Localized Delivery of Pilocarpine to Hypofunctional Salivary Glands through Electrospun Nanofiber Mats: An Ex Vivo and In Vivo Study.

Dry mouth or xerostomia is a frequent medical condition among the polymedicated elderly population. Systemic pilocarpine is included in the first line of pharmacological therapies for xerostomia. However, the efficacy of existing pilocarpine formulations is limited due to its adverse side effects and multiple daily dosages. To overcome these drawbacks, a localized formulation of pilocarpine targeting the salivary glands (SG) was developed in the current study. The proposed formulation consisted of pilocarpine-loaded Poly(lactic-co-glycolic acid) (PLGA)/poly(ethylene glycol) (PEG) nanofiber mats via an electrospinning technique. The nanofiber mats were fully characterized for their size, mesh porosity, drug encapsulation efficiency, and in vitro drug release. Mat biocompatibility and efficacy was evaluated in the SG organ ex vivo, and the expression of proliferation and pro-apoptotic markers at the cellular level was determined. In vivo short-term studies were performed to evaluate the saliva secretion after acute SG treatment with pilocarpine-loaded nanofiber mats, and after systemic pilocarpine for comparison purposes. The outcomes demonstrated that the pilocarpine-loaded mats were uniformly distributed (diameter: 384 ± 124 nm) in a highly porous mesh, and possessed a high encapsulation efficiency (~81%). Drug release studies showed an initial pilocarpine release of 26% (4.5 h), followed by a gradual increase (~46%) over 15 d. Pilocarpine-loaded nanofiber mats supported SG growth with negligible cytotoxicity and normal cellular proliferation and homeostasis. Salivary secretion was significantly increased 4.5 h after intradermal SG treatment with drug-loaded nanofibers in vivo. Overall, this study highlights the strengths of PLGA/PEG nanofiber mats for the localized daily delivery of pilocarpine and reveals its potential for future clinical translation in patients with xerostomia.

Codelivery of anti-cancer agents via double-walled polymeric microparticles/injectable hydrogel: A promising approach for treatment of triple negative breast cancer.

Triple negative breast cancer (TNBC) is an aggressive sub-type of breast cancer that rarely responds to conventional chemotherapy. Therefore, novel agents or new routes need to be developed to improve treatment efficacy and diminish severe side-effects of anti-cancer agents in TNBC patients. This study explores a novel localized co-delivery platform with potential application against TNBC. Uniform core-shell microparticles encapsulating cisplatin (Cis-DDP) and paclitaxel (PTX) are fabricated using coaxial electrohydrodynamic atomization technique and subsequently are embedded into an injectable hydrogel. The hydrogel provides an additional diffusion barrier against Cis-DDP and confines premature release of drugs. In addition, the hydrogel can provide a versatile tool for retaining particles in the tumor resected cavity during the injection following debulking surgery and prevent surgical site infection due to its inherent antibacterial properties. The combination of Cis-DDP and PTX demonstrates a synergistic effect against MDA-MB-231 cell line assigned to three different mechanisms of action, including denaturation of DNA strands, stabilization of microtubules, and amplification of intracellular reactive oxygen species (ROS) and activation of caspase-3 pathways. The results show a significant accumulation of mitochondrial ROS insults in cells upon treatment that consequently causes programmed cells death. The performance of microparticles/hydrogel carrier is evaluated against three-dimensional MDA-MB-231 (breast cancer) 3D spheroids, where a superior efficacy and a greater reduction in spheroid growth are observed over 14 days, as compared with free-drug treatment. Overall, drug-loaded core-shell microparticles embedded into injectable hydrogel provides a promising strategy to treat aggressive cancers and a modular platform for a broad range of localized multidrug therapies customizable to the cancer type.

Enhanced intracellular delivery and controlled drug release of magnetic PLGA nanoparticles modified with transferrin.

Owing to the presence of multidrug resistance in tumor cells, conventional chemotherapy remains clinically intractable. To enhance the therapeutic efficacy of chemotherapeutic agents, targeting strategies based on magnetic polymeric nanoparticles modified with targeting ligands have gained significant attention in cancer therapy. In this study, we synthesized transferrin (Tf)-modified poly(D,L-lactic-co-glycolic acid) nanoparticles (PLGA NPs) loaded with paclitaxel (PTX) and superparamagnetic nanoparticle (MNP) using a solid-in-oil-in-water solvent evaporation method, followed by Tf adsorption on the surface of NPs. The Tf-modified magnetic PLGA NPs were characterized in terms of particle morphology and size, magnetic properties, encapsulation efficiency and drug release. Furthermore, the cytotoxicity and cellular uptake of the drug-loaded magnetic PLGA NPs were evaluated in both MCF-7 breast cancer and U-87 glioma cells in vitro. We found that Tf-modified PTX-MNP-PLGA NPs showed the highest cytotoxicity effect and cellular uptake efficiency under Tf receptor mediation in both MCF-7 and U-87 cells compared to unmodified PLGA NPs and free PTX. The cellular uptake efficiency of Tf-modified magnetic PLGA NPs appeared to be facilitated by the applied magnetic field, but the difference did not reach statistical significance. This study illustrates that this proposed formulation can be used as one new alternative treatment for patients bearing inaccessible tumors.

Electrohydrodynamic atomization: A two-decade effort to produce and process micro-/nanoparticulate materials.

Electrohydrodynamic atomization (EHDA), also called electrospray technique, has been studied for more than one century. However, since 1990s it has begun to be used to produce and process micro-/nanostructured materials. Owing to the simplicity and flexibility in EHDA experimental setup, it has been successfully employed to generate particulate materials with controllable compositions, structures, sizes, morphologies, and shapes. EHDA has also been used to deposit micro- and nanoparticulate materials on surfaces in a well-controlled manner. All these attributes make EHDA a fascinating tool for preparing and assembling a wide range of micro- and nanostructured materials which have been exploited for use in pharmaceutics, food, and healthcare to name a few. Our goal is to review this field, which allows scientists and engineers to learn about the EHDA technique and how it might be used to create, process, and assemble micro-/nanoparticulate materials with unique and intriguing properties. We begin with a brief introduction to the mechanism and setup of EHDA technique. We then discuss issues critical to successful application of EHDA technique, including control of composition, size, shape, morphology, structure of particulate materials and their assembly. We also illustrate a few of the many potential applications of particulate materials, especially in the area of drug delivery and regenerative medicine. Next, we review the simulation and modeling of Taylor cone-jet formation for a single and co-axial nozzle. The mathematical modeling of particle transport and deposition is presented to provide a deeper understanding of the effective parameters in the preparation, collection and pattering processes. We conclude this article with a discussion on perspectives and future possibilities in this field.

Injectable hydrogels: An emerging therapeutic strategy for cartilage regeneration.

The impairment of articular cartilage due to traumatic incidents or osteoarthritis has posed significant challenges for healthcare practitioners, researchers, and individuals suffering from these conditions. Due to the absence of an approved treatment strategy for the complete restoration of cartilage defects to their native state, the tissue condition often deteriorates over time, leading to osteoarthritic (OA). However, recent advancements in the field of regenerative medicine have unveiled promising prospects through the utilization of injectable hydrogels. This versatile class of biomaterials, characterized by their ability to emulate the characteristics of native articular cartilage, offers the distinct advantage of minimally invasive administration directly to the site of damage. These hydrogels can also serve as ideal delivery vehicles for a diverse range of bioactive agents, including growth factors, anti-inflammatory drugs, steroids, and cells. The controlled release of such biologically active molecules from hydrogel scaffolds can accelerate cartilage healing, stimulate chondrogenesis, and modulate the inflammatory microenvironment to halt osteoarthritic progression. The present review aims to describe the methods used to design injectable hydrogels, expound upon their applications as delivery vehicles of biologically active molecules, and provide an update on recent advances in leveraging these delivery systems to foster articular cartilage regeneration.

Cytocompatibility and Antibacterial Properties of Coaxial Electrospun Nanofibers Containing Ciprofloxacin and Indomethacin Drugs.

A coaxial nanofibrous scaffold of poly (ε-caprolactone) and gelatin/cellulose acetate encapsulating anti-inflammatory and antibacterial drugs was co-electrospun for skin tissue regeneration. Indomethacin and ciprofloxacin as model drugs were added to the core and the shell solutions, respectively. The effect of the drugs' presence and crosslinking on the scaffold properties was investigated. TEM images confirmed the core−shell structure of the scaffold. The fiber diameter and the pore size of the scaffold increased after crosslinking. The tensile properties of the scaffold improved after crosslinking. The crosslinked scaffold illustrated a higher rate of swelling, and a lower rate of degradation and drug release compared to the uncrosslinked one. Fitting the release data into the Peppas equation showed that Fickian diffusion was the dominant mechanism of drug release from the scaffolds. The results of biocompatibility evaluations showed no cytotoxicity and suitable adhesion and cell growth on the prepared core−shell structure. The antibacterial activity of the scaffolds was studied against one of the most common pathogens in skin wounds, where the existence of ciprofloxacin could prevent the growth of the Staphylococcus aureus bacteria around the scaffold. The obtained results suggested a new coaxial nanofibrous scaffold as a promising candidate for simultaneous tissue regeneration and controlled drug release.

Electrospun Shape Memory Polymer Micro-/Nanofibers and Tailoring Their Roles for Biomedical Applications.

Shape memory polymers (SMPs) as a relatively new class of smart materials have gained increasing attention in academic research and industrial developments (e.g., biomedical engineering, aerospace, robotics, automotive industries, and smart textiles). SMPs can switch their shape, stiffness, size, and structure upon being exposed to external stimuli. Electrospinning technique can endow SMPs with micro-/nanocharacteristics for enhanced performance in biomedical applications. Dynamically changing micro-/nanofibrous structures have been widely investigated to emulate the dynamical features of the ECM and regulate cell behaviors. Structures such as core-shell fibers, developed by coaxial electrospinning, have also gained potential applications as drug carriers and artificial blood vessels. The clinical applications of micro-/nanostructured SMP fibers include tissue regeneration, regulating cell behavior, cell growth templates, and wound healing. This review presents the molecular architecture of SMPs, the recent developments in electrospinning techniques for the fabrication of SMP micro-/nanofibers, the biomedical applications of SMPs as well as future perspectives for providing dynamic biomaterials structures.

Advanced Hydrogels for Cartilage Tissue Engineering: Recent Progress and Future Directions.

Cartilage is a tension- and load-bearing tissue and has a limited capacity for intrinsic self-healing. While microfracture and arthroplasty are the conventional methods for cartilage repair, these methods are unable to completely heal the damaged tissue. The need to overcome the restrictions of these therapies for cartilage regeneration has expanded the field of cartilage tissue engineering (CTE), in which novel engineering and biological approaches are introduced to accelerate the development of new biomimetic cartilage to replace the injured tissue. Until now, a wide range of hydrogels and cell sources have been employed for CTE to either recapitulate microenvironmental cues during a new tissue growth or to compel the recovery of cartilaginous structures via manipulating biochemical and biomechanical properties of the original tissue. Towards modifying current cartilage treatments, advanced hydrogels have been designed and synthesized in recent years to improve network crosslinking and self-recovery of implanted scaffolds after damage in vivo. This review focused on the recent advances in CTE, especially self-healing hydrogels. The article firstly presents the cartilage tissue, its defects, and treatments. Subsequently, introduces CTE and summarizes the polymeric hydrogels and their advances. Furthermore, characterizations, the advantages, and disadvantages of advanced hydrogels such as multi-materials, IPNs, nanomaterials, and supramolecular are discussed. Afterward, the self-healing hydrogels in CTE, mechanisms, and the physical and chemical methods for the synthesis of such hydrogels for improving the reformation of CTE are introduced. The article then briefly describes the fabrication methods in CTE. Finally, this review presents a conclusion of prevalent challenges and future outlooks for self-healing hydrogels in CTE applications.

An empirical model to evaluate the effects of environmental humidity on the formation of wrinkled, creased and porous fibre morphology from electrospinning.

Controlling environmental humidity level and thus moisture interaction with an electrospinning solution jet has led to a fascinating range of polymer fibre morphological features; these include surface wrinkles, creases and surface/internal porosity at the individual fibre level. Here, by cross-correlating literature data of far-field electrospinning (FFES), together with our experimental data from near-field electrospinning (NFES), we propose a theoretical model, which can account, phenomenologically, for the onset of fibre microstructures formation from electrospinning solutions made of a hydrophobic polymer dissolved in a water-miscible or polar solvent. This empirical model provides a quantitative evaluation on how the evaporating solvent vapour could prevent or disrupt water vapor condensation onto the electrospinning jet; thus, on the condition where vapor condensation does occur, morphological features will form on the surface, or bulk of the fibre. A wide range of polymer systems, including polystyrene, poly(methyl methacrylate), poly-L-lactic acid, polycaprolactone were tested and validated. Our analysis points to the different operation regimes associated FFES versus NFES, when it comes to the system's sensitivity towards environmental moisture. Our proposed model may further be used to guide the process in creating desirable fibre microstructure.

Solution Formulation and Rheology for Fabricating Extracellular Matrix-Derived Fibers Using Low-Voltage Electrospinning Patterning.

Composite formation and chemical cross-linking are common strategies in tuning the functionality and performance of biologically derived fibers fabricated by electrospinning. The modification to the initial polymeric solution changes the fiber-processing parameters and the associated fiber morphologies. Here, we investigated the gelatin solution formulation and how the addition of homogenized decellularized matrix particles (dCMps) can alter the processability of gelatin fibers produced by low-voltage electrospinning patterning. To produce water-insoluble fibers, the effect of a cross-linker addition was also separately investigated. In particular, we found that the electrospinnability of the solutions formulated with different concentrations of gelatin and dCMps and the morphology of the electrospun fibers were dependent on the rheological properties of the solutions. The solution dispersion rheology can be used as a useful indicator for guiding fiber processability and the fabrication strategy for patterning. The loss tangent associated with an oscillatory rheological test can be used to indicate the switch from an "extrusion-patterning" to a "drag-patterning" configuration. Fine-tuning of the cross-linking time can switch the thin fibrous film between a woven and a nonwoven structure. This study can be used as a guide to producing extracellular matrix fibers and films with specific microstructures suitable for tissue engineering applications.

Development of Nanoparticles for Drug Delivery to Brain Tumor: The Effect of Surface Materials on Penetration Into Brain Tissue.

Surface-modified poly(d,l-lactic-co-glycolic acid) PLGA nanoparticles (NPs) were fabricated via nanoprecipitation for obtaining therapeutic concentration of paclitaxel (PTX) in brain tumor. The cellular uptake and cytotoxicity of NPs were evaluated on C6 glioma cells in vitro, and BALB/c mice were used to study the brain penetration and biodistribution upon intravenous administration. Results showed that by finely tuning nanoprecipitation parameters, PLGA NPs coated with surfactants with a size around 150 nm could provide a sustained release of PTX for >2 weeks. Surface coatings could increase cellular uptake efficiency when compared with noncoated NPs, and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) showed the most significant enhancement. The in vivo evaluation of TPGS-PLGA NPs showed amplified accumulation (>800% after 96 h) of PTX in the brain tissue when compared with bare NPs and Taxol®. Therefore, PLGA-NPs with PLGA-TPGS coating demonstrate a promising approach to efficiently transport PTX across blood-brain barrier in a safer manner, with the advantages of easy formulation, lower production cost, and higher encapsulation efficiency.

Drug delivery systems for programmed and on-demand release.

With the advancement in medical science and understanding the importance of biodistribution and pharmacokinetics of therapeutic agents, modern drug delivery research strives to utilize novel materials and fabrication technologies for the preparation of robust drug delivery systems to combat acute and chronic diseases. Compared to traditional drug carriers, which could only control the release of the agents in a monotonic manner, the new drug carriers are able to provide a precise control over the release time and the quantity of drug introduced into the patient's body. To achieve this goal, scientists have introduced "programmed" and "on-demand" approaches. The former provides delivery systems with a sophisticated architecture to precisely tune the release rate for a definite time period, while the latter includes systems directly controlled by an operator/practitioner, perhaps with a remote device triggering/affecting the implanted or injected drug carrier. Ideally, such devices can determine flexible release pattern and intensify the efficacy of a therapy via controlling time, duration, dosage, and location of drug release in a predictable, repeatable, and reliable manner. This review sheds light on the past and current techniques available for fabricating and remotely controlling drug delivery systems and addresses the application of new technologies (e.g. 3D printing) in this field.

3D bioprinting of skin tissue: From pre-processing to final product evaluation.

Bioprinted skin tissue has the potential for aiding drug screening, formulation development, clinical transplantation, chemical and cosmetic testing, as well as basic research. Limitations of conventional skin tissue engineering approaches have driven the development of biomimetic skin equivalent via 3D bioprinting. A key hope for bioprinting skin is the improved tissue authenticity over conventional skin equivalent construction, enabling the precise localization of multiple cell types and appendages within a construct. The printing of skin faces challenges broadly associated with general 3D bioprinting, including the selection of cell types and biomaterials, and additionally requires in vitro culture formats that allow for growth at an air-liquid interface. This paper provides a thorough review of current 3D bioprinting technologies used to engineer human skin constructs and presents the overall pipelines of designing a biomimetic artificial skin via 3D bioprinting from the design phase (i.e. pre-processing phase) through the tissue maturation phase (i.e. post-processing) and into final product evaluation for drug screening, development, and drug delivery applications.

Effective co-delivery of nutlin-3a and p53 genes via core-shell microparticles for disruption of MDM2-p53 interaction and reactivation of p53 in hepatocellular carcinoma.

The tumor suppressor protein p53 is the most frequently inactivated, mutated, or deleted transcriptional factor in tumor cells. Recent studies have shown that the negative regulation of p53 by the murine double minute 2 (MDM2) protein in human cells interrupts the p53 apoptotic pathway and causes tumorigenesis. Therefore, the disruption of the MDM2-p53 complex by small molecules such as nutlin-3a and the administration of the active p53 protein can effectively restore the apoptotic activity of the p53 protein in tumor cells. This study aims to introduce a unique combined p53-based gene and chemotherapy approach using core-shell polymeric microparticles for the localized treatment of cancers. Core-shell microparticles were successfully fabricated in a single step using a modified electrohydrodynamic atomization (EHDA) technique, where the core and shell layers were loaded with nutlin-3a and ß-cyclodextrin-g-chitosan/p53 nanoparticles, respectively. The grafting of ß-cyclodextrin (ß-CD) onto chitosan chains demonstrated remarkable cellular uptake (∼5-fold) compared to pure chitosan at N/P = 6, attributed to a strong interaction and temporary disruption of the lipid bilayer in the cell membrane by the synthesized copolymer. The therapeutic efficiencies of single- and dual-agent loaded microparticle formulations were also evaluated and compared against free-drug treatment in terms of cell viability and intracellular expression of p53, caspase 3, and MDM2 proteins via an MTS assay, an enzyme-linked immunosorbent assay, and an immunostaining assay. The results revealed that the controlled and sustained release of both agents from the microparticles synergistically enhanced the anti-proliferative efficacy of the agents via the continuous overexpression of p53 and caspase 3 proteins over 5 days. However, MDM2 protein expression remained at the basal level over that period. The findings also indicated that nutlin-3a could impose excessive oxidative stress on cancer cells, where the overproduction of reactive oxygen species (ROS) with irreversible destructive effects on subcellular organelles such as the nucleus (DNA) and mitochondria could be considered as a secondary apoptotic pathway induced by nutlin-3a. Inspired by the observations, the proposed drug delivery system can serve as a unique and powerful drug and gene delivery system with a far-reaching application in human cancer therapy.

Synthesis of intracellular reduction-sensitive amphiphilic polyethyleneimine and poly(ε-caprolactone) graft copolymer for on-demand release of doxorubicin and p53 plasmid DNA.

UNLABELLED: This study aims to present a new intelligent polymeric nano-system used for combining chemotherapy with non-viral gene therapy against human cancers. An amphiphilic copolymer synthesized through the conjugation of low molecular weight polyethyleneimine (LMw-PEI) and poly(ε-caprolactone) (PCL) via a bio-cleavable disulfide linkage was successfully employed for the simultaneous delivery of drug and gene molecules into target cells. Compared to the conventional PCL copolymerization pathway, this paper represents a straightforward and efficient reaction pathway including the activation of PCL-diol hydroxyl end groups, cystamine attachment and LMw-PEI conjugation which are successfully performed at mild conditions as confirmed by FTIR and (1)H NMR. Thermal, morphological characteristics as well as biocompatibility of the copolymer were investigated. The copolymer showed great tendency to form positively charged nanoparticles (∼163.1nm, +35.3mV) with hydrophobic core and hydrophilic shell compartments implicating its potential for encapsulation of anti-cancer drug and plasmid DNA, respectively. The gel retardation assay confirmed that the nanoparticles could successfully inhibit the migration of pDNA at ∼5 nanoparticle/pDNAw/w. The in vitro cytotoxicity tests and LDH assay revealed that the cationic amphiphilic copolymer was essentially non-toxic in different carcinoma cell lines in contrast to branched PEI 25K. Moreover, the presence of redox sensitive disulfide linkages provided smart nanoparticles with on-demand release behavior in response to reducing agents such as cytoplasmic glutathione (GSH). Importantly, confocal microscopy images revealed that in contrast to free Dox, the nanoparticles were capable of faster internalizing into the cells and accumulating in the perinuclear region or even in the nucleus. Finally, the co-delivery of Dox and p53-pDNA using the copolymer displayed greater cytotoxic effect compared with the Dox-loaded nanoparticle counterpart as revealed by cell viability and Caspase 3 expression assay. These results suggest the copolymer as a promising candidate for the development of smart delivery systems. STATEMENT OF SIGNIFICANCE: We employed cystamine dihydrochloride as a disulfide linkage for the conjugation of PCL diol and low molecular weight PEI segments through a straightforward and efficient reaction pathway at mild conditions. The new copolymer was essentially non-toxic in different carcinoma cell lines and showed great tendency to form positively charged nanoparticles. Therefore, it can be utilized as a promising platform for simultaneous drug and gene delivery to aggressive cancers. The results of drug and gene co-delivery experiments confirmed the pivotal role of disulfide linkage on the controlled release of both drug and gene molecules in response to glutathione concentration gradient between extracellular and intracellular microenvironments. In addition, the co-delivery of doxorubicin and p53 plasmid DNA using the new copolymer displayed greater cytotoxic effect compared with single agent (i.e. Dox) loaded counterpart, which indicated the significance of rapid dissociation of therapeutic agents from the carrier for synergistic cytotoxic effects on cancer cells.

Double-Walled Microparticles-Embedded Self-Cross-Linked, Injectable, and Antibacterial Hydrogel for Controlled and Sustained Release of Chemotherapeutic Agents.

First-line cancer chemotherapy has been prescribed for patients suffered from cancers for many years. However, conventional chemotherapy provides a high parenteral dosage of anticancer drugs over a short period, which may cause serious toxicities and detrimental side effects in healthy tissues. This study aims to develop a new drug delivery system (DDS) composed of double-walled microparticles and an injectable hydrogel for localized dual-agent drug delivery to tumors. The uniform double-walled microparticles loaded with cisplatin (Cis-DDP) and paclitaxel (PTX) were fabricated via coaxial electrohydrodynamic atomization (CEHDA) technique and subsequently were embedded into injectable alginate-branched polyethylenimine. The findings show the uniqueness of CEHDA technique for simply swapping the place of drugs to achieve a parallel or a sequential release profile. This study also presents the simulation of CEHDA technique using computational fluid dynamics (CFD) that will help in the optimization of CEHDA's operating conditions prior to large-scale production of microparticles. The new synthetic hydrogel provides an additional diffusion barrier against Cis-DDP and confines premature release of drugs. In addition, the hydrogel can provide a versatile tool for retaining particles in the tumor resected cavity during the injection after debulking surgery and preventing surgical site infection due to its inherent antibacterial properties. Three-dimensional MDA-MB-231 (breast cancer) spheroid studies demonstrate a superior efficacy and a greater reduction in spheroid growth for drugs released from the proposed composite formulation over a prolonged period, as compared with free drug treatment. Overall, the new core-shell microparticles embedded into injectable hydrogel can serve as a flexible controlled release platform for modulating the release profiles of anticancer drugs and subsequently providing a superior anticancer response.

Coaxial electrohydrodynamic atomization: microparticles for drug delivery applications.

As cancer takes its toll on human health and well-being, standard treatment techniques such as chemotherapy and radiotherapy often fall short of ideal solutions. In particular, adverse side effects due to excess dosage and collateral damage to healthy cells as well as poor patient compliance due to multiple administrations continue to pose challenges in cancer treatment. Thus, the development of appropriately engineered drug delivery systems (DDS) for effective, controlled and sustained delivery of drugs is of interest for patient treatment. Moreover, the physiopathological characteristics of tumors play an essential role in the success of cancer treatment. Here, we present an overview of the application of double-walled microparticles for local drug delivery with particular focus on the electrohydrodynamic atomization (EHDA) technique and its fabrication challenges. The review highlights the importance of a combination of experimental data and computational simulations for the design of an optimal delivery system.

Encoding range minima and range top-2 queries.

We consider the problem of encoding range minimum queries (RMQs): given an array A[1..n] of distinct totally ordered values, to pre-process A and create a data structure that can answer the query RMQ(i,j), which returns the index containing the smallest element in A[i..j], without access to the array A at query time. We give a data structure whose space usage is 2n+o(n) bits, which is asymptotically optimal for worst-case data, and answers RMQs in O(1) worst-case time. This matches the previous result of Fischer and Heun, but is obtained in a more natural way. Furthermore, our result can encode the RMQs of a random array A in 1.919n+o(n) bits in expectation, which is not known to hold for Fischer and Heun's result. We then generalize our result to the encoding range top-2 query (RT2Q) problem, which is like the encoding RMQ problem except that the query RT2Q(i,j) returns the indices of both the smallest and second smallest elements of A[i..j]. We introduce a data structure using 3.272n+o(n) bits that answers RT2Qs in constant time, and also give lower bounds on the effective entropy of the RT2Q problem.