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Many defined approaches (DAs) for skin sensitization assessment based on the adverse outcome pathway (AOP) have been developed to replace animal testing because the European Union has banned animal testing for cosmetic ingredients. Several DAs have demonstrated that machine learning models are beneficial. In this study, we have developed an ensemble prediction model utilizing the graph convolutional network (GCN) and machine learning approach to assess skin sensitization. The model integrates in silico parameters and data from alternatives to animal testing of well-defined AOP to improve DA predictivity. Multiple ensemble models were created using the probability produced by the GCN with six physicochemical properties, direct peptide reactivity assay, KeratinoSens™, and human cell line activation test (h-CLAT), using a multilayer perceptron approach. Models were evaluated by predicting the testing set's human hazard class and three potency classes (strong, weak, and non-sensitizer). When the GCN feature was used, 11 models out of 16 candidates showed the same or improved accuracy in the testing set. The ensemble model with the feature set of GCN, KeratinoSens™, and h-CLAT produced the best results with an accuracy of 88% for assessing human hazards. The best three-class potency model was created with the feature set of GCN and all three assays, resulting in 64% accuracy. These results from the ensemble approach indicate that the addition of the GCN feature could provide an improved predictivity of skin sensitization hazard and potency assessment.

Exposure to microgravity affects human physiology in various ways, and astronauts frequently report skin-related problems. Skin rash and irritation are frequent complaints during space missions, and skin thinning has also been reported after returning to Earth. However, spaceflight missions for studying the physiological changes in microgravity are impractical. Thus, we used a previously developed 3D clinostat to simulate a microgravity environment and investigate whether physiological changes of the skin can be reproduced in a 3D in vitro setting. Our results showed that under time-averaged simulated microgravity (taSMG), the thickness of the endothelial cell arrangement increased by up to 59.75%, indicating skin irritation due to vasodilation, and that the diameter of keratinocytes and fibroblast co-cultured spheroids decreased by 6.66%, representing skin thinning. The α1 chain of type I collagen was upregulated, while the connective tissue growth factor was downregulated under taSMG. Cytokeratin-10 expression was significantly increased in the taSMG environment. The clinostat-based 3D culture system can reproduce physiological changes in the skin similar to those under microgravity, providing insight for understanding the effects of microgravity on human health before space exploration.

Controlling blood glucose levels in diabetic patients is important for managing their health and quality of life. Several algorithms based on model predictive control and reinforcement learning (RL) have been proposed so far, most of which use prior knowledge of physiological systems, the mathematical structure of blood glucose dynamics, and many episodes including failures for training the policy network in RL. To be smoothly adopted in clinical settings, we propose a fast online learning method underlining safety and interpretability. A random forest regressor and a dual attention network were exploited for glucose prediction and extension of state variables. The soft actor-critic network to determine insulin dosing was guided by proportional-integral-derivative (PID) control in the early phase, and an adaptive safe actor with suspension and additional insulin dosing was incorporated. The performance of the models was validated using an FDA-approved type 1 diabetes simulator. The results showed comparable outcomes with PID control. Using this system, glucose dynamics could be captured despite minimal prior knowledge. The extended state variables were correlated with basic states such as glucose, insulin, and meal intake, their derivatives, and their integrals, which can be fundamental elements of mathematical modeling of physiological responses. Attention scores and attribution scores in the prediction and control models represented the focused features and the internal operation of the models with interpretability. We expect this study to provide some insights on how RL can be practically adopted in clinical environments and how interpretability can provide hints of machines’ thoughts for clinical applications.

The surface of human silicone breast implants is covalently grafted at a high density with a 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymer. Addition of cross-linkers is essential for enhancing the density and mechanical durability of the MPC graft. The MPC graft strongly inhibits not only adsorption but also the conformational deformation of fibrinogen, resulting in the exposure of a buried amino acid sequence, γ377-395, which is recognized by inflammatory cells. Furthermore, the numbers of adhered macrophages and the amounts of released cytokines (MIP-1α, MIP-1β, IL-8, TNFα, IL-1α, IL-1β, and IL-10) are dramatically decreased when the MPC network is introduced at a high density on the silicone surface (cross-linked PMPC-silicone). We insert the MPC-grafted human silicone breast implants into Yorkshire pigs to analyze the in vivo effect of the MPC graft on the capsular formation around the implants. After 6 month implantation, marked reductions of inflammatory cell recruitment, inflammatory-related proteins (TGF-β and myeloperoxidase), a myoblast marker (α-smooth muscle actin), vascularity-related factors (blood vessels and VEGF), and, most importantly, capsular thickness are observed on the cross-linked PMPC-silicone. We propose a mechanism of the MPC grafting effect on fibrous capsular formation around silicone implants on the basis of the in vitro and in vivo results.

Melanoma is visible unlike other types of cancer, but it is still challenging to diagnose correctly because of the difficulty in distinguishing between benign nevus and melanoma. We conducted a robust investigation of melanoma, identifying considerable differences in local elastic properties between nevus and melanoma tissues by using atomic force microscopy (AFM) indentation of histological specimens. Specifically, the histograms of the elasticity of melanoma displayed multimodal Gaussian distributions, exhibiting the heterogeneous mechanical properties, in contrast with the unimodal distributions of elasticity in the benign nevus. We identified this notable signature was consistent regardless of blotch incidence by sex, age, anatomical site (e.g., thigh, calf, arm, eyelid, and cheek), or cancer stage (I, IV, and V). In addition, we found that the non-linearity of the force-distance curves for melanoma is increased compared to benign nevus. We believe that AFM indentation of histological specimens may technically complement conventional histopathological analysis for earlier and more precise melanoma detection.

Implants based on silicone elastomers, polydimethylsiloxane (PDMS), have been widely used for breast augmentation and reconstruction, but excessive foreign body reactions around implants often cause serious side effects such as capsular contracture. In our previous study, we covalently grafted 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymers on the surface of PDMS blocks by UV-induced polymerization and showed effective reduction of capsular formation around the MPC-grafted PDMS in rats. In the present study, we examined the efficacy of heat-induced polymerization of MPC grafting on silicone breast implants intended for humans, and analyzed the in vivo inhibitory effect against capsular formation and inflammation in pigs, which are closely related to humans in terms of epidermal structures and fibrotic processes. The heat-induced polymerization provided a thicker MPC-grafted surface and was more effective than UV-induced polymerization for the grafting of complex shaped non-transparent implants. After 24-week implantation in the submuscular pockets of Yorkshire pigs, the heat-induced MPC-grafted breast implants showed 45% smaller capsular thickness and 20-30% lower levels of inflammatory markers such as myeloperoxidase (MPO), transforming growth factor-β (TGF-β), and α-smooth muscle actin (α-SMA) in surrounding tissues compared to non-grafted implants. This study provides important information for future clinical trials of MPC-grafted silicone implants.

Gravity is omnipresent for all objects on Earth. However, in an environment of different gravitational stress (e.g., microgravity or partial gravity), cells and organs show different biological responses. So, researchers have attempted to achieve micro- or partial gravity on Earth through various approaches, such as parabolic flight or free fall. However, the duration of such ground experiments is highly limited, making it very difficult to conduct time-consuming tasks, such as cell culture. Thus, a three-dimensional (3D) clinostat is utilized as an alternative for experiments on the International Space Station. It provides time-averaged simulated micro- and partial gravity by using mechanical frames with two rotating actuators. This study proposes novel control algorithms for simulating micro- and partial gravity and validates them by applying it to the control of a manufactured 3D clinostat. First, the novel algorithm for time-averaged simulated microgravity (taSMG) provided a more uniformly distributed gravity field by reducing two poles the gravity-concentrated areas. The taSMG with reduced poles provides isotropic gravitational patterns, from which it is possible to minimize the unnecessary effect due to nonuniformity of the gravity vector direction. Second, the other suggested novel algorithm for time-averaged simulated partial gravity (taSPG) controls the pole sizes asymmetrically to generate the intended size of partial gravity. The suggested algorithms are based on mathematical models rather than totally randomized motions. Therefore, the convergence of gravity values, in the rotating frame over time, can be analytically predicted with improved accuracy compared with previously reported algorithms. The developed 3D clinostat hardware and algorithms will effectively provide well-validated taSMG and taSPG for cell growth experiments in future studies for space medicine.

The clinical use of bioactive molecules in bone regeneration has been known to have side effects, which result from uncontrolled and supraphysiological doses. In this study, we demonstrated the synergistic effect of two bioactive molecules, bone morphogenic protein-2 (BMP-2) and alendronate (ALN), by releasing them in a sequential manner. Collagen-hydroxyapatite composite scaffolds functionalized using BMP-2 are loaded with biodegradable microspheres where ALN is encapsulated. The results indicate an initial release of BMP-2 for a few days, followed by the sequential release of ALN after two weeks. The composite scaffolds significantly increase osteogenic activity owing to the synergistic effect of BMP-2 and ALN. Enhanced bone regeneration was identified at eight weeks post-implantation in the rat 8-mm critical-sized defect. Our findings suggest that the sequential delivery of BMP-2 and ALN from the scaffolds results in a synergistic effect on bone regeneration, which is unprecedented. Therefore, such a system exhibits potential for the application of cell-free tissue engineering.

Background: Robot surgery has become prevalent because of its various advantages as a progressive method based on empirical researches of conventional open surgery and minimally invasive surgery. However, the da Vinci surgical robot system, the most widely used and researched surgical robot, still requires an ergonomic improvement because of the uncomfortable posture in which it has to be operated. The stereo viewer—the current vision system of the da Vinci surgical robot—requires a user to maintain a posture wherein the user is looking down, which causes discomfort and results in musculoskeletal disorders. To overcome this limitation, a virtual reality (VR) head-mounted display (HMD) is proposed by previous researchers as an appropriate option to replace the stereo viewer, as it enables surgeons to move freely during surgery instead of having to look down on the stereo viewer. Presently, there is no direct comparison between the stereo viewer and a VR HMD by surgeons. Comparative evaluations were performed using peg transfer tasks, a questionnaire, and a NASA-Task Load Index (TLX). These were planned and performed by surgeons and novices to determine if the stereo viewer can be replaced by the VR HMD and to investigate whether the VR HMD has ergonomic.Results: Based on the results of peg transfer tasks, completion times when using VR HMD were shorter than those when using the stereo viewer. In these tasks, the participants performed more executions using the VR HMD compared to the stereo viewer. Based on the questionnaire, the participants favored the VR HMD compared to the stereo viewer, with respect to its visual and ergonomic performance. The modified NASA-TLX showed positive perceptions for the VR HMD.Conclusions: This comparative evaluation confirmed that the VR HMD can be employed as a potential alternative for the stereo viewer in a surgical robot system to achieve ergonomic improvements. The VR HMD improved the task performance of the surgical robot system, and it provided an ergonomic operation environment.

Powder metallurgy (PM) has undergone innovations through powder advances and novel process development. Another option for advancement of PM technology is exploitation of the extreme bimodality of nano/micro powder mixtures. The present study describes bimodal powder preparation involving dispersion of nickel nanoparticles onto the surface of a micro powder to facilitate the compaction ability and sinterability of the Ni micro powder. The bimodal powder is designed by synthesizing Ni nanoparticles by reactive RF thermal plasma from a Ni(OH)2 micro powder, selecting a spiky-shaped Ni micro powder as the supporting powder, and then filling the pockets on the surface of the micro powder with the nanoparticles. Simple 3-D turbulent mixing successfully produces spheroidized and smoothened micro-granules consisting of well-dispersed nanoparticles on the surface of the micro powder. Nanoparticle compaction is usually difficult, but the compaction behavior of the micro-granules is similar to that of the micro powder. The effect of nanoparticle addition on sinterability, investigated by dilatometry, includes double-stage sintering behavior of the micro-granule powder, whereas the spiky-shaped micro powder shows a typical monotonous sintering behavior. Consequently, the first shrinkage at low temperature arises from the enhanced sinterability of the nanoparticles, while the second shrinkage shows similar behavior to the micro powder. Within the scope of this study, the micro-granules show a higher relative density than the micro powder.

Background Microtia is a congenital deformity of the external ear that occurs in 1 of every 5000 births. Microtia reconstruction using traditional two-dimensional templates does not provide highly detailed ear shapes. Here, we describe the feasibility of using a three-dimensional (3D) ear model as a reference. Materials and methods Seven children aged from 11 to 16 (6 grade III and 1 grade II microtia) were recruited from Seoul National University Children's Hospital, Korea. We generated 3D–computer-aided design models of each patient's ear by performing 3D laser scanning for a mirror-transformed cast of their normal ear. The 3D-printed ear model was used in microtia reconstruction surgery following the Nagata technique, and its shape was compared with the casted ear model. Results One patient experienced irritation caused by accidently pouring resin into the external auditory meatus, and another had minor skin necrosis; both complications were successfully treated. The average percentage differences of the superior, inferior, anterior, posterior, and lateral views between the casted and 3D-printed ear models were 1.17%, 1.48%, 1.64%, 1.80%, and 5.44%, respectively (average: 2.31%), where the difference between the casted ear models and traditional two-dimensional templates were 16.03% in average. Conclusions Our results show that simple microtia reconstruction can be performed using 3D ear models. The 3D-printed ear models of each patient were consistent and accurately represented the thickness, depth, and height of the normal ear. The availability of the 3D-printed ear model in the operating room reduced the amount of unnecessary work during surgery.

Current alternatives to animal testing methods for skin irritation evaluation such as reconstructed human epidermis models are not fully representing physiological response caused by skin irritants. Skin irritation is physiologically induced by the dilation and increased permeability of endothelial cells. Thus, our objectives were to mimic physiological skin irritation using a skin-on-a-chip model and compare predictive capacities with a reconstructed human epidermis model to evaluate its effectiveness. To achieve our goals, the skin-on-a-chip model, consisting of three layers representing the epidermal, dermal and endothelial components, was adapted. Cell viability was measured using the OECD TG 439 protocol for test substance evaluation. The tight junctions of endothelial cells were also observed and measured to assess physiological responses to test substances. These parameters were used to physiologically evaluate cell-to-cell interactions induced by test substances and quantify model accuracy, sensitivity, and specificity. Based on in vivo data, the classification accuracy of twenty test substances using a dual-parameter chip model was 80%, which is higher than other methods. Besides, the chip model was more suitable for simulating human skin irritation. Therefore, it is important to note that the dual-parameter chip model possesses an enhanced predictive capacity and could serve as an alternative to animal testing for skin irritation.

Although many methods to assess sensitization have been investigated to replace animal testing, it is still imperative to develop an in vitro method to minimize the use of animals and to classify sensitizers. Recently, an assay using the human keratinocyte cell line (HaCaT) was developed as an alternative method. Our aim was to optimize this method and validate its ability to assess sensitization. The highest dose that resulted in 75% cell viability was determined for each test substance. Then, serial dilutions of the dose were applied to measure the levels of secreted proinflammatory cytokines. To optimize the assay, statistical analyses were performed to determine whether all of the doses tested were necessary to maintain the predictive values. Exclusion of the 0.5× dose did not change the predictive values drastically. To validate the optimized method, 22 substances were evaluated without the 0.5× dose, resulting in overall predictive values of 83.3% for sensitivity, 80.0% for specificity, and 81.8% for accuracy, which are comparable to results from other validated assays. These results suggest that statistical analysis can assist in development of alternative in vitro methods and that the optimized HaCaT cell assay is reproducible.

Recent advances in microfluidic cell cultures enable the construction of in vitro human skin models that can be used for drug toxicity testing, disease study. However, current in vitro skin model have limitations to emulate real human skin due to the simplicity of model. In this paper, we describe the development of ‘skin-on-a-chip’ to mimic the structures and functional responses of the human skin. The proposed model consists of 3 layers, on which epidermal, dermal and endothelial components originated from human, were cultured. The microfluidic device was designed for co-culture of human skin cells and each layer was separated by using porous membranes to allow interlayer communication. Skin inflammation and edema were induced by applying tumor necrosis factor alpha on dermal layer to demonstrate the functionality of the system. The expression levels of proinflammatory cytokines were analyzed to illustrate the feasibility. In addition, we evaluated the efficacy of therapeutic drug testing model using our skin chip. The function of skin barrier was evaluated by staining tight junctions and measuring a permeability of endothelium. Our results suggest that the skin-on-a-chip model can potentially be used for constructing in vitro skin disease models or for testing the toxicity of cosmetics or drugs.

2H-TaSe2 has been one of unique transition metal dichalcogenides exhibiting several phase transitions due to a delicate balance among competing electronic ground states. An unusual metallic state at high-T is sequentially followed by an incommensurate charge density wave (ICDW) state at ≈122 K and a commensurate charge density wave (CCDW) state at ≈90 K, and superconductivity at TC ~ 0.14 K. Upon systematic intercalation of Pd ions into TaSe2, we find that CCDW order is destabilized more rapidly than ICDW to indicate a hidden quantum phase transition point at x ~ 0.09–0.10. Moreover, TC shows a dramatic enhancement up to 3.3 K at x = 0.08, ~24 times of TC in 2H-TaSe2, in proportional to the density of states N(EF). Investigations of upper critical fields Hc2 in single crystals reveal evidences of multiband superconductivity as temperature-dependent anisotropy factor γH = "Equation missing", quasi-linear increase of "Equation missing", and an upward, positive-curvature in "Equation missing" near TC. Furthermore, analysis of temperature-dependent electronic specific heat corroborates the presence of multiple superconducting gaps. Based on above findings and electronic phase diagram vs x, we propose that the increase of N(EF) and effective electron-phonon coupling in the vicinity of CDW quantum phase transition should be a key to the large enhancement of TC in PdxTaSe2.

316L stainless steel is a well-established engineering material and lots of components are fabricated by either ingot metallurgy or powder metallurgy. From the viewpoints of material properties and process versatility, powder metallurgy has been widely applied in industries. Generally, stainless steel powders are prepared by atomization processes and powder characteristics, compaction ability, and sinterability are quite different according to the powder preparation process. In the present study, a nanoparticle dispersed micro-sphere powder is synthesized by pulse wire explosion of 316L stainless steel wire in order to facilitate compaction ability and sintering ability. Nanoparticles which are deposited on the surface of micro-powder are advantageous for a rigid die compaction while spherical micro-powder is not to be compacted. Additionally, double step sintering behavior is observed for the powder in the dilatometry of cylindrical compact body. Earlier shrinkage peak comes from the sintering of nanoparticle and later one results from the micro-powder sintering. Microstructure as well as phase composition of the sintered body is investigated.