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The production of solid lipid nanoparticles (SLNs) is challenging, especially when considering the incorporation of biologics. A novel in-house method of microfluidic production of biologic-encapsulated SLNs is proposed, using a variety of base materials for formulation to help overcome the barriers presented during manufacture and administration. Trypsin is used as a model drug for hydrophilic encapsulation whilst testosterone is employed as a positive non-biologic lipophilic control active pharmaceutical ingredient. Particle sizes obtained ranged from 160 to 320 nm, and a lead formulation has been identified from the combinations assayed, allowing for high encapsulation efficiencies (47–90%, respectively) of both the large hydrophilic and the small hydrophobic active pharmaceutical ingredients (APIs). Drug release profiles were analysed in vitro to provide useful insight into sustained kinetics, providing data towards future in vivo studies, which displayed a slow prolonged release for testosterone and a quicker burst release for trypsin. The study represents a large leap forward in the field of SLN production, especially in the field of difficult-to-encapsulate molecules, and the technique also benefits from being more environmentally sustainable due to the use of microfluidics. [ABSTRACT FROM AUTHOR]

Vat photopolymerisation (VP) three-dimensional printing (3DP) has attracted great attention in many different fields, such as electronics, pharmaceuticals, biomedical devices and tissue engineering. Due to the low availability of biocompatible photocurable resins, its application in the healthcare sector is still limited. In this work, we formulate photocurable resins based on urethane dimethacrylate (UDMA) combined with three different difunctional methacrylic diluents named ethylene glycol dimethacrylate (EGDMA), di(ethylene glycol) dimethacrylate (DEGDMA) or tri(ethylene glycol) dimethacrylate (TEGDMA). The resins were tested for viscosity, thermal behaviour and printability. After printing, the 3D printed specimens were measured with a digital calliper in order to investigate their accuracy to the digital model and tested with FT-IR, TGA and DSC. Their mechanical properties, contact angle, water sorption and biocompatibility were also evaluated. The photopolymerizable formulations investigated in this work achieved promising properties so as to be suitable for tissue engineering and other biomedical applications. [ABSTRACT FROM AUTHOR]

In this study, liposomes enclosing eugenol were prepared using microfluidics. Two lipids—1,2-dimyristoyl-sn-glycero-3-phosphocholine, 18:0 (DSPC) and 2-dimyristoyl-sn-glycero-3-phosphocholine, 14:0 (DMPC)—and microfluidic chips with serpentine and Y-shaped micromixing designs were used for the liposomal formulation. Minimum bactericidal concentration (MBC) values indicated that eugenol was more effective against Gram-negative than Gram-positive bacteria. Four different flow-rate ratios (FRR 2:1, 3:1, 4:1, 5:1) were explored. All liposomes' encapsulation efficiency (EE) was determined: 94.34% for DSPC 3:1 and 78.63% for DMPC 5:1. The highest eugenol release of 99.86% was observed at pH 4, DMPC 3:1 (Y-shaped chip). Liposomes were physically stable at 4, 20 and 37 °C for 60 days as determined by their size, polydispersity index (PDI) and zeta potential (ZP). The most stable liposomes were observed at FRR 5:1 for DSPC. EE, stability, and eugenol release studies proved that the liposomal formulations produced can be used as delivery vehicles to increase food safety. [ABSTRACT FROM AUTHOR]

The treatment strategy required for the effective healing of diabetic foot ulcer (DFU) is a complex process that is requiring several combined therapeutic approaches. As a result, there is a significant clinical and economic burden associated in treating DFU. Furthermore, these treatments are often unsuccessful, commonly resulting in lower-limb amputation. The use of drug-loaded scaffolds to treat DFU has previously been investigated using electrospinning and fused deposition modelling (FDM) 3D printing techniques; however, the rapidly evolving field of bioprinting is creating new opportunities for innovation within this research area. In this study, 3D-bioprinted scaffolds with different designs have been fabricated for the delivery of an antibiotic (levoflocixin) to DFU. The scaffolds were fully characterised by a variety of techniques (e.g. SEM, DSC/TGA, FTIR, and mechanical characterisation), demonstrating excellent mechanical properties and providing sustained drug release for 4 weeks. This proof of concept study demonstrates the innovative potential of bioprinting technologies in fabrication of antibiotic scaffolds for the treatment of DFU. [ABSTRACT FROM AUTHOR]

3D printing has provided a new prospective in the manufacturing of personalized medical implants, including fistulas for haemodialysis (HD). In the current study, an optimized fused modelling deposition (FDM) 3D printing method has been validated, for the first time, to obtain cylindrical shaped fistulas. Printing parameters were evaluated for the manufacturing of fistulas using blank and 0.25% curcumin-loaded filaments that were produced by hot melt extrusion (HME). Four different fistula types have been designed and characterized using a variety of physicochemical characterization methods. Each design was printed three times to demonstrate printing process accuracy considering outer and inner diameter, wall thickness, width, and length. A thermoplastic polyurethane (TPU) biocompatible elastomer was chosen, showing good mechanical properties with a high elastic modulus and maximum elongation, as well as stability at high temperatures with less than 0.8% of degradation at the range between 25 and 250 °C. Curcumin release profile has been evaluated in a saline buffer, obtaining a low release (12%) and demonstrating drug could continue release for a longer period, and for as long as grafts should remain in patient body. Possibility to produce drug-loaded grafts using one-step method as well as 3D printing process and TPU filaments containing curcumin printability has been demonstrated. [ABSTRACT FROM AUTHOR]

The advancement of healthcare therapies is under constant development due to changing demographics and evolving disease-states. To ensure continuous furtherance of the healthcare system capacity to treat such ailments, emerging technologies (ETs) are coming to the forefront of medicine. It's the hope that ETs are capable of covering a broad scope of therapeutic treatment areas, enabling novel pharmaceutical pathways to be established. Highlighted in this mini review are examples of focus ET areas, including additive manufacturing (AM), microfluidics (MFs), microelectromechanical systems (MEMS) and machine learning (ML), that have shown promising qualities and should be targeted further to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Objectives: To develop a sustained release 5-fluorouracil (5-FU) implant by three-dimensional (3D) printing to effectively prevent conjunctival fibrosis after glaucoma surgery. Methods: 3D-printed implants composed of polycaprolactone (PCL) and chitosan (CS) were fabricated by heat extrusion technology and loaded with 1% 5-FU. Light microscopy and scanning electron microscopy were used to study the surface morphology. The 5-FU concentration released over 8 weeks was measured by ultraviolet visible spectroscopy. The effects on cell viability, fibroblast contractility and the expression of key fibrotic genes were assessed in human conjunctival fibroblasts. Key findings: The PCL–CS-5-FU implant sustainably released 5-FU over 8 weeks and the peak concentration was over 6.1 μg/ml during weeks 1 and 2. The implant had a smooth surface and its total weight decreased by 3.5% after 8 weeks. The PCL–CS–5-FU implant did not affect cell viability in conjunctival fibroblasts and sustainably suppressed fibroblast contractility and key fibrotic genes for 8 weeks. Conclusions: The PCL–CS–5-FU implant was biocompatible and degradable with a significant effect in suppressing fibroblast contractility. The PCL–CS–5-FU implant could be used as a sustained release drug implant, replacing the need for repeated 5-FU injections in clinic, to prevent conjunctival fibrosis after glaucoma surgery. Graphical Abstract [ABSTRACT FROM AUTHOR]

Objectives: The process of 3D printing to produce microfluidic chips is becoming commonplace, due to its quality, versatility and newfound availability. In this study, a UV liquid crystal display (LCD) printer has been implemented to produce a progression of microfluidic chips for the purpose of liposomal synthesis. The emphasis of this research is to test the limitations of UV LCD printing in terms of resolution and print speed optimisation for the production of microfluidic chips. Key findings: By varying individual channel parameters such as channel length and internal geometries, the essential channel properties for optimal liposomal formulation are being investigated to act as a basis for future experimentation including the encapsulation of active pharmaceutical ingredients. Using the uniquely designed chips, liposomes of ≈120 nm, with polydispersity index values of ≤0.12 are able to be reproducibly synthesised. Conclusions: The influence of total flow rates and lipid choice is investigated in depth, to provide further clarification on how a microfluidic setup should be optimised. In-depth explanations of the importance of each channel parameter are also explained throughout, with reference to their importance for the properties of a successful liposome. [ABSTRACT FROM AUTHOR]

Nanomedicine has grown tremendously in recent years as a responsive strategy to find novel therapies for treating challenging pathological conditions. As a result, there is an urgent need to develop novel formulations capable of providing adequate therapeutic treatment while overcoming the limitations of traditional protocols. Lately, microfluidic technology (MF) and additive manufacturing (AM) have both acquired popularity, bringing numerous benefits to a wide range of life science applications. There have been numerous benefits and drawbacks of MF and AM as distinct techniques, with case studies showing how the careful optimization of operational parameters enables them to overcome existing limitations. Therefore, the focus of this review was to highlight the potential of the synergy between MF and AM, emphasizing the significant benefits that this collaboration could entail. The combination of the techniques ensures the full customization of MF-based systems while remaining cost-effective and less time-consuming compared to classical approaches. Furthermore, MF and AM enable highly sustainable procedures suitable for industrial scale-out, leading to one of the most promising innovations of the near future. [ABSTRACT FROM AUTHOR]

This study explored the synergistic effects of simultaneously using calcium and gallium cations in the cross-linking of alginate, detailing its effects on the characteristics of alginate compared to its single cation counterparts. The primary goal is to determine if there are any synergistic effects associated with the utilisation of multiple multivalent cations in polymer cross-linking and whether or not it could therefore be used in pharmaceutical applications such as wound healing. Given the fact divalent and trivalent cations have never been utilised together for cross-linking, an explanation for the mode of binding that occurs between the alginate and the cations during the cross-linking process and how it may affect the future applications of the polymer has been investigated. The calcium gallium alginate polymers were able to retain the antibacterial effects of gallium within the confines of the polymer matrix, possessing superior rheological properties, 6 times that of pure calcium and pure gallium, coupled with an improved swelling capacity that is 4 times higher than that of gallium alginate. [ABSTRACT FROM AUTHOR]

The utilization of alginate polymers for wound healing is well explored; however, little attention is paid toward the optimization of the manufacturing process, especially in regards to the final morphological and rheological properties that are imparted to the alginate matrix. This is important as it helps to establish a set of guidelines for the consistent fabrication of mechanically strong polymer wafers, which in the context of manufacturing and production contributes to the reduction in research and development time required. In this study, the order of application with respect to cross‐linking and freeze‐drying parameters has been investigated, which showed to result in distinct differences in terms of their overall morphology and mechanical strength. The application of freeze‐drying before cross‐linking results in the uniform distribution of cross‐links throughout the alginate wafer, thereby producing a mechanically strong polymer wafer that retains the dehydrated matrices original thickness and architecture. Based on the observed data, freeze‐drying prior to cross‐linking facilitates the increased permeation and distribution of the cross‐linker solution into the polymer matrix, thus resulting in the uniform distribution of ionic cross‐links, which is necessary to produce a more mechanically superior polymer matrix. [ABSTRACT FROM AUTHOR]

Objectives There is a requirement within ear therapeutics for a delivery system capable of safely delivering controlled doses to the inner ear. However, the anatomy and sensitivity of the inner ear make current delivery systems problematic and often ineffective. Therefore, a new delivery system is required to overcome these issues and provide a more efficacious system in the treatment of inner ear disease. This study assesses the potential of 3D printing (3DP) as a fabrication method for an implantable drug delivery system (DDS) to the inner ear. Key findings Three implantable designs of varying geometry were produced with fused deposition modelling (FDM) 3DP, each loaded with 0.25%, 0.5% and 1% levofloxacin; filaments prepared by hot-melt extrusion. Each implant was effective in providing sustained, therapeutic release of levofloxacin for at least 4 days and as such would be effective in therapeutic treatment of many common inner ear diseases, such as otitis media or Ménière's disease. Conclusions This proof-of-concept research was successful in utilising FDM as a fabrication method for a DDS capable of providing prolonged release directly to the inner ear and highlights the viability of 3DP in the fabrication of an inner ear DDS. [ABSTRACT FROM AUTHOR]

Objectives The traditional manufacturing methods of solid oral dosage forms (SODFs) are reported to be time-consuming, highly expensive and not tailored to the patient's needs. Three-dimensional printing (3DP) is an innovative emerging technology that can help to overcome these issues. The aim of this review is to describe the most employed 3DP technologies, materials and the state of the art on 3DP SODFs. Characterization techniques of 3DP SODFs, challenges and regulatory issues are also discussed. Key findings The interest in the investigation of the suitability of 3DP as an alternative strategy for the fabrication of SODFs is growing. Different 3DP technologies and starting materials have been investigated for the development of SODFs. Numerous SODFs with complex geometries and composition, and with different release patterns, have been successfully manufactured via 3DP. Despite that, just one 3DP SODF has reached the market. Summary 3DP can be a promising alternative to the classical SODFs manufacturing methods. However, numerous technically and regulatory challenges still need to be addressed in order 3DP to be extensively used in the pharmaceutical sector. [ABSTRACT FROM AUTHOR]

Bioprinting is an emerging technology with various applications in developing functional tissue constructs for the replacement of harmed or damaged tissues and simultaneously controlled drug delivery systems (DDSs) for the administration of several active substances, such as growth factors, proteins, and drug molecules. It is a novel approach that provides high reproducibility and precise control over the fabricated constructs in an automated way. An ideal bioink should possess proper mechanical, rheological, and biological properties essential to ensure proper function. Chitosan is a promising natural-derived polysaccharide to be used as ink because of its attractive properties, such as biodegradability, biocompatibility, low cost, and non-immunogenicity. This review focuses on 3D bioprinting technology for the preparation of chitosan-based hydrogel scaffolds for the regeneration of tissues delivering either cells or active substances to promote restoration. [ABSTRACT FROM AUTHOR]

Breast cancer is the second most common cancer worldwide, characterized by a high incidence and mortality rate. Despite the advances achieved in cancer management, improvements in the quality of life of breast cancer survivors are urgent. Moreover, considering the heterogeneity that characterizes tumors and patients, focusing on individuality is fundamental. In this context, 3D printing (3DP) and 4D printing (4DP) techniques allow for a patient-centered approach. At present, 3DP applications against breast cancer are focused on three main aspects: treatment, tissue regeneration, and recovery of the physical appearance. Scaffolds, drug-loaded implants, and prosthetics have been successfully manufactured; however, some challenges must be overcome to shift to clinical practice. The introduction of the fourth dimension has led to an increase in the degree of complexity and customization possibilities. However, 4DP is still in the early stages; thus, research is needed to prove its feasibility in healthcare applications. This review article provides an overview of current approaches for breast cancer management, including standard treatments and breast reconstruction strategies. The benefits and limitations of 3DP and 4DP technologies are discussed, as well as their application in the fight against breast cancer. Future perspectives and challenges are outlined to encourage and promote AM technologies in real-world practice. [ABSTRACT FROM AUTHOR]

Covid-19, alongside previous pandemics, has highlighted the need for the continued development of technologies that are at our disposal. Emerging technologies are those that show true promise in achieving such a goal and have begun to form sturdy independent research areas. Technological advances in healthcare must continually develop to ensure that the world is prepared for any future diseases that may ensue. As such, a strategic review into 43 manuscripts since 2019 has been conducted to determine the prominence of emerging technologies since the beginning of the Covid-19 pandemic. Relating to their use in a pandemic state, additive manufacturing (AM), biofabrication, microfluidics, biomedical microelectromechanical systems (BioMEMS), and artificial intelligence (AI) are described. Applications over the past 2–3 years, as well as future developments, are considered throughout. All the technologies mentioned in this review are sure to develop further, having shown their importance and value during the covid-19 pandemic. As research continues within the area, their efficacy will increase to the point where it likely will become gold standard for pandemic control. Combining certain technologies mentioned has also proved to have had great success in improving the final results obtained. [ABSTRACT FROM AUTHOR]

The implementation of peptide-based molecules within the medical field has vast potential, owing to their unique nature and predictable physicochemical profiles. However, peptide therapeutic usage is hindered by delivery-related challenges, meaning that their formulations must be altered to overcome these limitations. This process could be propelled by applying microfluidics (MFs) due to its highly controllable and adaptable attributes; however, therapeutic research within this field is extremely limited. Peptides possess multifunctional roles within therapeutic formulations, ranging from enhancing target specificity to acting as the active component of the medicine. Diagnostically, MFs are well explored in the field of peptides, as MFs provide an unsullied platform to provide fast yet accurate examinations. The capacity to add attributes, such as integrated sensors and microwells, to the MF chip, only enhances the attractiveness of MFs as a diagnostic platform. The structural individuality of peptides makes them prime candidates for diagnostic purposes, for example, antigen detection and isolation. Therefore, this review provides a useful insight into the current applications of MFs for peptide-based therapy and diagnostics and highlights potential gaps in the field that are yet to be explored or optimized. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cells (HSCs) maintain balanced blood cell production in a process called hematopoiesis. As humans age, their HSCs acquire mutations that allow some HSCs to disproportionately contribute to normal blood production. This process, known as age‐related clonal hematopoiesis, predisposes certain individuals to cancer, cardiovascular and pulmonary pathologies. There is a growing body of evidence suggesting that factors outside cells, such as extracellular vesicles (EVs), contribute to the disruption of stem cell homeostasis during aging. We have characterized blood EVs from humans and determined that they are remarkably consistent with respect to size, concentration, and total protein content, across healthy subjects aged 20–85 years. When analyzing EV protein composition from mass spectroscopy data, our machine‐learning‐based algorithms are able to distinguish EV proteins based on age and suggest that different cell types dominantly produce EVs released into the blood, which change over time. Importantly, our data show blood EVs from middle and older age groups (>40 years) significantly stimulate HSCs in contrast to untreated and EVs sourced from young subjects. Our study establishes for the first time that although EV particle size, concentration, and total protein content remain relatively consistent over an adult lifespan in humans, EV content evolves during aging and potentially influences HSC regulation. [ABSTRACT FROM AUTHOR]

A pandemic is the worst-case scenario in the field of infectious diseases. Innovative technologies have the potential to address the challenges associated with the manufacture of personalized drug delivery systems, biosensors, and medical devices during a pandemic. 3D-Printing, microfluidics, and Microelectromechanical systems (MEMS) can provide an important part on this fight, as are cheap, easy to be operated, capable to provide rapid detection and monitoring of a disease, and deliver medicines. This manuscript answers the question of how these emerging technologies can save lives during a pandemic by avoiding supply chain delays and also by providing rapid diagnostics, disease monitoring, or by offering personalized treatments. The manuscript covers recent approaches in the topic with a focus in manuscripts published in the last year and by emphasising recent regulatory considerations by regulatory agencies in the manufacturing of 3DP systems or other medical devices during COVID. New manufacturing techniques are emerging with the ability to address the challenges associated with the development of medical devices or diagnostics, during a pandemic. Are many challenges in order to achieve this and especially in short times that are required under a pandemic attack, which will also be covered in this manuscript. [ABSTRACT FROM AUTHOR]

The main aim of the research was to synthesize amphiphilic cyclodextrin (AMCD) by substituting C12 alkyl chain to a β-cyclodextrin (βCD) in a single step and to study its self-assembly in an aqueous medium. The drug delivery application of the AMCD was also evaluated by encapsulating tamoxifen citrate as a model hydrophobic drug. AMCD was able to self-assemble in aqueous media, forming nanovesicles of size < 200 nm, capable of encapsulating tamoxifen citrate (TMX). Molecular docking and MD simulation studies revealed the interaction between TMX and AMCD which formed a stable complex. TEM and AFM studies showed that nanovesicles were perfectly spherical having a smooth surface and a theoretical AMCD bilayer thickness of ~ 7.2 nm as observed from SANS studies. XRD and DSC studies revealed that TMX was amorphized and molecularly dispersed in AMCD bilayer which was released slowly following Fickian diffusion. AMCD has excellent hemocompatibility as opposed to βCD and no genotoxicity. IC50 of TMX against MCF-7 cell lines was significantly reduced from 11.43 to 7.96 μg/ml after encapsulation in nanovesicle because of nanovesicles being endocytosed by the MCF-7 cells. AMCD was well tolerated by IV route at a dose of > 2000 mg/kg in rats. Pharmacokinetic profile of TMX after encapsulation was improved giving 3-fold higher AUC; extended mean residence time is improving chances of nanovesicle to extravasate in tumor via EPR effect. [ABSTRACT FROM AUTHOR]

The fast development in materials science has resulted in the emergence of new pharmaceutical materials with superior physical and mechanical properties. Low-substituted hydroxypropyl cellulose is an ether derivative of cellulose and is praised for its multi-functionality as a binder, disintegrant, film coating agent and as a suitable material for medical dressings. Nevertheless, very little is known about the compaction behaviour of this polymer. The aim of the current study was to evaluate the compaction and disintegration behaviour of four grades of L-HPC namely; LH32, LH21, LH11, and LHB1. The macrometric properties of the four powders were studied and the compaction behaviour was evaluated using the out-of-die method. LH11 and LH22 showed poor flow properties as the powders were dominated by fibrous particles with high aspect ratios, which reduced the powder flow. LH32 showed a weak compressibility profile and demonstrated a large elastic region, making it harder for this polymer to deform plastically. These findings are supported by AFM which revealed the high roughness of LH32 powder (100.09 ± 18.84 nm), resulting in small area of contact, but promoting mechanical interlocking. On the contrary, LH21 and LH11 powders had smooth surfaces which enabled larger contact area and higher adhesion forces of 21.01 ± 11.35 nN and 9.50 ± 5.78 nN, respectively. This promoted bond formation during compression as LH21 and LH11 powders had low strength yield. [ABSTRACT FROM AUTHOR]

Polydopamine has been found to be a biocompatible polymer capable of supporting cell growth and attachment, and to have antibacterial and antifouling properties. Together with its ease of manufacture and application, it ought to make an ideal biomaterial and function well as a coating for implants. In this paper, atomic force microscope was used to measure the adhesive forces between polymer-, protein- or polydopamine-coated surfaces and a silicon nitride or polydopamine-functionalised probes. Surfaces were further characterised by contact angle goniometry, and solutions by circular dichroism. Polydopamine was further characterised with infrared spectroscopy and Raman spectroscopy. It was found that polydopamine functionalisation of the atomic force microscope probe significantly reduced adhesion to all tested surfaces. For example, adhesion to mica fell from 0.27 ± 0.7 to 0.05 ± 0.01 nN nm. The results suggest that polydopamine coatings are suitable to be used for a variety of biomedical applications. [ABSTRACT FROM AUTHOR]

Keywords: 3D printing; drug delivery; pharmacology; pharmaceutical sciences EN 3D printing drug delivery pharmacology pharmaceutical sciences 1365 1366 2 10/21/22 20221001 NES 221001 In the recent years, we have encountered significant advances in the manufacturing processes of medicinal products and medical devices, particularly after the recent pandemic and the turmoil in the supply chain. Some of the benefits of 3DP in the areas of Pharmacology and Pharmaceutical Sciences include the ability to generate solid dosage forms (e.g. tablets) of different shapes (e.g. Haribo for paediatric applications) and sizes, the manufacturing of multi-drug pills, to control the release (e.g. sustained, immediate) of the active pharmaceutical ingredients (APIs) in question, to make an eco-friendly production, cost-effective manufacturing and safer for manufacturing testing systems compared with alternative methods. Emerging technologies (ETs), such as 3D printing (3DP), 4D Printing, and bioprinting, are shaping the future of manufacturing and the delivery of traditional and new medicines and can be used to monitor diseases when combined with other ETs. [Extracted from the article]

Purpose: The present study reports a novel conjugate of gemcitabine (GEM) with bovine serum albumin (BSA) and thereof nanoparticles (GEM-BSA NPs) to potentiate the therapeutic efficacy by altering physicochemical properties, improving cellular uptake and stability of GEM. Methods: The synthesized GEM-BSA conjugate was extensively characterized by NMR, FTIR, MALDI-TOF and elemental analysis. Conjugation mediated changes in structural conformation and physicochemical properties were analysed by fluorescence, Raman and CD spectroscopy, DSC and contact angle analysis. Further, BSA nanoparticles were developed from BSA-GEM conjugate and extensively evaluated against in-vitro pancreatic cancer cell lines to explore cellular uptake pathways and therapeutic efficacy. Results: Various characterization techniques confirmed covalent conjugation of GEM with BSA. GEM-BSA conjugate was then transformed into NPs via high pressure homogenization technique with particle size 147.2 ± 7.3, PDI 0.16 ± 0.06 and ZP -19.2 ± 1.4. The morphological analysis by SEM and AFM revealed the formation of smooth surface spherical nanoparticles. Cellular uptake studies in MIA PaCa-2 (GEM sensitive) and PANC-1 (GEM resistant) pancreatic cell lines confirmed energy dependent clathrin internalization/endocytosis as a primary mechanism of NPs uptake. In-vitro cytotoxicity studies confirmed the hNTs independent transport of GEM in MIA PaCa-2 and PANC-1 cells. Moreover, DNA damage and annexin-V assay revealed significantly higher apoptosis level in case of cells treated with GEM-BSA NPs as compared to free GEM. Conclusions: GEM-BSA NPs were found to potentiate the therapeutic efficacy by altering physicochemical properties, improving cellular uptake and stability of GEM and thus demonstrated promising therapeutic potential over free drug. [ABSTRACT FROM AUTHOR]

Using a combination of experimental and computational approaches, the interaction between anastellin, a recombinant fragment of fibronectin, and representative biomaterial surfaces has been examined. Anastellin and superfibronectin have been seen to exhibit antiangiogenic properties and other properties that may make it suitable for consideration for incorporation into biomaterials. The molecular interaction was directly quantified by atomic force microscope (AFM)-based force spectroscopy, complemented by adsorption measurements using quartz crystal microbalance (QCM). Using AFM, it was found that the anastellin molecule facilitates a stronger adhesion on polyurethane films (72.0 pN nm−1) than on poly (methyl methacrylate) films (68.6 pN nm−1). However, this is not consistent with the QCM adsorption measurements, which show no significant difference. Molecular dynamics simulations of the behavior of anastellin on polyurethane in aqueous solution were performed to rationalize the experimental data, and show that anastellin is capable of rapid adsorption to PU while its secondary structure is stable upon adsorption in water. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 737-745, 2017. [ABSTRACT FROM AUTHOR]

Scaling rules were developed and tested for a continuous twin screw wet granulation process using three scales (11, 16, and 24 mm barrel diameter) of twin screw granulators (TSG). The distributive feed screw configuration used produced high porosity granules (50-60%) with broad bimodal size distributions, especially in the 16 and 24 mm TSGs. Three dimensionless numbers, Froude number (Fr), liquid-to-solid ratio (LSR), and powder feed number (PFN), were identified and their effect on granule size distribution (GSD), porosity and liquid distribution tested. Granule size increased with increasing LSR as expected. However, Fr and PFN had no significant effect on d10 or d50 and only a small effect on d90. In contrast, granulator scale had a strong effect on GSD, with d90 increasing almost linearly with barrel diameter. This is consistent with breakage of large granules being a dominant mechanism and directly controlled by the geometry of the screw. © 2016 American Institute of Chemical Engineers AIChE J, 63: 921-932, 2017 [ABSTRACT FROM AUTHOR]

Inkjet printing technology was used to apply insulin polymeric layers on metal microneedles for transdermal delivery. A range of various polymers such as gelatin (GLN), polyvinyl caprolactame-polyvinyl acetate-polyethylene glycol (SOL), poly(2-ethyl-2-oxazoline) (POX) and trehalose (THL) were assessed for their capacity to form thin uniform and homogeneous layers that preserve insulin intact. Atomic force microscopy (AFM) showed homogeneous insulin-polymer layers without any phase separation while SOL demonstrated the best performance. Circular discroism (CD) analysis of rehydrated films showed that insulin's alpha helices and β-sheet were well preserved for THL and SOL. In contrast, GLN and POX insulin layers revealed small band shifts indicating possible conformational changes. Insulin release in Franz diffusion cells from MNs inserted into porcine skin showed rapid release rates for POX and GLN within the first 20 min. Inkjet printing was proved an effective approach for transdermal delivery of insulin in solid state. [ABSTRACT FROM AUTHOR]

Cholesterol plays a strategic role in liposome composition; however, the quantity used to achieve an appropriate formulation has not been yet clarified. Therefore, by screening arrangement of lipids and cholesterol ratio, the main aim of this study is to investigate the most suitable amount of cholesterol in lipids in order to prepare stable and controlled drug release vehicles. For the preparation of liposomes, DMPC, DPPC and DSPC phospholipids were used and combined with different molar ratios of cholesterol (e.g. 100, 80-20, 70-30, 60-40 and 50-50 %). Stability studies were conducted by storing the formulations at 37 and 50 °C for 30 days and by analysing them by AFM, DLS and FT-IR. By detecting the two most stable formulations from the stability results, drug encapsulation and in vitro release studies in PBS were performed by encapsulating atenolol and quinine. The release results were validated using a simulation model to ensure the reliability and suitable interpretation of the data. The generated model showed a good correlation between the prediction and the in vitro obtained results. By using 70:30 % ratio (known in literature as 2:1), it is possible to reach the most stable formulation to guarantee a controlled and reproducible release for drugs with different physicochemical characteristics and pharmaceutical applications. [ABSTRACT FROM AUTHOR]

A thrust balance characterization of a low powered Quad Confinement Thruster is presented for high levels of propellant flow. The nominal flow rate for this device is between 1 and 2 sccm of xenon propellant. This paper extends the operating range, and investigates the performance at two high flow conditions of 10 and 20 sccm. Power is varied incrementally between 20 and 200 W in order to characterize the performance versus power trends of the device. It was found that for these high flow regimes the propellant is underutilized, and a proportion of the increased thrust can likely be attributed to a hot gas expansion of the neutral xenon rather than the generation of additional accelerated ions. The thrust was increased from 1 (nominal) to 3.3 mN at 200 W of input power for the 20 sccm condition. However, the performance penalty in terms of the specific impulse was considerable. The specific impulse under these conditions dropped below 200 s, where the nominal condition is 1000 s. A compromise between increased thrust and decreased performance was found at 10 sccm of flow: 3 mN of thrust at 300 s specific impulse. [ABSTRACT FROM PUBLISHER]

Silica nanoparticles have been shown to have great potential as drug delivery systems (DDS), however, their fabrication often involves harsh chemicals and energy intensive laborious methods. This work details the employment of a bioinspired "green" method for the controlled synthesis of silica, use of the products to entrap and release drug molecules and their cytotoxicity in order to develop novel DDS. Bioinspired silica synthesis occurs at pH 7, room temperature and in less than 5 minutes, resulting in a rapid, cheaper and greener route. Drugs were loaded into silica during the silica formation, thus allowing a one step and one pot method for simultaneous silica synthesis and drug loading. We established that the drug release profile can be modulated by synthetic parameters, which can allow design of tailored DDS. A systematic investigation using a two level factorial design was adopted in order to identify the key synthetic parameters and quantify their effects on silica formation, drug loading and drug release. The observation that these new DDS are considerably less cytotoxic than their current counterparts, and exhibit additional benefits such as green synthesis and ease of functionalization, strengthens the argument for their future use in DDS and other biomedical applications. [ABSTRACT FROM AUTHOR]

This study reports scale-up and shelf-stability of curcumin encapsulated poly(lactic acid- co-glycolic acid) (PLGA) nanoparticles. The curcumin encapsulated PLGA nanoparticles were prepared by emulsification solvent evaporation/diffusion, and large quantities were made by varying the homogenisation time (5, 15 and 30 min). The particle size decreased as the homogenisation duration increased from 5 to 30 min, and the particles were spherical as confirmed by atomic force microscopy. For the large-scale preparations, the mean particles size was found to be 288.7 ± 3.4 (polydispersity index 0.15 ± 0.01) with curcumin entrapment 52.5 ± 4.3 %, which were comparable to the lab-scale preparations. The curcumin encapsulated nanoparticles were freeze-dried using sucrose (5 %, w/ v) as a cryoprotectant. The freeze-dried nanoparticles were subjected to 6-month stability study as per the International Conference on Harmonisation guideline at room temperature and refrigerated storage conditions. Intermediate sampling was done (monthly), and the nanoparticles were thoroughly characterised for particle size, entrapment efficiency, surface morphology and crystallinity, which were compared to fresh preparations. The curcumin encapsulated PLGA nanoparticles were found to be stable at refrigerated as well as room temperature storage test conditions indicated by their particle characteristics. X-ray diffraction results confirm amorphous nature of curcumin on nano-encapsulation that stays intact after freeze drying and 6-month stability testing. Together these data offer possibility of producing large quantities of polymer nanoparticles that are suitable for room as well as refrigerated storage conditions opening up possibilities to conduct repeated dosings in a chronic setting or regulatory toxicology studies of such nanomedicines. [ABSTRACT FROM AUTHOR]

Overcoming the intractable challenge of imaging of label-free, drug encapsulated nanoparticles in tissues in vivo would directly address associated regulatory concerns over 'nanotoxicology'. Here we demonstrate the utility of Atomic Force Microscopy (AFM) for visualising label-free, drug encapsulated polyester particles of ∼280 nm distributed within tissues following their intravenous or peroral administration to rodents. A surprising phenomenon, in which the tissues' mechanical stiffness was directly measured (also by AFM) and related to the number of embedded nanoparticles, was utilised to generate quantitative data sets for nanoparticles localisation. By coupling the normal determination of a drug's pharmacokinetics/pharmacodynamics with post-sacrifice measurement of nanoparticle localisation and number, we present for the first time an experimental design in which a single in vivo study relates the PK/PD of a nanomedicine to its toxicokinetics. [ABSTRACT FROM AUTHOR]

We report on a pronounced specific-ion effect on the intermolecular and chiral organization, supramolecular structure formation, and resulting materials properties for a series of low molecular weight peptide-based hydrogelators, observed in the presence of simple inorganic salts. This effect was demonstrated using aromatic short peptide amphiphiles, based on fluorenylmethoxycarbonyl (Fmoc). Gel-phase materials were formed due to molecular self-assembly, driven by a combination of hydrogen bonding and π-stacking interactions. Pronounced morphological changes were observed by atomic force microscopy (AFM) for Fmoc-YL peptide, ranging from dense fibrous networks to spherical aggregates, depending on the type of anions present. The gels formed had variable mechanical properties, with G′ values between 0.8 kPa and 2.4 kPa as determined by rheometry. Spectroscopic analysis provided insights into the differential mode of self-assembly, which was found to be dictated by the hydrophobic interactions of the fluorenyl component, with comparable H-bonding patterns observed in each case. The efficiency of the anions in promoting the hydrophobic interactions and thereby self-assembly was found to be consistent with the Hofmeister anion sequence. Similar effects were observed with other hydrophobic peptides, Fmoc-VL and Fmoc-LL. The effect was found to be less pronounced for a less hydrophobic peptide, Fmoc-AA. To get more insights into the molecular mechanism, the effect of anions on sol-gel equilibrium was investigated, which indicates the observed changes result from the specific-ion effects on gels structure, rather than on the sol-gel equilibrium. Thus, we demonstrate that, by simply changing the ionic environment, structurally diverse materials can be accessed providing an important design consideration in nanofabrication via molecular self-assembly. [ABSTRACT FROM AUTHOR]

Solid lipid nanoparticles (SLNs) loaded with ibuprofen (IBU) were prepared by solvent-free high-pressure homogenization (HPH). The produced SLNs consisted of stearic acid, triluarin or tripalmitin as lipid matrixes and various stabilizers. The produced empty and IBU-loaded SLNs were characterized for particle size stability over 8 months. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were implemented to characterize the IBU state of freeze-dried SLNs. IBU was found to be in both amorphous and crystalline form within the lipid matrix. The lyophilized powders showed increased dissolution rates for IBU depending on the lipid nature. SLNs were incubated in Caco-2 cells for 24 h showing negligible cell cytotoxicity up to 15 mg/mL. [ABSTRACT FROM AUTHOR]

In conventional drug administration, drug molecules cross multiple biological barriers, distribute randomly in the tissues, and can release insufficient concentrations at the desired pathological site. Controlling the delivery of the molecules can increase the concentration of the drug in the desired location, leading to improved efficacy, and reducing the unwanted effects of the molecules under investigation. Nanoparticles (NPs), have shown a distinctive potential in targeting drugs due to their unique properties, such as large surface area and quantum properties. A variety of NPs have been used over the years for the encapsulation of different drugs and biologics, acting as drug carriers, including lipid-based and polymeric NPs. Applying NP platforms in medicines significantly improves the disease diagnosis and therapy. Several conventional methods have been used for the manufacturing of drug loaded NPs, with conventional manufacturing methods having several limitations, leading to multiple drawbacks, including NPs with large particle size and broad size distribution (high polydispersity index), besides the unreproducible formulation and high batch-to-batch variability. Therefore, new methods such as microfluidics (MFs) need to be investigated more thoroughly. MFs, is a novel manufacturing method that uses microchannels to produce a size-controlled and monodispersed NP formulation. In this review, different formulation methods of polymeric and lipid-based NPs will be discussed, emphasizing the different manufacturing methods and their advantages and limitations and how microfluidics has the capacity to overcome these limitations and improve the role of NPs as an effective drug delivery system. [ABSTRACT FROM AUTHOR]

3D printing is an emerging technology aiming towards personalized drug delivery, among many other applications. Microneedles (MN) are a viable method for transdermal drug delivery that is becoming more popular for delivery through the skin. However, there is a need for a faster fabrication process with potential for easily exploring different geometries of MNs. In the current study, a digital light processing (DLP) method of 3D printing for fabrication of hollow MN arrays using commercial UV curable resin was proposed. Print quality was optimised by assessing the effect of print angle on needle geometries. Mechanical testing of MN arrays was conducted using a texture analyser. Angled prints were found to produce prints with geometries closer to the CAD designs. Curing times were found to affect the mechanical strength of MNs, with arrays not breaking when subjected to 300 N of force but were bent. Overall, DLP process produced hollow MNs with good mechanical strength and depicts a viable, quick, and efficient method for the fabrication of hollow MN arrays. [ABSTRACT FROM AUTHOR]

Microfluidic technique has emerged as a promising tool for the production of stable and monodispersed nanoparticles (NPs). In particular, this work focuses on liposome production by microfluidics and on factors involved in determining liposome characteristics. Traditional fabrication techniques for microfluidic devices suffer from several disadvantages, such as multistep processing and expensive facilities. Three-dimensional printing (3DP) has been revolutionary for microfluidic device production, boasting facile and low-cost fabrication. In this study, microfluidic devices with innovative micromixing patterns were developed using fused deposition modelling (FDM) and liquid crystal display (LCD) printers. To date, this work is the first to study liposome production using LCD-printed microfluidic devices. The current study deals with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes with cholesterol (2:1) prepared using commercial and 3D-printed microfluidic devices. We evaluated the effect of microfluidic parameters, chip manufacturing, material, and channel design on liposomal formulation by analysing the size, PDI, and ζ-potential. Curcumin exhibits potent anticancer activity and it has been reported that curcumin-loaded liposomes formulated by microfluidics show enhanced encapsulation efficiency when compared with other reported systems. In this work, curcumal liposomes were produced using the developed microfluidic devices and particle sizing, ζ-potential, encapsulation efficiency, and in vitro release studies were performed at 37 °C. [ABSTRACT FROM AUTHOR]

Icaritin is a promising anti-hepatoma drug that is currently being tested in a phase-III clinical trial. A novel combination of amorphization and nanonization was used to enhance the oral bioavailability of icaritin. Amorphous icaritin nanoparticles (AINs) were prepared by a reactive precipitation technique (RPT). Fourier transform infrared spectrometry was used to investigate the mechanism underlying the formation of amorphous nanoparticles. AINs were characterized via scanning electron microscopy, X-ray powder diffraction, and differential scanning calorimetry. Our prepared AINs were also evaluated for their dissolution rates in vitro and oral bioavailability. The resultant nanosized AINs (64 nm) were amorphous and exhibited a higher dissolution rate than that derived from a previous oil-suspension formulation. Fourier transform infrared spectroscopy (FTIR) revealed that the C=O groups from the hydrophilic chain of polymers and the OH groups from icaritin formed hydrogen bonds that inhibited AIN crystallization and aggregation. Furthermore, an oral administration assay in beagle dogs showed that Cmax and AUClast of the dried AINs formulation were 3.3-fold and 4.5-fold higher than those of the oil-suspension preparation (p < 0.01), respectively. Our results demonstrate that the preparation of amorphous drug nanoparticles via our RPT may be a promising technique for improving the oral bioavailability of poorly water-soluble drugs. [ABSTRACT FROM AUTHOR]

Three-dimensional printing of poly(ε-caprolactone) (PCL) is a consolidated scaffold manufacturing technique for bone regenerative medicine. Simultaneously, the mesenchymal stem/stromal cell (MSC) secretome is osteoinductive, promoting scaffold colonization by cells, proliferation, and differentiation. The present paper combines 3D-printed PCL scaffolds with lyosecretome, a freeze-dried formulation of MSC secretome, containing proteins and extracellular vesicles (EVs). We designed a lyosecretome 3D-printed scaffold by two loading strategies: (i) MSC secretome adsorption on 3D-printed scaffold and (ii) coprinting of PCL with an alginate-based hydrogel containing MSC secretome (at two alginate concentrations, i.e., 6% or 10% w/v). A fast release of proteins and EVs (a burst of 75% after 30 min) was observed from scaffolds obtained by absorption loading, while coprinting of PCL and hydrogel, encapsulating lyosecretome, allowed a homogeneous loading of protein and EVs and a controlled slow release. For both loading modes, protein and EV release was governed by diffusion as revealed by the kinetic release study. The secretome's diffusion is influenced by alginate, its concentration, or its cross-linking modes with protamine due to the higher steric hindrance of the polymer chains. Moreover, it is possible to further slow down protein and EV release by changing the scaffold shape from parallelepiped to cylindrical. In conclusion, it is possible to control the release kinetics of proteins and EVs by changing the composition of the alginate hydrogel, the scaffold's shape, and hydrogel cross-linking. Such scaffold prototypes for bone regenerative medicine are now available for further testing of safety and efficacy. [ABSTRACT FROM AUTHOR]

Medical conditions such as trachoma, keratoconus and Fuchs endothelial dystrophy can damage the cornea, leading to visual deterioration and blindness and necessitating a cornea transplant. Due to the shortage of donor corneas, hydrogels have been investigated as potential corneal replacements. A key factor that influences the physical and biochemical properties of these hydrogels is how they are crosslinked. In this paper, an overview is provided of different crosslinking techniques and crosslinking chemical additives that have been applied to hydrogels for the purposes of corneal tissue engineering, drug delivery or corneal repair. Factors that influence the success of a crosslinker are considered that include material composition, dosage, fabrication method, immunogenicity and toxicity. Different crosslinking techniques that have been used to develop injectable hydrogels for corneal regeneration are summarized. The limitations and future prospects of crosslinking strategies for use in corneal tissue engineering are discussed. It is demonstrated that the choice of crosslinking technique has a significant influence on the biocompatibility, mechanical properties and chemical structure of hydrogels that may be suitable for corneal tissue engineering and regenerative applications. [ABSTRACT FROM AUTHOR]

Additive manufacturing (AM), also known as three-dimensional (3D) printing, enables fabrication of custom-designed and personalized 3D constructs with high complexity in shape and composition. AM has a strong potential to fabricate oral tablets with enhanced customization and complexity as compared to tablets manufactured using conventional approaches. Despite these advantages, AM has not yet become the mainstream manufacturing approach for fabrication of oral solid dosage forms mainly due to limitations of AM technologies and lack of diverse printable drug formulations. In this review, AM of oral tablets are summarized with respect to AM technology. A detailed review of AM methods and materials used for the AM of oral tablets is presented. This article also reviews the challenges in AM of pharmaceutical formulations and potential strategies to overcome these challenges. [ABSTRACT FROM AUTHOR]

Extemporaneous oral liquid preparations are commonly used when there is no commercially available dosage form for adjustable dosing. In most cases, there is a lack of stability data to allow for an accurately assigned shelf life and storage conditions to give greater confidence of product safety and efficacy over its shelf life. The aim of this study was to evaluate the physical, chemical and microbiological stability of an extemporaneous oral liquid suspension of losartan potassium, 5 mg/mL, used to treat paediatric hypertension in Our Lady's Children's Hospital Crumlin, Ireland. The losartan content of extemporaneous oral suspensions, prepared with and without addition of water, was measured by UV and confirmed by HPLC analysis. Suspensions were stored at 4 °C and room temperature (RT) and were monitored for changes in; pH, colour, odour, re-dispersibility, Total Aerobic Microbial Count, Total Yeast and Mould Count and absence of E. coli. Results showed that suspensions prepared by both methods, stored at 4 °C and RT, were physically and microbiologically stable over 28 days. Initial losartan content of all suspensions was lower than expected at 80–81% and did not change significantly over the 28 days. HPLC and NMR did not detect degradation of losartan in the samples. Suspensions prepared in water showed 100% losartan content. The reduced initial losartan content was confirmed by HPLC and was related to the acidic pH of the suspension vehicle. Physiochemical properties of the drug are important factors for consideration in the selection of suspension vehicle for extemporaneous compounding of oral suspensions as they can influence the quality, homogeneity and efficacy of these preparations. [ABSTRACT FROM AUTHOR]

Beta-adrenocepetor antagonists (beta-blockers) alter the nanostructure of lysozyme amyloids, resulting in different drug release profiles. [ABSTRACT FROM AUTHOR]