Microneedle Array-Based Platforms for Future Theranostic Applications.

Theranostics involves finding the biomarkers of a disease, fighting them through site specific drug delivery and following them for prognosis of the disease. Microneedle array technology has been used for drug delivery and extended for continuous monitoring of analytes present in the skin compartment. We envisage the use of microneedle arrays for future theranostic applications. The potential of combining microneedle array-based drug delivery and diagnostics as part of closed-loop control system for the management of diseases and delivery of precision drugs in individual patients is reported in this paper.

Improving the repeatability of heterochromatic flicker photometry for measurement of macular pigment optical density.

BACKGROUND: Heterochromatic flicker photometry (HFP) is a psychophysical technique used to measure macular pigment optical density (MPOD). We used the MPS 9000 (MPS) HFP device. Our aim was to determine if the repeatability of the MPS could be improved to make it more suitable for monitoring MPOD over time. METHODS: Intra-session repeatability was assessed in 25 participants (aged 20-50 years). The resulting data was explored in detail, e.g., by examining the effect of removal and adjustment of data with less than optimal quality parameters. A protocol was developed for improved overall reliability, which was then tested in terms of inter-session repeatability in a separate group of 27 participants (aged 19-52 years). RESULTS: Removal and adjustment of data reduced the intra-session coefficient of repeatability (CR) by 0.04, on average, and the mean individual standard deviation by 0.004. Raw data observation offered further insight into ways of improving repeatability. The proposed protocol resulted in an inter-session CR of 0.08. CONCLUSIONS: Removal and adjustment of less than optimal data improved repeatability, and is therefore recommended. To further improve repeatability, in brief we propose that each patient perform each part of the test twice, and a third time where necessary (described in detail by the protocol). Doing so will make the MPS more useful in research and clinical settings.

Comparison of colour contrast sensitivity in eyes at high risk of neovascular age-related macular degeneration with and without subsequent choroidal neovascular membrane development.

BACKGROUND: Neovascular age-related macular degeneration (nAMD) is a leading cause of blind registrations in the elderly. Unfortunately, it is difficult to detect the early stage of the disease, when treatment is more likely to be successful. Subjects with very early disease are likely to have abnormal macular function, even in the pre-symptomatic stage. In this study, colour vision was evaluated to establish if subjects at high risk of developing nAMD can be identified, thus allowing earlier diagnosis and possible treatment. METHODS: Colour contrast sensitivity (CCS) was evaluated over time in the fellow unaffected eye of subjects with unilateral nAMD. Participants were divided into Group 1 (182 participants) or Group 2 (15 participants) according to whether nAMD did not or did develop in the study period respectively and the two groups were compared. RESULTS: CCS was increased (i.e. worse colour vision) compared with the age-matched reference range in a high proportion of fellow eyes in both Groups 1 and 2. Global mean CCS values did not show statistically significant differences between the two groups. However, there was a statistically significant difference between mean Group 1 CCS values and the last CCS value prior to nAMD diagnosis from Group 2 subjects. CONCLUSION: This study shows that in patients with unilateral nAMD, colour vision is frequently abnormal in the fellow unaffected eye. Abnormal CCS does not predict the development of nAMD within the 12 month period of the study and therefore it is not a viable screening tool for this pathology.

Design, fabrication, and characterisation of a silicon microneedle array for transdermal therapeutic delivery using a single step wet etch process.

The fabrication of silicon in-plane microneedle arrays from a simple single wet etch step is presented. The characteristic 54.7° sidewall etch angle obtained via KOH etching of (100) orientation silicon wafers has been used to create a novel microneedle design. The KOH simultaneously etches both the front and back sides of the wafer to produce V shaped grooves, that intersect to form a sharp pyramidal six-sided microneedle tip. This method allows fabrication of solid microneedles with different geometries to determine the optimal microneedle length and width for effective penetration and minimally invasive drug delivery. A modified grooved microneedle design can also be used to create a hollow microneedle, via bonding of two grooved microneedles together, creating an enclosed hollow channel. The microneedle arrays developed, effectively penetrate the skin without significant indentation, thereby enabling effective delivery of active ingredients via either a poke and patch application using solid microneedles or direct injection using hollow microneedles. This simple, scalable and cost effective method utilises KOH to etch the silicon wafer in-plane, allowing microneedles with variable length of several mm to be fabricated, as opposed to out-of-plane MNs, which are geometrically restricted to dimensions less than the thickness of the wafer. These microneedle arrays have been used to demonstrate effective delivery of insulin and hyaluronic acid into the skin.

Measuring macular pigment optical density in vivo: a review of techniques.

BACKGROUND: Macular pigment has been the focus of much attention in recent years, as a potential modifiable risk factor for age-related macular degeneration. This interest has been heightened by the ability to measure macular pigment optical density (MPOD) in vivo. METHOD: A systematic literature search was undertaken to identify all available papers that have used in vivo MPOD techniques. The papers were reviewed, and all relevant information was incorporated into this article. RESULTS: Measurement of MPOD is achievable with a wide range of techniques, which are typically categorized into one of two groups: psychophysical (requiring a response from the subject) or objective (requiring minimal input from the subject). The psychophysical methods include heterochromatic flicker photometry and minimum motion photometry. The objective methods include fundus reflectometry, fundus autofluorescence, resonance Raman spectroscopy and visual evoked potentials. Even within the individual techniques, there is often much variation in how data is obtained and processed. CONCLUSION: This review comprehensively details the procedure, instrumentation, assumptions, validity and reliability of each MPOD measurement technique currently available, along with their respective advantages and disadvantages. This leads us to conclude that development of a commercial instrument, based on fundus reflectometry or fundus autofluorescence, would be beneficial to macular pigment research and would support MPOD screening in a clinical setting.

Colour contrast sensitivity in eyes at high risk of neovascular age-related macular degeneration.

PURPOSE: To generate the first published reference database of colour contrast sensitivity in eyes at high risk of neovascular age-related macular degeneration and to explore this important feature in quality of vision. BACKGROUND: Quality of vision depends on many factors. Changes in chromatic contrast sensitivity remain largely unexplored in eyes at high risk of neovascular age-related macular degeneration; they may however not only be relevant for quality of life but also an early indicator of the onset of the disease, so it is important to have a means to evaluate any variation in colour contrast sensitivity, especially in view of the likely increase in neovascular age-related macular degeneration as the population ages. METHODS: This prospective longitudinal study evaluated colour contrast sensitivity along the protan and tritan colour axes in 145 eyes at high risk of neovascular age-related macular degeneration. RESULTS: Colour contrast sensitivity showed statistically significant correlations with age and visual acuity, but not gender nor laterality (i.e. whether the right or left eye was being tested). There was significant variability among individuals, especially for the tritan axis, with some subjects well within normal limits for age and others with very poor colour contrast sensitivity. CONCLUSION: This study has generated the first published colour contrast sensitivity reference database for eyes at high risk of neovascular age-related macular degeneration. It has also shown a high inter-individual variability of colour contrast sensitivity in eyes at high risk of neovascular age-related macular degeneration, but the significance of this is unclear. Further work is required to establish if eyes with high colour contrast sensitivity thresholds (i.e. poor colour vision) have a higher risk of developing neovascular age-related macular degeneration over time, and this is the subject of ongoing work.

Hollow silicon microneedle fabrication using advanced plasma etch technologies for applications in transdermal drug delivery.

A novel production process flow is presented here for the manufacture of hollow silicon microneedles using deep reactive-ion etching (DRIE) technology. The patent-pending three-step process flow has been developed to produce multiple arrays of sharp-tipped, hollow microneedles, which facilitate easy insertion and controlled fluid injection into excised skin samples. A bevelled tip and vertical sidewalls for the microneedle have been achieved with good uniformity, despite >45% open etch area. Processing steps and etch challenges are discussed, and preliminary skin testing results are presented, showing effective needle insertion and delivery of fluorescent dye into ex vivo skin from human breast tissue.

Macular pigment optical density in young adults of South Asian origin.

PURPOSE: To assess the range of macular pigment optical density (MPOD) in a healthy group of young adults of South Asian origin; to investigate whether any dietary factors or personal characteristics were related to intersubject variations in MPOD; and to compare the mean MPOD of the South Asian group with the mean MPOD of a white group. METHODS: Heterochromatic flicker photometry was used to measure the macular pigment (MP) levels of 169 healthy volunteers, of which 117 were Asian and 52 were white. In addition, the Asian participants completed a questionnaire pertaining to the various physical, ocular, lifestyle, dietary, and environmental factors that may be associated with MPOD or AMD. RESULTS: The mean MPOD of the Asian subjects was 0.43 ± 0.14. The male participants had a higher mean MPOD than the females (0.47 ± 0.13 vs. 0.41 ± 0.14, P < 0.01). Possible associations also emerged between MPOD and form of refractive correction, and iris color. No MPOD associations were found for the other variables examined in the questionnaire. The mean MPOD of the white subject group was 0.33 ± 0.13, which was significantly lower than the Asian group (P < 0.0005). CONCLUSIONS: This study adds to the currently limited information on MPOD in South Asians, and while a comparison between Asians and Whites was not the main focus here, highly significant differences between these two ethnicities were revealed. This provokes the possibility that South Asian individuals could have a lower risk for AMD, and it warrants further study.

The role of macular pigment assessment in clinical practice: a review.

This review compares the results of studies that have investigated the impact of lutein and zeaxanthin supplementation on macular pigment optical density (MPOD) with those that have investigated the reliability of techniques used to measure macular pigment optical density. The review will focus on studies that have used heterochromatic flicker photometry for measurement of macular pigment optical density, as this is the only technique that is currently available commercially to clinicians. We identified articles that reported on supplementation with lutein and/or zeaxanthin and/or meso-zeaxanthin on macular pigment optical density measurement techniques published in peer-reviewed journals, through a multi-staged, systematic approach. Twenty-four studies have investigated the repeatability of MPOD measurements using heterochromatic flicker photometry. Of these, 10 studies provided a coefficient of repeatability or data from which the coefficient could be calculated, with a range in values of 0.06 to 0.58. The lowest coefficient of repeatability assessed on naïve subjects alone was 0.08. These values tell us that, at best, changes greater than 0.08 can be considered clinically significant and at worst, only changes greater than 0.58 can be considered clinically significant. Six studies assessed the effect of supplementation with up to 20 mg/day lutein on macular pigment optical density measured using heterochromatic flicker photometry and the mean increase in macular pigment optical density ranged from 0.025 to 0.09. It seems reasonable to conclude that the chance of eliciting an increase in macular pigment optical density during six months of daily supplementation with between 10 and 20 mg lutein that is of sufficient magnitude to be detected by using heterochromatic flicker photometry on an individual basis is small. Commercially available heterochromatic flicker photometers for macular pigment optical density assessment in the clinical environment appear to demonstrate particularly poor coefficient of repeatability values. Clinicians should exercise caution when considering the purchase of these instruments for potential monitoring of macular pigment optical density in response to supplementation in individual patients.

Clinical evaluation of the MPS 9000 Macular Pigment Screener.

BACKGROUND/AIMS: The MPS 9000 uses a psychophysical technique known as heterochromatic flicker photometry to measure macular pigment optical density (MPOD). Our aim was to determine the measurement variability (noise) of the MPS 9000. METHODS: Forty normally sighted participants who ranged in age from 18 to 50 years (25.4+/-8.2 years) were recruited from staff and students of Aston University (Birmingham, UK). Data were collected by two operators in two sessions separated by 1 week in order to assess test repeatability and reproducibility. RESULTS: The overall mean MPOD for the cohort was 0.35+/-0.14. There was no significant negative correlation between MPS 9000 MPOD readings and age (r=-0.192, p=0.236). Coefficients were 0.33 and 0.28 for repeatability, and 0.25 and 0.26 for reproducibility. There was no significant correlation between mean and difference MPOD values for any of the four pairs of results. CONCLUSIONS: When MPOD is being monitored over time then any change less than 0.33 units should not be considered clinically significant as it is very likely to be due to measurement noise. The size of the coefficient appears to be positively correlated with MPOD.