Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors.

Radiotherapy (RT), a common cancer treatment, unintentionally harms surrounding tissues, including the skin, and hinders wound healing years after treatment. This study aims to understand the mechanisms behind these late-onset adverse effects. We compare skin biopsies from previously irradiated (RT) and non-irradiated (RT) sites in breast cancer survivors who underwent RT years ago.

The biomechanics of wounds at physiologically relevant levels: Understanding skin's stress-shielding effect for the quantitative assessment of healing.

Wounds are responsible for the decrease in quality of life of billions of people around the world. Their assessment relies on subjective parameters which often delays optimal treatments and results in increased healthcare costs. In this work, we sought to understand and quantify how wounds at different healing stages (days 1, 3, 7 and 14 post wounding) change the mechanical properties of the tissues that contain them, and how these could be measured at clinically relevant strain levels, as a step towards quantitative wound tracking technologies.

Rapid mechanosensitive migration and dispersal of newly divided mesenchymal cells aid their recruitment into dermal condensates.

Embryonic mesenchymal cells are dispersed within an extracellular matrix but can coalesce to form condensates with key developmental roles. Cells within condensates undergo fate and morphological changes and induce cell fate changes in nearby epithelia to produce structures including hair follicles, feathers, or intestinal villi. Here, by imaging mouse and chicken embryonic skin, we find that mesenchymal cells undergo much of their dispersal in early interphase, in a stereotyped process of displacement driven by 3 hours of rapid and persistent migration followed by a long period of low motility.

The developmental basis of fingerprint pattern formation and variation.

Fingerprints are complex and individually unique patterns in the skin. Established prenatally, the molecular and cellular mechanisms that guide fingerprint ridge formation and their intricate arrangements are unknown. Here we show that fingerprint ridges are epithelial structures that undergo a truncated hair follicle developmental program and fail to recruit a mesenchymal condensate.

In vivo, in situ and ex vivo comparison of porcine skin for microprojection array penetration depth, delivery efficiency and elastic modulus assessment.

With the development of wearable technologies, the interfacial properties of skin and devices have become much more important. For research and development purposes, porcine skin is often used to evaluate device performance, but the differences between in vivo, in situ and ex vivo porcine skin mechanical properties can potentially misdirect investigators during the development of their technology. In this study, we investigated the significant changes to mechanical properties with and without perfusion (in vivo versus in vitro tissue).

Immune response and reactogenicity of an unadjuvanted intradermally delivered human papillomavirus vaccine using a first generation Nanopatch™ in rhesus macaques: An exploratory, pre-clinical feasibility assessment.

The human papillomavirus (HPV) 9-valent, recombinant vaccine (Gardasil™9) helps protect young adults (males and females) against anogenital cancers and genital warts caused by certain HPV genotypes (ref. Gardasil™9 insert). This vaccine is administered intramuscularly (IM).

Cellular metabolism and pore lifetime of human skin following microprojection array mediation.

Skin-targeting microscale medical devices are becoming popular for therapeutic delivery and diagnosis. We used cryo-SEM, fluorescence lifetime imaging microscopy (FLIM), autofluorescence imaging microscopy and inflammatory response to study the puncturing and recovery of human skin ex vivo and in vivo after discretised puncturing by a microneedle array (Nanopatch®). Pores induced by the microprojections were found to close by ~25% in diameter within the first 30 min, and almost completely close by ~6 h.

A low inflammatory, Langerhans cell-targeted microprojection patch to deliver ovalbumin to the epidermis of mouse skin.

In a low inflammatory skin environment, Langerhans cells (LCs) - but not dermal dendritic cells (dDCs) - contribute to the pivotal process of tolerance induction. Thus LCs are a target for specific-tolerance therapies. LCs reside just below the stratum corneum, within the skin's viable epidermis.

Space- and time-resolved investigation on diffusion kinetics of human skin following macromolecule delivery by microneedle arrays.

Microscale medical devices are being developed for targeted skin delivery of vaccines and the extraction of biomarkers, with the potential to revolutionise healthcare in both developing and developed countries. The effective clinical development of these devices is dependent on understanding the macro-molecular diffusion properties of skin. We hypothesised that diffusion varied according to specific skin layers.

Sensors for Fetal Hypoxia and Metabolic Acidosis: A Review.

This article reviews existing clinical practices and sensor research undertaken to monitor fetal well-being during labour. Current clinical practices that include fetal heart rate monitoring and fetal scalp blood sampling are shown to be either inadequate or time-consuming. Monitoring of lactate in blood is identified as a potential alternative for intrapartum fetal monitoring due to its ability to distinguish between different types of acidosis.

Allometric scaling of skin thickness, elasticity, viscoelasticity to mass for micro-medical device translation: from mice, rats, rabbits, pigs to humans.

Emerging micro-scale medical devices are showing promise, whether in delivering drugs or extracting diagnostic biomarkers from skin. In progressing these devices through animal models towards clinical products, understanding the mechanical properties and skin tissue structure with which they interact will be important. Here, through measurement and analytical modelling, we advanced knowledge of these properties for commonly used laboratory animals and humans (~30 g to ~150 kg).

The hyperelastic and failure behaviors of skin in relation to the dynamic application of microscopic penetrators in a murine model.

Unlabelled: In-depth understanding of skin elastic and rupture behavior is fundamental to enable next-generation biomedical devices to directly access areas rich in cells and biomolecules. However, the paucity of skin mechanical characterization and lack of established fracture models limits their rational design. We present an experimental and numerical study of skin mechanics during dynamic interaction with individual and arrays of micro-penetrators.

The changing shape of vaccination: improving immune responses through geometrical variations of a microdevice for immunization.

Micro-device use for vaccination has grown in the past decade, with the promise of ease-of-use, painless application, stable solid formulations and greater immune response generation. However, the designs of the highly immunogenic devices (e.g.

Characterising the material properties at the interface between skin and a skin vaccination microprojection device.

Unlabelled: The rapid emergence of micro-devices for biomedical applications over the past two decades has introduced new challenges for the materials used in the devices. Devices like microneedles and the Nanopatch, require sufficient strength to puncture skin often with sharp-slender micro-scale profiles, while maintaining mechanical integrity. For these technologies we sought to address two important questions: 1) On the scale at which the device operates, what forces are required to puncture the skin? And 2) What loads can the projections/microneedles withstand prior to failure.

Inactivated poliovirus type 2 vaccine delivered to rat skin via high density microprojection array elicits potent neutralising antibody responses.

Polio eradication is progressing rapidly, and the live attenuated Sabin strains in the oral poliovirus vaccine (OPV) are being removed sequentially, starting with type 2 in April 2016. For risk mitigation, countries are introducing inactivated poliovirus vaccine (IPV) into routine vaccination programs. After April 2016, monovalent type 2 OPV will be available for type 2 outbreak control.

Formulations for microprojection/microneedle vaccine delivery: Structure, strength and release profiles.

To develop novel methods for vaccine delivery, the skin is viewed as a high potential target, due to the abundance of immune cells that reside therein. One method, the use of dissolving microneedle technologies, has the potential to achieve this, with a range of formulations now being employed. Within this paper we assemble a range of methods (including FT-FIR using synchrotron radiation, nanoindentation and skin delivery assays) to systematically examine the effect of key bulking agents/excipients - sugars/polyols - on the material form, structure, strength, failure properties, diffusion and dissolution for dissolving microdevices.

Microprojection arrays to immunise at mucosal surfaces.

The buccal mucosa (inner cheek) is an attractive site for delivery of immunotherapeutics, due to its ease of access and rich antigen presenting cell (APC) distribution. However, to date, most delivery methods to the buccal mucosa have only been topical-with the challenges of: 1) an environment where significant biomolecule degradation may occur; 2) inability to reach the APCs that are located deep in the epithelium and lamina propria; and 3) salivary flow and mucous secretion that may result in removal of the therapeutic agent before absorption has taken place. To overcome these challenges and achieve consistent, repeatable targeted delivery of immunotherapeutics to within the buccal mucosa (not merely on to the surface), we utilised microprojection arrays (Nanopatches-110 μm length projections, 3364 projections, 16 mm2 surface area) with a purpose built clip applicator.

Dry-coated live viral vector vaccines delivered by nanopatch microprojections retain long-term thermostability and induce transgene-specific T cell responses in mice.

The disadvantages of needle-based immunisation motivate the development of simple, low cost, needle-free alternatives. Vaccine delivery to cutaneous environments rich in specialised antigen-presenting cells using microprojection patches has practical and immunological advantages over conventional needle delivery. Additionally, stable coating of vaccine onto microprojections removes logistical obstacles presented by the strict requirement for cold-chain storage and distribution of liquid vaccine, or lyophilised vaccine plus diluent.

Elastic modulus and viscoelastic properties of full thickness skin characterised at micro scales.

The recent emergence of micro-devices for vaccine delivery into upper layers of the skin holds potential for increased immune responses using physical means to target abundant immune cell populations. A challenge in doing this has been a limited understanding of the skin elastic properties at the micro scale (i.e.

Which jump variables should be used to assess explosive leg muscle function?

Purpose: The main purpose of this study was to determine the relationships between countermovement jump (CMJ) variables and acceleration and maximum speed performance.

Methods: Twenty-three elite Australian football players were tested on a CMJ, which yielded several kinematic and kinetic variables describing leg muscle function. A 40 m sprint was also conducted to assess acceleration (10 m time) and an estimate of maximum speed (flying 20 m time).

The viscoelastic, hyperelastic and scale dependent behaviour of freshly excised individual skin layers.

Micro-devices using mechanical means to target skin for improved drug and vaccine delivery have great promise for improved clinical healthcare. Fully realizing this promise requires a greater understanding of key micro-biomechanical properties for each of the different skin layers - that are both the mechanical barriers and biological targets of these devices. Here, we performed atomic force microscopy indentation on a micro-nano scale to quantify separately, in fresh mouse skin, the viscous and elastic behaviour of the stratum corneum, viable epidermis and dermis.

Improving the reach of vaccines to low-resource regions, with a needle-free vaccine delivery device and long-term thermostabilization.

Dry-coated microprojections can deliver vaccine to abundant antigen-presenting cells in the skin and induce efficient immune responses and the dry-coated vaccines are expected to be thermostable at elevated temperatures. In this paper, we show that we have dramatically improved our previously reported gas-jet drying coating method and greatly increased the delivery efficiency of coating from patch to skin to from 6.5% to 32.

Improved DNA vaccination by skin-targeted delivery using dry-coated densely-packed microprojection arrays.

HSV-2-gD2 DNA vaccine was precisely delivered to immunologically sensitive regions of the skin epithelia using dry-coated microprojection arrays. These arrays delivered a vaccine payload to the epidermis and the upper dermis of mouse skin. Immunomicroscopy results showed that, in 43 ± 5% of microprojection delivery sites, the DNA vaccine was delivered to contact with professional antigen presenting cells in the epidermal layer.

Surface-modified microprojection arrays for intradermal biomarker capture, with low non-specific protein binding.

Minimally invasive biosensors are of great interest for rapid detection of disease biomarkers for diagnostic screening at the point-of-care. Here we introduce a device which extracts disease-specific biomarkers directly from the upper dermis, without the needle and syringe or resource-intensive blood processing. Using antigen-specific antibodies raised in mice as a model system, we confirm the analytical specificity and sensitivity of the antibody capture and extraction in comparison to the conventional methods based on needle/syringe blood draw followed by processing and antigen-specific ELISAs.