Temporal Delivery Research Articles

Enhancing COVID-19 Vaccine Efficacy: Dual Adjuvant Strategies with TLR7/8 Agonists and Glycolipids.

The controlled release of immunostimulatory agents represents a promising strategy to enhance vaccine efficacy while minimizing side effects. This study aimed to improve the efficacy of the RBD-Fc-based COVID-19 vaccine through combining of an iNKT cell agonist and a TLR7/8 agonist using covalent conjugation and temporal delivery. We hypothesized that these combinations would yield a more balanced Th1/Th2 immune response. For covalent conjugation, we employed an uncleavable linker and a self-immolative disulfide linker to conjugate α-galactosylceramide (αGC) to imidazoquinoline (IMDQ). The αGC-SS-IMDQ-Ac conjugate, designed with a prodrug strategy for controlled TLR7/8 agonist release, elicited a higher IFN-γ/IL-4 T cell response ratio than individual adjuvants or their admixture. In the temporal delivery approach, administering IMDQ followed by αGC after 2 h resulted in the highest IgG2a/IgG1 ratio, significantly surpassing other groups. A 6 h delay between glycolipid and IMDQ injections yielded balanced IgG responses, enhancing IgG, IgG1, and IgG2a levels synergistically.

Design of an Efficient QOS Aware Trust-Based Security Model with Bioinspired Sidechains for Healthcare Deployments

Increased adoption of blockchain technology in healthcare systems has paved the way for transparent and secure data management. However, the inherent difficulties of scalability, performance, and security in blockchain networks necessitate the development of efficient models to ensure Quality of Service (QoS) and reliability. In this paper, we propose a novel QoS-aware trust-based security model for healthcare blockchain deployments that addresses these challenges by taking temporal energy consumption, temporal delay, temporal throughput, and temporal Packet Delivery Ratio (PDR) levels into account when selecting miner nodes. For efficient miner node selection, our model employs trust-based analysis. While for the formation of sidechains an efficient Grey Wolf Optimizer (GWO) Model is used, which is a metaheuristic technique inspired by hunting behaviour of Wolves in real-time scenarios. Effectively balancing the trade-off between exploration and exploitation, the GWO algorithm enables the selection of optimal miner nodes that meet the desired QoS requirements. By incorporating temporal metrics, our model adapts dynamically to changing network conditions, ensuring optimal resource utilization and enhanced network performance levels. To assess the efficacy of our proposed model, we ran extensive simulations and compared its performance to that of existing sidechaining models. The outcomes demonstrate significant enhancements in multiple aspects. In comparison to state-of-the-art sidechaining models, our model achieves an impressive 8.5% reduction in delay, 3.9% reduction in energy consumption, 4.5% increase in throughput, and 2.5% improvement in PDR levels. These enhancements demonstrate the efficacy and efficiency of our healthcare blockchain deployment models. The proposed model has applications in a variety of real-time healthcare scenarios. It can be used in electronic health record (EHR) systems where data integrity, confidentiality, and accessibility are crucial. By ensuring QoS-aware miner node selection, our model contributes to dependable and efficient data management, allowing for streamlined access to patient records while maintaining the necessary security standards. Moreover, the trust-based approach of our model improves the overall security of healthcare blockchain deployments. Our model reduces the risks associated with malicious or compromised miner nodes by incorporating trustworthiness metrics such as reputation and behavior analysis. This is especially important in the healthcare industry, where the sensitive nature of patient data necessitates stringent security measures.

Dosimetric calibration of anatomy-specific ultra-high dose rate electron irradiation platform for preclinical FLASH radiobiology experiments.

FLASH radiation therapy (RT) offers a promising avenue for the broadening of the therapeutic index. However, to leverage the full potential of FLASH in the clinical setting, an improved understanding of the biological principles involved is critical. This requires the availability of specialized equipment optimized for the delivery of conventional (CONV) and ultra-high dose rate (UHDR) irradiation for preclinical studies. One method to conduct such preclinical radiobiological research involves adapting a clinical linear accelerator configured to deliver both CONV and UHDR irradiation. We characterized the dosimetric properties of a clinical linear accelerator configured to deliver ultra-high dose rate irradiation to two anatomic sites in mice and for cell-culture FLASH radiobiology experiments. Delivered doses of UHDR electron beams were controlled by a microcontroller and relay interfaced with the respiratory gating system. We also produced beam collimators with indexed stereotactic mouse positioning devices to provide anatomically specific preclinical treatments. Treatment delivery was monitored directly with an ionization chamber, and charge measurements were correlated with radiochromic film measurements at the entry surface of the mice. The setup for conventional dose rate irradiation utilized the same collimation system but at increased source-to-surface distance. Monte Carlo simulations and film dosimetry were used to characterize beam properties and dose distributions. The mean electron beam energies before the flattening filter were 18.8 MeV (UHDR) and 17.7 MeV (CONV), with corresponding values at the mouse surface of 17.2 and 16.2 MeV. The charges measured with an external ion chamber were linearly correlated with the mouse entrance dose. The use of relay gating for pulse control initially led to a delivery failure rate of 20% (±1 pulse); adjustments to account for the linac latency improved this rate to<1/20. Beam field sizes for two anatomically specific mouse collimators (4 × 4 cm2 for whole-abdomen and 1.5 × 1.5 cm2 for unilateral lung irradiation) were accurate within<5% and had low radiation leakage (<4%). Normalizing the dose at the center of the mouse (∼0.75cm depth) produced UHDR and CONV doses to the irradiated volumes with>95% agreement. We successfully configured a clinical linear accelerator for increased output and developed a robust preclinical platform for anatomically specific irradiation, with highly accurate and precise temporal and spatial dose delivery, for both CONV and UHDR irradiation applications.

3D bioprinting of dense cellular structures within hydrogels with spatially controlled heterogeneity

Embedded bioprinting is an emerging technology for precise deposition of cell-laden or cell-only bioinks to construct tissue like structures. Bioink is extruded or transferred into a yield stress hydrogel or a microgel support bath allowing print needle motion during printing and providing temporal support for the printed construct. Although this technology has enabled creation of complex tissue structures, it remains a challenge to develop a support bath with user-defined extracellular mimetic cues and their spatial and temporal control. This is crucial to mimic the dynamic nature of the native tissue to better regenerate tissues and organs. To address this, we present a bioprinting approach involving printing of a photocurable viscous support layer and bioprinting of a cell-only or cell-laden bioink within this viscous layer followed by brief exposure to light to partially crosslink the support layer. This approach does not require shear thinning behavior and is suitable for a wide range of photocurable hydrogels to be used as a support. It enables multi-material printing to spatially control support hydrogel heterogeneity including temporal delivery of bioactive cues (e.g. growth factors), and precise patterning of dense multi-cellular structures within these hydrogel supports. Here, dense stem cell aggregates are printed within methacrylated hyaluronic acid-based hydrogels with patterned heterogeneity to spatially modulate human mesenchymal stem cell osteogenesis. This study has significant impactions on creating tissue interfaces (e.g. osteochondral tissue) in which spatial control of extracellular matrix properties for patterned stem cell differentiation is crucial.

AAPM Task Group Report 267: A joint AAPM GEC-ESTRO report on biophysical models and tools for the planning and evaluation of brachytherapy.

Brachytherapy utilizes a multitude of radioactive sources and treatment techniques that often exhibit widely different spatial and temporal dose delivery patterns. Biophysical models, capable of modeling the key interacting effects of dose delivery patterns with the underlying cellular processes of the irradiated tissues, can be a potentially useful tool for elucidating the radiobiological effects of complex brachytherapy dose delivery patterns and for comparing their relative clinical effectiveness. While the biophysical models have been used largely in research settings by experts, it has also been used increasingly by clinical medical physicists over the last two decades. A good understanding of the potentials and limitations of the biophysical models and their intended use is critically important in the widespread use of these models. To facilitate meaningful and consistent use of biophysical models in brachytherapy, Task Group 267 (TG-267) was formed jointly with the American Association of Physics in Medicine (AAPM) and The Groupe Européen de Curiethérapie and the European Society for Radiotherapy & Oncology (GEC-ESTRO) to review the existing biophysical models, model parameters, and their use in selected brachytherapy modalities and to develop practice guidelines for clinical medical physicists regarding the selection, use, and interpretation of biophysical models. The report provides an overview of the clinical background and the rationale for the development of biophysical models in radiation oncology and, particularly, in brachytherapy; a summary of the results of literature review of the existing biophysical models that have been used in brachytherapy; a focused discussion of the applications of relevant biophysical models for five selected brachytherapy modalities; and the task group recommendations on the use, reporting, and implementation of biophysical models for brachytherapy treatment planning and evaluation. The report concludes with discussions on the challenges and opportunities in using biophysical models for brachytherapy and with an outlook for future developments.

Investigation of the Impact of Temporal Dose Delivery Patterns of Ion Irradiation with the Local Effect Model.

We present an extension of the Local Effect Model (LEM) to include time-dose relationships for predicting effects of protracted and split-dose ion irradiation at arbitrary LET. With this kinetic extension, the spatial and temporal induction and processing of DNA double strand breaks (DSB) in cellular nuclei can be simulated for a wide range of ion radiation qualities, doses and dose rates. The key concept of the extension is based on the joint spatial and temporal coexistence of initial DSB, leading to the formation of clustered DNA damage on the µm scale (as defined e.g., by the size scale of Mbp chromatin loops), which is considered to have an increased cellular lethality as compared to isolated, single DSB. By simulating the time dependent induction and repair of DSB and scoring of isolated and clustered DSB upon irradiation, the impact of dose rate and split dose on the cell survival probability can be computed. In a first part of this work, we systematically analyze the predicted impact of protraction in dependence of factors like dose, LET, ion species and radiosensitivity as characterized by the photon LQ-parameters. We establish links to common concepts that describe dose rate effects for low LET radiation. We also compare the model predictions to experimental data and find agreement with the general trends observed in the experiments. The relevant concepts of our approach are compared to other models suitable for predicting time effects. We investigate an apparent analogy between spatial and temporal concentration of radiation delivery, both leading to increased effectiveness, and discuss similarities and differences between the general dependencies of these clustering effects on their impacting factors. Finally, we conclude that the findings give additional support for the general concept of the LEM, i.e. the characterization of high LET radiation effects based on the distinction of just two classes of DSB (isolated DSB and clustered DSB).

Stochastic metapopulation dynamics of a threatened amphibian to improve water delivery

AbstractWater extraction and climate change are altering the availability of surface water globally, thereby contributing to amphibian population declines. The managed delivery of water to benefit environmental values (environmental watering) is a promising conservation technique that can support amphibian recruitment and maintain viable populations. Environmental water can be delivered in various spatial patterns and with different frequencies, but comparing the effectiveness of competing strategies is complicated by variable and interactive environmental processes. We built a spatially explicit, stochastic, hydroecological metapopulation model to compare the effects of five environmental‐watering scenarios on the probability of persistence of threatened southern bell frogs (Litoria raniformis) in a major river reach in southern Australia. We compared a no‐intervention control to two managed watering frequencies (moderate and frequent) delivered in two spatial designs (managed wetlands grouped or spread across the reach). More frequent water provision to intervention sites improved the reach‐wide (metapopulation) probability of persistence, and spreading intervention sites across the reach improved persistence more than grouping intervention sites together. When re‐examined under severe drought conditions, L. raniformis had a 0.04 probability of persistence without intervention, which improved to 0.56 with high watering frequency. Model‐guided environmental water provision can improve reach‐wide persistence of amphibian metapopulations by guiding spatial and temporal delivery patterns to reduce the risk of extinction.

Quantitative study of spatial and temporal variation in retinal capillary network perfusion in rat eye by in vivo confocal imaging

Microvascular dysfunction is the underlying pathological process in many systemic diseases. However, investigation into its pathogenesis is impeded by the accessibility and complexity of the microvasculature within different organs, particularly for the central nervous system. The retina as an extension of the cerebrum provides a glimpse into the brain through which the microvasculature can be observed. Two major questions remain unanswered: How do the microvessels regulate spatial and temporal delivery to satisfy the varying cellular demands, and how can we quantify blood perfusion in the 3D capillary network? Here, quantitative measurements of red blood cell (RBC) speed in each vessel in the field were made in the in vivo rat retinal capillary network using an ultrafast confocal technique with fluorescently labelled RBCs. Retinal RBC speed and number were found to vary remarkably between microvessels ranging from 215 to 6641 microns per second with significant variations spatially and temporally. Overall, the RBC speed was significantly faster in the microvessels in the superficial retina than in the deep retina (estimated marginal means of 2405 ± 238.2 µm/s, 1641 ± 173.0 µm/s respectively). These observations point to a highly dynamic nature of microvasculature that is specific to its immediate cellular environment and is constantly changing.

Advancements in Macrophage-Targeted Drug Delivery for Effective Disease Management.

Macrophages play a crucial role in tissue homeostasis and the innate immune system. They perform essential functions such as presenting antigens, regulating cytokines, and responding to inflammation. However, in diseases like cancer, cardiovascular disorders, and autoimmune conditions, macrophages undergo aberrant polarization, which disrupts tissue regulation and impairs their normal behavior. To address these challenges, there has been growing interest in developing customized targeted drug delivery systems specifically designed for macrophage-related functions in different anatomical locations. Nanomedicine, utilizing nanoscale drug systems, offers numerous advantages including improved stability, enhanced pharmacokinetics, controlled release kinetics, and precise temporal drug delivery. These advantages hold significant promise in achieving heightened therapeutic efficacy, specificity, and reduced side effects in drug delivery and treatment approaches. This review aims to explore the roles of macrophages in major diseases and present an overview of current strategies employed in targeted drug delivery to macrophages. Additionally, this article critically evaluates the design of macrophage-targeted delivery systems, highlighting limitations and discussing prospects in this rapidly evolving field. By assessing the strengths and weaknesses of existing approaches, we can identify areas for improvement and refinement in macrophage-targeted drug delivery.

DFQIoV: Design of a Dynamic Fan-Shaped-Clustering Model for QoS-aware Routing in IoV Networks

Internet of Vehicles (IoV) is a steadily growing field of research that deals with highly ad-hoc wireless networks. These networks require design of high-speed &amp; high-efficiency routing models, that can be applied to dynamically changing network scenarios. Existing models that perform this task are highly complex and require larger delays for estimation of dynamic routes. While, models that have faster performance, do not consider comprehensive parameters, which limits their applicability when used for large-scale network scenarios. To overcome these limitations, this text proposes design of a novel dynamic fan-shaped clustering model for QoS-aware routing in IoV networks. The model initially collects network information sets including node positions, &amp; energy levels, and combines them with their temporal packet delivery &amp; throughput performance levels. These aggregated information sets are processed via a hybrid bioinspired fan shaped clustering model, that aims at optimization of routing performance via deployment of dynamic clustering process. The model performs destination-aware routing process which assists in reducing communication redundances. This is done via a combination of Elephant Herding Optimization (EHO) with Particle Swarm Optimization (PSO), which integrates continuous learning for router level operations. The integrated model is able to reduce communication delays by 5.9%, while improving energy efficiency by 8.3%, throughput by 4.5%, and packet delivery performance by 1.4% under different network scenarios. Due to which the proposed model is capable of deployment for a wide variety of dynamic network scenarios.

How Does Temporal and Sequential Delivery of Multiple Growth Factors Affect Vascularization Inside 3D Hydrogels?

AbstractVasculogenesis and angiogenesis are leveraged by orchestrated secretion of several growth factors. Mimicking this process in vitro can maximize vascularization inside 3D cell cultures. While the role of individual growth factors, such as vascular endothelial growth factor, Ephrin‐B2, angiopoietins, and platelet‐derived growth factor‐BB (PDGF‐BB) is well studied, the temporal influence of growth factor secretion, and the effect of their concentrations and combinations on in vitro vascularization inside hydrogels, have not been systematically investigated. Here, combinations of angiopoietin‐1, angiopoietin‐2, and PDGF‐BB improve vascularization of a human umbilical vein endothelial cells‐fibroblast coculture inside polyethylene glycol‐based hydrogels the most, while the optimal concentrations and time points of growth factor addition are determined. Moreover, fibroblasts, pericytes, and mesenchymal stem cells (MSCs) are compared as supporting cells, of which MSCs best promote vascularization in coculture. Additionally, the resulting blood vessels align with magnetically oriented rod‐shaped microgels when cultured inside the Anisogel. To mimic fibrosis, transforming growth factor‐beta is added, resulting in significantly smaller vessels and more collagen secretion. This in vitro study reveals that a cascade of growth factors can improve vascular formation in 3D hydrogels, which is important to create viable tissue‐engineered constructs for therapies and in vitro healthy and diseased tissue models.

Computational and experimental characterizations of the spatiotemporal activity and functional role of TGF-β in the synovial joint

TGF-β is a prominent anabolic signaling molecule associated with synovial joint health. Recent work has uncovered mechanochemical mechanisms that activate the latent form of TGF-β (LTGF-β) in the synovial joint—synovial fluid (SF) shearing or cartilage compression—pointing to mechanobiological phenomena, whereby enhanced TGF-β activity occurs during joint stimulation. Here, we implement computational and experimental models to better understand the role of mechanochemical-activated TGF-β (aTGF-β) in regulating the functional biosynthetic activities of synovial joint tissues. Reaction-diffusion models describe the pronounced role of extracellular chemical reactions—load-induced activation, reversible ECM-binding, and cell-mediated internalization—in modulating the spatiotemporal distribution of aTGF-β in joint tissues. Of note, aTGF-β from SF shearing predominantly acts on cells in peripheral tissue regions (superficial zone [SZ] chondrocytes and synoviocytes) and aTGF-β from cartilage compression acts on chondrocytes through all cartilage layers. Further, ECM reversible binding sites in cartilage act to modulate the temporal delivery of aTGF-β to cells, creating a dynamic where short durations of joint activity give rise to extended periods of aTGF-β exposure at moderated doses. Ex vivo tissue models were subsequently utilized to characterize the influence of physiologic aTGF-β activity regimens in regulating functional biosynthetic activities. Physiologic exposure regimens of aTGF-β in SF induce strong 4-fold to 9-fold enhancements in the secretion rate of the synovial biolubricant, PRG4, from SZ cartilage and synovium explants. Further, aTGF-β inhibition in cartilage over 1-month culture leads to a pronounced loss of GAG content (30–35% decrease) and tissue softening (60–65% EY reduction). Overall, this work advances a novel perspective on the regulation of TGF-β in the synovial joint and its role in maintaining synovial joint health.

Structure of breeding calls in three closely related bird species (Calidris Merrem, 1804; Scolopacidae)

We studied calls of three sandpiper species to document species’ similarities and differences. We hypothesized that functionally different calls would differ in degree of divergence. We studied two nuptial calls (complex “Song” and rhythmically repeated aerial call, RRC) of males, and a general-purpose call (“alarm” trill, AT) given by parents of both sexes in the presence of humans and other potential predators, in great knot, Calidris tenuirostris (Horsfeld, 1821); surfbird, Calidris virgata (Gmelin, 1789); and red knot, Calidris canutus (Linnaeus, 1758). Calls diverged unevenly across species—RRCs and Song diverged the most and ATs the least. Vocalizations of great knot and surfbird were most similar to one another, in agreement with a recently proposed phylogeny. Despite species differences in single acoustic traits, calls were evolutionarily conservative at higher structural levels, such as rhythmic temporal delivery of RRCs and harmonic structure (e.g., the fundamental frequency was suppressed in some call types). Some acoustic qualities that differed across species were similar across call types within species (e.g., tonality in red knot calls). Trait similarity across different calls suggests that a species’ calls cannot evolve independently of one another: common mechanisms of vocal production across different calls may impede differentiation within a species’ repertoire.

Postoperative Antibiotics Confer No Protective Association After Fat Grafting for Breast Reconstruction.

Autologous fat grafting after breast reconstruction is a commonly used technique to address asymmetry and irregularities in breast contour. While many studies have attempted to optimize patient outcomes after fat grafting, a key postoperative protocol that lacks consensus is the optimal use of perioperative and postoperative antibiotics. Reports suggest that complication rates for fat grafting are low relative to rates after reconstruction and have been shown to not be correlated to antibiotic protocol. Studies have additionally demonstrated that the use of prolonged prophylactic antibiotics do not lower the complication rates, stressing the need for a more conservative, standardized antibiotic protocol. This study aims to identify the optimal use of perioperative and postoperative antibiotics that optimizes patient outcomes. Patients in the Optum Clinformatics Data Mart who underwent all billable forms of breast reconstruction followed by fat grafting were identified via Current Procedural Terminology codes. Patients meeting inclusion criteria had an index reconstructive procedure at least 90 days before fat grafting. Data concerning these patient's demographics, comorbidities, breast reconstructions, perioperative and postoperative antibiotics, and outcomes were collected via querying relevant reports of Current Procedural Terminology; International Classification of Diseases, Ninth Revision; International Classification of Diseases, Tenth Revision; National Drug Code Directory, and Healthcare Common Procedure Coding System codes. Antibiotics were classified by type and temporal delivery: perioperatively or postoperatively. If a patient received postoperative antibiotics, the duration of antibiotic exposure was recorded. Outcomes analysis was limited to the 90-day postoperative period. Multivariable logistic regression was performed to ascertain the effects of age, coexisting conditions, reconstruction type (autologous or implant-based), perioperative antibiotic class, postoperative antibiotic class, and postoperative antibiotic duration on the likelihood of any common postoperative complication occurring. All statistical assumptions made by logistic regression were met successfully. Odds ratios and corresponding 95% confidence intervals were calculated. From more than 86 million longitudinal patient records between March 2004 and June 2019, our study population included 7456 unique records of reconstruction-fat grafting pairs, with 4661 of those pairs receiving some form of prophylactic antibiotics. Age, prior radiation, and perioperative antibiotic administration were consistent independent predictors of increased all-cause complication likelihood. However, administration of perioperative antibiotics approached a statistically significant protective association against infection likelihood. No postoperative antibiotics of any duration or class conferred a protective association against infections or all-cause complications. This study provides national, claims-level support for antibiotic stewardship during and after fat grafting procedures. Postoperative antibiotics did not confer a protective benefit association against infection or all-cause complication likelihood, while administering perioperative antibiotics conferred a statistically significant increase in the likelihood that a patient experienced postoperative complication. However, perioperative antibiotics approach a significant protective association against postoperative infection likelihood, in line with current guidelines for infection prevention. These findings may encourage the adoption of more conservative postoperative prescription practices for clinicians who perform breast reconstruction, followed by fat grafting, reducing the nonindicated use of antibiotics.

Computation of Voxel-by-Voxel Dose Rates in Patients for Proton Pencil Beam Dose Delivery

<h3>Purpose/Objective(s)</h3> Proton beam radiotherapy is most commonly delivered using the pencil beam scanning (PBS) technique. However, the vast majority of clinical outcome data is based on patients treated with the passive scattering technique. The overall dose distributions delivered with these techniques are fairly similar, with an advantage in conformity noted for PBS. Major differences between these two modalities can be observed in the temporal dose delivery pattern. The passive scattering technique uniformly delivers dose across the cross section of the entire target simultaneously, while the dose in PBS is delivered point-by-point, resulting in a much higher local instantaneous dose rate. Recent studies have shown that ultra-high dose rate (FLASH) irradiations can change the biological response to radiation. This work presents an analytical tool to compute voxel-wise maximum dose rates for clinical PBS treatment plans. <h3>Materials/Methods</h3> The scripting environment of our treatment planning system was used to develop software to compute dose rate distributions for clinical pencil beam scanning treatment plans. The basis of the computation is an accurate model of the delivery timing properties of the accelerator and scanning system. The minimum temporal resolution supported is 1 ms. This captures the timing of single spots but excludes the beam pulse structure of our cyclotron (ns). With the timing model and a given spot map we compute the average dose rate over a time interval of interest for each voxel. The latter is an input parameter determined by the user. To validate the tool, test beams in a simple solid water geometry were generated in the treatment planning system and corresponding dose rate distributions produced. Single point measurements with custom-made diode and electronics were used to verify computations against experimentation for a range of proton energies and depths. <h3>Results</h3> For dose rate calculations recording the maximum value observed in any 1 ms time interval during the field's delivery, we observe peak values of 186 Gy/min and 273 Gy/min for 110 MeV and 150 MeV protons, respectively. On average, the agreement of calculations and measurements was -0.9% with a standard deviation of 4.1%. <h3>Conclusion</h3> The software enables accurate local instantaneous dose rate calculations for clinically deliverable treatment plans. This may be important to use as a basis to better understand clinical results. In addition to standard PBS treatments, the observed dose rates may be relevant when considering the out of field areas in FLASH treatments.

Interpolyelectrolyte Complexes as an Emerging Technology for Pharmaceutical Delivery of Polypeptides

Polyelectrolyte complexes and the derivatives thereof comprise some of the most promising vehicles for the encapsulation and delivery of macromolecular therapeutics. In particular, protein therapeutics, which present a host of special considerations, can often be effectively packaged and delivered using interpolyelectrolyte complexes. While the technologies are still in the developmental phase, there are numerous examples of complexes where control is exerted over spacial and temporal delivery of a model protein cargo or candidate protein therapeutic agent. Here we provide a historical and practical background to promote a deeper understanding of interpolyelectrolyte complexes and the derivative technologies. Additionally, we review the physical principles underlying the association of polyelectrolyte complexes and the application of those principles to novel strategies and technologies driving interpolyelectrolyte complexation. Then, the application of polyelectrolyte complex technology to protein therapeutics is discussed in detail including discussions of several types of protein cargo with a special emphasis on Brain-Derived Neurotrophic Factor. Finally, we focus on the use of stealth polymers in block ionomer complexes, specifically PEG; its benefits, flaws, and possible alternatives. Comprehensive understanding of the field may promote the continued development of derivative technologies for the delivery of particularly intransigent protein therapeutics, much as has been accomplished for small molecule drugs. We also aim to link current advances to the historical developments which inaugurated the field. With consideration to the field, industrial and academic researchers can utilize the discussed technologies and continue to elucidate novel modalities for a myriad of therapeutic and commercial applications.

Temporal grafter network: Rethinking LSTM for effective video recognition

Long short-term memory (LSTM) networks are widely used to handle temporal or sequential data, and have great potential for video recognition. Existing LSTM-based video recognition methods either insert LSTM modules at the end of 2D convolutional neural networks (CNNs), called global LSTM methods, or build networks solely by stacking multiple LSTM modules. Unfortunately, these LSTM-based video recognition methods are not competitive, compared to state-of-the-art 3D CNNs or two-stream CNNs. In order to fully explore the potential of LSTM, this paper rethinks its role in video recognition network architectures and proposes a novel Temporal Grafter Network (TGN). Specifically, we develop an efficient and effective variant of convolutional LSTM module, which is grafted between different stages of very deep 2D CNNs for temporal modeling and delivery. Our TGN can capture local motion patterns of varying scales inherent in feature maps from high to low resolutions, while attending to the spatial context information and modeling global temporal dependency across the whole video. The proposed TGN can capture and transmit temporal information throughout very deep 2D CNNs, overcoming the downsides of existing LSTM-based methods and being able to make full use of the potential of LSTM for effective video recognition and early action recognition. We perform extensive ablation study to verify the effectiveness of our proposed methods, and experiments on three widely used video benchmarks show that our methods can achieve performance matching or better than the state-of-the-arts.

Lipid-based Nanocarriers Loaded with Taxanes for the Management of Breast Cancer: Promises and Challenges

Breast cancer is the leading cause of deaths worldwide among women. Taxanes (most propitious class of diterpenes) have shown dynamic potentials in the treatment of early and metastatic breast cancer. However, challenges like poor bioavailability, low tissue-permeability, compromised aqueous solubility, and dose-dependent side-effects limit the clinical applications of these drugs. Henceforth, to overcome these challenges, various nanotechnology-based drug delivery systems are being explored for the delivery of taxanes in the management of breast cancer. One such promising nanocarrier category is lipid-based nanocarriers, which employ the meritorious features of a variety of lipids, both of natural and synthetic origin. It is also known that lipid uptake plays a significant role in breast cancer cells proliferation and tumor genesis. However, lipid-based nanocarriers could be a great choice to nanoencapsulate the poorly soluble and permeable taxanes for breast cancer management. These systems have an immense promise of bioavailability enhancement, spatial and temporal taxane delivery, improved efficacy, reduced dosing frequency, and even mild inhibition of the P-gp efflux mechanism. Apart from these promises, these carriers are not yet available for the benefit of the end-user. The present review will not only discuss the merits, progress, and promises of these systems but also ponder upon the various challenges faced by these carriers to reach the clinics for the benefit of the patients afflicted with breast cancer.

Overview on pulsatile drug delivery system

Traditionally, drugs are released in an immediate or extended fashion. However, in recent years, pulsatile drug release systems are gaining growing interest. Pulsatile drug delivery systems are developed to deliver drug according to circadian behavior of diseases. The product follow a sigmoidal drug release profile characterized by a time period of no release (lag time) followed by a rapid and complete drug release. Pulsatile systems are gaining a lot of interest as they deliver the drug at the right site of action at the right time and in the right amount, thus providing spatial and temporal delivery and increasing patient compliance. Pulsatile release systems can be classified in multiple-pulse and single-pulse systems. A popular class of single-pulse systems is that of rupturable dosage forms. Other systems consist of a drug-containing core, covered by a swelling layer and an outer insoluble, but semipermeable polymer coating or membrane. The potential benefits of chronotherapeutics have been investigated and established for number of diseases like asthma, arthritis, cancer, diabetes, epilepsy, hypertension, ulcer, hypercholesterolemia etc.

Using UV-Responsive Nanoparticles to Provide In Situ Control of Growth Factor Delivery and a More Constant Release Profile from a Hydrogel Environment.

Nanoparticles are popular delivery vehicles, but their diffusional release results in inconstant drug delivery. Here, we flatten the delivery profile into a more constant, zero-order profile. Brain-derived neurotrophic factor (BDNF) is attached to photoactive titanium dioxide nanoparticles and loaded into a nanofibrous self-assembling peptide (SAP) hydrogel. Different UV exposure conditions show three distinct profiles, including a counterintuitive decrease in release after UV exposure. We propose that the adsorption of the freed growth factor onto the hydrogel nanofibers affects release. Nanoparticles diffuse from the hydrogel readily, carrying the bound growth factor, but the freed growth factor (released from the nanoparticles by UV) instead interacts with─and is released less readily from─the hydrogel. UV shifts growth factor from nanoparticles to the hydrogel, therefore changing the diffusional release. Through midpoint UV exposure, we achieve a flattened delivery profile─unusual for diffusion─by changing in situ the amount of growth factor bound to the diffusing nanoparticles. With nanoparticle diffusion alone, we observed an increasing release profile with 36% of release in the first 6 h and 64% in the second 6 h. With midway UV exposure, this was controlled to 49 and 51%, respectively. The release of an unbound (soluble) control growth factor, glial cell-line derived neurotrophic factor (GDNF), was not affected by UV treatment, demonstrating the potential for independent control of temporal delivery profiles in a multiagent material.