Parents' perceptions of microneedle-mediated monitoring as an alternative to blood sampling in the monitoring of their infants

OBJECTIVES: Microneedle (MN) arrays could offer a pain-free, minimally invasive approach to monitoring. This is envisaged to be particularly beneficial for younger patients, but parents' views to date are unknown. The aim of this study was to explore parental perceptions of MN-mediated ISF monitoring, as an alternative to the use of conventional blood sampling, and to understand the important factors for technique approval.

METHODS: Semi-structured interviews were conducted with parents with recent experience of a premature birth. Recruitment was through the Northern Ireland premature infant charity, Tinylife. Interviews progressed until data saturation was reached and thematic analysis employed.

KEY FINDINGS: The study included 16 parents. Parental support for MN-mediated monitoring was evident, alongside the unpopularity of traditional blood sampling in neonates. Factors facilitating MN approval included the opportunity for pain reduction, the simplicity of the procedure, the potential for increased parental involvement and the more favourable appearance, owing to the minute size of MNs and similarities with a sticking plaster. Confirmation of correct application, a pain-free patch removal and endorsement from trusted healthcare professionals were important.

CONCLUSION: These findings will inform researchers in the field of MN development and enlighten practitioners regarding parental distress resulting from conventional blood sampling. Further work is necessary to understand MN acceptability among practitioners. This work should assist in the development of an acceptable MN device and facilitate the reduction of parental distress.

Patient safety and beyond: what should we expect from microneedle arrays in the transdermal delivery arena?

Research based upon microneedle (MN) arrays has intensified recently. While the initial focus was on biomolecules, the field has expanded to include delivery of conventional small-molecule drugs whose water solubility currently precludes transdermal administration. Much success has been achieved, with peptides, proteins, vaccines, antibodies and even particulates delivered by MN in therapeutic/prophylactic doses. Recent innovations have focused on enhanced formulation design, scalable manufacture and extension of exploitation to minimally invasive patient monitoring, ocular delivery and enhanced administration of cosmeceuticals. Only two MN-based drug/vaccine delivery products are currently marketed, partially due to limitations with older MN designs based upon silicon and metal. Even the more promising polymeric MN have raised a number of regulatory and manufacturability queries that the field must address. MN arrays have tremendous potential to yield real benefits for patients and industry and, through diligence, innovation and collaboration, this will begin to be realised over the next 3-5 years.

Laser-engineered dissolving microneedle arrays for protein delivery: potential for enhanced intradermal vaccination

OBJECTIVES: We aimed to highlight the utility of novel dissolving microneedle (MN)-based delivery systems for enhanced transdermal protein delivery. Vaccination remains the most accepted and effective approach in offering protection from infectious diseases. In recent years, much interest has focused on the possibility of using minimally invasive MN technologies to replace conventional hypodermic vaccine injections.

METHODS: The focus of this study was exploitation of dissolving MN array devices fabricated from 20% w/w poly(methyl vinyl ether/maleic acid) using a micromoulding technique, for the facilitated delivery of a model antigen, ovalbumin (OVA).

KEY FINDINGS: A series of in-vitro and in-vivo experiments were designed to demonstrate that MN arrays loaded with OVA penetrated the stratum corneum and delivered their payload systemically. The latter was evidenced by the activation of both humoral and cellular inflammatory responses in mice, indicated by the production of immunoglobulins (IgG, IgG1, IgG2a) and inflammatory cytokines, specifically interferon-gamma and interleukin-4. Importantly, the structural integrity of the OVA following incorporation into the MN arrays was maintained.

CONCLUSION: While enhanced manufacturing strategies are required to improve delivery efficiency and reduce waste, dissolving MN are a promising candidate for 'reduced-risk' vaccination and protein delivery strategies.

An Integrated Toolkit for the Conservation of Stone-Built Heritage

Rapid in situ diagnosis of damage is a key issue in the preservation of stone-built cultural heritage. This is evident in the increasing number of congresses, workshops and publications dealing with this issue. With this increased activity has come, however, the realisation that for many culturally significant artefacts it is not possible either to remove samples for analysis or to affix surface markers for measurement. It is for this reason that there has been a growth of interest in non-destructive and minimally invasive techniques for characterising internal and external stone condition. With this interest has come the realisation that no single technique can adequately encompass the wide variety of parameters to be assessed or provide the range of information required to identify appropriate conservation. In this paper we describe a strategy to address these problems through the development of an integrated `tool kit' of measurement and analytical techniques aimed specifically at linking object-specific research to appropriate intervention. The strategy is based initially upon the acquisition of accurate three-dimensional models of stone-built heritage at different scales using a combination of millimetre accurate LiDAR and sub-millimetre accurate Object Scanning that can be exported into a GIS or directly into CAD. These are currently used to overlay information on stone characteristics obtained through a combination of Ground Penetrating Radar, Surface Permeametry, Colorimetry and X-ray Fluorescence, but the possibility exists for adding to this array of techniques as appropriate. In addition to the integrated three-dimensional data array provided by superimposition upon Digital Terrain Models, there is the capability of accurate re-measurement to show patterns of surface loss and changes in material condition over time. Thus it is possible to both record and base-line condition and to identify areas that require either preventive maintenance or more significant pre-emptive intervention. In pursuit of these goals the authors are developing, through a UK Government supported collaboration between University Researchers and Conservation Architects, commercially viable protocols for damage diagnosis, condition monitoring and eventually mechanisms for prioritizing repairs to stone-built heritage. The understanding is, however, that such strategies are not age-constrained and can ultimately be applied to structures of any age.

Hydrogel-Forming Microneedle Arrays Allow Detection of Drugs and Glucose In Vivo: Potential for Use in Diagnosis and Therapeutic Drug Monitoring

We describe, for the first time the use of hydrogel-forming microneedle (MN) arrays for minimally-invasive extraction and quantification of drug substances and glucose from skin in vitro and in vivo. MN prepared from aqueous blends of hydrolysed poly(methyl-vinylether-co-maleic anhydride) (11.1% w/w) and poly(ethyleneglycol) 10,000 daltons (5.6% w/w) and crosslinked by esterification swelled upon skin insertion by uptake of fluid. Post-removal, theophylline and caffeine were extracted from MN and determined using HPLC, with glucose quantified using a proprietary kit. In vitro studies using excised neonatal porcine skin bathed on the underside by physiologically-relevant analyte concentrations showed rapid (5 min) analyte uptake. For example, mean concentrations of 0.16 μg/mL and 0.85 μg/mL, respectively, were detected for the lowest (5 μg/mL) and highest (35 μg/mL) Franz cell concentrations of theophylline after 5 min insertion. A mean concentration of 0.10 μg/mL was obtained by extraction of MN inserted for 5 min into skin bathed with 5 μg/mL caffeine, while the mean concentration obtained by extraction of MN inserted into skin bathed with 15 μg/mL caffeine was 0.33 μg/mL. The mean detected glucose concentration after 5 min insertion into skin bathed with 4 mmol/L was 19.46 nmol/L. The highest theophylline concentration detected following extraction from a hydrogel-forming MN inserted for 1 h into the skin of a rat dosed orally with 10 mg/kg was of 0.363 μg/mL, whilst a maximum concentration of 0.063 μg/mL was detected following extraction from a MN inserted for 1 h into the skin of a rat dosed with 5 mg/kg theophylline. In human volunteers, the highest mean concentration of caffeine detected using MN was 91.31 μg/mL over the period from 1 to 2 h post-consumption of 100 mg Proplus® tablets. The highest mean blood glucose level was 7.89 nmol/L detected 1 h following ingestion of 75 g of glucose, while the highest mean glucose concentration extracted from MN was 4.29 nmol/L, detected after 3 hours skin insertion in human volunteers. Whilst not directly correlated, concentrations extracted from MN were clearly indicative of trends in blood in both rats and human volunteers. This work strongly illustrates the potential of hydrogel-forming MN in minimally-invasive patient monitoring and diagnosis. Further studies are now ongoing to reduce clinical insertion times and develop mathematical algorithms enabling determination of blood levels directly from MN measurements.

Microneedle arrays as transdermal and intradermal drug delivery systems: Materials science, manufacture and commercial development

Transdermal drug delivery offers a number of advantages for the patient, due not only its non-invasive and convenient nature, but also factors such as avoidance of first pass metabolism and prevention of gastrointestinal degradation. It has been demonstrated that microneedle arrays can increase the number of compounds amenable to transdermal delivery by penetrating the skin's protective barrier, the stratum corneum, and creating a pathway for drug permeation to the dermal tissue below. Microneedles have been extensively investigated in recent decades for drug and vaccine delivery as well as minimally invasive patient monitoring/diagnosis. This review focuses on a range of critically important aspects of microneedle technology, namely their material composition, manufacturing techniques, methods of evaluation and commercial translation to the clinic for patient benefit and economic return. Microneedle research and development is finally now at the stage where commercialisation is a realistic possibility. However, progress is still required in the areas of scaled-up manufacture and regulatory approval.

Microneedle Technology

Microneedles (MNs) are minimally invasive devices consisting of numerous micron-sized projections amassed on a baseplate, designed to enhance transdermal drug delivery. When applied to the skin, the needles puncture the outermost layer, the stratum corneum, forming aqueous conduits through which drugs can diffuse to the dermal microcirculation. With an average length of 50-900 μm, MNs are short enough to avoid stimulation of dermal nerves and do not induce bleeding, yet gain access to the skin's rich microcirculation for drug delivery. MNs have been extensively investigated for drug and vaccine delivery, demonstrating their efficacy at increasing the number of compounds amenable to delivery through the skin. This chapter discusses the materials and fabrication methods involved in MN production, alongside the different types of MN arrays and their delivery capabilities. The field has expanded to consider novel applications of MNs including minimally invasive patient monitoring, ocular delivery and enhanced administration of cosmeceuticals. Patient usage and effects on the skin are also considered in terms of safety, efficacy and acceptability. The next steps in MN development are to focus on the scale-up of manufacturing processes, a challenge considering the number of small-scale methods detailed in the literature. Regulatory guidance is awaited to direct this, alongside provision of clearer patient instruction for safe and effective use of MN devices. MNs have tremendous potential to yield real benefits for patients and industry and with continued research in the key areas highlighted, this will begin to be realised over the next number of years.

Challenges in molecular testing in non-small-cell lung cancer patients with advanced disease

Lung cancer diagnostics have progressed greatly in the previous decade. Development of molecular testing to identify an increasing number of potentially clinically actionable genetic variants, using smaller samples obtained via minimally invasive techniques, is a huge challenge. Tumour heterogeneity and cancer evolution in response to therapy means that repeat biopsies or circulating biomarkers are likely to be increasingly useful to adapt treatment as resistance develops. We highlight some of the current challenges faced in clinical practice for molecular testing of EGFR, ALK, and new biomarkers such as PDL1. Implementation of next generation sequencing platforms for molecular diagnostics in non-small-cell lung cancer is increasingly common, allowing testing of multiple genetic variants from a single sample. The use of next generation sequencing to recruit for molecularly stratified clinical trials is discussed in the context of the UK Stratified Medicine Programme and The UK National Lung Matrix Trial.

In vivo safety of trypan blue use in vitreoretinal surgery

Purpose: The purpose of this study was to evaluate "in vivo" safety of trypan blue (TB) in patients undergoing TB-assisted internal limiting membrane or epiretinal membrane peeling. Methods: Prospective study including 21 patients (21 eyes) with full-thickness macular hole and/or epiretinal membrane undergoing TB-assisted internal limiting membrane/epiretinal membrane peeling. Main outcome measures included distance visual acuity, near visual acuity, amplitude of P50 and N95 of the pattern electroretinogram, and fundus autofluorescence; these were assessed preoperatively, at 6 months (n = 21) and 12 months (n = 10) postoperatively. Results: There was a statistically significant improvement in distance visual acuity, near visual acuity, P50, and N95 amplitude at 6 months and 12 months postoperatively. The mean logarithm of the minimum angle of resolution distance visual acuity and near visual acuity improved from baseline by 0.31 (SD 0.37) and 0.17 (SD 0.31) at 6 months, respectively, and by 0.4 (SD 0.25) and 0.35 (SD 0.28) at 12 months, respectively. The mean P50 and N95 component amplitudes improved by 28% compared with baseline at 6 months (P50 0.4 [SD 0.8]; N95 0.53 [SD 1.07]) and by 63% at 12 months (P50 0.9 [0.85]; N95 1.04 [1.34]). Autofluorescence did not demonstrate damage to the retinal pigment epithelium attributable to TB. Conclusion: No deleterious effects of TB were observed in this study. Copyright © 2011 Lippincott Williams &Wilkins.

Physician recommendation for invasive prenatal testing: the case of the 'precious baby'

Do clinicians manage pregnancies conceived by assisted reproductive technologies (ART) differently from spontaneous pregnancies?

Clinicians decisions about prenatal testing during pregnancy depend, at least partially, on the method of conception.

Research thus far has shown that patients decisions regarding prenatal screening are different in ART pregnancies compared with spontaneous ones, such that ART pregnancies may be considered more valuable or precious than pregnancies conceived without treatment.

In this cross-sectional study, preformed during the year 2011, 163 obstetricians and gynecologists in Israel completed an anonymous online questionnaire.

Clinicians were randomly assigned to read one of two versions of a vignette describing the case of a pregnant woman. The two versions differed only with regard to the method of conception (ART; n 78 versus spontaneous; n 85). Clinicians were asked to provide their recommendations regarding amniocentesis.

The response rate among all clinicians invited to complete the questionnaire was 16.7. Of the 85 clinicians presented with the spontaneous pregnancy scenario, 37 (43.5) recommended amniocentesis. In contrast, of the 78 clinicians presented with the ART pregnancy scenario, only 15 (19.2) recommended the test. Clinicians were 3.2 (95 confidence interval [CI]: 1.66.6) times more likely to recommend amniocentesis for a spontaneous pregnancy than for an ART pregnancy.

The study is limited by a low response rate, the relatively small sample and the hypothetical nature of the decision, as clinician recommendations may have differed in an actual clinical setting.

Our findings show that fertility history and use of ART may affect clinicians recommendations regarding amniocentesis following receipt of screening test results. This raises the question of how subjective factors influence clinicians decisions regarding other aspects of pregnancy management.

There was no funding source to this study. The authors declare no conflicts of interest.

Non-invasive antidromic neurostimulation:A simple effective method for improving bladder storage

Patients with intractably diminished bladder storage function are encountered frequently by neurourologists, occasionally requiring reconstructive surgery for appropriate resolution. Although sacral neuromodulation is a recognized effective therapeutic modality, present techniques are technically demanding, invasive, and expensive. This study investigated the effect of non-invasive third sacral nerve (S3) stimulation on bladder activity during filling cystometry. One hundred forty-six patients underwent standard urodynamic filling cystometry that was then immediately repeated. Patients in the study group (n = 74) received antidromic transcutaneous sacral neurostimulation during the second fill and the control group (n = 72) underwent a second fill without neurostimulation. A statistically significant increase in bladder storage capacity without a corresponding rise in detrusor pressure was observed in the neurostimulated patients. This improvement in functional capacity is an encouraging finding that further supports the use of this non-invasive treatment modality in clinical practice. Neurourol. Urodynam. 20:73-84. 2001. (C) 2001 Wiley-Liss, Inc.

Ultrasound entropy may be a new non-invasive measure of pre-clinical vascular damage in young hypertensive patients

Background: The identification of pre-clinical microvascular damage in hypertension by non-invasive techniques has proved frustrating for clinicians. This proof of concept study investigated whether entropy, a novel summary measure for characterizing blood velocity waveforms, is altered in participants with hypertension and may therefore be useful in risk stratification.

Methods: Doppler ultrasound waveforms were obtained from the carotid and retrobulbar circulation in 42 participants with uncomplicated grade 1 hypertension (mean systolic/diastolic blood pressure (BP) 142/92 mmHg), and 26 healthy controls (mean systolic/diastolic BP 116/69 mmHg). Mean wavelet entropy was derived from flow-velocity data and compared with traditional haemodynamic measures of microvascular function, namely the resistive and pulsatility indices.

Results: Entropy, was significantly higher in control participants in the central retinal artery (CRA) (differential mean 0.11 (standard error 0.05 cms(-1)), CI 0.009 to 0.219, p 0.017) and ophthalmic artery (0.12 (0.05), CI 0.004 to 0.215, p 0.04). In comparison, the resistive index (0.12 (0.05), CI 0.005 to 0.226, p 0.029) and pulsatility index (0.96 (0.38), CI 0.19 to 1.72, p 0.015) showed significant differences between groups in the CRA alone. Regression analysis indicated that entropy was significantly influenced by age and systolic blood pressure (r values 0.4-0.6). None of the measures were significantly altered in the larger conduit vessel.

Conclusion: This is the first application of entropy to human blood velocity waveform analysis and shows that this new technique has the ability to discriminate health from early hypertensive disease, thereby promoting the early identification of cardiovascular disease in a young hypertensive population.