In order to obtain the optimal electrode layout and ice melting effect of cast conductive asphalt concrete steel bridge deck pavement, firstly, pouring conductive asphalt concrete was prepared; secondly, different electrode materials and layout methods were selected to test the heating rate of the specimen from start to 120 min, and the electrode materials and layout methods were optimized. Then, the finite element analysis software ANSYS was used to build the model for heating and ice melting simulation, and the indoor test was used to further verify the ice melting effect of the cast conductive asphalt coagulation with or without the insulation layer. Finally, the thermal-structural coupling analysis of cast conductive asphalt concrete steel bridge deck pavement was carried out using ANSYS finite element software. The results showed that the stainless steel electrode material had the best heating effect, and the electrode thickness in the range of 0.1~3mm had no effect on the heating effect. The intermediate heating rate of the upper surface of the stainless steel sheet electrode cast conductive asphalt concrete in the left and right external electrodes was 8 °C/h, while the intermediate heating rate of the upper surface of the stainless steel mesh electrode cast conductive asphalt concrete was 12.9 °C/h. The layout of the left and right buried stainless steel metal mesh was able to effectively improve the snow melting efficiency; ANSYS finite element ice melting simulation was used to obtain the variation law of ice melting efficiency and a temperature field of cast conductive asphalt concrete. The indoor ice melting test showed that when melting the same thickness ice layer at 50 V voltage, it took 240 min with an insulation layer and 720 min without an insulation layer, which was three times that of the ice with an insulation layer, which further verifies the superiority of its ice melting effect. The most unfavorable load position of pavement under load and temperature field was determined. The maximum tensile stress and compressive stress of the pavement surface were transverse, and the maximum shear stress of the pavement bottom was transverse. The proportion of China’s land area in the cold region is large, and there is snow and ice in winter . GroutinAs a new type of snow-removal technology, pouring conductive asphalt concrete has the advantages of high de-icing efficiency, good compliance with the bridge deck, no water seepage and low energy consumption ,10,11,12In summary, at this stage, the research on cast conductive asphalt concrete steel bridge deck pavement is more comprehensive, and has achieved good results in practical application. The resistivity of conductive asphalt concrete and the ways to reduce the contact resistance have also made significant progress. However, the electrode materials used for conductive asphalt concrete are relatively simple, and the electrode layout is not comprehensive. In order to expand the snow-melting and ice-melting effect of cast-in-place conductive asphalt concrete steel bridge deck pavement, this paper first prepared cast-in-place conductive asphalt concrete, and then selected different electrode materials and layout methods. The best electrode materials and layout methods were selected by conducting an electric heating test of cast-in-place conductive asphalt concrete. On this basis, the finite element simulation of ice melting was carried out, and the ice melting research was carried out in the laboratory. Finally, the internal stress and strain of cast-in-place conductive asphalt concrete steel bridge deck under ice melting conditions were analyzed.The asphalt used in this paper is SBS modified asphalt from Zhengzhou Zhengfa Municipal Construction Co., Ltd. , which belongs to I-D modified asphalt. Its basic technical indicators and requirements are shown in The aggregate used for this paper is basalt rolling crushed stone, and the mineral powder is limestone powder. The amount is about 20–30%, or even higher, while the amount of asphalt is approximately 8–12%. The performance indexes of aggregate and mineral powder are shown in It has been found that carbon fiber length of 9 mm has a good dispersion effect; therefore this study selected flake graphite, and carbon fiber length of 9 mm. For graphite and carbon fiber technical indicators, see The electrode materials are mainly divided into metal materials and non-metal materials. The metal electrode is a metal material with a bare surface and strong conductive ability. Metal material has high strength, and the surface-treated metal has stronger corrosion resistance. Compared with non-metallic materials, a metal electrode is easier to prepare and lay out. Therefore, metal electrodes are selected for layout comparison.Commonly used metal electrode materials are copper, iron, stainless steel, zinc and aluminum. The material properties are shown in The comparison of electrodes requires the preparation of cast conductive asphalt concrete. The gradation selection of cast conductive asphalt mixture used in this paper is shown in The dosage of pouring conductive asphalt concrete is: SBS modified asphalt dosage 13.2%, Sasobit modifier 3% , graphite 40% , carbon fiber dosage 0.4% . The preparation process is shown in The electrode layout has a significant impact on the thermoelectric effect of conductive asphalt concrete. The electrodes are arranged in two ways: external and internal. The external are left and right external. The sheet electrode with an electrode size of 300 mm × 50 mm is selected. The internal is left and right internal. The L-shaped hole and no-hole and mesh electrodes are selected. The electrode arrangement scheme is shown in In order to reduce the influence of contact resistance, graphite is spread on the side of the specimen. The electrode plates are copper, aluminum, iron, stainless steel and zinc, and the sizes are 300 mm × 50 mm × 0.1 mm. The electrode plates are welded to the wire. After embedding the temperature sensor, the pouring conductive asphalt concrete with electrodes is wrapped with foam insulation material, and then the electric heating test is carried out. The temperature sensor is embedded as shown in It can be seen from For the left and right buried electrodes, the greater the coverage of the electrode in conductive asphalt concrete, the more conductive pathways, and the better the heating effect. The electrodes are divided into the following five electrode forms when the left and right electrodes are buried: (1) the electrode height is designed to be 25 mm, and the electrode width is designed to be 250 mm, in the form of straight and mesh electrodes. (2) The electrode sizes of L-type straight plate with and without holes are 25 mm in upper L height, 25 mm in lower L length and 250 mm in width. (3) The length and width of the full thickness electrode with holes is 300 mm length × 50 mm width. The number of holes is arranged according to the average electrode length, and the aperture is 13 mm.The layout process of the stainless steel straight electrode and the mesh electrode is to lay conductive asphalt concrete 15 mm at the bottom of the test die, then lay the electrode 20 mm away from the edge of the test die, and cast the electrode to 50 mm. The L-type electrode with holes and the L-type electrode without holes is first poured 15 mm conductive asphalt concrete at the bottom of the test die. The electrode is then laid on the pouring conductive asphalt concrete, and the conductive asphalt concrete is poured to 50 mm thicknesses. The full-thickness electrode plate with holes is first embedded in the test mold, and the conductive asphalt concrete is slowly poured to full thickness. The specimen molding is shown in The pouring conductive asphalt concrete specimen is wrapped with polyethylene foam, and the temperature sensor is placed in the low temperature box. The layout of the temperature sensor is shown in From The finite element calculation software ANSYS is used to verify the temperature rise test of the pouring conductive asphalt concrete, and the effect of the electrode layout optimization is further clarified. The finite element simulation of the melting ice and snow of the pouring conductive asphalt concrete is then carried out. In line with the indoor melting ice and snow test, the reliability of the finite element simulation of the melting ice effect of the pouring conductive asphalt concrete is verified, which reflects the effect of the electrode layout optimization scheme on the actual pavement melting ice.The latent heat is often taken into account in the phase change analysis of ice. The enthalpy of ice at various temperatures is shown in Under the condition of temperature change and electric conduction, the resistivity of electrodes and castable conductive asphalt concrete will change to some extent. Contact resistance will also be generated, due to the contact tightness between electrodes and wires and between electrodes and castable conductive asphalt concrete, which will bring a huge amount of calculation to the model processing. In order to simplify the model and reduce the amount of calculation, the following assumptions are made according to the actual situation: (1) various materials used in the model are homogeneous and continuous materials. (2) Without considering the contact resistance between the electrode and the pouring conductive asphalt concrete, the contact between the two solids is close. (3) Without considering the contact thermal resistance between the electrode and the pouring conductive asphalt concrete, the contact between the two solids is close. (4) Each physical parameter does not change with the change of temperature, which is a fixed value and does not consider the influence of low temperature box radiation. (5) The ice layer is homogeneous and isotropic material, and the melting process of the ice layer is reflected by temperature, without considering the evaporation in the melting process of the ice layer. (6) The steel plate material is isotropic and the bonding between the structural layers is good.2·K, and the convective heat transfer coefficient between the stainless steel and the air is 10 W/m2·K when natural convection occurs. The latent heat of the melting process of the ice block is reflected in the enthalpy change value, without considering radiation.The finite element thermal analysis environment temperature is set to −10 °C, and the pouring conductive asphalt concrete melting ice and snow model is shown in 2·K. When there is no insulation analysis, the insulation layer is removed, and the convective heat transfer is applied to the outer surface of the model, without considering the thickness of the adhesive layer. After the parameter has been applied, the analysis model is established, and the unit properties are assigned after each part is bonded. The model is divided and then meshed, as shown in In the finite element modeling with an insulation layer, because the bottom plate means that the insulation is good, the insulation adhesive layer and steel plate are omitted, and the conductive asphalt concrete layer and ice layer only are established. The convective heat transfer coefficient of ice and air is 34 W/mFirstly, the initial temperature of the model is set to −10 °C. Secondly, the convective heat transfer and voltage are applied. The convective heat transfer is applied to the outer surface of the model in the form of surface load. Depending on the different materials, different convective heat transfer coefficients are set up. The ambient temperature is −10 °C. Zero V is applied on the electrode side and a given voltage is applied on the side. The solution is set to transient analysis. The solution time is set to 8 h . Because the temperature rises slowly without an insulation layer, the solution time is set to 20 h  without an insulation layer. The temperature field distribution nephogram solved is shown in It can be seen from The composition of the environment and transportation in China is complex, and the overload phenomenon is serious, resulting in a large impact of temperature and load coupling. Therefore, it is necessary to study the internal force of the cast conductive asphalt concrete steel bridge deck pavement system under the coupling effect of snow melting temperature and vehicle load .3, the elastic modulus is 2.1 × 105 MPa, the Poisson’s ratio is 0.3, the linear expansion coefficient is 1.13 × 10−5, the density of CGA-10 is 2500 kg/m3, the elastic modulus is 300 MPa, the Poisson’s ratio is 0.3, and the linear expansion coefficient is 2.56 × 10−5. The composition of the orthotropic steel bridge deck model selected for analysis is: transverse plate width 4.8 m, transverse bridge with eight trapezoidal stiffeners, longitudinal four diaphragms, plate length 3.75 × 3 m = 11.25 m  steel. The density of 16Mnq steel is 7800 kg/m25 m see . The sizIt has been found that the most unfavorable load position in the longitudinal direction of the orthotropic steel bridge deck is mid-span. In order to obtain the most unfavorable load position in the transverse direction of the bridge under the combined action of temperature and vehicle, the load is transversely added to three special positions in the middle of the mid-span two diaphragms, and the three load positions are distributed as follows:Load position 1 applies vehicle load as a uniform load to the center of two adjacent stiffeners, load position 2 applies the load as a uniformly distributed load to a uniformly symmetrical positive above the edge of a stiffener as the center, load position 3 applies the load as a uniform load to the center of a stiffener, and the specific load position is shown in Select the thickness of 0.1 mm, 0.3 mm, 0.6 mm, 1 mm, 3 mm stainless steel electrode patch on the left and right sides of the pouring conductive asphalt concrete heating, and analyze the reasons, the specific heating situation as shown in It can be seen from The ice melting test was carried out on the gating conductive asphalt concrete slab connection power supplies with left- and right-embedded stainless steel metal mesh. The bottom and surrounding of asphalt concrete were wrapped with insulation materials, and the voids were sealed with sealing mortar. The temperature sensors were arranged according to the embedded electrode mode to detect the temperature rise and the starting time of ice melting. When the surface temperature of the gating conductive asphalt concrete was 0 °C, it marked the beginning of ice melting, and the end time of ice melting was observed by visual measurement. A 2 mm-thick ice layer formed on the surface of the asphalt concrete board, which was supported by a tray and placed in a low temperature test box. The temperature of the low temperature box was adjusted to −10 °C, and placed in the water, and the board at the same time froze into ice (12 h). A small opening was opened in the insulation film border to make the melted water flow into the tray. The electrode received a 50 V voltage. The test process is shown in In order to verify the snow melting effect of cast conductive asphalt concrete and explore the efficiency of snow melting, it is necessary to consider the temperature distribution of the whole upper surface. To this end, the upper surface temperature was determined by the average temperature of each point on the upper surface. The temperature difference of each point on the upper surface measured by the experiment was between 1 °C and 2 °C. The temperature rise of the upper surface of the cast conductive asphalt concrete slab during the ice melting process was measured as shown in It can be seen from The ice melting test of castable conductive asphalt concrete without an insulation layer placed the castable conductive asphalt concrete slab with temperature sensors directly on the tray and in a low-temperature test box. The ice block was formed by 165.6 g of water, broken into ice flakes and evenly distributed on the upper surface of the test block. The temperature of the low-temperature box was set to −10 °C. After 12 h of storage, the slightly melted water was consolidated with the test block again, and the temperature of the whole system reached −10 °C. The test process is shown in The average surface temperature and lowest temperature of the cast conductive asphalt concrete during the test was recorded as shown in It can be seen from 2. In order to more intuitively represent the safety of voltage input, the converted voltage is 50V to 80 V, and the de-icing time under different voltages and different ice thicknesses is obtained, as shown in The initial temperature of the ice layer was −10 °C. When the surface temperature of the ice layer reached 0 °C, it was considered that the ice melting had ended. Therefore, the temperature of the nodes on the surface of the ice layer picked up, and the time when the temperature reached 0°C was the melting-ice end time. The recommended reasonable input power within the reasonable de-icing time is 400–1000 W/mIt can be seen from Compared with the indoor test, the melting time of the finite element simulation was shorter than that of the actual, but the difference was not large. The reason is that the actual ice layer was not evenly heated, the melted water was not discharged in time, and the evaporated water took away part of the heat. The uneven heating of the ice layer made the ice-layer floor void, the heat transfer was slow, and the melting time was prolonged. The combination of indoor test and finite element simulation further verified the effectiveness of cast conductive asphalt concrete ice melting and the reliability of finite element simulation.By comparing the melting ice of cast conductive asphalt concrete with or without a heat insulation layer, it can be concluded that the melting time of small plate without a heat insulation layer is much slower than that with a heat insulation layer. In the case of no heat insulation, the ice in the middle of the upper surface melts first, and the water flow diffuses outward, which makes the surrounding ice melt slowly, but the duration is relatively long, which is quite different from that with heat insulation. When melting the same thickness of ice and snow, it only takes 240 min with a heat insulation layer, while it takes 720 min without a heat insulation layer, which is 3 times that with heat insulation. Because the ice chips were used in the test without a heat insulation layer, the time required for melting ice and snow without the heat insulation layer may be longer. Therefore, the pavement structure with the thermal insulation layer is more conducive to snow removal and ice removal.Since the bottom of the pavement layer is steel plate, once the pavement layer cracks, it will affect the performance of the bridge deck. Rainwater infiltration in the thin part of the adhesive layer will rust the steel bridge deck, affecting its service life and strength. Therefore, it is necessary to analyze the tensile stress and strain of the pavement surface to take effective preventive measures.ANSYS finite element analysis software was used to calculate the longitudinal and transverse stresses on the surface of the pavement layer of the steel bridge under the action of temperature and single wheel uniform load. The calculation results are shown in Under the condition of constant elastic modulus, the transverse maximum tensile stress and compressive stress on the surface of steel bridge deck pavement without a temperature field were much larger than the longitudinal maximum tensile stress and compressive stress. Because the pavement was a three-dimensional space body, the maximum principal stress was not easy to determine, so the transverse tensile stress can be used as an index of pavement design.The maximum tensile stress of the pavement surface under different loading positions were for loading position 1, loading position 2, and loading position 3, 0.3588 MPa, 0.3599 MPa, and 0.4130 MPa, respectively. When the temperature field was applied, the difference of longitudinal and transverse stress values on the surface of the pavement layer decreased, but the transverse tensile and compressive stress values were still greater than the longitudinal tensile and compressive stress values. The maximum tensile stress on the surface of the pavement layer was 0.4511 MPa, 0.4554 MPa and 0.4783 MPa at loading position 1, 2 and 3, respectively, which increased by 25.7%, 26.5% and 15.8%, respectively. Therefore, it can be seen that the temperature field increases the surface tensile stress of the pavement layer. The transverse tensile stress under the action of load position 3 was still the largest, and load position 3 can be used as the most unfavorable transverse load position.The location of the maximum tensile stress in the transverse direction of the pavement surface was 2.4 m, 2.4 m and 2.64 m in the transverse direction of the bridge deck according to the position sequence of the load position. The temperature field had no effect on the location of the maximum tensile stress, but the effect of the temperature field made the maximum compressive stress of the pavement surface smaller.The results shown in Using ANSYS finite element analysis software, the longitudinal and transverse strains on the surface of the pavement layer in the middle span of the steel bridge under the action of temperature and single wheel uniform load were calculated. The calculation results are shown in From the results shown in Sliding between the anti-rust adhesive layer and the bottom layer of the asphalt mixture will make the pavement layer and the bridge deck slide. Therefore, it is necessary to select an adhesive layer with good adhesion, to prevent shear failure between layers. Therefore, the shear stress at the bottom of the pavement layer is an important indicator in controlling shear failure.Using ANSYS finite element analysis software, the longitudinal and transverse shear stress between the bottom of the steel bridge mid-span pavement layer and the steel plate, under the action of temperature and single wheel uniform load was calculated. The calculation results are shown in From the results shown in Using ANSYS finite element analysis software, the longitudinal and transverse shear strains between the bottom surface of the pavement layer and the steel plate in the middle span of the steel bridge under the action of temperature and single wheel uniform load were calculated. The calculation results are shown in It can be seen from the results shown in The stainless steel sheet electrode material used in pouring conductive asphalt concrete has an excellent heating rate, convenient construction, low cost, high safety, and can maintain its stable conductivity during snow melting and ice melting.The electrode layout scheme of pouring asphalt concrete based on melting snow was analyzed. The effects of different electrode layout schemes and electrode thickness on heating rate and snow removal were compared and evaluated. Finally, it was concluded that the buried stainless steel metal mesh was the optimal electrode layout.In the process of finite element simulation of the influence of different voltage inputs on the ice melting thickness, the larger the voltage input, the shorter the ice melting time. With the increase in voltage, the difference in large ice melting time becomes smaller, and the pavement structure with a thermal insulation layer can improve the ice melting efficiency more effectively. The snow melting and deicing time difference between the simulation and the indoor test was short, and the finite element simulation results are credible.The most unfavorable load position of pouring conductive asphalt concrete steel bridge deck pavement under single wheel load and temperature field is mid-span load position 3, and the maximum tensile stress and maximum compressive stress on the pavement surface are transverse. Through comparative analysis, it was found that the maximum transverse stress of the pavement surface increases slightly when the temperature field exists, and the unfavorable loading position remains unchanged. The temperature field has little effect on the low shear stress and shear strain of the pavement.


Background and Objectives: In the literature, spinal navigation and robot-assisted surgery improved screw placement accuracy, but the majority of studies only qualitatively report on screw positioning within the vertebra. We sought to evaluate screw placement accuracy in relation to a preoperative trajectory plan by three-dimensional quantification to elucidate technical benefits of navigation for lumbar pedicle screws. Materials and Methods: In 27 CT-navigated instrumentations for degenerative disease, a dedicated intraoperative 3D-trajectory plan was created for all screws. Final screw positions were defined on postoperative CT. Trajectory plans and final screw positions were co-registered and quantitatively compared computing minimal absolute differences (MAD) of screw head and tip points (mm) and screw axis (degree) in 3D-space, respectively. Differences were evaluated with consideration of the navigation target registration error. Clinical acceptability of screws was evaluated using the Gertzbein–Robbins (GR) classification. Results: Data included 140 screws covering levels L1-S1. While screw placement was clinically acceptable in all cases (GR grade A and B in 112 (80%) and 28 (20%) cases, respectively), implanted screws showed considerable deviation compared to the trajectory plan: Mean axis deviation was 6.3° ± 3.6°, screw head and tip points showed mean MAD of 5.2 ± 2.4 mm and 5.5 ± 2.7 mm, respectively. Deviations significantly exceeded the mean navigation registration error of 0.87 ± 0.22 mm (p < 0.001). Conclusions: Screw placement was clinically acceptable in all screws after navigated placement but nevertheless, considerable deviation in implanted screws was noted compared to the initial trajectory plan. Our data provides a 3D-quantitative benchmark for screw accuracy achievable by CT-navigation in routine spine surgery and suggests a framework for objective comparison of screw outcome after navigated or robot-assisted procedures. Factors contributing to screw deviations should be considered to assure optimal surgical results when applying navigation for spinal instrumentation. Spinal pedicle screw fixation is a surgical technique widely used for treatment of a large range of pathologies  . BecauseA number of prospective as well as retrospective works were published to demonstrate the accuracy of navigated or robotic screw placement. In the literature, screw accuracy has predominantly been evaluated according to the screw position within the vertebra on postoperative CT as noted in a meta-analysis performed by Aoude et al. . SeveralThe literature abounds on comparisons of navigated or robotic screw placement to free-hand placement under fluoroscopy but only a few studies focused on direct evaluation of screw results after robotic-assisted or navigated placement with regard to screw trajectory plans ,11,12,13While GR grade and other 2-dimensional assessments were sufficient to show how the used guidance technology helped to improve surgical results in comparison to free-hand techniques, the specific 3-dimensional evaluation of how reliable a trajectory plan can be transferred to the surgical site is required for accurate comparison of navigated and robotic results in order to fully elucidate the technical benefits of these technologies in spine surgery.In this study, we compared final screw positions of CT-navigated lumbar and sacral pedicle screws with corresponding intraoperative screw trajectory plans and performed 3D-quantitative assessment of placement accuracy to address this issue for navigated spinal instrumentations.n = 1660), we randomly selected n = 30 cases with lumbosacral surgery performed by a single surgeon for this analysis. All cases in this study had intraoperative CT (NavCT) for navigated screw insertion as well as postoperative CT (ControlCT) to validate screw positions.We performed a retrospective evaluation of prospectively collected data. From a consecutive institutional registry of CT-navigated spinal instrumentations with dedicated screw planning performed at the authors’ institution between January 2010 and December 2018 . ®, Depuy Synthes Company, Raynham, MA, USA; XIA®, Stryker Corporation, Kalamazoo, MI, USA) were used, adapting length and diameter to the patient’s individual anatomy. All navigation procedures were performed based on intraoperative CT  covering the desired spinal levels. Patient registration was performed using “point-to-point navigation” as described previously ..14].Eventually, one has to be aware of the risk for the aforementioned technical errors to conjoin during the procedure, leading to an amplification of initially small deviations to yield a larger final amount .As we illustrated by our GR evaluation, screw outcome was clinically acceptable in all implanted screws. This satisfactory result puts the specific clinical relevance of our quantitative analysis into question. There are multiple approaches to elucidate “minimal clinically important differences” (MCID) in spine surgery, which essentially discusses the impact of measured statistical differences on the health of a patient . RegardiBy 3D-quantitative analysis we were also able to demonstrate possible differences in accuracy to robotic procedures, which has not been done previously. While our screws were placed within 5 mm of the planned position with a mean deflection of 6°, Jiang et al. reported greater accuracy by robotic implantation with 4 mm and 4° overall deviation, respectively .While this difference will unlikely have a current impact with regard to MCID, future aspects of spinal instrumentation have to be considered to perceive the potential significance: computer assisted screw planning with subsequent guided instrumentation has the potential to improve screw stability and to reduce screw-associated complications by optimization of screw positioning under consideration of local bone quality, corresponding fastening strength and other anatomical constraints ,36,37. TAn aspect of clinical relevance in navigated surgery were significantly greater screw variances at the sacral compared to all lumbar levels . While eThe monocentric and retrospective nature of our study entails a potential for selection bias limiting the generalizability of our results. Our approach of random sampling of cases from a consecutive cohort reflects our efforts to identify a representative sample of routine surgical cases in an academic spine center. The limitation to a single surgeon was chosen since a focused adherence to planned screw paths during surgery was required for evaluation of navigated screw accuracy. This prerequisite was provided given the surgeon’s individual technique for instrumentation and adherence to planned screw trajectories was checked in surgery reports, additionally.n = 140 screw positions covering spinal levels L1-S1 from an institution with extensive experience in CT-based spinal navigation. While lumbar pedicles usually are of round diameter and are aligned with the superior endplates, thoracic pedicle anatomy can be significantly narrower and with steep inclination angles, which has possible implications for screw placement and accuracy in a planned vs. actual comparison. Moreover, the impact of severe spinal pathology e.g., high-grade spondylolisthesis or spinal deformities was not specifically evaluated in our study. Hence, reported accuracy cannot generally be transferred to the thoracic spine or to other spinal pathologies treated.Since all screws were planned by a single surgeon, our findings can only carefully be generalized to other surgeons and setups. Even though the planned vs. actual comparison performed in our study should apply similarly for other surgeons, the influence of individual preferences for screw placement, alternative screw trajectories  and the influence of different navigation systems on accuracy has not been investigated in our study. Our series overlooks n = 3) were excluded from the analysis due to shifts affecting the cranially located vertebrae.The accuracy of the co-registration of intraoperative navCT with postoperative controlCT impacted on the quality of our quantitative measurements. Problems with rigid co-registration can originate from spinal alignment changes and segmental shifts induced during the respective procedures. In order to minimize this bias, appropriate co-registration was visually verified by two independent spinal surgeons blinded to trajectory plans. Cases with non-satisfactory co-registrations (There is a potential for measurement bias when screw positions or angular deviations are compared by manual measurements, as it was described by several studies performing quantitative comparisons ,7,12,14.Screw placement was clinically acceptable in all screws evaluated in this analysis but nevertheless, considerable deviation in implanted screws was noted compared to the initial trajectory plan. Our data provides a 3D-quantitative benchmark for screw accuracy achievable by CT-navigation in routine spine surgery and suggests a framework for future objective comparison of screw outcome after navigated and robot-assisted procedures. Factors contributing to screw deviations should be considered to assure optimal surgical results when applying navigation for spinal instrumentation.


Morus alba) as an antidiabetic herb in China, and we found that chalcomoracin, one of the specific Diels–Alder adducts in mulberry leaf, had prominent α-glucosidase inhibitory activity and has the potential to be a substitute for current hypoglycemic drugs such as acarbose, which have severe gastrointestinal side effects. In this study, chalcomoracin was effectively isolated from mulberry leaves, and its α-glucosidase inhibition was studied via enzymatic kinetics, isothermal titration (ITC) and molecular docking. The results showed that chalcomoracin inhibited α-glucosidase through both competitive and non-competitive manners, and its inhibitory activity was stronger than that of 1-doxymycin (1-DNJ) but slightly weaker than that of acarbose. ITC analysis revealed that the combination of chalcomoracin and α-glucosidase was an entropy-driven spontaneous reaction, and the molecular docking results also verified this conclusion. During the binding process, chalcomoracin went into the “pocket” of α-glucosidase via hydrophobic interactions, and it is linked with residues Val544, Asp95, Ala93, Gly119, Arg275 and Pro287 by hydrogen bonds. This study provided a potential compound for the prevention and treatment of diabetes and a theoretical basis for the discovery of novel candidates for α-glycosidase inhibitors.Diabetes is a chronic metabolic disease, whereas α-glucosidases are key enzymes involved in the metabolism of starch and glycogen. There is a long history of the use of mulberry leaf (the leaf of  Diabetes mellitus is a chronic and metabolic disease. Every year, about 834,000 people in China die from various complications triggered by diabetes ,2, such Morus alba, which is widely cultivated from the south to north in China. As we know, mulberry is one of the most commonly used TCMs listed in the Chinese Pharmacopoeia, which has been proved to have satisfactory antidiabetic effects since as early as in the 11th century in China, as recorded in the Compendium of Materia Medica. At present, mulberry leaf tea has been developed in various forms as a functional food in the prevention and treatment of diabetes in China  denotes the concentration of substrate and PNPG  and chalcomoracin  solutions of different concentrations were prepared, as well as the α-glucosidase solution (0.2 U/mL). The reaction rate was determined by plotting the enzymatic reaction rate (1/V) against the reciprocal (1/(S)) of PNPG concentration to obtain a Lineweaver–Burk double reciprocal plot to judge the type of inhibition. The relevant parameters were obtained through the following form :1V=KmVmaThe thermodynamic changes during the binding process of chalcomoracin and α-glucosidase were determined using ITC. Firstly, all the solutions of chalcomoracin and α-glucosidase were treated with ultrasonic degassing to meet the high sensitivity of ITC. Tris–HCl buffer solution (pH 7.4) was used for both the sample cell and reference cell, and the pH difference between the cells should be less than 0.1 . Then, 1Molecular docking analysis was carried out to predict the binding sites between chalcomoracin and α-glucosidase molecules using the MOE 2014.09 (Molecular Operating Environment) software, which helped to further study the inhibition mechanism. MOE is a drug discovery software platform that integrates visualization, modeling and simulations, as well as methodology development, in one package. MOE scientific applications are used by biologists, medicinal chemists and computational chemists in pharmaceutical, biotechnology and academic research. The operation is as follows: download the crystal structure file of α-glucosidase with Protein Data Bank (PDB) ID of 5 kzw from the RCSB PDB database; use the MOE 2014 software to delete all solvents, ligands, etc., except for the protein; and then use the “Loop Modeler” module of the software to refer to the complete protein sequence. Complete missing fragments of proteins in crystal structure files and check for other structural errors. Then, use the Schrödinger 2018.4  to search for the binding pocket on the processed protein and dock the small molecule into it, both of which obtain the best results recommended by the software by default. Finally, use the PyMol software  to draw the molecular binding mode map obtained by docking.In this study, a Diels–Alder addition compound in mulberry leaves, chalcomoracin, was extracted and purified using a simple and efficient manner. It was proved that chalcomoracin had a good inhibitory effect on α-glucosidase. The inhibitory mode of chalcomoracin was studied via enzymatic kinetics from the point of molecular reaction, ITC from the point of thermodynamics and molecular docking from the point of computer simulation. Based on the above studies, it was proved that chalcomoracin in mulberry leaves was expected to be developed into a α-glucosidase-targeted drug for lowering postprandial blood glucose and health food for the treatment and prevention of diabetes. However, the presented work only involved in vitro studies; further in vivo research on the hypoglycemic activity and mechanism study is expected.


In this study, we analyze how these F1FO-ATPase inhibitory proteins have evolved. The phylogeny of the α-proteobacterial ε showed that it diverged in its C-terminal side, thus losing both the inhibitory function and the ATP-binding/sensor motif that controls this inhibition. The losses of inhibitory function and the ATP-binding site correlate with an evolutionary divergence of non-inhibitory α-proteobacterial ε and mitochondrial δ subunits from inhibitory bacterial and chloroplastidic ε subunits. Here, we confirm the lack of inhibitory function of wild-type and C-terminal truncated ε subunits of P. denitrificans. Taken together, the data show that ζ evolved to replace ε as the primary inhibitor of the F1FO-ATPase of free-living α-proteobacteria. However, the ζ inhibitory function was also partially lost in some symbiotic α-proteobacteria and totally lost in some strictly parasitic α-proteobacteria such as the Rickettsiales order. Finally, we found that ζ and IF1 likely evolved independently via convergent evolution before and after the endosymbiotic origin mitochondria, respectively. This led us to propose the ε and ζ subunits as tracer genes of the pre-endosymbiont that evolved into the actual mitochondria.The F It can synthesize or hydrolyze MgATP according to the kinetic and thermodynamic conditions in the energy-transducing membranes of bacteria, mitochondria, and chloroplasts . Th. Th1 is  F1s see . Howeverirection ,42,44,501 with FO at the central rotor. Because of this key structural function, its β-barrel connecting F1 and FO sectors is strictly preserved. On the other hand, the C-terminal domain of bacterial ε, is partially inhibitory in some bacterial F1-ATPases such as those of E. coli, Bacillus PS3, and so on. However, it is highly variable and therefore non-inhibitory in α-proteobacteria such as P. denitrificans. Taking into account the functional, structural, and now phylogenetic evidence, the available data show that ε is a structural but non-inhibitory subunit in α-proteobacteria as it is its homologous δ subunit in mitochondria. This non-inhibitory but structural role of ε was likely transferred from α-proteobacteria to mitochondria during mitochondrial endosymbiosis. Later, the previous α-proteobacterial ε evolved, thus becoming the actual structural δ subunit of the central rotor of the mitochondrial F-ATP synthase. The ε subunit is an essential structural subunit of the F-ATP synthase encoded as such in the ATP operon, connecting F1 and FO sectors, consistent with the supernumerary and regulatory role of this subunit. Its intrinsically disordered N-terminal side (IDPr) is strictly preserved, whereas its C-terminal α-helical side is much more variable. In contrast to ε, the preserved ζ N-terminus harbors the functional inhibitory domain. On the contrary, in the inhibitory ε subunits, the C-terminal side holds the inhibitory segment. This explains the high conservation of the N-terminal sides of ζ and ε and the highly variable C-termini of both subunits. The primary function of ζ is inhibitory, so the non-inhibitory C-terminal side varies significantly across the α-proteobacterial class. These variations are surely coupled to the changes in the different β and α subunits of F1, where the C terminus of ζ forms an anchoring domain interacting with α and β of the F1 portion of the α-proteobacterial F-ATP synthases [In α-proteobacteria, the ζ subunit is essentially an exclusive ORF of this class, and the αPATPsζ gene is located outside both of the ATP operons of α-proteobacterial Fynthases ,42,44. 1 or not, the low identity and similarity between these proteins, the lack of ζ in eukaryotes, and the absence of IF1 in procaryotes, particularly in α-proteobacteria, strongly suggest that ζ and IF1  evolved separately by convergent evolution into the actual inhibitory proteins that prevent wasteful F1FO-ATPase in α-proteobacteria, mitochondria, and non-α-proteobacteria, respectively. Since the ζ subunit does not seem to be a predecessor of mitochondrial IF1 and as ζ is absent in strictly parasitic α-proteobacteria that could be closer to the mitochondrial pre-endosymbionts, we propose that the ζ and ε subunits of the α-proteobacterial F-ATP synthase might be considered from now on as evolutionary tracers to look for the candidates to be closer to the pre-endosymbiont selected by nature to evolve among the α-proteobacteria to become the actual mitochondria. Those α-proteobacteria lacking ζ might be the ones that are more likely to be closer to the mitochondrial pre-endosymbiont, invoked by Lynn Margulis and others [1FO-ATPase of α-proteobacteria, which eventually became the non-inhibitory mitochondrial δ subunit. Later, when the mitochondrial endosymbiosis was established, the mitochondrial F1FO-ATP synthases acquired more supernumerary subunits that induce the dimerization and oligomerization of the mtATP synthase which give its shape to the mitochondrial cristae. These mtATP synthase dimers and oligomers are, by the way, also stabilized by the mitochondrial inhibitor protein (IF1) [1, which was acquired with two main functions: to prevent wasteful mitochondrial F1FO-ATPase activity through its inhibitory N-terminal domain and to stabilize the F-ATP synthase dimers and oligomers by its own dimerization of the C-terminus. This IF1 and other F-ATP synthases dimerizing and oligomerizing proteins give their curved shape to the mitochondrial cristae, and so the inner mitochondrial membrane surface available to produce enough ATP is increased to fulfill the large bioenergetic demands of the expensive eukaryotic lifestyle.Although we still may have to show more clearly whether ζ is the evolutionary predecessor of IFd others ,13,75,76in (IF1) ,108. The


Self‐injectable therapy has several advantages in the treatment of metabolic disorders. However, frequent injections with needles impair patient compliance and medication adherence. Therefore, we develop a fully implantable device capable of on‐demand administration of self‐injection drugs via noninvasive manual button clicks on the outer skin. The device is designed to infuse the drug only at the moment of click actuation, which allows for an accurate and reproducible drug infusion, and also prevents unwanted drug leakage. Using a mechanical means of drug infusion, this implantable device does not contain any electronic compartments or batteries, making it compact, and semi‐permanent. When tested in animals, the device can achieve subcutaneous injection‐like pharmacokinetic and pharmacodynamic effects for self‐injection drugs such as exenatide, insulin, and glucagon. With one‐time implantation, the device inside the body can administer an accurate dose of drugs on‐demand and, more importantly, without needles.To address these problems, we developed an implantable drug delivery device actuated via mechanical means. Taking into account ease of use, we developed a fully implantable button click device (BCD) in this study, which contains a button to be manually clicked on the outer skin for device actuation for the administration of a bolus of a drug. The BCD described here is rod‐shaped for easy implantation. The button in the BCD is located at one end of the rod‐shaped body, and the body is small enough to be gripped with the fingers. Therefore, the button can be found through the skin over the implanted BCD, and can be pressed with the fingers, noninvasively. The click actuation is created when the button is pressed to a certain level, which generates a constant pushing force. Thus, at the time of clicking, a specific amount of a drug can be accurately infused, and the drug dose can easily be controlled by varying the number of button clicks. The BCD is also equipped with a drug container and refill port. The refill port can be found and accessed from outside the body after implantation, thereby allowing multiple drug replenishments and semi‐permanent use without device replacement surgery.We evaluated a fully implantable BCD for noninvasive delivery of a self‐injection drug. We used exenatide, a short‐acting glucagon‐like peptide‐1 (GLP‐1) receptor agonist, which is prescribed for diabetic patients, to be self‐injected once or twice per day.22.1Veroclear and SUP706 were purchased from Stratasys (Rehovot) as 3D‐printing and supporting materials, respectively. The stainless‐steel springs were purchased from Tohatsu. Polyurethane films, 100 μm in thickness, and Teflon molds, were obtained from CY International and 3DMD, respectively. Rubber piston stoppers were obtained by disassembly from a 0.3 ml BD ultra‐fine insulin syringe. Medical epoxy (Epo‐tek 301) was purchased from Epoxy Technology. Phosphate‐buffered saline (PBS) and formalin were obtained from Thermo Fisher Scientific. The check valves were purchased from Minivalve. Trifluoracetic acid (TFA) was purchased from Sigma‐Aldrich. Exenatide (MW = 4187 Da) was purchased from Cosmogenetech. Both insulin and glucagon were obtained from NovoNordisk.2.2The constituent units of the BCD were created by 3D CAD using Autodesk Fusion 360 (Autodesk), and then fabricated with a 3D printer . The printed units were assembled using medical epoxy, as depicted in Figure 2.3n = 3) were each filled with 0.92 ml of an exenatide solution (5 mg ml−1), and clicked while being fully immersed in 30 ml of pH 7.4 PBS at 37°C. The exenatide concentration in the medium was measured using high‐performance liquid chromatography , using a C18 column  at 25°C. The mobile phase of acetonitrile and water (containing 0.1% TFA) was delivered at a flow rate of 1 ml min−1 with a linear gradient elution, in which the acetonitrile content was 20% for the first 2 min and gradually increased to 80% until 6 min. The injection volume and UV absorbance were set at 10 μl and 215 nm, respectively.To test the performance of the BCD in vitro, the BCDs  and male Zucker Diabetic Fatty  rats. The animals were housed in a pathogen‐free facility with controlled temperature, humidity, and 12:12 h light/dark cycle. The Wistar rats were provided with standard chow and water ad libitum. The ZDF rats were fed with Purina #5008  chow and water ad libitum. To implant the BCD, an animal was anesthetized via isoflurane inhalation, and the dorsal area was shaved and sterilized with betadine. A 3‐mm incision was made, and the BCD was implanted into the subcutaneous pocket. The wound was closed with a surgical suture and disinfected with betadine. All animal experimental procedures were approved by the Institutional Animal Care and Use Committee at Seoul National University Hospital Biomedical Research Institute .2.5g for 10 min to collect the plasma, which was then stored at −20°C until measurement. The exenatide concentration in blood plasma was measured using an exenatide enzyme immunoassay (EIA) Kit (Merck Millipore).For the pharmacokinetic (PK) tests, the Wistar rats were divided into two groups: (1) animals treated with subcutaneous injections of exenatide (Inj‐Ex), and (2) animals implanted with the exenatide‐loaded BCD (BCD‐Ex), to which 50 μg of exenatide was administered via subcutaneous injection or button click, respectively. At 0, 15, 30, 60, 120, and 180 min after administration, 200 μl of blood was drawn from the tail vein. The blood sample was centrifuged at 30002.6−1 paracetamol solution was administered orally. Blood was collected 0, 30, 60, 120, and 180 min after administration, and the blood plasma was obtained by centrifugation at 3000g for 10 min. Then, 10 μl of collected plasma was mixed with 90 μl of methanol, and 50 μl of the supernatant was transferred and evaporated in a SpeedVac (Thermo Fisher Scientific) under vacuum. The residue was dissolved in a mixture of DI water and acetonitrile , which was measured by HPLC mass spectrometry (LCMS)  with a C18 column . A mobile phase composed of DI water adjusted to pH 2.5 and acetonitrile  was fed at a continuous flow rate of 0.5 ml min−1, and the detection wavelength was set at 207 nm. Mass spectrometric detection (Agilent 6120 Quadrupole LCMS system) was performed with an Ion Spray source set at 350°C and 4000 V. Electrospray ionization in positive ion mode was employed, and quantification was performed by selected‐reaction monitoring transition (152 ➝ 153).We used the ZDF rats to compare the gastric emptying rate after 28 days of treatment in four different groups: (1) animals treated with subcutaneous injections of PBS without exenatide ; (2) animals implanted and clicked with PBS‐loaded BCD without exenatide ; (3) animals treated with subcutaneous injections of exenatide , and (4) animals implanted with the exenatide‐loaded BCD . For all animals, 10 μl of 5 mg ml−1 exenatide solution or PBS was administered twice per day for 28 days. Each animal was fasted overnight and then a 50 mg kg2.7−1) was administered by oral gavage. At scheduled times after administration, blood was collected, and blood plasma was obtained by centrifugation at 3000g for 10 min. The plasma glucose level was measured with a glucometer (Accu‐chek Performa). The plasma insulin level was measured with an insulin ELISA Kit (Merck Millipore).For the oral glucose tolerance tests, we used the ZDF rats after 28 days of treatment in four different groups: Inj‐Ex, Inj‐PBS, BCD‐Ex, and BCD‐PBS. The animal was fasted overnight and a glucose solution (1 g kg2.8−1) prepared in 0.09 M citrate buffered saline (pH 4.0) to destroy the beta‐cells of the pancreas. Three days after the STZ injection, the plasma glucose level was measured with a glucometer, and the animals with a plasma glucose level > 400 mg dl−1 were screened for use. Among them, we employed two distinct animal models of hyperglycemia and hypoglycemia, respectively. For a hyperglycemic condition, the animals were used as they were with a blood glucose level of >400 mg dl−1.−1 were screened for use.n = 4) and BCD‐Insulin (n = 4), respectively. For this, we utilized a commercially available insulin solution . The hypoglycemic animals were treated with 100‐μg glucagon by SC injections or an implanted BCD: Inj‐Glucagon (n = 4) and BCD‐Glucagon (n = 4), respectively. To prepare a glucagon solution (1 mg ml−1), glucagon powder  was dissolved in sterile DI water. After administration, the plasma glucose level was measured with a glucometer at scheduled times.For this experiment, we employed a Type 1 diabetic animal model, streptozotocin (STZ)‐induced diabetic rats.2.9To examine the implant safety, the animals in the BCD‐Ex group were sacrificed by carbon dioxide inhalation, and the tissue was harvested from four different locations around the BCD: adjacent to the button, outlet, refill port, and wall Figure . The tis2.10To examine the efficacy of the exenatide, the epididymal fat pads were biopsied at the end of the experiments. The tissue was fixed in 10% formalin and embedded in paraffin, which was sectioned into 4‐μm‐thick slices. Slices of adipose tissue were mounted on glass slides and stained with H&E.2.11t tests were used. Differences were considered to be statistically significant when p < 0.05.The data were presented as means ± SD. Statistical analysis was performed using GraphPad Prism 7 (GraphPad Software). The differences among the groups were tested using one‐way analysis of variance (ANOVA) or two‐way ANOVA followed by Tukey's honestly significant difference post hoc test for multiple comparisons. To compare the means of two groups, Student's 33.1The BCD was designed to deliver a specific amount of drug only when the button in the implanted BCD is pressed by fingers through the skin. Therefore, as depicted in Figure As shown in Figure 3.2The working principle of the BCD described here is based on click actuation, as shown in Figure −2) and the pain threshold (32.1 ± 15.3 N cm−2).The click actuation of the BCD is a response to a sudden, rapid downward movement of the piston when the piston spring is decompressed, with the lug freed from the notch end. This response occurs only above the predetermined button pressing depth, and at this depth, the piston spring is compressed to the same extent. Therefore, for every click actuation, the piston spring is decompressed to deliver the same pushing force to the barrel, thereby producing an accurate, reproducible amount of drug infusion Movie . This re3.3To test the performance of the BCD, we filled the drug container with a solution of a self‐injection drug, exenatide,3.4n = 3), BCD‐PBS (n = 3), Inj‐Ex (n = 4), and BCD‐Ex (n = 4). For the Inj‐Ex and BCD‐Ex, the same dose of exenatide (50 μg) was administered twice per day for 28 days. Clicking the button of the BCD implanted under the skin did not appear to cause significant pain or discomfort to the animals during the testing period  and time to reach Cmax (Tmax) for both groups. Thus, the areas under the plasma drug concentration‐time curve (AUC) were also similar, at 3170 ± 162.9 ng ml−1 min for the Inj‐Ex and 3414 ± 193.2 ng ml−1 min for the BCD‐Ex. When the BCD was clicked after replenishment with a fresh exenatide solution while still implanted  and BCD‐Insulin (n = 4). For hyperglycemia, glucagon was delivered by subcutaneous injections or BCD button clicks, respectively: Inj‐Glucagon (n = 4) and BCD‐Glucagon (n = 4).The fully implantable BCD described here is designed to deliver drugs on‐demand, using noninvasive button clicks over the skin. In this aspect, the BCD can be also used for delivery of other self‐injection drugs, such as insulin or glucagon. In general, prandial insulin is injected two or three times daily before each meal,In the Type 1 diabetic model, we assessed the changes in plasma glucose levels. When hyperglycemic, animals administered insulin showed a decrease in plasma glucose level Figure . An incr3.6To assess the biocompatibility of the device, we performed a histological analysis of the tissues surrounding the implanted BCD, with the tissues biopsied at the end of in vivo experiments (the BCD‐Ex). The tissues adjacent to the button, outlet, refill port, and wall of the BCD were prepared separately, stained with H&E, and assessed by a professional pathologist (C. L.) Figure . In all 4Recent developments in self‐injectable therapies have transformed our ability to effectively treat widespread metabolic disorders.An implantable drug delivery device has been suggested as a promising alternative to frequent injections.To allow an accurate amount of drug infusion, we used click actuation, rather than simple squeezing, for infusion. During button press and release, the lug in the piston is guided in a designated path and controlled distance set in the notch, so the pressure change in the barrel can be accurate and reproducible Figures . This feClick actuation also adds safety features to the BCD. Once clicked, the button must be released completely to fill the barrel and pressed again to provide a dose of the drug. Thus, even when the button is fully pressed and maintained, an unwanted overdose, or continuous leak of drug is prevented. The notch is vertically‐bent to form the notch end, where the lug can be locked to fix the piston in position when the button is not pressed Figure . BecauseWe found that the BCD could deliver an accurate amount of a drug, such as exenatide, insulin, or glucagon, which was as effective as conventional injections in an animal model of metabolic disease Figures , 4, 5. A2  and a length of about 8 cm. This would increase the length of the drug container up to 5 cm, while the actuator could remain around 3 cm, as in the prototype in this study, because the BCD can be operated with simple button clicks without complex control units and batteries, hence a small fixed volume of the actuator. Therefore, this entire dimension could still be much smaller than the clinically approved implantable pump (diameter = ca. 8 cm and thickness = ca. 2 cm).For clinical application, several improvements to the prototype of the BCD should be made. To be accepted by the patients, the body of the BCD may need to be round and cylindrical in shape, to minimize the sensation of a foreign body. The BCD needs to be compact while still containing enough drug solution that replenishment is only infrequently needed. A clinically approved implantable insulin pump that recommends replenishment every 3 months contains about 13–15 ml of the drug in the reservoir.hormone, peripheral vasodilators, anabolic hormones, etc.For better patient convenience, the use of a mobile app can be envisioned to notify the time for replenishment,5In summary, we have developed a semi‐permanent, fully implantable BCD capable of on‐demand bolus drug administration with easy manual button clicks, to replace needled self‐injection therapies. After a single implantation, the BCD can infuse a precise amount of a drug only when clicked with the fingers, noninvasively, from outside the body. Our in vivo experimental results indicated that use of the BCD produced pharmacokinetic profiles and the PD effects equivalent to those produced by subcutaneous injection. Therefore, we concluded that the semi‐permanent BCD is a promising treatment platform, transforming the clinical landscape of self‐injectable therapies in a noninvasive way.Yong Chan Cho, Cho Rim Kim, Seung Ho Lee, and Young Bin Choy are listed as inventors on the pending patents (PCT/KR2020/015827 and KR 10‐2020‐0009763) filed by SNU R&DB for the button‐click devices described in this article. This technology has been transferred to ToBios Inc., where Y.B.C. is a founding member. The other authors declare no conflict of interests.Cho Rim Kim: conceptualization, methodology, validation, investigation, data curation, and writing—original draft. Yong Chan Cho: conceptualization, methodology, validation, investigation, data curation, and writing—original draft. Seung Ho Lee: conceptualization, methodology, validation, investigation, data curation, and writing—original draft. Jae Hoon Han: validation and investigation. Min Ji Kim: validation and investigation. Han Bi Ji: validation and investigation. Se‐Na Kim: validation and investigation. Chang Hee Min: validation and investigation. Byung Ho Shin: validation, investigation, data curation. Cheol Lee: methodology, validation, investigation, data curation. Young Min Cho: methodology, validation, investigation, data curation. Young Bin Choy: conceptualization, methodology, supervision, project administration, funding acquisition, and writing—original draft.https://publons.com/publon/10.1002/btm2.10320.The peer review history for this article is available at DATA S1 Supporting Information.Click here for additional data file.Movie S1 Drug infusion by button clicks with the BCD.Click here for additional data file.Movie S2 Reproducible liquid infusion by button clicks with the BCD.Click here for additional data file.Movie S3 Profile of force applied on the button of the BCD during click actuation.Click here for additional data file.Movie S4 Button click applied while the BCD was still implanted. When the BCD was clicked, the animal without anesthesia did not show any sign of pain or discomfort.Click here for additional data file.Movie S5 Drug replenishment while the BCD was still implanted, using a 31 G syringe needle.Click here for additional data file.


Electrolytes play an important role in the internal structure and dynamics of water-rich satellites and potentially water-rich exoplanets. However, in planets, the presence of a large high-pressure ice mantle is thought to hinder the exchange and transport of electrolytes between various liquid and solid deep layers. Here we show, using first-principles simulations, that up to 2.5 wt% NaCl can be dissolved in dense water ice at interior conditions of water-rich super-Earths and mini-Neptunes. The salt impurities enhance the diffusion of H atoms, extending the stability field of recently discovered superionic ice, and push towards higher pressures the transition to the stiffer ice X phase. Scaling laws for thermo-compositional convection show that salts entering the high pressure ice layer can be readily transported across. These findings suggest that the high-pressure ice mantle of water-rich exoplanets is permeable to the convective transport of electrolytes between the inner rocky core and the outer liquid layer. Hot cubic ice is shown to retain dissolved salt in its lattice, suggesting the mantle of water-rich exoplanets is more permeable to electrolytes than assumed, which has implications on its properties and on the element cycles inside such planets. While an interface between liquid water and a silicate mantle favors hydrothermal reactions releasing nutrients in the ocean, the presence of an underlying high-pressure ice mantle might prevent the transport of electrolytes7 due to their insolubility in ice VI8. Nevertheless molecular ice VII has been shown to include non-negligible amounts of halides within their structures at conditions similar to large icy moon interiors14. These experimental results have recently been confirmed by the discovery of salty ice VII inclusions trapped in diamonds formed in the Earth mantle15.Water-rich exoplanets and icy moons are promising environments for the development of biological reactions. The extent and the composition of a potential ocean depends on the solubility and the availability of the various electrolytes. Both in situ measurements by planetary missions and aqueous alteration processes observed in chondrites suggest that salts based on Na16. At these conditions, bcc H2O ice undergoes multiple transitions due to changes in the distribution and the dynamics of the H atoms. Below 30–40 GPa and 800 K, ice VII (space group Pn-3m) is the stable phase. It has a static orientational disorder of the H2O molecules. The H atoms occupy the half-diagonals of the bcc O sub-lattice and the arrangement of H2O molecules form a strong hydrogen-bond (HB) network with O-H2O molecules due to the symmetrization of the O-H2O molecules are fully dissociated; this ionic ice is labelled ice X18. Increasing the temperature in ice VII activates a dynamic orientational disorder of the H2O molecules19. Increasing both pressure and temperature leads to the combination of both orientational and translational motions of the H atoms and results in an onset of H diffusion characterizing the superionic regime26.The ability of ice VII to retain salts in its structure results from its body-centered cubic (bcc) sub-lattice of O atoms, which is a common characteristic of all ice phases between 2 GPa and 300 K to at least 270 GPa and 2000 K30. For instance, the transition between superionic ice VII″ and ice VII′ is associated with a first-order transition, a dip in the elastic constants and a strong decrease of the electrical conductivity24. The completion the hydrogen bond symmetrization makes ice X stiffer than other bcc ices and preliminary investigation of its rheology predict a change of slip-system around 250 GPa28.These transitions strongly influence the compressibility, elasticity and transport properties of bcc ice31 and breaks the connectivity of its hydrogen bond network13. In particular, the presence of halides increases the rotational disorder of water molecules and decreases the role of quantum effects in the O-H32, which shifts the transition to ice X by about 40 GPa at ambient temperature12. Nevertheless, the stability of salt-bearing ice is not known at conditions typical of water-rich super-Earths, i.e., up to a few megabars and few thousand Kelvin. The inclusion mechanism of NaCl in bcc ice remains debated and its influence on the development of the superionicity have not been investigated yet.The inclusion of salt in ice VII decreases its melting temperatureHere we compute the solubility and the properties of NaCl-bearing water ice along the 1600 K isotherm at relevant conditions for the interiors of water-rich exoplanets presenting a high-pressure ice mantle. Our approach is based on first-principles molecular dynamics simulations (DFT-MD) and extensive thermodynamic modeling. Then, based on our results and analytical considerations, we investigate how the presence of salt would influence the convection and the transport of electrolytes in the high-pressure ice layer of large water-rich exoplanets.31 suggested three different and competing structural mechanisms for the inclusion of the Na+ and Cl− ions in the bcc structure of ice VII. Based on experiments on NaCl-bearing ice, Frank9 inferred that both Na+ and Cl− ions occupy octahedral face-centered sites. Based on experiments on LiCl-bearing ice, another group33 proposed that Cl− substitutes a water molecule and Na+ remains in an octahedral site. Based on energy and size considerations, the same group suggested that both Na+ and Cl− substitute H2O molecules on the bcc sites (double substitution mechanism). X-ray diffraction (XRD) measurements of natural Cl-bearing ice VII at ambient temperature15 revealed the same substitution sites on the bcc lattice.Several experimental studies+ and Cl− ions in cubic water ice at 1600 K. We perform a direct crystallization of a salty water solution. We start with two equilibrated solutions in the fluid domain at 1600 K and 30 GPa, one NaCl·126H2O and one NaCl·30H2O  with different configurations of Na and Cl in the bcc O sub-lattice and the resulting properties are averaged over the different configurations.2O), the O-Na and the O-Cl distances respectively differ from the O-O distance by −14% and by +6%. The differences change to −9.5% and +8% at higher densities . To identify the different regimes, we perform a three-body analysisThe comparison of the shortest OH distance to the shortest OO distance allows us to monitor the symmetrization of the O-Ha-Hb → Oab) and OH-rotations (Oa-Hb → Oa-Hc) allows us to quantify dynamical disorders and to distinguish all other bcc phases in our simulations. Ice VII is not dynamically disordered and both OH-rotation and H-translation rates would be equal to zero. Plastic ice (free rotations of H2O molecules) would have a positive OH-rotation rate and a H-translation rate equal to zero. Non-diffusive ices VII′ and X would have H-translations without any OH-rotation. The presence of both H-translations and OH-rotations indicates that H atoms are diffusing: this characterizes the superionic regime. In this case, superionic ice VII″ is distinguished from superionic ices VII′ and X by a OH-rotation rate greater than the H-translation rate. Figure 2O ice both H-translations and OH-rotations are activated up to ~150 GPa, indicating that H atoms diffuse below this pressure at the time-scale of our simulations and that pure ice is in a superionic regime. Below 52 GPa, pure ice is affected by more OH-rotations than H-translations and is in the superionic VII″ phase. Above 150 GPa, only H-translations are observed in pure ice indicating that ice is in its non-diffusive ice X form (OH = OO/2 at these conditions).Counting the number of H-translations . As a consequence, the pressure at which the OH-rotation rate equals the H-translation rate, i.e., the transition pressure between superionic ice VII″ and superionic ice VII′ (or superionic ice X depending on the relation between the OH and OO distances), increases with the NaCl concentration. Also, above 2.5 wt% NaCl, we found that the OH-rotation rate never reaches zero, indicating that salty ice is superionic at all sample pressure at 1600 K. The enhanced orientational disorder in salty ice is caused by both the inability of Na to form any bonds with H, and by the absence of covalent Cl-H bonds. Only O-Hsee Fig. .2.s−1 (2.s−1) in ice with NaCl concentrations lower than 5.0 wt% although both OH-rotational and H-translational disorder still persist , These changes in bonding regime are reflected in the variation of the proton diffusion Fig.  and elecsee Fig. . In partist Fig. . For larnds Fig. .In summary, the inclusion of salt distorts the bcc sub-lattice, increases the orientational disorder and weakens the hydrogen-bond network of the ice. This shifts the superionic VII″ - VII′ - X transition sequence towards higher pressure with increasing salt concentrations see Fig. . TherefoThe entire phase diagram of ice at high pressure and temperature is affected by the presence of salt, with the phase boundaries pushed to higher pressures Fig. . The ampIn solid solutions, the configurations that present the major contribution are generally separated by high energy barriers although their own energies can be very close or similar. As such, the transition paths between configurations cannot be sampled directly by standard molecular dynamics. Then statistical methods need to be employed to estimate the configuration entropy, as described in the methodology section, which depends on the number of configurations accessible to the system, i.e., the Na, Cl, and O arrangements in the bcc sub-lattice. As we investigate the solubility and properties of salty ice along the 1600 K isotherm, we validate the statistical approach by a second set of calculations exploring all possible arrangements for two concentrations at 100 GPa and 1600 K.2O). Assuming that H2O-bearing B2-type NaCl is the only phase that forms close to the NaCl end-member term, and that its free energy of mixing has only a small negative incursion, the common tangent to the two free energy curves intersects the curve of NaCl-bearing H2O free energy of mixing close to its minimum. This suggests that the inclusion of NaCl in water ice at 1600 K between 80 and 200 GPa is thermodynamically favorable up to ~2.5 wt% NaCl. At these conditions, salty superionic ice always presents both a larger volume  and a larger density than pure water ice  in ice VII at lower pressures and temperatures14. A solubility of 2.5 wt% is still consistent with the observation of temperature-induced exsolution of some NaCl above 500 K in NaCl-doped ice VII whose initial concentration was higher10. The volume increase due to the addition of salt contrasts with the XRD measurements of Frank et al.10. but agrees with all previously mentioned studies13.At 1600 K and 100 GPa, the Gibbs free energy of mixing is negative up to 5–10 wt% NaCl depending on the estimation of the configuration entropy and presents a minimum at 2.5 wt% NaCl  and increases the density by about 0.5% compared to pure ice, as the positive change in specific volume due to the addition of salt is compensated by its higher molecular weight. These changes are expected to influence the dynamics of a high-pressure ice mantle, in a variety of different ways, depending on the planet characteristics. A full understanding of salt transport between the rocky core and the ocean by convection in the high-pressure ice layer requires complex fluid dynamical double-diffusive models including complexities such as phase changes, pressure-, temperature- and composition-dependence of physical properties, and possibly partial melting⊕ with 50 wt% H2O, an Earth-like core, absent or very thin atmosphere, and a surface temperature of 300 K . It is depicted in Fig. Given that salts and other electrolytes are a necessary (but of course not sufficient) condition for habitability in a (sub-)surface ocean, it is interesting to evaluate if salt can be involved in a global cycle, i.e., if salt and other electrolytes could be transported throughout the high-pressure ice mantle by convection. In the following, we develop our reasoning and provide numerical applications to a hypothetical planet of 1 M2O layers . The value of 41. We here consider the situation, a priori less favorable for transfer of salts to the ocean, where no melting occurs and salts flow to the ice layer by diffusion, with a diffusion coefficient D. The relevant value entering B is the density increase from salts in the thermal boundary layer, with a thickness 48. In the same time, the concentration of salts increases in a layer of thickness Considering an adiabatic profile in the Hmentclass2pt{minim−12 m2 s−1 (see Methods), leads to a very small buoyancy number which implies a very limited effect of salts against thermal convection. Moreover, the style of convection expected in an ice layer bounded above by an ocean shows focused hot plumes with a diffuse return flow46; the up-welling material melts when it reaches the ocean45, therefore releasing salts there  given that the total amount of H2O is large enough to reach the liquid/solid transition. If the surface temperature is very high, the conditions in the water layer may never intersect the melting line. In the case of an exoplanet with a very low surface temperature without atmosphere, a layer of ice VI could cap the ice VII layer, and the phase change VII to VI in up-welling plumes could lead to ex-solving NaCl to make a polycrystalline assemblage8. The gross density of the assemblage should be similar to that of salt-doped ice VII and, according to the discussion surrounding Eq.  simulations with the Vienna Ab initio Simulation Package52 (VASP v4.6 and v5.2). To model the atoms, we use the PAW potentials54 with the following electronic configurations: O:55 is used to approximate the exchange-correlation term. Most DFT-MD simulations are performed with 56. Time steps of 0.5 or 1 fs are employed in all simulations. DFT-MD are either performed in the NVT, i.e., constant Number of particles, Volume, and Temperature, and NPT, i.e., constant Number of particles, Pressure, and Temperature, ensembles. For NVT sampling, temperature is controlled using velocity rescaling (isokinetic) as no difference was observed for averaged properties when using a Nose-Hoover thermostat58. Isobaric-isothermal simulations are performed with Raman-Parrinello molecular dynamics59 and a Langevin thermostat.We study the behavior of NaCl-bearing dense Hmentclass2pt{minimw, pressure P, and temperature T. The estimation of the thermodynamic stability of the binary system requires the calculation of the Gibbs free energy of mixing 2O and B2-type NaCl. We estimate the vibrational contribution to the entropy and the corrections for the nuclear quantum effects by computing the partial vibrational spectra from the velocity autocorrelation functions and using the two phases thermodynamic memory function model (2PT-MF)62. We estimate the configuration entropy for the H2O-rich part of the solid-solution taking advantage of recent developments in the computation of mixture thermodynamics based on reduced configuration space sampling63.First we compute the free energies of the two end-members: HF from which we deduced the configuration entropy and weighted thermodynamic properties. From the resulting data points, we construct the Helmholtz free energy surface at 1600 K over the entire volume range of interest. By derivation we obtained the Gibbs free energy of the solution as function of pressure and NaCl concentration (see section S2).Then we perform a series of NVT simulations with different concentrations of NaCl at different volumes Table ; at eachR = 250, 126 and 52) to have a correct value of the configuration entropy; the two approaches yield about 5% difference in the mass fraction of NaCl that can be dissolved in the ice.Nevertheless as we sample a subset of the configuration space, the configuration entropy is likely underestimated. Second we perform NVT simulations at 100 GPa for all possible configurations at three NaCl concentrations  in the ice is required to calculate the buoyancy number B of a thermal boundary layer enriched in salt at the bottom of the ice mantle. In order to provide a reasonable order of magnitude for this quantity, we consider that D is similar to the diffusivity of O atoms DO, possible in our calculations only in the presence of vacancies. To estimate DO, we perform an additional DFT-MD run in a defective ice X structure with 126 H2O and two H2O vacancies. The simulation is done in the NVT ensemble (1600 K and a corresponding pressure of 110 GPa) with a time step of 1 fs. During the duration of this long simulation (97.5 ps of statistics after 2.5 ps of equilibration), we observe a total of 17 jumps, enough to obtain a linear regime in the mean square displacement (see Fig. DO, and thus D, likely represents an upper bound.The diffusivity of NaCl (see Fig.  and a diWe use scaling laws obtained in the context of the dynamics of the Earth mantle to estimate the feasibility of solute transport by convection in the high-pressure ice layer from the rocky core of icy exoplanets to the overlying ocean. The first important control dimensionless number for this process, the Rayleigh number Eq. , dependsmentclass2pt{minimD was estimated from DFT-MD as detailed in the previous section. To estimate the temperature difference ΔT across the boundary layer, we use the scaling of the dimensionless heat flux as function of the Rayleigh number46 as 41.The second important dimensionless control number is the buoyancy number which balances the density change from composition and that from temperature. Thermal convection in the ice layer proceeds by diffusive growth of a boundary layer until its thickness mentclass2pt{minimSupplementary InformationPeer Review File