Towards skin-on-a-chip for screening the dermal absorption of cosmetics.

Over the past few decades, there have been increasing global efforts to limit or ban the use of animals for testing cosmetic products. This ambition has been at the heart of international endeavours to develop new in vitro and animal-free approaches for assessing the safety of cosmetics. While several of these new approach methodologies (NAMs) have been approved for assessing different toxicological endpoints in the UK and across the EU, there remains an absence of animal-free methods for screening for dermal absorption; a measure that assesses the degree to which chemical substances can become systemically available through contact with human skin. Here, we identify some of the major technical barriers that have impacted regulatory recognition of an in vitro skin model for this purpose and propose how these could be overcome on-chip using artificial cells engineered from the bottom-up. As part of our future perspective, we suggest how this could be realised using a digital biomanufacturing pipeline that connects the design, microfluidic generation and 3D printing of artificial cells into user-crafted synthetic tissues. We highlight milestone achievements towards this goal, identify future challenges, and suggest how the ability to engineer animal-free skin models could have significant long-term consequences for dermal absorption screening, as well as for other applications.

3D printed superparamagnetic stimuli-responsive starfish-shaped hydrogels.

Magnetic-stimuli responsive hydrogels are quickly becoming a promising class of materials across numerous fields, including biomedical devices, soft robotic actuators, and wearable electronics. Hydrogels are commonly fabricated by conventional methods that limit the potential for complex architectures normally required for rapidly changing custom configurations. Rapid prototyping using 3D printing provides a solution for this. Previous work has shown successful extrusion 3D printing of magnetic hydrogels; however, extrusion-based printing is limited by nozzle resolution and ink viscosity. VAT photopolymerization offers a higher control over resolution and build-architecture. Liquid photo-resins with magnetic nanocomposites normally suffer from nanoparticle agglomeration due to local magnetic fields. In this work, we develop an optimised method for homogenously infusing up to 2 wt % superparamagnetic iron oxide nanoparticles (SPIONs) with a 10 nm diameter into a photo-resin composed of water, acrylamide and PEGDA, with improved nanoparticle homogeneity and reduced agglomeration during printing. The 3D printed starfish hydrogels exhibited high mechanical stability and robust mechanical properties with a maximum Youngs modulus of 1.8 MPa and limited shape deformation of 10% when swollen. Each individual arm of the starfish could be magnetically actuated when a remote magnetic field is applied. The starfish could grab onto a magnet with all arms when a central magnetic field was applied. Ultimately, these hydrogels retained their shape post-printing and returned to their original formation once the magnetic field had been removed. These hydrogels can be used across a wide range of applications, including soft robotics and magnetically stimulated actuators.

Applying machine learning methods to enable automatic customisation of knee replacement implants from CT data.

The aim of this study was to develop an automated pipeline capable of designing custom total knee replacement implants from CT scans. The developed pipeline firstly utilised a series of machine learning methods including classification, object detection, and image segmentation models, to extract geometrical information from inputted DICOM files. Statistical shape models then used the information to create femur and tibia 3D surface model predictions which were ultimately used by computer aided design scripts to generate customised implant designs. The developed pipeline was trained and tested using CT scan images, along with segmented 3D models, obtained for 98 Korean Asian subjects. The performance of the pipeline was tested computationally by virtually fitting outputted implant designs with 'ground truth' 3D models for each test subject's bones. This demonstrated the pipeline was capable of repeatably producing highly accurate designs, and its performance was not impacted by subject sex, height, age, or knee side. In conclusion, a robust, accurate and automatic, CT-based total knee replacement customisation pipeline was shown to be feasible and could afford significant time and cost advantages over conventional methods. The pipeline framework could also be adapted to enable customisation of other medical implants.

A computational design of experiments based method for evaluation of off-the-shelf total knee replacement implants.

A methodology to explore the design space of off-the-shelf total knee replacement implant designs is outlined. Generic femur component and tibia plate designs were scaled to thousands of sizes and virtually fitted to 244 test subjects. Various implant designs and sizing requirements between genders and ethnicities were evaluated. 5 sizes optimised via the methodology produced a good global fit for most subjects. However, clinically significant over/underhang was present in 19% of subjects for tibia plates and 25% for femur components, reducing to 11/20% with 8 sizes. The analysis highlighted subtly better fit performance was obtained using sizes with unequal spacing.

An automated design pipeline for transparent facial orthoses: A clinical study.

STATEMENT OF PROBLEM: Transparent facial orthoses (TFOs) are commonly used for the treatment of craniomaxillofacial trauma and burns to prevent hypertrophic and keloid scarring. A TFO is typically customized to the patient's facial contours and relies on a precise fit to ensure good rehabilitative performance. A smart method of TFO design and manufacture is needed which does not require an experienced prosthetist, allowing for rapidly produced, well-fitting TFOs. Whether the rapid application reduces the final level of patient scarring is unclear. PURPOSE: The purpose of this clinical study was to determine whether a scalable, automated design-through-manufacture pipeline for patient specific TFO fabrication would be successful. MATERIAL AND METHODS: The automated pipeline received a 3-dimensional (3D) facial scan captured from a depth sensitive mobile phone camera. The scan was cleaned, aligned, and fit to a template mesh, with a known connectivity. The resultant fitted scan was passed into an automated design pipeline, outputting a 3D printable model of a custom TFO. The TFOs were fabricated with 3D printing and were both physically and digitally evaluated to test the fidelity of a digital fit testing system. RESULTS: A total of 10 individuals were scanned with 5 different scanning technologies (STs). All scans were passed through an automated fitting pipeline and categorized into 2 groups. Each ST was digitally fitted to a ground truth scan. In this manner, a Euclidean distance map was built to the actual facial geometry for each scan. Heatmaps of 3D Euclidean distances were made for all participant faces. CONCLUSIONS: The ability to automatically design and manufacture a custom fitted TFO using commercially available 3D scanning and 3D printing technology was successfully demonstrated. After considering equipment size and operational personnel requirements, vat polymerization (VP) technology was found to be the most promising route to TFO manufacture.

A computational tool for automatic selection of total knee replacement implant size using X-ray images.

Purpose: The aim of this study was to outline a fully automatic tool capable of reliably predicting the most suitable total knee replacement implant sizes for patients, using bi-planar X-ray images. By eliminating the need for manual templating or guiding software tools via the adoption of convolutional neural networks, time and resource requirements for pre-operative assessment and surgery could be reduced, the risk of human error minimized, and patients could see improved outcomes. Methods: The tool utilizes a machine learning-based 2D-3D pipeline to generate accurate predictions of subjects' distal femur and proximal tibia bones from X-ray images. It then virtually fits different implant models and sizes to the 3D predictions, calculates the implant to bone root-mean-squared error and maximum over/under hang for each, and advises the best option for the patient. The tool was tested on 78, predominantly White subjects (45 female/33 male), using generic femur component and tibia plate designs scaled to sizes obtained for five commercially available products. The predictions were then compared to the ground truth best options, determined using subjects' MRI data. Results: The tool achieved average femur component size prediction accuracies across the five implant models of 77.95% in terms of global fit (root-mean-squared error), and 71.79% for minimizing over/underhang. These increased to 99.74% and 99.49% with ±1 size permitted. For tibia plates, the average prediction accuracies were 80.51% and 72.82% respectively. These increased to 99.74% and 98.98% for ±1 size. Better prediction accuracies were obtained for implant models with fewer size options, however such models more frequently resulted in a poor fit. Conclusion: A fully automatic tool was developed and found to enable higher prediction accuracies than generally reported for manual templating techniques, as well as similar computational methods.

Anti-inflammatory properties of S53P4 bioactive glass implant material.

OBJECTIVES: To assess whether the dissolution products of S53P4 bioactive glass (BG) affect cellular response of macrophages and clinically relevant peri­implant cell populations to dental implant particles in vitro. Cells chosen were human gingival fibroblasts (HGFs), osteoblasts and bone marrow derived stromal cells (HBMSCs). METHODS: Melt-derived S53P4 bioactive glass were prepared. HGFs, Saos-2 human osteoblastic cell line, HBMSCs and macrophages, derived from THP-1 human monocytic cell line, were cultured in the presence of particles from commercially pure titanium (Ti-CP4), grade 5 titanium alloy (Ti-6Al-4V), titanium-zirconium alloy (Ti-15Zr) or zirconia (Zr) (with respective diameters of 34.1 ± 3.8, 33.3 ± 4.4, 97.8 ± 8.2 and 71.3 ± 6.1 µm) with or without S53P4 dissolution products (conditioned media contained 327.30 ± 2.01 ppm Ca, 51.34 ± 0.41 ppm P and 61.48 ± 1.17 ppm Si, pH 8.01 ± 0.21). Inflammatory and macrophage polarisation markers including TNF-ɑ, IL-1, IL-6 and CD206 were quantified using enzyme-linked immunosorbent assay (ELISA). RESULTS: The presence of Ti-6Al-4V implant particles significantly induced the expression of pro-inflammatory markers in all tested cell types. S53P4 BG dissolution products regressed the particle induced up-regulation of pro-inflammatory markers and, appeared to suppress M1 macrophage polarisation. CONCLUSIONS: Implant particles, Ti-6Al-4V in particular, resulted in significant inflammatory responses from cells. S53P4 BG may possess anti-inflammatory properties and potentially mediate macrophage polarisation behaviour. CLINICAL SIGNIFICANCE: The findings highlight that the use and benefits of BG is a promising field of study. Authors believe more collective efforts are required to fully understand the reliability, efficiency and exact mechanisms of action of BG in the search for new generation of treatment modalities in dentistry.

Toward Mass Customization Through Additive Manufacturing: An Automated Design Pipeline for Respiratory Protective Equipment Validated Against 205 Faces.

Respiratory protective equipment (RPE) is traditionally designed through anthropometric sizing to enable mass production. However, this can lead to long-standing problems of low-compliance, severe skin trauma, and higher fit test failure rates among certain demographic groups, particularly females and non-white ethnic groups. Additive manufacturing could be a viable solution to produce custom-fitted RPE, but the manual design process is time-consuming, cost-prohibitive and unscalable for mass customization. This paper proposes an automated design pipeline which generates the computer-aided design models of custom-fit RPE from unprocessed three-dimensional (3D) facial scans. The pipeline successfully processed 197 of 205 facial scans with <2 min/scan. The average and maximum geometric error of the mask were 0.62 mm and 2.03 mm, respectively. No statistically significant differences in mask fit were found between male and female, Asian and White, White and Others, Healthy and Overweight, Overweight and Obese, Middle age, and Senior groups.

Post-lockdown abatement of COVID-19 by fast periodic switching.

COVID-19 abatement strategies have risks and uncertainties which could lead to repeating waves of infection. We show-as proof of concept grounded on rigorous mathematical evidence-that periodic, high-frequency alternation of into, and out-of, lockdown effectively mitigates second-wave effects, while allowing continued, albeit reduced, economic activity. Periodicity confers (i) predictability, which is essential for economic sustainability, and (ii) robustness, since lockdown periods are not activated by uncertain measurements over short time scales. In turn-while not eliminating the virus-this fast switching policy is sustainable over time, and it mitigates the infection until a vaccine or treatment becomes available, while alleviating the social costs associated with long lockdowns. Typically, the policy might be in the form of 1-day of work followed by 6-days of lockdown every week (or perhaps 2 days working, 5 days off) and it can be modified at a slow-rate based on measurements filtered over longer time scales. Our results highlight the potential efficacy of high frequency switching interventions in post lockdown mitigation. All code is available on Github at https://github.com/V4p1d/FPSP_Covid19. A software tool has also been developed so that interested parties can explore the proof-of-concept system.

Effects of beverage carbonation on lubrication mechanisms and mouthfeel.

The perception of carbonation is an important factor in beverage consumption which must be understood in order to develop healthier products. Herein, we study the effects of carbonated water on oral lubrication mechanisms involved in beverage mouthfeel and hence taste perception. Friction was measured in a compliant PDMS-glass contact simulating the tongue-palate interface (under representative speeds and loads), while fluorescence microscopy was used to visualise both the flow of liquid and oral mucosal pellicle coverage. When carbonated water is entrained into the contact, CO2 cavities form at the inlet, which limit flow and thus reduce the hydrodynamic pressure. Under mixed lubrication conditions, when the fluid film thickness is comparable to the surface roughness, this pressure reduction results in significant increases in friction (>300% greater than under non-carbonated water conditions). Carbonated water is also shown to be more effective than non-carbonated water at debonding the highly lubricious, oral mucosal pellicle, which again results in a significant increase in friction. Both these transient mechanisms of starvation and salivary pellicle removal will modulate the flow of tastants to taste buds and are suggested to be important in the experience of taste and refreshment. For example this may be one reason why flat colas taste sweeter.

The effect of transient conditions on synovial fluid protein aggregation lubrication.

Little is known about the prevailing lubrication mechanisms in artificial articular joints and the way in which these mechanisms determine implant performance. The authors propose that interfacial film formation is determined by rheological changes local to the contact and is driven by aggregation of synovial fluid proteins within the contact inlet region. A direct relationship between contact film thickness and size of the protein aggregation within the inlet region has been observed. In this paper the latest experimental observations of the protein aggregation mechanism are presented for conditions which more closely mimic joint kinematics and loading. Lubricant films were measured for a series of bovine calf serum solutions for CoCrMo femoral component sliding against a glass disc. An optical interferometric apparatus was employed to study the effects of transient motion on lubricant film formation. Central film thickness was measured as a function of time for a series of transient entrainment conditions; start-up motion, steady-state and non-steady-state uni-directional sliding, and bi-directional sliding. The size of the inlet aggregations was found to be dependent upon the type of transient condition. Thick protective protein films were observed to build up within the main contact region for all uni-directional tests. In contrast the inlet aggregation was not observed for bi-directional tests. Contact film thickness and wear was found to be directly proportional to the presence of the inlet protein phase. The inlet phase and contact films were found to be fragile when disrupted by surface scratches or subjected to reversal of the sliding direction.

On the matter of synovial fluid lubrication: implications for Metal-on-Metal hip tribology.

Artificial articular joints present an interesting, and difficult, tribological problem. These bearing contacts undergo complex transient loading and multi axes kinematic cycles, over extremely long periods of time (>10 years). Despite extensive research, wear of the bearing surfaces, particularly metal-metal hips, remains a major problem. Comparatively little is known about the prevailing lubrication mechanism in artificial joints which is a serious gap in our knowledge as this determines film formation and hence wear. In this paper we review the accepted lubrication models for artificial hips and present a new concept to explain film formation with synovial fluid. This model, recently proposed by the authors, suggests that interfacial film formation is determined by rheological changes local to the contact and is driven by aggregation of synovial fluid proteins. The implications of this new mechanism for the tribological performance of new implant designs and the effect of patient synovial fluid properties are discussed.

Synovial fluid lubrication of artificial joints: protein film formation and composition.

Despite design improvements, wear of artificial implants remains a serious health issue particularly for Metal-on-Metal (MoM) hips where the formation of metallic wear debris has been linked to adverse tissue response. Clearly it is important to understand the fundamental lubrication mechanisms which control the wear process. It is usually assumed that MoM hips operate in the ElastoHydrodynamic Lubrication (EHL) regime where film formation is governed by the bulk fluid viscosity; however there is little experimental evidence of this. The current paper critically examines synovial fluid lubrication mechanisms and the effect of synovial fluid chemistry. Two composition parameters were chosen; protein content and pH, both of which are known to change in diseased or post-operative synovial fluid. Film thickness and wear tests were carried out for a series of model synovial fluid solutions. Two distinct film formation mechanisms were identified; an adsorbed surface film and a high-viscosity gel. The entrainment of this gel controls film formation particularly at low speeds. However wear of the femoral head still occurs and this is thought to be due primarily to a tribo-corrosion mechanisms. The implications of this new lubrication mechanism and the effect of different synovial fluid chemistries are examined. One important conclusion is that patient synovial fluid chemistry plays an important role in determining implant wear and the likelihood of failure.