A Novel Intraoperative Ultrasound Probe for Transsphenoidal Surgery: First-in-human study.

Background. Ultrasound has been explored as an alternative, less bulky, less time-consuming and less expensive means of intraoperative imaging in pituitary surgery. However, its use has been limited by the size of its probes relative to the transsphenoidal corridor. We developed a novel prototype that is more slender than previously reported forward-viewing probes and, in this report, we assess its feasibility and safety in an initial patient cohort. Method. The probe was integrated into the transsphenoidal approach in patients with pituitary adenoma, following a single-centre prospective proof of concept study design, as defined by the Innovation, Development, Exploration, Assessment and Long-Term Study (IDEAL) guidelines for assessing innovation in surgery (IDEAL stage 1 - Idea phase). Results. The probe was employed in 5 cases, and its ability to be used alongside the standard surgical equipment was demonstrated in each case. No adverse events were encountered. The average surgical time was 20 minutes longer than that of 30 contemporaneous cases operated without intraoperative ultrasound. Conclusion. We demonstrate the safety and feasibility of our novel ultrasound probe during transsphenoidal procedures to the pituitary fossa, and, as a next step, plan to integrate the device into a surgical navigation system (IDEAL Stage 2a - Development phase).

Synthesis and characterisation of cationic quaternary ammonium-modified polyvinyl alcohol hydrogel beads as a drug delivery embolisation system.

To extend the platform of clinically utilised chemoembolic agents based on ion-exchange systems to support the delivery of anionic drugs, a series of PVA-based beads was produced with different levels of (3-acrylamidopropyl)trimethylammonium chloride (APTA) in their formulation. The beads were characterised to confirm composition and the effect of formulation variation on physical properties was assessed. Suspension polymerisation was shown to successfully produce uniformly spherical copolymer beads with APTA content up to 60 wt%. Equilibrium water content and resistance to compression both increased with increasing APTA content in the formulation. Confocal laser scanning microscopy was used with model drugs to demonstrate that by increasing APTA content, compounds between the molecular weight range 70-250 kDa could permeate the microsphere structures. Interaction with anionic drugs was modelled using multivalent dyes. Dyes with multi-binding sites had increased interaction with the polymer, slowing the release and also demonstrating a reduced rate of elution from beads with higher charge density. The model drug release studies demonstrate that these systems can be engineered for different potential anionic drugs for local therapeutic delivery in the clinic.

Medical device regulatory challenges in the UK are affecting innovation and its potential benefits.

The increase in regulatory challenges on medical technology developed and deployed in the UK is having a negative impact on innovation. In this paper we show how the limited capacity of Approved and Notified Bodies is one more barrier in the innovation pipeline, that could push more teams to consider applying for FDA approval instead of UKCA marking, potentially limiting how much our patients benefit from the world-leading research undertaken in UK universities.

The Safety of Digital Mental Health Interventions: Systematic Review and Recommendations.

BACKGROUND: Evidence suggests that digital mental health interventions (DMHIs) for common mental health conditions are effective. However, digital interventions, such as face-to-face therapies, pose risks to patients. A safe intervention is considered one in which the measured benefits outweigh the identified and mitigated risks. OBJECTIVE: This study aims to review the literature to assess how DMHIs assess safety, what risks are reported, and how they are mitigated in both the research and postmarket phases and building on existing recommendations for assessing, reporting, and mitigating safety in the DMHI and standardizing practice. METHODS: PsycINFO, Embase, and MEDLINE databases were searched for studies that addressed the safety of DMHIs. The inclusion criteria were any study that addressed the safety of a clinical DMHI, even if not as a main outcome, in an adult population, and in English. As the outcome data were mainly qualitative in nature, a meta-analysis was not possible, and qualitative analysis was used to collate the results. Quantitative results were synthesized in the form of tables and percentages. To illustrate the use of a single common safety metric across studies, we calculated odds ratios and CIs, wherever possible. RESULTS: Overall, 23 studies were included in this review. Although many of the included studies assessed safety by actively collecting adverse event (AE) data, over one-third (8/23, 35%) did not assess or collect any safety data. The methods and frequency of safety data collection varied widely, and very few studies have performed formal statistical analyses. The main treatment-related reported AE was symptom deterioration. The main method used to mitigate risk was exclusion of high-risk groups. A secondary web-based search found that 6 DMHIs were available for users or patients to use (postmarket phase), all of which used indications and contraindications to mitigate risk, although there was no evidence of ongoing safety review. CONCLUSIONS: The findings of this review show the need for a standardized classification of AEs, a standardized method for assessing AEs to statically analyze AE data, and evidence-based practices for mitigating risk in DMHIs, both in the research and postmarket phases. This review produced 7 specific, measurable, and achievable recommendations with the potential to have an immediate impact on the field, which were implemented across ongoing and future research. Improving the quality of DMHI safety data will allow meaningful assessment of the safety of DMHIs and confidence in whether the benefits of a new DMHI outweigh its risks. TRIAL REGISTRATION: PROSPERO CRD42022333181; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=333181.

OxVent: Design and evaluation of a rapidly-manufactured Covid-19 ventilator.

BACKGROUND: The manufacturing of any standard mechanical ventilator cannot rapidly be upscaled to several thousand units per week, largely due to supply chain limitations. The aim of this study was to design, verify and perform a pre-clinical evaluation of a mechanical ventilator based on components not required for standard ventilators, and that met the specifications provided by the Medicines and Healthcare Products Regulatory Agency (MHRA) for rapidly-manufactured ventilator systems (RMVS). METHODS: The design utilises closed-loop negative feedback control, with real-time monitoring and alarms. Using a standard test lung, we determined the difference between delivered and target tidal volume (VT) at respiratory rates between 20 and 29 breaths per minute, and the ventilator's ability to deliver consistent VT during continuous operation for >14 days (RMVS specification). Additionally, four anaesthetised domestic pigs (3 male-1 female) were studied before and after lung injury to provide evidence of the ventilator's functionality, and ability to support spontaneous breathing. FINDINGS: Continuous operation lasted 23 days, when the greatest difference between delivered and target VT was 10% at inspiratory flow rates >825 mL/s. In the pre-clinical evaluation, the VT difference was -1 (-90 to 88) mL [mean (LoA)], and positive end-expiratory pressure (PEEP) difference was -2 (-8 to 4) cmH2O. VT delivery being triggered by pressures below PEEP demonstrated spontaneous ventilation support. INTERPRETATION: The mechanical ventilator presented meets the MHRA therapy standards for RMVS and, being based on largely available components, can be manufactured at scale. FUNDING: Work supported by Wellcome/EPSRC Centre for Medical Engineering,King's Together Fund and Oxford University.

Comparison of DC Bead-irinotecan and DC Bead-topotecan drug eluting beads for use in locoregional drug delivery to treat pancreatic cancer.

DC Bead is a drug delivery embolisation system that can be loaded with doxorubicin or irinotecan for the treatment of a variety of liver cancers. In this study we demonstrate that the topoisomerase I inhibitor topotecan hydrochloride can be successfully loaded into the DC Bead sulfonate-modified polyvinyl alcohol hydrogel matrix, resulting in a sustained-release drug eluting bead (DEBTOP) useful for therapeutic purposes. The in vitro drug loading capacity, elution characteristics and the effects on mechanical properties of the beads are described with reference to our previous work with irinotecan hydrochloride (DEBIRI). Results showed that drug loading was faster when the solution was agitated compared to static loading and a maximum loading of ca. 40-45 mg topotecan in 1 ml hydrated beads was achievable. Loading the drug into the beads altered the size, compressibility moduli and colour of the bead. Elution was shown to be reliant on the presence of ions to perform the necessary exchange with the electrostatically bound topotecan molecules. Topotecan was shown by MTS assay to have an IC(50) for human pancreatic adenocarcinoma cells (PSN-1) of 0.22 and 0.27 microM compared to 28.1 and 19.2 microM for irinotecan at 48 and 72 h, respectively. The cytotoxic efficacy of DEBTOP on PSN-1 was compared to DEBIRI. DEPTOP loaded at 6 & 30 mg ml(-1), like its free drug form, was shown to be more potent than DEBIRI of comparable doses at 24, 48 & 72 h using a slightly modified MTS assay. Using a PSN-1 mouse xenograft model, DEBIRI doses of 3.3-6.6 mg were shown to be well-tolerated (even with repeat administration) and effective in reducing the tumour size. DEBTOP however, was lethal after 6 days at doses of 0.83-1.2 mg but demonstrated reasonable efficacy and tolerability (again with repeat injection possible) at 0.2-0.4 mg doses. Care must therefore be taken when selecting the dose of topotecan to be loaded into DC Bead given its greater potency and potential toxicity.

Unusual behaviour induced by phase separation in hydrogel microspheres.

Hydrogel microspheres with the capability to interact with charged species such as various drugs by ion-exchange processes are useful in a variety of biomedical applications. Such systems have been developed to allow active loading of the microsphere with chemotherapeutic agents in the hospital pharmacy for subsequent locoregional therapy of tumours in the liver by drug-eluting bead chemoembolization (DEB-TACE). A variety of microspherical embolisation systems have been described, all based upon hydrogels bearing anionic functionalities to allow interaction with cationically charged drugs. We have recently prepared a series of microspheres bearing cationic functionality and have observed some unusual behaviour induced by phase-separation that occurs during the synthesis of the microspheres. The phase-separation results in the core of the microsphere being enriched in cationic polymer component compared to the outer polyvinyl alcohol (PVA)-based phase. For certain formulations, subsequent swelling in water results in the PVA-rich skins separating from the charged cores. Ion-exchange interactions with model compounds bearing multi-anionic groups create differential contraction of the charged core relative to the skin, resulting in an unusual "golf-ball" appearance to the surface of the microspheres. STATEMENT OF SIGNIFICANCE: The authors believe that the unusual behaviour of the microspheres reported in this paper is the first observation of its kind resulting from phase-separation during synthesis. This could have novel applications in drug delivery for systems that can respond by shedding their skin or altering the surface area to volume ratio upon loading a drug.

Towards Hypoxia-responsive Drug-eluting Embolization Beads.

Drug release from chemoembolization microspheres stimulated by the presence of a chemically reducing environment may provide benefits for targeting drug resistant and metastatic hypoxic tumours. A water-soluble disulfide-based bifunctional cross-linker bis(acryloyl)-(l)-cystine (BALC) was synthesised, characterised and incorporated into a modified poly(vinyl) alcohol (PVA) hydrogel beads at varying concentrations using reverse suspension polymerisation. The beads were characterised to confirm the amount of cross-linker within each formulation and its effects on the bead properties. Elemental and UV/visible spectroscopic analysis confirmed the incorporation of BALC within the beads and sizing studies showed that in the presence of a reducing agent, all bead formulations increased in mean diameter. The BALC beads could be loaded with doxorubicin hydrochloride and amounts in excess of 300mg of drug per mL of hydrated beads could be achieved but required conversion of the carboxylic acid groups of the BALC to their sodium carboxylate salt forms. Elution of doxorubicin from the beads demonstrated a controlled release via ionic exchange. Some formulations exhibited an increase in size and release of drug in the presence of a reducing agent, and therefore demonstrated the ability to respond to an in vitro reducing environment.

Physical hydrogels with self-assembled nanostructures as drug delivery systems.

INTRODUCTION: As an essential complement to chemically crosslinked hydrogels, drug delivery systems based on physical hydrogels with self-assembled nanostructures are gaining increasing attention, owing to potential advantages of reduced toxicity, convenience of in situ gel formation, stimuli-responsiveness, reversible sol-gel transition, and improved drug loading and delivery profiles. AREAS COVERED: In this review, drug delivery systems based on physical hydrogels are discussed according to their self-assembled nanostructures, such as micelles, layer-by-layer constructs, supramolecular inclusion complexes, polyelectrolyte complexes and crystalline structures. The driving forces of the self-assembly include hydrophobic interaction, hydrogen bonding, electrostatic interaction, π-π stacking and weak van der Waals forces. Stimuli-responsive properties of physical hydrogels, including thermo- and pH-sensitivity, are considered with particular focus on self-assembled nanostructures. EXPERT OPINION: Fabricating self-assembled nanostructures in drug delivery hydrogels, via physical interactions between polymer-polymer and polymer-drug, requires accurately controlled macro- or small molecular architecture and a comprehensive knowledge of the physicochemical properties of the therapeutics. A variety of nanostructures within hydrogels, with which payloads may interact, provide useful means to stabilize the drug form and control its release kinetics.