Encapsulation of Cadmium-Free InP-based Quantum Dots in Cross-Linked Core-Shell Microparticles via Coaxial Electrospraying.

Quantum dots (QDs) are inorganic semiconductor nanocrystals capable of emitting light. The current major challenge lies in the use of heavy metals, which are known to be highly toxic to humans and pose significant environmental risks. Researchers have turned to indium (In) as a promising option for more environmentally benign QDs, specifically indium phosphide (InP). A significant obstacle remains in sustaining the long-term photostability of InP-based QDs when exposed to the environment. To tackle this, electrospraying is used in this work to protect indium phosphide/zinc selenide/zinc sulfide (InP/ZnSe/ZnS) QDs by embedding them within polymer core-shell microparticles of poly[(lauryl methacrylate)-co-(ethylene glycol dimethacrylate)]/poly(methyl methacrylate) (poly(LMA-co-EGDMA)/PMMA). During the flight of droplets, the liquid monomer core of LMA and EGDMA with QDs is encapsulated by the solid shell of PMMA formed due to solvent evaporation, resulting in a liquid-core/solid-shell particle structure. After that, the captured core of monomers is polymerized into a cross-linked polymer with the embedded QDs via a thermal initiation. They demonstrate how a successful core-shell particle formation is achieved to produce structures for initially liquid monomer systems via coaxial electrospraying that are used for cross-linked polymers, which are of major interest for the encapsulation of InP-based QDs for generally improved photostability over pristine QDs.

The application of electrosprayed minocycline-loaded PLGA microparticles for the treatment of glioblastoma.

The survival of patients with glioblastoma multiforme (GBM), the most common and invasive form of malignant brain tumors, remains poor despite advances in current treatment methods including surgery, radiotherapy, and chemotherapy. Minocycline is a semi-synthetic tetracycline derivative that has been widely used as an antibiotic and more recently, it has been utilized as an antiangiogenic factor to inhibit tumorigenesis. The objective of this study was to investigate the utilization of electrospraying process to fabricate minocycline-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles with high drug loading and loading efficiency and to evaluate their ability to induce cell toxicity in human glioblastoma (i.e., U87-MG) cells. The results from this study demonstrated that solvent mixture of dicholoromethane (DCM) and methanol is the optimal solvent combination for minocycline and larger amount of methanol (i.e., 70:30) resulted in a higher drug loading. All three solvent ratios of DCM:methanol tested produced microparticles that were both spherical and smooth, all in the micron size range. The electrosprayed microparticles were able to elicit a cytotoxic response in U87-MG glioblastoma cells at a lower concentration of drug compared to the free drug. This work provides proof of concept to the hypothesis that electrosprayed minocycline-loaded PLGA microparticles can be a promising agent for the treatment of GBM and could have potential application for cancer therapies.

Improving mass transfer rates in microbial cell immobilization system for environmental applications: Synergistic interaction of cells on crude oil biodegradation.

Among the various techniques used to clean up polluted environments, bioremediation is the most cost-effective and eco-friendly option. The diversity of microbial communities in a consortium can significantly affect the biodegradability of hazardous organic pollutants, particularly for in situ bioremediation processes. This is largely attributed to interactions between members of a consortium. In this study, the effect of internal diffusion limitations in substrate model biodegradation was firstly examined by immobilized bacterial cells at different particle sizes produced by the electrospray technique. According to the obtained results, for particles with large size, the effectiveness factors (η) were about 0.58-0.67, and the resistance to diffusive on the biodegradation rate was significant, while with decreasing the particle size, η increases and approaches about 1. After selection of suitable bead size, heavy crude oil biodegradation was investigated using a consortium consisting of three oil-degrading bacterial strains at different treatment systems. The removal rate in the suspended co-culture system stands at minimum value of 38% with all three strains which is an indicator of negative interactions among consortium members. Independent immobilization of microorganisms minimizes the competition and antagonistic interactions between strains and leads to more crude oil removal, so that, the biodegradation rate reached 60%.

A Brief Review on the Electrohydrodynamic Techniques Used to Build Antioxidant Delivery Systems from Natural Sources.

Extracts from plants have been one of the main sources of antioxidants, namely polyphenols. The associated drawbacks, such as instability against environmental factors, low bioavailability, and loss of activity, must be considered during microencapsulation for a better application. Electrohydrodynamic processes have been investigated as promising tools to fabricate crucial vectors to minimize these limitations. The developed microstructures present high potential to encapsulate active compounds and for controlling their release. The fabricated electrospun/electrosprayed structures present different benefits when compared with structures developed by other techniques; they present a high surface-area-to-volume ratio as well as porosity, great materials handling, and scalable production-among other advantages-which make them able to be widely applied in different fields, namely in the food industry. This review presents a summary of the electrohydrodynamic processes, main studies, and their application.

Evaluation of the quality features of electrospray-coated pineapple slices with pomegranate and grape seed oil-enriched emulsions.

The quality characteristics of pineapple slices coated with emulsions enriched with pomegranate seed oil (PSO) and grape seed oil (GSO) by electrospray coating (ESC) and dip-coating (DC) methods were investigated. The ESC method was evaluated as an alternative to conventional DC. Pineapple slices were stored in clear polystyrene cups for seven days at 5 °C and 80% RH. The weight loss (%), pH, titratable acidity, color, firmness, total antioxidant activity (TAA), total phenolic content (TPC), microbiological, and sensory qualities of fresh-cut pineapple slices were evaluated. Coated samples had significantly lower weight loss values than the non-coated samples after 7 days of storage. The usage of GSO-enriched emulsion with the ESC method was found to be more successful in preserving the titratable acidity. Although all the samples exhibited a significant decrease in yellowness (b*), the electrospray-coated pineapple slices had the highest. Incorporating GSO into the emulsions helped protect the tissue of the fresh-cut pineapples, regardless of the coating method used. The TPC and TAA values of the samples coated by the ESC method with emulsions enriched with PSO showed a lower decrease compared to other treatments. It was determined that the ESC method was more successful in preserving the sensory qualities of fresh-cut pineapples. These findings suggested that using ESC as a coating method with EO-enriched emulsions has positive effects on the quality features of fresh-cut pineapples. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-023-05839-4.

Mechanistic understanding and potential application of electrospraying in food processing: a review.

Electrospraying (ESPR) is a cost effective, flexible, and facile method that has been used in the pharmaceutical industry, and thanks to its wide variety of uses such as bioactive compound encapsulation, micronization, and food product coating, which have received a great attention in the food market. It uses a jet of polymer solution for processing food and food-derived products. Droplet size can be extremely small up to nanometers and can be regulated by altering applied voltage and flow rate. Compared to conventional techniques, it is simple, cost effective, uses less solvent and products are obtained in one step with a very high encapsulation efficiency (EE). Encapsulation provided using it protects bioactives from moisture, thermal, oxidative, and mechanical stresses, and thus provides them a good storage stability which will help in increasing the application of these ingredients in food formulation. This technique has an enormous potential for increasing the shelf life of fruit and vegetables through coating and improvement of eating quality. This study is aimed at overviewing the operating principles of ESPR, working parameters, applications, and advantages in the food sector. The article also covers new ESPR techniques like supercritical assisted ESPR and ESPR assisted by pressurized gas (EAPG) which have high yield as compared to conventional ESPR. This article is enriched with good information for research and development in ESPR techniques for development of novel foods.

Rational Process Design for Facile Fabrication of Dual Functional Hybrid Membrane of MOF and Electrospun Nanofiber towards High Removal Efficiency of PM2.5 and Toxic Gases.

The application of nanofiber (NF) and porous metal-organic framework (MOF) has increasingly attracted attention for the protection of public health. This composite platform provides the physical sieving of particulate matters (PMs) and capturing gases, serving as an outstanding filtering medium with lightweight and multifunctionality. Herein, process design and optimization are performed to produce a multifunctional membrane comprised NFs and MOF particles. Electrospinning/electrospray techniques are used to fabricate a hybrid membrane of poly(vinyl alcohol) NF and Fe-BTC as an adsorptive MOF on a macroporous nonwoven (NW). Three types of filters are prepared by varying the order of processing steps, that is, MOF/NF/NW, MOF+NF/NW, and NF/MOF/NW, to elucidate the effect of the fabrication process in the filtration of air pollutant. The optimal filtration performance is achieved in MOF+NF/NW system: the highest filtration efficiency (97%) and outstanding gas capturing efficiencies (≈60% and ≈35% decreases from initial NH3 and H2 S concentrations, respectively). However, when air permeability and filtration efficiency are considered, the most desirable configuration for personal protection equipment (PPE) is NF/MOF/NW system, which effectively enabled comfortable breathing without compromising the lightweight and multifunctional performance.

Microencapsulated sodium fusidate to impart antibacterial properties into cotton dressings for traumatic wounds.

This research aimed to investigate the use of microencapsulated sodium fusidate to impart antibacterial properties into conventional cotton gauze used to treat traumatic wounds. The microcapsules were prepared with sodium fusidate dissolved in ethanol as the active substance (core) and calcium alginate as the wall material (shell) using an electrospraying method. The microcapsules were then loaded into a 1% solution of chitosan, and conventional sterile cotton gauze fabric was impregnated in this suspension and dried at room temperature. The microcapsules obtained were examined with Fourier transform infrared spectroscopy to confirm the constituents, and by scanning electron microscopy to examine the size and distribution of the microcapsules. The results showed that microcapsules with sodium fusidate as the core material were produced in a size range of 50-200µm. The antibacterial properties of these gauze samples were tested for resistance to both Gram-positive and Gram-negative bacteria. The samples showed antibacterial properties against Gram-positive bacteria (Staphylococcus aureus) only, with an average inhibition zone of 31.67±2.89mm in diameter. The antibacterial effect of the treated gauze samples was tested after washing to investigate the strength of the binding agent, to find out whether the samples maintained antibacterial properties after two hand-rubbed washes. Its absorption capacity, rate of absorbency and air permeability values were 555±4.51%, 1.25±0.04 seconds and 408±2.65cm3/cm2/seconds, respectively. The research findings have established the possibility of imparting antibacterial properties into sterile cotton gauze using microencapsulation of sodium fusidate.

A guide to oral vaccination: Highlighting electrospraying as a promising manufacturing technique toward a successful oral vaccine development.

Most vaccines approved by regulatory bodies are administered via intramuscular or subcutaneous injections and have shortcomings, such as the risk of needle-associated blood infections, pain and swelling at the injection site. Orally administered vaccines are of interest, as they elicit both systemic and mucosal immunities, in which mucosal immunity would neutralize the mucosa invading pathogen before the onset of an infection. Hence, oral vaccination can eliminate the injection associated adverse effects and enhance the person's compliance. Conventional approaches to manufacturing oral vaccines, such as coacervation, spray drying, and membrane emulsification, tend to alter the structural proteins in vaccines that result from high temperature, organic and toxic solvents during production. Electrohydrodynamic processes, specifically electrospraying, could solve these challenges, as it also modulates antigen release and has a high loading efficiency. This review will highlight the mucosal immunity and biological basis of the gastrointestinal immune system, different oral vaccine delivery approaches, and the application of electrospraying in vaccines development.

A novel approach to production of Chlorella protothecoides oil-loaded nanoparticles via electrospraying method: Modeling of critical parameters for particle sizing.

Bioactive compounds in algae have chain rings that protect the tissue from chemical damage and disease symptoms. In addition, algal bioactive agents have the ability to stimulate the immune system, protective and therapeutic effects against many diseases, including various types of cancers, coronary heart disease, premature aging, and arthritis. These bioactive compounds also have antioxidant, anticoagulant, antiviral, and anti-inflammatory properties. It is very important to encapsulate these algal compounds for preserving bioactive properties. Two of the most efficient methods used for encapsulation are electrospraying and microemulsion techniques. Although electrospraying is a novel technique to produce nanoparticles in recent years, microemulsion is more conventional method compared with electrospraying. In this study, Chlorella protothecoides oil was encapsulated by using sodium alginate and chitosan biopolymers, and the effects of production parameters of electrospraying and microemulsion methods on the particle size and loading efficiency were investigated. Statistical modeling of critical parameters for particle sizing in microemulsion method and electrospraying technique, which is a novel approach to obtain microalgal oil-loaded nanoparticles, was also presented. It was seen that electrospraying is suitable for obtaining smaller nanoparticles (123.9-610 nm), homogeneous distribution, and higher oil loading efficiency (60%-77%) compared with microemulsion method (756.9-1128.2 nm and 57%-73%).

New prospects in skin regeneration and repair using nanophased hydroxyapatite embedded in collagen nanofibers.

This study reflects an exploitation of a composite matrix produced by electrospinning of collagen and electrospraying of nanophased hydroxyapatite (nanoHA), for skin regeneration applications. The main goal was to evaluate the effect of nanoHA, as source of localized calcium delivery, on human dermal fibroblasts, keratinocytes, and human mesenchymal stem cells (hMSCs) growth, proliferation, differentiation, and extracellular matrix production. This study revealed that calcium ions provided by nanoHA significantly enhanced cellular growth and proliferation rates and prevented adhesion of pathogenic bacteria strains typically found in human skin flora. Moreover, hMSCs were able to differentiate in both osteogenic and adipogenic lineages. Rat subcutaneous implantation of the membranes also revealed that no adverse reaction occurred. Therefore, the mechanically fit composite membrane presents a great potential to be used either as cell transplantation scaffold for skin wound regeneration or as wound dressing material in plastic surgery, burns treatment or skin diseases.

Coaxial Alginate Hydrogels: From Self-Assembled 3D Cellular Constructs to Long-Term Storage.

Alginate as a versatile naturally occurring biomaterial has found widespread use in the biomedical field due to its unique features such as biocompatibility and biodegradability. The ability of its semipermeable hydrogels to provide a favourable microenvironment for clinically relevant cells made alginate encapsulation a leading technology for immunoisolation, 3D culture, cryopreservation as well as cell and drug delivery. The aim of this work is the evaluation of structural properties and swelling behaviour of the core-shell capsules for the encapsulation of multipotent stromal cells (MSCs), their 3D culture and cryopreservation using slow freezing. The cells were encapsulated in core-shell capsules using coaxial electrospraying, cultured for 35 days and cryopreserved. Cell viability, metabolic activity and cell-cell interactions were analysed. Cryopreservation of MSCs-laden core-shell capsules was performed according to parameters pre-selected on cell-free capsules. The results suggest that core-shell capsules produced from the low viscosity high-G alginate are superior to high-M ones in terms of stability during in vitro culture, as well as to solid beads in terms of promoting formation of viable self-assembled cellular structures and maintenance of MSCs functionality on a long-term basis. The application of 0.3 M sucrose demonstrated a beneficial effect on the integrity of capsules and viability of formed 3D cell assemblies, as compared to 10% dimethyl sulfoxide (DMSO) alone. The proposed workflow from the preparation of core-shell capsules with self-assembled cellular structures to the cryopreservation appears to be a promising strategy for their off-the-shelf availability.

Curcumin, the active substance of turmeric: its effects on health and ways to improve its bioavailability.

Turmeric (Curcuma longa L.) is a spice utilized widely in India, China, and Southeast Asia as an aromatic stimulant, a food preservative, and coloring material. The commonly used names of turmeric are castor saffron, turmeric, and saffron root. Turmeric is a yellow-orange polyphenolic natural substance derived from C. longa rhizomes. It has been used to treat common inflammatory diseases, tumors, biliary diseases, anorexia, cough, topical wounds, diabetic injuries, liver disorders, rheumatism, and sinusitis. Extensive studies on the biological properties and pharmacological consequences of turmeric extracts have been conducted in recent years. Curcumin, the primary yellow biocomponent of turmeric, has anti-inflammatory, antioxidant, anticarcinogenic, antidiabetic, antibacterial, antiprotozoal, antiviral, antifibrotic, immunomodulatory, and antifungal properties. Defense assessment tests showed that curcumin is tolerated well at high doses, without adverse effects. Thus, curcumin is a highly active biological material with the potential to treat different diseases in modern medicine. This review article focuses on curcumin's biological characteristics. The most popular methods for curcumin encapsulation are also discussed. Several effective techniques and approaches have been proposed for curcuminoid capsulation, including nanocomplexing, gelation, complex coacervation, electrospraying, and solvent-free pH-driven encapsulation. This review also highlights curcumin's chemical properties, allowing the readers to expand their perspectives on its use in the development of functional products with health-promoting properties. © 2021 Society of Chemical Industry.

Electrohydrodynamic processing of natural polymers for active food packaging: A comprehensive review.

The active packaging materials fabricated using natural polymers is increasing in recent years. Electrohydrodynamic processing has drawn attention in active food packaging due to its potential in fabricating materials with advanced structural and functional properties. These materials have the significant capability in enhancing food's quality, safety, and shelf-life. Through electrospinning and electrospray, fibers and particles are encapsulated with bioactive compounds for active packaging applications. Understanding the principle behind electrohydrodynamics provides fundamentals in modulating the material's physicochemical properties based on the operating parameters. This review provides a deep understanding of electrospray and electrospinning, along with their advantages and recent innovations, from food packaging perspectives. The natural polymers suitable for developing active packaging films and coatings through electrohydrodynamics are intensely focused. The critical properties of the packaging system are discussed with characterization techniques. Furthermore, the limitations and prospects for natural polymers and electrohydrodynamic processing in active packaging are summarized.

An investigation of alkaline phosphatase enzymatic activity after electrospinning and electrospraying.

The high target specificity and multifunctionality of proteins has led to great interest in their clinical use. To this end, the development of delivery systems capable of preserving their bioactivity and improving bioavailability is pivotal to achieve high effectiveness and satisfactory therapeutic outcomes. Electrohydrodynamic (EHD) techniques, namely electrospinning and electrospraying, have been widely explored for protein encapsulation and delivery. In this work, monoaxial and coaxial electrospinning and electrospraying were used to encapsulate alkaline phosphatase (ALP) into poly(ethylene oxide) fibres and particles, respectively, and the effects of the processing techniques on the integrity and bioactivity of the enzyme were assessed. A full morphological and physicochemical characterisation of the blend and core-shell products was performed. ALP was successfully encapsulated within monolithic and core-shell electrospun fibres and electrosprayed particles, with drug loadings and encapsulation efficiencies of up to 21% and 99%, respectively. Monoaxial and coaxial electrospinning were equally effective in preserving ALP function, leading to no activity loss compared to fresh aqueous solutions of the enzyme. While the same result was observed for monoaxial electrospraying, coaxial electrospraying of ALP caused a 40% reduction in its bioactivity, which was attributed to the high voltage (22.5 kV) used during processing. This demonstrates that choosing between blend and coaxial EHD processing for protein encapsulation is not always straightforward, being highly dependent on the chosen therapeutic agent and the effects of the processing conditions on its bioactivity.

Development, Optimization, and Pharmacokinetics Study of Bufalin/Nintedanib Co-loaded Modified Albumin Sub-microparticles Fabricated by Coaxial Electrostatic Spray Technology.

Coaxial electrostatic spray technology has received extensive attention in fabricating micro/nanoparticles for drug delivery. However, there are few reports on applying this technology in preparing albumin nanoparticles. In this study, the bufalin (BF) and nintedanib (NDNB) co-loaded ursodeoxycholic acid and p-biguanides benzoic acid decorated albumin sub-microparticles (BN-DUB subMPs) were fabricated by coaxial electrostatic spray technology and optimized by central composite design. Five percent of albumin (contained 0.7% polyethylene oxide) solution was selected as the shell solution which ejected through outer axis with the flow rate of 0.07 mm/min, while the core solution which contained by BF and NDNB ethanol solution was ejected through inner axis with the flow rate of 0.05 mm/min. In vitro cell studies revealed that the modified albumin possessed good biocompatibility. What's more, the BN-DUB subMPs enhanced the inhibitory effect on the growth of LLC cells efficiently. The pharmacokinetics study showed that the t1/2 and AUC0-t of BN-DUB subMPs increased significantly compared with that of the drug solution, which indicated the improved in vivo stability of modified albumin nanoparticles. Thus, this study provided a novel and simple technical platform for the development of albumin-based drug carriers.

Three-dimensional bio-printed constructs consisting of human umbilical-derived mesenchymal stem cells promote cell viability, proliferation, and differentiation in vitro.

The aim of this study was to investigate the effect of three-dimensional (3D) bio-printed constructs consisting of human umbilical-derived mesenchymal stem cells (HUMSCs) on cell viability, proliferation and differentiation in vitro. Functional 3D bio-printed microspheres consisting of HUMSCs were constructed using electrostatic inkjet technique. The parameters used for the synthesis of 3D bio-printed tissue constructs were first optimized. The viability, proliferation and differentiation of 3D cultured HUMSCs were assessed. The results of scanning electron microscopy (SEM) showed that isolated HUMSCs exhibited fibroblast-like spindle adherent growth. The optimized printing parameters were 6 kV voltage, 10 mL/h flow, 15 cm receiving height, and alginate: water ratio of 1:1 mixed at 37 °C. Compared with 2D cultured HUMSCs, the 3D cultured HUMSCs have better viability, proliferation and differentiation ability. The results obtained in this study indicate that 3D bio-printed tissue constructs promote HUMSC viability, proliferation, and neural differentiation in vitro.

In vitro and in vivo evaluation of microneedles coated with electrosprayed micro/nanoparticles for medical skin treatments.

AIM: Microneedles (MNs) create micropunctures and deliver drugs or nutrients deep into skin layer. We demonstrated that MNs, coated with electrosprayed nanoparticles loaded with functional molecules, are useful for transdermal delivery. METHODS: Electrospraying was utilised to generate drug-loaded nanoparticles and to create uniform coating on MNs. Process parameters and release kinetics were evaluated in vitro. The in vivo efficacy of insulin-coated MNs was investigated using diabetic rats. RESULTS: Electrosprayed micro/nanoparticles loaded with dye or insulin were coated on MNs with particle size of 515 ± 286 and 522 ± 261 nm, respectively. Optimally coated MNs resulted in >70% transfer rate into porcine skins. Insulin-coated MNs were applied to diabetic rats resulting in reduction of blood glucose levels fluctuations, compared to subcutaneous injections. CONCLUSIONS: Electrospraying is shown to be an effective method to coat MNs with drug-loaded nanoparticles. Coated MNs provide a promising platform for cosmetic, drug and protein delivery applications.

Sustained Release of Levobupivacaine, Lidocaine, and Acemetacin from Electrosprayed Microparticles: In Vitro and In Vivo Studies.

In this study, we explored the release characteristics of analgesics, namely levobupivacaine, lidocaine, and acemetacin, from electrosprayed poly(D,L-lactide-co-glycolide) (PLGA) microparticles. The drug-loaded particles were prepared using electrospraying techniques and evaluated for their morphology, drug release kinetics, and pain relief activity. The morphology of the produced microparticles elucidated by scanning electron microscopy revealed that the optimal parameters for electrospraying were 9 kV, 1 mL/h, and 10 cm for voltage, flow rate, and travel distance, respectively. Fourier-transform infrared spectrometry indicated that the analgesics had been successfully incorporated into the PLGA microparticles. The analgesic-loaded microparticles possessed low toxicity against human fibroblasts and were able to sustainably elute levobupivacaine, lidocaine, and acemetacin in vitro. Furthermore, electrosprayed microparticles were found to release high levels of lidocaine and acemetacin (well over the minimum therapeutic concentrations) and levobupivacaine at the fracture site of rats for more than 28 days and 12 days, respectively. Analgesic-loaded microparticles demonstrated their effectiveness and sustained performance for pain relief in fracture injuries.

Encapsulation of ß-Carotene by Emulsion Electrospraying Using Deep Eutectic Solvents.

The encapsulation ß-carotene in whey protein concentrate (WPC) capsules through the emulsion electrospraying technique was studied, using deep eutectic solvents (DES) as solvents. These novel solvents are characterized by negligible volatility, a liquid state far below 0 °C, a broad range of polarity, high solubilization power strength for a wide range of compounds, especially poorly water-soluble compounds, high extraction ability, and high stabilization ability for some natural products. Four DES formulations were used, based on mixtures of choline chloride with water, propanediol, glucose, glycerol, or butanediol. ß-Carotene was successfully encapsulated in a solubilized form within WPC capsules; as a DES formulation with choline chloride and butanediol, the formulation produced capsules with the highest carotenoid loading capacity. SEM micrographs demonstrated that round and smooth capsules with sizes around 2 µm were obtained. ATR-FTIR results showed the presence of DES in the WPC capsules, which indirectly anticipated the presence of ß-carotene in the WPC capsules. Stability against photo-oxidation studies confirmed the expected presence of the bioactive and revealed that solubilized ß-carotene loaded WPC capsules presented excellent photo-oxidation stability compared with free ß-carotene. The capsules developed here clearly show the significant potential of the combination of DES and electrospraying for the encapsulation and stabilization of highly insoluble bioactive compounds.