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This paper provides an analysis of microfluidic techniques for the production of nanoscale lipid-based vesicular systems. In particular we focus on the key issues associated with the microfluidic production of liposomes. These include, but are not limited to, the role of lipid formulation, lipid concentration, residual amount of solvent, production method (including microchannel architecture), and drug loading in determining liposome characteristics. Furthermore, we propose microfluidic architectures for the mass production of liposomes with a view to potential industrial translation of this technology.

The cytoplasm is the largest part of the cell by volume and hence its rheology sets the rate at which cellular shape changes can occur. Recent experimental evidence suggests that cytoplasmic rheology can be described by a poroelastic model, in which the cytoplasm is treated as a biphasic material consisting of a porous elastic solid meshwork (cytoskeleton, organelles, macromolecules) bathed in an interstitial fluid (cytosol). In this picture, the rate of cellular deformation is limited by the rate at which intracellular water can redistribute within the cytoplasm. However, direct supporting evidence for the model is lacking. Here we directly validate the poroelastic model to explain cellular rheology at short timescales using microindentation tests in conjunction with mechanical, chemical and genetic treatments. Our results show that water redistribution through the solid phase of the cytoplasm (cytoskeleton and macromolecular crowders) plays a fundamental role in setting cellular rheology at short timescales. It has been suggested that the cytoplasm of living cells can be described as a porous elastic meshwork bathed in an interstitial fluid. Microindentation tests now show that intracellular water redistribution plays a fundamental role in cellular rheology and that at physiologically relevant timescales cellular responses to mechanical stresses are consistent with such a poroelastic model.

AimThe aim of this in silico study was to investigate the effect of particle size, flow rate, and tidal volume on drug targeting to small airways in patients with mild COPD.MethodDesign of Experiments (DoE) was used with an in silico whole lung particle deposition model for bolus administration to investigate whether controlling inhalation can improve drug delivery to the small conducting airways. The range of particle aerodynamic diameters studied was 0.4 – 10 µm for flow rates between 100 – 2000 mL/s (i.e., low to very high), and tidal volumes between 40 – 1500 mL.ResultsThe model accurately predicted the relationship between independent variables and lung deposition, as confirmed by comparison with published experimental data. It was found that large particles (~ 5 µm) require very low flow rate (~ 100 mL/s) and very small tidal volume (~ 110 mL) to target small conducting airways, whereas fine particles (~ 2 µm) achieve drug targeting in the region at a relatively higher flow rate (~ 500 mL/s) and similar tidal volume (~ 110 mL).ConclusionThe simulation results indicated that controlling tidal volume and flow rate can achieve targeted delivery to the small airways (i.e., > 50% of emitted dose was predicted to deposit in the small airways), and the optimal parameters depend on the particle size. It is hoped that this finding could provide a means of improving drug targeting to the small conducting airways and improve prognosis in COPD management.

Chronic infections represent a major clinical challenge due to the enhanced antimicrobial tolerance of biofilm-dwelling bacteria. To address this challenge, an ultrasound-responsive nanoscale drug delivery platform (nanodroplets) is presented in this work, loaded with four different antimicrobial agents, capable of simultaneous biofilm disruption and targeted antimicrobial delivery. When loaded, a robust protective effect against clinically-derived MRSA and ESBL Gram-positive and Gram-negative planktonic isolates was shown in vitro. Upon application of therapeutic ultrasound, an average 7.6-fold, 44.4-fold, and 25.5-fold reduction was observed in the antibiotic concentrations compared to free drug required to reach the MBC, MBEC and complete persister eradication levels, respectively. Nanodroplets substantially altered subcellular distribution of encapsulated antimicrobials, enhancing accumulation of antimicrobials by 11.1-fold within the biofilm-residing bacteria’s cytoplasm compared to treatment with unencapsulated drugs. These findings illustrate the potential of this multifunctional platform to overcome the critical penetration and localization limitations of antimicrobials within biofilms, opening potential new avenues in the treatment of chronic clinical infections.

Encapsulated microbubbles are well established as highly effective contrast agents for ultrasound imaging. There remain, however, some significant challenges to fully realize the potential of microbubbles in advanced applications such as perfusion mapping, targeted drug delivery, and gene therapy. A key requirement is accurate characterization of the viscoelastic surface properties of the microbubbles, but methods for independent, nondestructive quantification and mapping of these properties are currently lacking. We present here a strategy for performing these measurements that uses a small fluorophore termed a “molecular rotor” embedded in the microbubble surface, whose fluorescence lifetime is directly related to the viscosity of its surroundings. We apply fluorescence lifetime imaging to show that shell viscosities vary widely across the population of the microbubbles and are influenced by the shell composition and the manufacturing process. We also demonstrate that heterogeneous viscosity distributions exist within individual microbubble shells even with a single surfactant component.

Hypoxia has been shown to be a key factor inhibiting the successful treatment of solid tumours. Existing strategies for reducing hypoxia, however, have shown limited efficacy and/or adverse side effects. The aim of this study was to investigate the potential for reducing tumour hypoxia using an orally delivered suspension of surfactant-stabilised oxygen nanobubbles. Experiments were carried out in a mouse xenograft tumour model for human pancreatic cancer (BxPc-3 cells in male SCID mice). A single dose of 100 μL of oxygen saturated water, oxygen nanobubbles or argon nanobubbles was administered via gavage. Animals were sacrificed 30 minutes post-treatment (3 per group) and expression of hypoxia-inducible-factor-1α (HIF1α) protein measured by real time quantitative polymerase chain reaction and Western blot analysis of the excised tumour tissue. Neither the oxygen saturated water nor argon nanobubbles produced a statistically significant change in HIF1α expression at the transcriptional level. In contrast, a reduction of 75% and 25% in the transcriptional and translational expression of HIF1α respectively (p<0.001) was found for the animals receiving the oxygen nanobubbles. This magnitude of reduction has been shown in previous studies to be commensurate with an improvement in outcome with both radiation and drug-based treatments. In addition, there was a significant reduction in the expression of vascular endothelial growth factor (VEGF) in this group and corresponding increase in the expression of arrest-defective protein 1 homolog A (ARD1A).

Transarterial chemoembolization (TACE) is an image-guided minimally invasive treatment for liver cancer which involves delivery of chemotherapy and embolic material into tumor-supplying arteries to block blood flow to a liver tumor and to deliver chemotherapy directly to the tumor. However, the released drug diffuses only less than a millimeter away from the beads. To enhance the efficacy of TACE, the development of microbubbles electrostatically bound to the surface of drug-eluting beads loaded with different amounts of doxorubicin (0–37.5 mg of Dox/mL of beads) is reported. Up to 400 microbubbles were bound to Dox-loaded beads (70–150 microns). This facilitated ultrasound imaging of the beads and increased the release rate of Dox upon exposure to high intensity focused ultrasound (HIFU). Furthermore, ultrasound exposure (1 MPa peak negative pressure) increased the distance at which Dox could be detected from beads embedded in a tissue-mimicking phantom, compared with a no ultrasound control.

Acoustically driven bubbles produce a range of mechanical, thermal and chemical effects that can be exploited in drug delivery applications. Significant improvements in the targeting, distribution and efficacy of both current and emerging therapeutics can be achieved, from small molecules to biologics and nucleic-acid-based drugs. This Review describes how specially designed cavitation nuclei in the form of solid, liquid or gas particles can enable the triggered release of drugs, promote the permeabiliziation of challenging biological barriers and enhance drug delivery through tissue regions where diffusion alone is inadequate. Scalable strategies for mapping and controlling cavitation activity to harness its therapeutic potential at depth within the body are discussed, alongside current and emerging applications for the treatment of diseases, including cancer and stroke.This Review describes how acoustic cavitation can be used to improve the delivery of drugs for the treatment of diseases such as cancer and stroke. Methods for seeding cavitation, treatment monitoring, and current and future clinical applications are described.

Ultrasound-mediated cavitation shows great promise for improving targeted drug delivery across a range of clinical applications. Cavitation nuclei—sound-sensitive constructs that enhance cavitation activity at lower pressures—have become a powerful adjuvant to ultrasound-based treatments, and more recently emerged as a drug delivery vehicle in their own right. The unique combination of physical, biological, and chemical effects that occur around these structures, as well as their varied compositions and morphologies, make cavitation nuclei an attractive platform for creating delivery systems tuned to particular therapeutics. In this review, we describe the structure and function of cavitation nuclei, approaches to their functionalization and customization, various clinical applications, progress toward real-world translation, and future directions for the field.

Background Various exercise thresholds have been evaluated to predict athlete performance. However, a systematic review of the literature assessing the association between lactate-based exercise thresholds and 2000 m rowing ergometer performance is still lacking. These may have utility in the prediction of 2000 m rowing ergometer performance due to the close relationship between metabolic parameters and development of endurance capacity. The aim of the present study is to review and assess the extent, quality, and reliability of lactate-based exercise testing and methodologies in their association with 2000 m rowing ergometer performance, and to discuss the potential implications for performance prediction. Methods The systematic review was performed following PRISMA 2020 guidelines. The databases searched were EMBASE, MEDLINE and SPORTDiscus. The initial search took place in July 2022, with an update search performed in September 2023, and again in August 2024. Studies which reported a lactate test and its correlation to 2000 m ergometer performance were included. No meta-analysis was performed. Results Twenty-four studies comprising 797 athletes (513 male, 257 female, 27 not stated) met the eligibility criteria for inclusion in the review. The most commonly used testing protocol involved the use of incremental step-tests. A range of exercise intensity parameters, lactate-based exercise thresholds and interpretation methodologies were employed. Of these, the power or velocity at a blood lactate concentration of 4 mmol l −1 was the most common test, with correlation coefficients ranging from 0.53 to 0.96 suggesting that 28–92% of the variance in rowing performance can be explained by this metric. Six studies that rated as GOOD on the risk of bias assessment found very strong correlations > 0.85 ( p  < 0.05). Conclusions This systematic review found that there is good evidence that the power generated at a blood lactate concentration of 4 mmol l −1 correlates strongly to 2000 m rowing ergometer performance and may have useful predictive power. However, the review also identified the varying quality of the available literature, with a variety of parameters, exercise protocols, testing methods, and performance metrics being used to report performance making it difficult to compare results between studies. Other tests such as V ˙ O 2 at a blood lactate concentration of 4 mmol l −1 and power at the initial non-linear inflection blood lactate threshold merit further investigation as the extent and reliability of the available data is currently insufficient to draw firm conclusions. Protocol registration: The protocol was registered on Open Science Framework on 17/11/2022. https://doi.org/10.17605/OSF.IO/D8YCE Key Points The power or velocity that a rower is able to achieve on an ergometer before the concentration of lactate in their blood reaches 4 mmol l −1 correlates strongly to their 2000 m ergometer performance. The evidence suggests that power generated at the non-linear inflection blood lactate threshold and V̇O 2 at 4 mmol l −1 also have the potential to be useful, but further research needs to be conducted. The exercise protocols and performance metrics used to calculate a lactate-based exercise threshold vary between studies. The significant heterogeneity in testing methodology makes it difficult to compare results between studies. The reports rarely provide statistical analysis and often conduct studies on a small number of participants making reliability assessment difficult. However, this study found that in aggregate, the findings of power/velocity at 4 mmol l −1 are consistent.