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Fibrous constructs with incorporated cinnamon‐extract have previously been shown to have potent antifungal abilities. The question remains to whether these constructs are useful in the prevention of bacterial infections in fiber form and what the antimicrobial effects means in terms of toxicity to the native physiological cells. In this work, cinnamon extract containing poly (ε‐caprolactone) (PCL) fibers were successfully manufactured by pressurized gyration and had an average size of ∼2 μm. Cinnamon extract containing PCL fibers were tested against Escherichia coli, Staphylococcus aureus, Methicillin resistant staphylococcus aureus, and Enterococcus faecalis bacterial species to assess their antibacterial capacity; it was found that these fibers were able to reduce viable cell numbers of the bacterial species up to two orders of magnitude lower than the control group. The results of the antibacterial tests were assessed by scanning electron microscopy (SEM). The constructs were also tested under indirect MTT tests where they showed little to no toxicity, similar to the control groups. Additionally, cell viability fluorescent imaging displayed no significant toxicity issues with the fibers, even at their highest tested concentration. Here we present a viable method for the production the non‐toxic and naturally abundant cinnamon extracted fibers for numerous biomedical applications., Cinnamon directly extracted into a polycaprolactone polymer base was spun with pressurized gyration to produce a high yield of cinnamon‐extracted bandage‐like fibers. These fibers where then characterized and tested for cytotoxity and antibacterial activity against Escherichia coli, Staphylococcus aureus, Methicillin Resistant Staphylococcus aureus and Enterococcus faecalis.

Forming polymeric core–sheath nanofibers is gaining prominence owing to their numerous potential applications, most notably in functional scenarios such as antiviral filtration, which is attracting significant attention due to the current COVID pandemic. This study has successfully designed and constructed a novel pressurized gyration vessel to fabricate core–sheath polymer nanofibers. Several water-soluble and water-insoluble polymer combinations are investigated. Both polyethylene oxide and polyvinyl alcohol were used as the core while both poly(lactic acid) (PLA) and poly(caprolactone) (PCL) were used as the sheath; PLA and PCL were used as core and sheath, in different instances; respectively. The fluid behavior of the core–sheath within the vessel was studied with and without applied pressure using computational fluid dynamics to simulate the core–sheath flow within the chamber. A high-speed camera was used to observe the behavior of jetted solutions at core–sheath openings, and the best scenario was achieved using 6000 rpm spinning speed with 0.2 MPa (twice atmospheric) applied pressure. The surface morphology of core–sheath fibers was studied using a scanning electron microscope, and focused ion beam milling assisted scanning electron microscopy was used to investigate the cross-sectional features of the produced fibers. Laser confocal scanning microscopy was also used to verify the core–sheath structure of the fibers, which were further characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry. Thus, using a variety of polymer combinations, we show, both theoretically and experimentally, how core–sheath fibers evolve in a vessel that can serve as a scalable manufacturing pressurized gyration production process.

The combination of oral antidiabetic drugs, pioglitazone, metformin, and glibenclamide, which also exhibit the strongest anti-inflammatory action among oral antidiabetic drugs, were loaded into chitosan/gelatin/polycaprolactone (PCL) by electrospinning and polyvinyl pyrrolidone (PVP)/PCL composite nanofibrous scaffolds by pressurized gyration to compare the diabetic wound healing effect. The combination therapies significantly accelerated diabetic wound healing in type-1 diabetic rats and organized densely packed collagen fibers in the dermis, it also showed better regeneration of the dermis and epidermis than single drug-loaded scaffolds with less inflammatory cell infiltration and edema. The formation of the hair follicles started in 14 days only in the combination therapy and lower proinflammatory cytokine levels were observed compared to single drug-loaded treatment groups. The combination therapy increased the wettability and hydrophilicity of scaffolds, demonstrated sustained drug release over 14 days, has high tensile strength and suitable cytocompatibility on L929 (mouse fibroblast) cell and created a suitable area for the proliferation of fibroblast cells. Consequently, the application of metformin and pioglitazone-loaded chitosan/gelatin/PCL nanofibrous scaffolds to a diabetic wound area offer high bioavailability, fewer systemic side effects, and reduced frequency of dosage and amount of drug.

A significant proportion of urinary tract infection (UTI) patients experience recurrent episodes, due to deep tissue infection and treatment-resistant bacterial reservoirs. Direct bladder instillation of antibiotics has proved disappointing in treating UTI, likely due to the failure of infused antibiotics to penetrate the bladder epithelium and accumulate to high enough levels to kill intracellular bacteria. This work investigates the use of nitrofurantoin loaded poly(lactic-co-glycolic acid) (PLGA) particles to improve delivery to intracellular targets for the treatment of chronic UTI. Using electrohydrodynamic atomisation, we produced particles with an average diameter of 2.8 μm. In broth culture experiments, the biodegradable particles were effective against a number of UTI-relevant bacterial strains. Dye-loaded particles demonstrated that intracellular delivery was achieved in all cells in 2D cultures of a human bladder epithelial progenitor cell line in a dose-dependent manner, achieving far higher efficiency and concentration than equivalent quantities of free drug. Time-lapse video microscopy confirmed that delivery occurred within 30 min of administration, to 100% of cells. Moreover, the particles were able to deliver the drug to cells through multiple layers of a 3D human bladder organoid model causing minimal cell toxicity, displaying superior killing of bacterial reservoirs harboured within bladder cells compared with unencapsulated drug. The particles were also able to kill bacterial biofilms more effectively than the free drug. These results illustrate the potential for using antibiotic-loaded microparticles to effectively treat chronic UTIs. Such a delivery method could be extrapolated to other clinical indications where robust intracellular delivery is required, such as oncology and gene therapy.

This novel face mask is designed to be a reusable respirator with a small and highly efficient disposable fabric filter. Respirator material requirements are reduced by 75% compared to traditional designs and allow repeated cleaning or sterilization. The probability of virus particle inhalation is reduced using novel air filtration pathways, through square-waveform design to increase filter airflow. Air enters the mask from right and left side filters, while the area in front of the mouth is isolated. Clear epoxy is used for a transparent frame, allowing lip-reading, and mask edges contain a silicone seal preventing bypass of the filters. The mask is manufactured using silicone molds, eliminating electricity requirements making it economical and viable in developing countries. Computational fluid dynamics numerical studies and Fluent ANSYS software were used to simulate airflow through the filter to optimize filter air path geometry and validate mask design with realistic human requirements. The breathing cycle was represented as a transient function, and N95 filter specifications were selected as a porous medium. The novel design achieved 1.2 × 10−3 kg s−1, 20% higher than human requirements, with air streamlines velocity indicating local high speed, forcing and trapping virus particles against filter walls through centrifugal forces.

Suspensions containing 8 and 10 wt% polyacrylonitrile (PAN) and 1, 2, 3, 5, 7 and 10 wt% graphene oxide (GO) were prepared using a special mixing routine and fibres were generated from these mixtures by pressurised gyration. The combination of pressure and gyration speed was effective in controlling the fibre morphology and fibre diameter which ranged from 1 to 20 μm. Fibres were pyrolysed to remove the polymer and only the 10 wt% PAN fibres survived. The microstructure of the pre- and post-pyrolysis products were characterised by scanning electron microscopy, both with and without focussed ion beam etching, Fourier-transformed infrared and Raman spectroscopies. Pyrolysed fibre electrical conductivities were measured and only those containing 1 and 2 wt% GO were conductive.

Viral infections alone are a significant cause of morbidity and mortality worldwide and have a detrimental impact on global healthcare and socioeconomic development. The discovery of novel antiviral treatments has gained tremendous attention and support with the rising number of viral outbreaks. In this work, carbonaceous materials, including graphene nanoplatelets and graphene oxide nanosheets, were investigated for antiviral properties. The materials were characterised using scanning electron microscopy and transmission electron microscopy. Analysis showed the materials to be two‐dimensional with lateral dimensions ranging between 1 – 4 µm for graphene oxide, 110 ± 0.11nm for graphene nanoplatelets. Antiviral properties were assessed against a DNA virus model microorganism at concentrations of 0.5, 1.0 and 2.0 wt/v%. Both carbonaceous nanomaterials exhibited potent antiviral properties and gave rise to a viral reduction of 100% across all concentrations tested. Graphene oxide nanosheets were then incorporated into polymeric fibres and their antiviral behaviour was examined after 3 and 24 hours. A viral reduction of ~39% was observed after 24 hours of exposure. The research presented here showcases, for the first time, the antiviral potential of several carbonaceous nanomaterials, also included in a carrier polymer. These outcomes can be translated and implemented in many fields and devices to prevent viral spread and infection.

Wound dressings made from natural polymers are an important aspect of biomaterials. Protein-based materials are less likely to instigate an immunogenic response and have the capacity to degrade in vivo, also without triggering an inflammatory response. Therefore, gelatin (GEL) was chosen and combined with bacterial cellulose (BC) to produce nanofibres and the potential of an all-natural polymer construct was determined. GEL and BC were successfully electrospun with metformin (Met) and glybenclamide (Gb) using a portable, point of need electrospinning set up. The virgin fibre group exhibited a significant effect on the proliferation of L929 (mouse fibroblast) cells but all fibre samples can safely be applied on wound site without risk of cytotoxicity. According to the results obtained by animal tests, the GEL-BC-Gb group showed better recovery than the GEL-BC-Met group. Diabetic wounds treated with GEL-BC-Met were characterized by moderate re-epithelialization and partially organized granulation tissue. Moderate to complete re-epithelialization and well-formed granulation tissue were observed in diabetic wounds treated with GEL-BC-Gb. The histologic scores obtained on day 14 confirmed that the GEL-BC-Gb group played a stronger wound-healing role compared to the GEL-BC-Met group. The highest decrease of TNF-α level was observed in the GEL-BC-Gb group at the end of the experiment but there is no significant difference between drug-loaded fibre groups. Therefore, topical administration of Met and Gb in a sustained release form has a high potential for diabetic wound healing with high bioavailability and fewer systemic side effects but Gb showed better improvement according to the results of the animal tests.

The aim of this study is to investigate the potential of microfluidic techniques to generate microporous structures, with potential utility as scaffolds, with a highly uniform architecture, possessing an antibacterial activity. Scaffolds were prepared by introducing N2 gas to gelatin (GE)–water or gelatin/hyaluronic acid (GE/HA)–water mixtures to form microbubbles at the interface. The effect of solution temperature on microbubble stability and their structural integrity were studied. A solution temperature of 40 °C produced the best results due to the higher solution viscosity. The effect of different cross-linking concentrations on scaffold swelling ratio was investigated. A concentration of 5% glutaraldehyde was found to be optimal and was chosen to cross-link structure and conduct subsequent degradation and antibacterial experiments. HA was incorporated into the scaffolds owing to its ability to make stable and highly absorbent scaffolds. This led to a decrease in the degradation rate and the introduc...

In order to provide more effective treatment strategies for the rapid healing of diabetic wounds, novel therapeutic approaches need to be developed. The therapeutic potential of peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone hydrochloride (PHR) in two different release kinetic scenarios, burst release and sustained release, was investigated and compared with in vitro and in vivo tests as potential wound healing dressings. PHR-loaded fibrous mats were successfully fabricated using polyvinyl-pyrrolidone and polycaprolactone by scalable pressurized gyration. The results indicated that PHR-loaded fibrous mats expedited diabetic wound healing in type-1 diabetic rats and did not show any cytotoxic effect on NIH/3T3 (mouse embryo fibroblast) cells, albeit with different release kinetics and efficacies. The wound healing effects of fibrous mats are presented with histological and biochemical evaluations. PHR-loaded fibrous mats improved neutrophil infiltration, oedema, and inflammation and increased epidermal regeneration and fibroblast proliferation, but the formation of hair follicles and completely improved oedema were observed only in the sustained release form. Thus, topical administration of PPAR-γ agonist in sustained release form has high potential for the treatment of diabetic wounds in inflammatory and proliferative phases of healing with high bioavailability and fewer systemic side effects.

Poly(glycerol sebacate) (PGS) was discovered in the previous decade and is a promising bioelastomer with tuneable mechanical, biodegradable and biocompatible properties. Despite of these superiorities, PGS possesses solubility and processability disadvantages. To overcome these drawbacks of PGS, blends could be formed with a polymer which is soluble in a common solvent with PGS prepolymer, having a melting temperature above the crosslinking temperature and which can be removed from the structure after crosslinking. In this study, PGS fibers were fabricated for the first time using pressurized gyration as scaffolds. Fibers were obtained through blending the synthesized PGS prepolymer with poly(vinyl alcohol) (PVA) to overcome solubility/melting drawbacks of crosslinked PGS polymer. Obtained fiber diameters have a narrow size distribution which did not change after thermal crosslinking. After the washing procedure, ∼25% decrease in the average fiber diameter was observed due to the PVA removal. Resulting PGS fibers were characterized in terms of chemical structure, morphology, and cell viability. Fibroblast cell adhesion and spreading on three-dimensional fiber networks were determined by microscopy. PGS fibers supported cell adhesion and proliferation. After 7 days of cell-PGS fiber interactions, cell proliferation and spreading increased without any toxicity.

Bacterial Cellulose (BC) has over recent decades shown great versatility in wound healing dressings, but is difficult to spin fibers with at high concentrations. An investigation into the preparation of bandage-like fibrous meshes is carried out to determine the optimal blend of polycaprolactone (PCL) and polylactic acid (PLA) as a suitable carrier for BC. Using a simple centrifugal spinning setup, polymer blends of PCL, PLA and BC are investigated as a ternary system to determine the most suitable composition with a focus on achieving maximal BC concentration. It is found that BC content in the fibers above 10 wt % reduced product yield. By creating blends of PLA-PCL fibers, we can create a more suitable system in terms of yield and mechanical properties. The fibrous samples are examined for yield, fiber morphology using scanning electron microscopy, mechanical properties using tensile testing and chemical characteristics using Fourier-transform infrared spectroscopy. A fibrous scaffold with &gt, 30 wt % BC was produced with enhanced mechanical properties owing to the blending of PLA and PCL.

Pressure-coupled infusion gyration (PCIG) is a novel promising technique for economical and effective mass production of nanofibres with desirable geometrical characteristics. The average diameter of spun fibres significantly influences the structural, mechanical and physical properties of the produced fibre mats. Having a comprehensive understanding of the significant effects of PCIG experimental variables on the spun fibres is beneficial. In this work, response surface methodology was used to explore the interaction effects and the optimal PCIG experimental variables for achieving the desired morphological characteristics of fibres. The effect of experimental variables, namely solution concentration, infusion (flow) rate, applied pressure and rotational speed, was studied on the average fibre diameter and standard deviations. A numerical model for the interactional influences of experimental variables was developed and optimized with a nonlinear interior point method that can be used as a framework for selecting the optimal conditions to obtain poly-ethylene oxide fibres with desired morphology (targeted average diameter and narrow standard deviation). The adequacy of the models was verified by a set of validation experiments. The results proved that the predicted optimal conditions were able to achieve the average diameter that matched the pre-set desired value with less than 10% of difference.

[Image: see text] Electrospinning is increasingly becoming a viable means of producing drug delivery vehicles for oral delivery, particularly as issues of manufacturing scalability are being addressed. In this study, electrospinning is explored as a taste-masking manufacturing technology for bitter drugs. The taste-masking polymer Eudragit E PO (E-EPO) was electrospun, guided by a quality by design approach. Using a design of experiment, factors influencing the production of smooth fibers were investigated. Polymer concentration, solvent composition, applied voltage, flow rate, and gap distance were the parameters examined. Of these, polymer concentration was shown to be the only statistically significant factor within the ranges studied (p-value = 0.0042). As the concentration increased, smoother fibers were formed, coupled with an increase in fiber diameter. E-EPO (35% w/v) was identified as the optimum concentration for smooth fiber production. The optimized processing conditions identified were a gap distance of 175 mm, an applied voltage of between 15 and 20 kV, and a flow rate of 1 mL/h. Using this knowledge, the production optimization of electrospun E-EPO with chlorpheniramine maleate (CPM), a bitter antihistamine drug, was explored. The addition of CPM in drug loads of 1:6 up to 1:10 CPM/E-EPO yielded smooth fibers that were electrospun under conditions similar to placebo fibers. Solid-state characterization showed CPM to be molecularly dispersed in E-EPO. An electronic tasting system, or E-tongue, indicated good taste-masking performance as compared to the equivalent physical mixtures. This study therefore describes a means of producing, optimizing, and assessing the performance of electrospun taste-masked fibers as a novel approach to the formulation of CPM and potentially other bitter drug substances.

WOS: 000467668800012 In the last decade, nerve tissue engineering has attracted much attention due to the incapability of self-regeneration. Nerve tissue regeneration is mainly based on scaffold induced nanofibrous structures using both bio and synthetic polymers. The produced nanofibrous scaffolds have to be similar to the natural extracellular matrix and should provide an appropriate environment for cells to attach onto. Nanofibrous scaffolds can support or regenerate cells of tissue. Electrospinning is an ideal method for producing the nanofibrous scaffolds. In this study, Bacterial cellulose (BC)/Poly (epsilon-caprolactone) (PCL) blend nanofibrous scaffolds were successfully prepared by electrospinning for nerve tissue induced repair. The produced nanofibrous scaffolds contain well defined interconnected nanofiber networks with hollow micro/nanobeads. Firstly, in-vitro biocompatibilities of nanofibrous scaffolds were tested with L2929 murine fibroblasts and improved cell adhesion and proliferation was observed with polymer blends compared with PCL only. The primary cell culture was performed with dorsal root ganglia (DRG) cells on nanofibrous samples and the samples were found suitable for enhancing neural growth and neurite outgrowth. Based on these results, the BC/PCL (50:50 wt.%) nanofibrous scaffolds exhibited nerve-like branching and are excellent candidate for potential biomimetic applications in nerve tissue engineering regeneration.

This issue of Interface Focus is a collection of papers on ‘The biomedical applications of graphene’. The idea to put together this theme issue evolved during discussions between Prof. Peter N.T. Wells CBE, FREng, FMedSci, FRS and myself in mid-2016. Very sadly, about a year ago, Prof. Wells passed away. However, before that and even in the various last stages of his life he was intensely involved in planning this theme issue with me. I am deeply indebted to him for his contributions towards this and I dedicate this theme issue to him as a memorial.

An electrohydrodynamic printer designed and constructed in our laboratory was used to fabricate polycaprolactone nasal septal scaffolds. Three different polymer concentrations (15 wt.%, 18 wt.% and 23 wt.%) were used. The generated scaffolds, each with a unique architecture, were evaluated using PeakForce Quantitative Nanomechanical Mapping (QNM) Atomic Force Microscopy (AFM) to measure Young's modulus using the Dejaguin–Müller–Toporov (DMT) model. In addition, this allowed estimation of adhesion forces, deformation and dissipation energy of the scaffolds. The degree of crystallinity and purity of the polymer in the scaffolds were characterized by differential scanning calorimetry and Fourier transform infrared spectroscopy. Keywords: Electrohydrodynamic, Direct-write, Polymer, Polycaprolactone, Scaffold, Nasal, Septal

WOS: 000444951400014 PubMed ID: 29806201 Electrospun nanofibrous scaffolds are promising regenerative wound dressing options but have yet to be widely used in practice. The challenge is that nanofibre productions rely on bench-top apparatuses, and the delicate product integrity is hard to preserve before reaching the point of need. Timing is critically important to wound healing. The purpose of this investigation is to produce novel nanofibrous scaffolds using a portable, hand-held gun, which enables production at the wound site in a time-dependent fashion, thereby preserving product integrity. We select bacterial cellulose, a natural hydrophilic biopolymer, and polycaprolactone, a synthetic hydrophobic polymer, to generate composite nanofibres that can tune the scaffold hydrophilicity, which strongly affects cell proliferation. Composite scaffolds made of 8 different ratios of bacterial cellulose and polycaprolactone were successfully electrospun. The morphological features and cell-scaffold interactions were analysed using scanning electron microscopy. The biocompatibility was studied using Saos-2 cell viability test. The scaffolds were found to show good biocompatibility and allow different proliferation rates that varied with the composition of the scaffolds. A nanofibrous dressing that can be accurately moulded and standardised via the portable technique is advantageous for wound healing in practicality and in its consistency through mass production. UCL The authors wish to thank UCL for part supporting the visits of Esra Altun and Mehmet Onur Aydogdu.

Ultra fine short fibres have a variety of applications. Short aligned fibres or a mixture of short and long fibres can reinforce brittle materials, alter the appearance, texture and durability of synthetic fibres, and adjust the strength, toughness and stiffness of a composite material. Among electrospun products, short fibres are usually produced by secondary processing of continuous as-spun fibres. However, this is not entirely straightforward or cost-effective due to the efficiency of the secondary process and the relatively low tensile strength of the electrospun ultrafine fibres. Besides, sub-micrometre size fibres with an average aspect ratio (AR) 3000 under the same spinning conditions.

Electrohydrodynamic (EHD) processing has attracted substantial interest in the technological and pharmaceutical sectors in recent years. Given the complexity of the process, exploring new ideas for EHD electrospraying and electrospinning delivery is a challenge. In this article, the design, construction and testing of a portable handheld EHD multi-needle device are described to produce multifunctional particles and fibers. Solid and encapsulated polymer particles and fibers were generated in order to study the performance of the device. The intrinsic properties of the feed solution/suspension and the processing conditions were adjusted to ensure robustness of the process and give uniform and reproducible products, with diameters ranging from the sub-micrometer scale to a few micrometers. These products have a broad range of applications in many advanced industrial sectors e.g. drug delivery systems, wound dressing patches, low calorie food products and cosmetics. © 2012 Elsevier B.V.

The preparation of capsules for medical and industrial use can be achieved via several conventional routes, yielding either hard or soft receptacles, depending on the type and the content of the material to be encapsulated. Together with tablets, capsules are amongst the most commonly used means of administering medication and this makes progress in capsule preparation technology a key area of drug delivery research. Here we uncover new technology for the preparation of capsules with porous chambers. The novelty is signified in the use of an electrohydrodynamic process engineering route and its potential is elucidated using a polymeric material; polymethylsilsesquioxane, which can be converted into an identical ceramic form by means of simple pyrolysis. Thus, both polymeric and ceramic capsules have been prepared. The effects of process control parameters such as the applied voltage and flow rate, on the characteristics of the capsules prepared are discussed.

The preparation of microbubble suspensions is an important feature of medical engineering research. Recently, co-axial electrohydrodynamic atomization was used in our laboratory for the first time to prepare microbubble suspensions. In this paper, using a model glycerol-air system, we investigate in detail the characteristics of this microbubbling process. Modes of microbubbling are elucidated with respect to applied voltage and liquid and air flow rates. Thus, a parametric plot is constructed to identify a liquid and gas flow rate regime, which allows continuous microbubbling. This map provides a basis for the selection of a suitable combination of liquid and gas flow rates particularly in relation to yield and bubble size. The mechanism of microbubbling in microfluidic systems is compared with that of microbubbling by co-axial electrohydrodynamic atomization to identify the advantages and the limiting factors of the latter. Stability of microbubbles prepared by this method in terms of variation of diameter as a function of time is compared with previous literature on the dissolution of microbubbles with an air core and suggests the need for further work to stabilize the bubbles.

The feasibility of producing a hollow microsphere with a single hole in its shell by coaxial electrohydrodynamic atomization (CEHDA) is demonstrated. Polymethylsilsesquioxane (PMSQ) was used as a model shell material encapsulating a core of a volatile liquid, perfluorohexane (PFH), which was subsequently evaporated to produce the hollow microspheres. The diameters of the microspheres and of the single surface pore were controlled by varying the flow rate of the components, the concentration of the PMSQ solution, and the applied voltage in the CEHDA process. The particles were characterized by scanning electron microscopy, and the ranges obtained were 275-860 nm for the microsphere diameter and 35-135 nm for the pore size. The process overcomes several of the key problems associated with existing methods of monoporous microsphere formation including removing the need for elevated temperatures, multiple processing steps, and the use of surfactants and other additives.

Drug-delivery systems with a unique capability to respond to a given stimulus can improve therapeutic efficacy. However, development of such systems is currently heavily reliant on responsive polymeric materials and pursuing this singular strategy limits the potential for clinical translation. In this report, with a model system used for drug-release studies, we demonstrate a new strategy: how a temperature-responsive non-toxic, volatile liquid can be encapsulated and stored under ambient conditions and subsequently programmed for controlled drug release without relying on a smart polymer. When the stimulus temperature is reached, controlled encapsulation of different amounts of dye in the capsules is achieved and facilitates subsequent sustained release. With different ratios of the liquid (perfluorohexane): dye in the capsules, enhanced controlled release with real-time response is provided. Hence, our findings offer great potential for drug-delivery applications and provide new generic insights into the development of stimuli drug-release systems.