Michael L. Crichton's research while affiliated with Heriot-Watt University and other places

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. To achieve this, we used digital image correlation and mechanical testing on a mouse model of wound healing to map the global and local tissue strains. We found no significant differences in the elastic and viscoelastic properties of wounded vs unwounded skin when samples were measured in bulk, presumably as these were masked by the protective mechanisms of skin, which redistributes the applied loads to mitigate high stresses and reduce tissue damage. By measuring local strain values and observing the distinct patterns they formed, it was possible to establish a connection between the healing phase of the tissue (determined by the time post-injury and the observed histological features) and the overall mechanical behaviour. Importantly, these parameters were measured from the surface of the tissue, using physiologically relevant strains without increasing the tissue's damage. Adaptations of these approaches for clinical use have the potential to aid in the identification of skin healing problems, such as excessive inflammation or lack of mechanical progression over time. An increase, decrease, or lack of change in the elasticity and viscoelasticity parameters, can be indicative of wound state, thus ultimately leading to improved diagnostic outcomes.

The use of digital technologies in managing bowel conditions has been a topic of interest among healthcare practitioners. The objectives of this paper were to provide information about the types of digital technologies that have been used for bowel management and the context of the studies; identify the gaps and challenges in digital technologies for bowel management and propose new methods and techniques for the application of digital technologies in bowel management. A scoping review was conducted following the principles of Preferred Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). A search was conducted on six academic databases. 1891 papers were retrieved from the initial search; however, 6 papers were included based on the inclusion and exclusion criteria. The findings suggest that published work focused mainly on a research context and with a narrow focus targeting sub-categories of bowel conditions and not implemented in the context of everyday use. The findings also illustrate the variety of early-stage developments focused on increasing support for severe bowel dysfunction, for example, through biofeedback to aid muscle control training, or the placement of artificial anal sphincters to increase rectal perception. However, technology to support bowel management for broader populations with less severe or variable symptoms appears limited. Future work would be to conduct empirical research in the application of advanced technologies such as on-organ sensors in managing bowel conditions. Full paper: https://www.storre.stir.ac.uk/retrieve/fd86cac9-33fe-43da-bd7b-5ef3aca265e3/HCist%20OnOrgan%20Sept%20copy%20%281%29.pdf

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 h of rapid and persistent migration followed by a long period of low motility. The cell division plane and the elevated migration speed and persistence of newly born mesenchymal cells are mechanosensitive, aligning with tissue tension, and are reliant on active WNT secretion. This behaviour disperses mesenchymal cells and allows daughters of recent divisions to travel long distances to enter dermal condensates, demonstrating an unanticipated effect of cell cycle subphase on core mesenchymal behaviour.

Bowel related problems ranging from faecal incontinence, dysmotility, or bowel obstructions, are a prevalent health issue that affects over 6.5 million people in the UK. These are life-altering issues that cause distress, embarrassment, and can often be painful. Understanding the intestinal transit patterns that lead to (or are a result of) the mentioned issues is key to provide patients and their carers with strategies to regain control of their daily activities. With this goal in mind, we are developing on-organ sensors that can detect changes in the bowel when stool is passing, and send signals to a telemetric platform that provides the user with real-time transit data in a discrete manner. This is a multi-disciplinary project where different issues have been tackled: from achieving patient and doctors’ acceptance (using questionnaires and focus groups), to the development and validation of the sensors, and finally, to the creation of an app for the end users.

In this work, we propose a new quantitative way of evaluating acute compartment syndrome (ACS) by dynamic mechanical assessment of soft tissue changes. First, we have developed an animal model of ACS to replicate the physiological changes during the condition. Secondly, we have developed a mechanical assessment tool for quantitative pre-clinical assessment of ACS. Our hand-held indentation device provides an accurate method for investigations into the local dynamic mechanical properties of soft tissue and for in-situ non-invasive assessment and monitoring of ACS. Our compartment syndrome model was developed on the cranial tibial and the peroneus tertius muscles of a pig's leg (postmortem). The compartment syndrome pressure values were obtained by injecting blood from the bone through the muscle. To enable ACS assessment by a hand-held indentation device we combined three main components: a load cell, a linear actuator and a 3-axis accelerometer. Dynamic tests were performed at a frequency of 0.5 Hz and by applying an amplitude of 0.5 mm. Another method used to observe the differences in the mechanical properties inside the leg was a 3D Digital Image Correlation (3D-DIC). Videos were taken from two different positions of the pig's leg at different pressure values: 0 mmHg, 15 mmHg and 40 mmHg. Two strains along the x axis (Exx) and y axis (Eyy) were measured. Between the two pressure cases (15 mmHg and 40 mmHg) a clear deformation of the model is visible. In fact, the bigger the pressure, the more visible the increase in strain is. In our animal model, local muscle pressures reached values higher than 40 mmHg, which correlate with observed human physiology in ACS. In our presentation we will share our dynamic indentation results on this model to demonstrate the sensitivity of our measurement techniques. Compartment syndrome is recognised as needing improved clinical management tools. Our approach provides both a model that reflects physiological behaviour of ACS, and a method for in-situ non-invasive assessment and monitoring.

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. Their spatial pattern is established by a Turing reaction-diffusion system, based on signaling between EDAR, WNT, and antagonistic BMP pathways. These signals resolve epithelial growth into bands of focalized proliferation under a precociously differentiated suprabasal layer. Ridge formation occurs as a set of waves spreading from variable initiation sites defined by the local signaling environments and anatomical intricacies of the digit, with the propagation and meeting of these waves determining the type of pattern that forms. Relying on a dynamic patterning system triggered at spatially distinct sites generates the characteristic types and unending variation of human fingerprint patterns.

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 of 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 three hours of rapid and persistent migration, followed by a long period of low motility. The cell division plane and the elevated migration speed and persistence of newly born mesenchymal cells are mechanosensitive, aligning with tension in the tissue. This early G1 migratory behaviour disperses mesenchymal cells and allows the daughters of recent divisions to travel long distances to enter dermal condensates, demonstrating an unanticipated effect of a cell cycle sub-phase on core mesenchymal behaviour. Highlights After mesenchymal cell division the speed and persistence of daughter cell migration is elevated for 180 minutes Mesenchymal cell division and migration are directed by tissue tension Newly born mesenchymal cells are uniquely responsive to tissue strain Newly born mesenchymal cells are preferentially recruited to dermal condensates Increased dispersal of newly born cells enables long distance travel to dermal condensates Graphical abstract

Cutaneous wound healing typically results in scarring; however, chronic wounds (CWs) represent a global and escalating health burden causing substantial morbidity and mortality. Estimated to cost Medicare up to $96.8 billion pa and with a profound paucity of effective therapeutics, novel interventions to improve healing are urgently needed. In this study, we assess the impact of manipulating the melanocortin 1 receptor (MC1R) on acute wound healing using a selective agonist, BMS-470539 (MC1R-Ag). MC1R agonism resulted in accelerated wound closure and reepithelialisation in wildtype but not MC1Re/e mice, which harbour a non-functional receptor. MC1R-Ag improved wound perfusion and lymphatic drainage by promoting angiogenesis and lymphangiogenesis, reducing local oxidative stress and inflammation with a knock-on effect of reduced scarring. To assess whether manipulating MC1R would be of benefit in pathological healing, we developed a novel murine model of chronic cutaneous wounds. By combining advanced age and locally elevated oxidative stress, factors shown to be present in most human CWs regardless of their category, resultant wounds expand 5-fold into the surrounding tissue, produce exudate and generate slough. Histological comparisons to human CWs demonstrate robust recapitulation of the hallmarks of human disease, including hyperproliferative epidermis, fibrinous exudate and vasculitis. Crucially, our model facilitates the in vivo study of candidate therapies to rescue derailed healing responses. We have identified that abrogation of MC1R signalling, using MC1Re/e mice, exacerbates CWs with enhanced exudate and NETosis. In contrast, topical administration of an MC1R agonist following ulcer debridement rescues the healing response, highlighting MC1R agonism as a candidate therapeutic approach for human CWs. We anticipate that our unique model will become a valuable tool to elucidate mechanisms of ulcer development and persistence.

This paper presents findings from a small-scale research study eliciting students’ perceptions of benefits and challenges of working in interdisciplinary groups to solve an engineering challenge using problem-based learning. Penultimate and final year undergraduates and postgraduate MSc students in the School of Engineering and Physical Sciences at a Scottish university, studying Robotics, Mechanical, Chemical, Electrical and Software Engineering worked in interdisciplinary groups of five on a project to provide solutions to the United States National Academy of Engineering Grand Challenges (NAEGC). Students were surveyed twice, using closed and open questions before and towards the end of the project. Data were analysed using a thematic approach. Findings showed that most students saw benefits to problem-based working with students from other disciplines, citing increased awareness of approaches, future ‘real world’ professional preparation and efficiency in problem solving. However, challenges around scheduling meetings and concerns around cross-discipline collaboration indicate that universities should provide training for students before undertaking such problem-based projects, to ensure maximum educational benefits. In addition, greater emphasis needs to be put on students’ awareness of the added benefits of development of the ‘soft skills’ needed for future professional practice.

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). The device focus for this study was a skin-targeting Nanopatch vaccine microneedle device, employed to assess the variance to key skin engagement parameters – penetration depth and delivery efficiency – due to different tissue conditions. The patches were coated with fluorescent or ¹⁴C radiolabelled formulations for penetration depth and delivery efficiency quantification in vivo, and at time points up to 4 h post mortem. An immediate cessation of blood circulation saw mean microneedle penetration depth fell from ∼100 μm to ∼55 μm (∼45%). Stiffening of underlying tissues as a result of rigor mortis then augmented the penetration depths at the 4 h timepoint back to ∼100 μm, insignificantly different (p = 0.0595) when compared with in vivo. The highest delivery efficiency of formulation into the skin (dose measured in the skin excluding leftover dose on skin and patch surfaces) was also observed at this time point of ∼25%, up from ∼2% in vivo. Data obtained herein progresses medical device development, highlighting the need to consider the state and muscle tissues when evaluating prototypes on cadavers.