in a HoMS is highly desired, which could endow it with more fascinating properties. However, such a structure has been barely reported due to the highly challenging fabrication. Here, we develop a controllable synthesis strategy to realize such a structure, which is applicable for diverse cores and shells. Additionally, cores and shells could be tuned to be homogeneous or heterogeneous, with the core and shell number well controlled. In situ TEM analysis verifies that the inner shell confines the expansion orientation of cores, while the outer shell maintains a stable interface. In addition to energy storage, such structure is also promising for multi-drug co-delivery and sequential responsive release as well as tandem catalysis applications.

General Synthesis of Multiple‐Cores@Multiple‐Shells Hollow Composites and Their Application to Lithium‐Ion Batteries

AbstractRational nanostructure design has proved fruitful in addressing the bottlenecks of diverse fields. Especially hollow multi‐shelled structures (HoMS) have stood out due to their temporal–spatial ordering mass transfer and buffering effect. Localizing multiple cores in a HoMS is highly desired, which could endow it with more fascinating properties. However, such a structure has been barely reported due to the highly challenging fabrication. Here, we develop a controllable synthesis strategy to realize such a structure, which is applicable for diverse cores and shells. Additionally, cores and shells could be tuned to be homogeneous or heterogeneous, with the core and shell number well controlled. In situ TEM analysis verifies that the inner shell confines the expansion orientation of cores, while the outer shell maintains a stable interface. In addition to energy storage, such structure is also promising for multi‐drug co‐delivery and sequential responsive release as well as tandem catalysis applications.

Facile Fabrication of Anisotropic Multicompartmental Microfibers Using Charge Reversal Electrohydrodynamic Co-Jetting.

Anisotropic microstructures are utilized in various fields owing to their unique properties, such as reversible shape transitions or on-demand and sequential release of drug combinations. In this study, anisotropic multicompartmental microfibers composed of different polymers are prepared via charge reversal electrohydrodynamic (EHD) co-jetting. The combination of various polymers, such as thermoplastic polyurethane, poly(D,L-lactide-co-glycolide), poly(vinyl cinnamate), and poly(methyl methacrylate), results in microfibers with distinct compositional boundaries. Charge reversal during EHD co-jetting enables facile fabrication of multicompartmental microfibers with the desired composition and tunable inner architecture, broadening their spectrum of potential applications, such as functional microfibers and cell scaffolds with multiple physical and chemical properties.

Bone fracture microenvironment responsive hydrogel for timing sequential release of cargoes

Regulating biological events by releasing bioactive molecules in accordance with the natural repair process is recognized to enable to promote the repair process. To this end, a novel hydrogel delivery system that can respond to the bone fracture microenvironment signal to timingly and sequentially release bioactive molecules was designed for the first time. The hydrogel system was synthesized by Michael addition reaction via maleimide-end-capped eight-armed poly (ethylene glycol) (8-arm-PEG-Mal) and matrix metalloproteinases-7 (MMP7) sensitive peptides. Nanoparticles developed previously by us were employed here to encapsulate the cargoes and release them once taken by cells. One type of cargo-loaded nanoparticles was embedded into the hydrogel through physical embedding, while the other was modified by MMP7 sensitive peptides followed by covalently bonding into the hydrogel. The results showed that 80% of physically embedded nanoparticles could be released in the first three days. Once MMP7 appeared after three days according to the natural regeneration process, the chemically bonded nanoparticles were released sharply along with hydrogel degradation, and the cumulative release could reach 100%. In addition, the hydrogel system was applied to release microRNA (miRNA)-loaded nanoparticles to identify its timing sequential release effect. It was also confirmed that the nanoparticles discharged could be taken by macrophages to further regulate their behaviors in the future. Overall, this release system realized the delivery of different cargoes in an accurate and timing sequential way according to the natural principle of bone reconstruction, providing a new design strategy of drug delivery system for accelerating bone tissue repair.

Limited plasticity of anatomical and hydraulic traits in aspen trees under elevated CO2 and seasonal drought.

The timing of abiotic stress elicitors on wood formation largely affects xylem traits that determine xylem efficiency and vulnerability. Nonetheless, seasonal variability of elevated CO2 (eCO2) effects on tree functioning under drought remains largely unknown. To address this knowledge gap, 1-year-old aspen (Populus tremula L.) trees were grown under ambient (±445 ppm) and elevated (±700 ppm) CO2 and exposed to an early (spring/summer 2019) or late (summer/autumn 2018) season drought event. Stomatal conductance and stem shrinkage were monitored in vivo as xylem water potential decreased. Additional trees were harvested for characterization of wood anatomical traits and to determine vulnerability and desorption curves via bench dehydration. The abundance of narrow vessels decreased under eCO2 only during the early season. At this time, xylem vulnerability to embolism formation and hydraulic capacitance during severe drought increased under eCO2. Contrastingly, stomatal closure was delayed during the late season, while hydraulic vulnerability and capacitance remained unaffected under eCO2. Independently of the CO2 treatment, elastic, and inelastic water pools depleted simultaneously after 50% of complete stomatal closure. Our results suggest that the effect of eCO2 on drought physiology and wood traits are small and variable during the growing season and question a sequential capacitive water release from elastic and inelastic pools as drought proceeds.

Sequential drug delivery by injectable macroporous hydrogels for combined photodynamic-chemotherapy

With hollow mesoporous silica (hMSN) and injectable macroporous hydrogel (Gel) used as the internal and external drug-loading material respectively, a sequential drug delivery system DOX-CA4P@Gel was constructed, in which combretastatin A4 phosphate (CA4P) and doxorubicin (DOX) were both loaded. The anti-angiogenic drug, CA4P was initially released due to the degradation of Gel, followed by the anti-cell proliferative drug, DOX, released from hMSN in tumor microenvironment. Results showed that CA4P was mainly released at the early stage. At 48 h, CA4P release reached 71.08%, while DOX was only 24.39%. At 144 h, CA4P was 78.20%, while DOX release significantly increased to 61.60%, showing an obvious sequential release behavior. Photodynamic properties of porphyrin endow hydrogel (ϕΔ(Gel) = 0.91) with enhanced tumor therapy effect. In vitro and in vivo experiments showed that dual drugs treated groups have better tumor inhibition than solo drug under near infrared laser irradiation, indicating the effectivity of combined photodynamic-chemotherapy.

A Sequential Dual-Model Strategy Based on Photoactivatable Metallopolymer for On-Demand Release of Photosensitizers and Anticancer Drugs.

The synergistic combination of chemotherapy and photodynamic therapy has attracted considerable attention for its enhanced antitumoral effects; however, it remains challenging to successfully delivery photosensitizers and anticancer drugs while minimizing drug leakage at off‐target sites. A red‐light‐activatable metallopolymer, Poly(Ru/PTX), is synthesized for combined chemo‐photodynamic therapy. The polymer has a biodegradable backbone that contains a photosensitizer Ru complex and the anticancer drug paclitaxel (PTX) via a singlet oxygen (1O2) cleavable linker. The polymer self‐assembles into nanoparticles, which can efficiently accumulate at the tumor sites during blood circulation. The distribution of the therapeutic agents is synchronized because the Ru complex and PTX are covalently conjugate to the polymer, and off‐target toxicity during circulation is also mostly avoided. Red light irradiation at the tumor directly cleaves the Ru complex and produces 1O2 for photodynamic therapy. Sequentially, the generated 1O2 triggers the breakage of the linker to release the PTX for chemotherapy. Therefore, this novel sequential dual‐model release strategy creates a synergistic chemo‐photodynamic therapy while minimizing drug leakage. This study offers a new platform to develop smart delivery systems for the on‐demand release of therapeutic agents in vivo.

Characterization, Density and In Vitro Controlled Release Properties of Mimosa (Acacia mearnsii) Tannin Encapsulated in Palm and Sunflower Oils.

Simple SummaryThe utilization of tannin in mitigating enteric methane suffers a setback in terms of dietary intake and digestibility because of the tannin’s astringency and instability in the gastrointestinal tract. Microencapsulation of tannin using lipids could mask its bitter taste and ensure its controlled release at the target site. This study aimed to encapsulate Acacia mearnsii tannin extract with palm and sunflower oils, and to evaluate the efficacy of the encapsulated tannins with regards to encapsulation efficiency, density, and release of tannin in media, simulating the rumen, abomasum and the small intestine. Mimosa tannin was encapsulated in palm oil or sunflower oil using a double emulsion method. The findings showed that encapsulated mimosa tannins in the palm oil and sunflower oil had high encapsulation efficiencies with smaller sizes and were lower in density compared to the unencapsulated mimosa tannin. The amount of tannins released by the unencapsulated tannin after 24 h in rumen (94%), abomasum (92%) and small intestine (96%) simulated buffers, were reduced to 24%, 21% and 19%, respectively, for the sunflower oil microparticle and 18%, 20% and 16%, respectively, for the palm oil microparticle in the same buffers and periods. Palm oil and sunflower oil successfully encapsulated the mimosa tannin and controlled its release in the gastrointestinal tract simulated media without compromising rumen fermentation.Tannin has gained wider acceptance as a dietary supplement in contemporary animal nutrition investigations because of its potential to reduce enteric methane emission. However, a major drawback to dietary tannin intake is the bitter taste and instability in the gastrointestinal tract (GIT). The utilization of fats as coating materials will ensure appropriate masking of the tannin’s aversive taste and its delivery to the target site. The aims of this study were to encapsulate mimosa tannin with palm oil or sunflower oil, and to assess the microcapsules in terms of encapsulation efficiency, morphology, density, and in vitro release of tannin in media simulating the rumen (pH 5.6), abomasum (pH 2.9) and small intestine (pH 7.4). The microencapsulation of mimosa tannin in palm or sunflower oils was accomplished using a double emulsion technique. The results revealed that encapsulated mimosa tannins in palm oil (EMTP) and sunflower oil (EMTS) had high yields (59% vs. 58%) and encapsulation efficiencies (70% vs. 68%), respectively. Compared to unencapsulated mimosa tannin (UMT), the morphology showed that the encapsulated tannins were smaller in size and spherical in shape. The UMT had (p < 0.01) higher particle density (1.44 g/cm3) compared to 1.22 g/cm3 and 1.21 g/cm3 for the EMTS and EMTP, respectively. The proportion of tannins released by the UMT after 24 h in the rumen (94%), abomasum (92%) and small intestine (96%) simulated buffers, reduced (p < 0.01) to 24%, 21% and 19% for the EMTS and 18%, 20% and 16% for the EMTP in similar media and timeframe. The release kinetics for the encapsulated tannins was slow and steady, thus, best fitted by the Higuchi model while the UMT dissolved quickly, hence, only fitted to a First order model. Sequential tannin release also indicated that the EMTS and EMTP were stable across the GIT. It was concluded that the microencapsulation of mimosa tannin in palm or sunflower oils stabilized tannins release in the GIT simulated buffers with the potential to modify rumen fermentation. Further studies should be conducted on the palm and sunflower oils microcapsules’ lipid stability, fatty acid transfer rate in the GIT and antioxidant properties of the encapsulated tannins.

Recognizing the Role of the Posterolateral Corner in Patients Undergoing Total Knee Arthroplasty for Fixed Varus Deformity.

PurposeVarus deformity is the commonest presentation of the arthritic knee requiring surgical intervention. While correctable deformities lend themselves to realignment options like unicompartmental replacement, fixed deformities often need a total knee replacement. Current treatment options for patients with fixed coronal varus malalignment undergoing total knee arthroplasty include varying degrees of medial soft tissue releases, often leading to infringement of the medial collateral ligament complex and increased use of constrained options. We describe the role of the posterolateral (PL) tether in a select subgroup of patients needing release to achieve correction and minimising use of constrained options.Patients and MethodsA total of 384 patients with fixed varus deformity were retrospectively evaluated and categorised on the basis of weight bearing x-rays into four groups, namely, knees with angulation (F1), angulation with subluxation and torsion (F2), medial translation (F3) and deformity with major medial bone loss (F4). From this cohort, we identified patients with a tight PL tether that needed release to achieve good correction. These were predominantly in the F2 and F3 subgroups. Functional scores and outcomes were evaluated at a mean follow-up of 120.23 months.ResultsF1 cohort achieved good correction with medial soft tissue release, while F2 and F3 cohorts often needed a PL release. While functional outcomes and scores were comparable in both groups, survivorship was better in the group where release was done.ConclusionWe recognise the role of the PL tether in a subgroup of patients with recalcitrant fixed varus deformities. Sequential release helped achieve good outcomes with minimal use of constrained options.Level of EvidenceThree.