Analysis of variable (ANOVA) for Nuc.
\r\n\t
\r\n\tContamination with biomedical waste and its impact on the environment are global concerns. Biomedical waste that has not been collected and disposed in accordance with the regulations can become a total environmental hazard and cause negative impact on human health and the environment. Medical centers including hospitals, clinics, and places where diagnosis and treatment are conducted generate waste that is highly hazardous and put people under risk of fatal diseases. On the other hand, food waste is commonly produced in all the steps of food life cycle, such as during agricultural production, industrial manufacturing, processing and distribution, and is even consumer-generated within private households. Food waste mostly contains high-value components such as phytochemicals, proteins, flavor compounds, polysaccharides, and fibers, which can be reused as nutraceuticals and functional ingredients. Adsorption is a practicable separation method for purification, along with bulk separation where surface characteristics and pore structures are the main properties in determining equilibrium rate. Managing waste materials on the whole is often unsatisfactory, especially in developing countries, and the unreasonable disposal of waste is a major issue worldwide. The following issues will be of particular interest for this book: effects of waste on environment and health, biomedical waste - storage, management, treatment, and disposal, biomedical waste contamination, food waste, potential applications of low-cost sorbents in agricultural and food sectors, biosorbents and bioadsorbents, adsorption of modified agricultural and biological wastes (biosorption), compounds recovered from food waste, and agricultural and food waste-derived sorbents.
The outward convex corrugated tube heat exchanger (CTHE) is a novel kind of shell and tube heat exchangers, which can be applied in many applications. Designing this kind of heat exchangers is considerable flexibility because the geometrical structure can be varied easily by altering the tube diameter, length, and arrangement [1, 2]. The exchanger can be designed for suffering high pressure condition. The exchangers are applied primarily for single phase and phase change heat transfer application. They could also be used for heat transfer applications with high operating temperature and/or pressure.
\nFigure 1 shows a bundle of outward convex corrugated tubes (CT) fabricated in the tubesheets, which is the most significant components in the CTHE. Two kinds of fluids flow inside and outside of CT, respectively. Except the tube bundles, the major components of this exchanger also include shell, front-end head, and rear-end head.
\nThe schematic of out outward convex corrugated tube heat exchangers.
The exchangers could be widely used in industry for the following reasons. (a) Wide capacity and operating conditions, such as from high vacuum to ultrahigh pressure (over 100 MPa) and from cryogenics to high temperatures (about 1100°C). (b) Special operating conditions: vibration, heavy fouling, highly viscous fluids, erosion, corrosion, toxicity, radioactivity, multicomponent mixtures, and so on. (c) The most versatile exchangers, made from a variety of metal and nonmetal materials (such as graphite, glass, and Teflon) and range in size from small to supergiant surface area. (d) Extensively applications: petroleum-refining and chemical industries; as steam generators, condensers, boiler feedwater heaters, and oil cooler in power plants; as condensers and evaporators in some air-conditioning and refrigeration applications; in waste heat recovery applications; and in environmental control [3, 4, 5].
\nThe main difference between the CTHE and traditional heat exchangers is the adopted tube type. Traditionally, the inward intermittent or continuous type corrugated tubes are employed, as an example for both helically corrugated and transverse corrugated tubes, owing to their ease of realization. However, in engineering devices, it is necessary to adopt CT, which could be conveniently and periodically inspected with complete accessibility [6].
\nA schematic view of the CT configuration currently investigated is shown in Figure 2. The structure parameters of the outward corrugated tube include inner diameter (D), tube length (L), corrugation height (H), corrugation pitch (p), corrugation crest radius (R), and corrugation trough radius (r).
\nThe real and schematic view of the outward convex corrugated tube.
The design and improvement of the CT are considered a significant aspect of researches in terms of heat and mass transfer. Almost all of the heat transfer augmentation techniques have been introduced to improve the overall thermo-hydraulic performance. Thus, these techniques achieved reductions in the size and cost of heat exchangers.
\nManufacture consideration could be divided into manufacturing equipment, processing, and other qualitative criteria. The equipment considerations determine which design could be selected, which include existing and new tooling, availability and limitations of equipment, offline production, and investment funding. Processing considerations make sure how individual parts and components of a heat exchanger are manufactured and assembled, which including manufacture of individual parts, stacking of a heat exchanger core and eventual brazing, mounting of pipes, washing/cleaning of the exchanger, and leak testing in the system. When a heat exchanger is designed, the manufacturing equipment and the complete processing considerations must be evaluated previously, particularly for an extended surface heat exchanger [11, 12].
\nIn the novel tube and shell heat exchanger, the structure of the outward convex corrugated tube is special, composed of alternating corrugated segment and straight pipe section. The main difference from traditional heat exchanger is the adopted structure, so the manufacture processing for the novel tube type is highlighted in this section. The working conditions of the heat exchanger are mainly for high temperature and pressure operation condition. To ensure the safe operation of heat exchanger, a thick-walled stainless steel tube with strong pressure resistance is selected as the base tube. For example, the mechanical properties of stainless steel tube material are as follows: yield strength is 390 MPa, material hardening index is 0.148, material strength coefficient is 764 MPa, material anisotropy coefficient is 0.83, material modulus of elasticity is 207GPa, and Poisson ratio is 0.28.
\nThe outward convex corrugated tube is manufactured according to high pressure hydraulic bulking based on the smooth stainless steel tube. The hydraulic bulking equipment is 10,000 KN. As shown in Figure 3(a), the equipment is assembled with 400 MPa internal high-pressure forming system, which is mainly composed of the supercharger, two horizontal push cylinder hydraulic servo system, and computer control system. The manufacturing process needs to be supplemented with the corresponding mold, installed on the hydraulic bulking equipment. The mold consists of three parts, which includes upper module as shown in Figure 3(b), lower module as shown in Figure 3(c) and sealing punch. The inner mosaic block with corrugation shape is inserted in the mold as shown in Figure 3(d). High pressure liquid (water or oil) is provided inside the smooth stainless steel tube and finally hydroforms the outward convex corrugated tube.
\nThe hydraulic bulging machine and mold. Based on the modified order as the above sticky. (a) Hydraulic bulking equipment; (b) upper module; (c) lower module; (d) inner mosaic block.
In order to test the heat transfer and resistance performance of the corrugated tube heat exchangers, experimental study on the corrugated tube heat exchanger must be performed. We adopted steady-state techniques to establish the relationship between Nu and Re. Different data acquisition and reduction methods are used, depending on whether the test fluid is primarily a gas (air) or a liquid. A gas to gas heat exchange will be conducted in our experimental test.
\nThe schematic of the experimental apparatus for outward corrugated tube is depicted in Figure 4. The system comprises a screw air compressor (the highest discharging pressure is 1.3 MPa, and the air displacement is fixed at 1.81 m3/min), two pressure-regulating valves (0.3 MPa on the hot circuit and 0.9 MPa on the cold circuit), a heater (the temperature range is 50–500°C), a test section (operating with two groups of switching valves), a measuring system (two critical Venturi flowmeters, two pressure transducers, and two temperature transducers), a data acquisition system (DAS), and a pipe system (304 stainless steel tube).
\nSystem drawing of test bed. 1. Screw air compressor, 2. Pressure-regulating valve in hot circuit, 3. Pressure-regulating valve in cold circuit, 4. Critical Venturi flowmeter in hot circuit, 5. Critical flow meters in cold circuit, 6. Air heater, 7. Switching valves in hot circuit, 8. Switching valves in cold circuit, 9. Test section, 10. Data acquisition system, 11. Muffler.
The experimental medium was air, which was compressed by the helical-lobe compressor to a pressure of 1.25 MPa. The system is made of stainless steel devices and consists of the hot circuit and cold circuit. The pressure-regulating valves adjust the air pressure to 0.3 MPa on the hot circuit and 0.9 MPa on the cold circuit with an accuracy of ±2%. The critical Venturi flowmeters control the mass flow rate in the hot and cold circuits. The air in the hot circuit is heated by the heater exchanger and then flows into the tube side of the test section, whereas the air in the cold circuit directly flows into the shell side. The section has a detachable structure, which enables convenient changes in various tube components. Moreover, the valve group in the vicinity of the test section makes the air flow into the tube, through either inlet of the tube side or the shell side, thus creating a uniform-current flow and a counter-current flow for each respective flow direction. Finally, the hot air and the cold air complete the heat exchange in the annular tubes of the test section, and then noise of them will be reduced through the muffler.
\nIn the measuring system, the mass flow rates can be measured with two critical Venturi flowmeters on both circuits, with an accuracy of ±0.2%. The flow meter in the hot circuit was installed before the air heater because hot air may damage the flow meter or reduce the measurement accuracy (precision). After the heater, a temperature transducer was installed to monitor the air temperature. The DAS obtained the flow rate signal, which was transferred to a programmable logic controller (PLC) in the industrial personal computer (IPC), and the accuracy of the transformation module was ±0.05%. The pressure and temperature transducers were installed at the inlet and outlet of the section to measure the pressure and temperature of the air on both sides. All thermocouples were calibrated with an accuracy of ±0.1% of the test data. The pressure drop of the test section was measured with pressure transducers, which have an accuracy of ±0.2% and a measuring range of 0–5 kPa. The values were collected and displayed on the IPC and were automatically recorded.
\nThe uncertainty is estimated with the method suggested by Kline and Moffat. As mentioned above, the measurement uncertainties of tube length and tube diameters are about 0.05 and 0.1%, respectively. In addition, the measurement accuracy of temperature is 0.14%, the measurement error of the differential pressure meter is 2.06%, and the critical Venturi flowmeter has a precision of 3.11%. According to the uncertainty propagation equation, the uncertainties in the values of experimental parameters like the Reynolds number, Nusselt number, and friction factor are 3.89, 4.41, and 4.87%, respectively.
\nThe main purpose of our experimental study is to construct the relationship among the heat transfer rate q, heat transfer surface area A, heat capacity rate c of each fluid, overall heat transfer coefficient U, and fluid terminal temperatures [10]. To conduct the heat transfer analysis of an exchanger, the basic relationships that are applied for this purpose are the energy balance based on the first law of thermodynamics, as outlined in Eq. (1).
\nwhere \n
As shown in Figure 5, a two-fluid counterflow exchanger is considered to present variables relating to its thermal performance. Although flow arrangement may be different for different exchangers, the basic concept of modeling remains the same. The following analysis is intended to introduce important variables for heat exchanger.
\nThe energy balance for the hot and cold fluids of a two-fluid heat exchanger.
If the fluids do not undergo a phase change and have constant specific heats with di = cp · dT, heat transfer rate released from the hot fluid (Qh) and absorbed by the cold air (Qc) can be expressed as
\nand
\nThe subscripts h and c refer to the hot and cold fluids, and the numbers 1 and 2 designate the fluid inlet and outlet conditions, respectively.
\nThus, the average value of the heat transfer rate is calculated as
\nEq. (5) reflects a convection-conduction heat transfer phenomenon in a two-fluid heat exchanger. The temperature difference between the hot and cold fluids (ΔT = Th−Tc) constantly changes along with heat exchanger. Therefore, in order to conveniently analyze the heat transfer performance of heat exchanger, it is important to establish an appropriate mean value of the temperature difference between the hot and cold fluids such that the total heat transfer rate Q between the fluids can be determined from
\nThe heat transfer rate Q is proportional to the heat transfer area A, the average overall heat transfer coefficient based on the area U, and mean temperature difference \n
\n\n
In the experiments, the tube-wall temperature was not measured directly. The heat transfer coefficient of the tube side (hi) is determined from:
\nwhere ri and ro are the inner radius and outer radius of the test tube, respectively. Ai and Ao are the inner and outer surface area of the tube, respectively. k is the thermal conductivity of tube material, L is the length of the heat exchange tube, and hi and ho are the heat transfer coefficients for inside and outside flows, respectively.
\nThe Nusselt number can be calculated as
\nwhere D is the characteristic diameter; the thermal conductivity k is calculated from the fluid properties at the local mean bulk fluid temperature.
\nThe Reynolds number is based on the average flow rate of the test section.
\nwhere μ is the dynamic viscosity of the working fluid, and u is the mean velocity.
\nThe friction factor (f) can be written as
\nwhere Δp is the pressure drop in the test section.
\nThe performance evaluation criterion (PEC) is a dimensionless ratio, which is used for the evaluation of the overall performance of the enhanced tube and defined as follows:
\nWhen PEC > 1, it indicates that the enhanced tube has an advantage over the smooth tube; otherwise, the corrugated heat transfer component compares unfavorably with the smooth tube.
\nFor the engineering applications and to design exchangers, the prediction of heat and mass transfer performance is important. We presented experimental data on the Nusselt numbers for turbulent regimes. In our experimental study, the hot fluid is at the tube side, and the cold fluid is at the shell side.
\nThe heat transfer and resistance performance of corrugated tube are compared to smooth tube, aiming to reflect the superior of the corrugated tube. Ratio of Nu in the corrugated tube to that in the smooth tube (Nuc/Nus) and ratio of f in the corrugated tube to that in the smooth tube (fc/fs) are adopted to indicate the enhancement degree of heat transfer and flow resistance performance.
\nFigure 6 shows the effect of Rec (Re of the cold fluid) on Nuc/Nus, fc/fs, and PEC, along with the changing Reh (Re of the hot fluid). The figure exhibits that with the increase of Re, Nuc/Nus, fc/fs, and PEC decline. The decreasing rate of Nuc/Nus and PEC is almost linear, but fc/fs is decelerated.
\nFlow and mass transfer performance. (a) Nuc/Nus; (b) f/fs; (c) PEC.
The first task to accomplish in a numerical simulation is the definition of the geometry followed by the mesh generation. The geometry of the design needs to be created from the initial design. Any modeling software can be used for modeling and shifted to other simulation software for analysis purpose.
\nFigure 7 shows a schematic view of the structural parameters for corrugated tube investigated in this chapter, which include inner diameter (D), tube length (L), corrugation height (H), corrugation pitch (P), corrugation crest radius (R), and corrugation trough radius (r). Since the investigated corrugated tubes are used in tube-shell type heat exchanger, the flow region inside of tube is named “tube side” and out of tube is named “shell side.”
\nStructure parameters of outward convex corrugated tube.
Mesh generation is the process of subdividing a region to be modeled into a set of small control volumes. In general, a control volume model is defined by a mesh network, which is made up of the geometric arrangement of control volumes and nodes. Nodes represent points at which features such as displacements are calculated. Control volumes are bounded by set of nodes and also defined by the number of mesh. One or more values of dependent flow variable (e.g. velocity, pressure, temperature, etc.) will be contained in each control volume. Usually, these represent some type of locally averaged values. Numerical algorithms representing approximation to the conservation law of mass, momentum, and energy are then used to compute these variables in each control volume.
\nMesh generation is often considered as the most important and most time consuming part of CFD simulation [13]. The quality of the mesh plays a direct role on the quality of the analysis, regardless of the flow solver used. In this work, a 3D non-uniform mesh system of hexahedral elements was established via the professional mesh generation software ICEM to accurately control the size and number of cells in the domain, as illustrated in Figure 8. The near-wall vicinity should be present drastic velocity and temperature gradients, so a high density of gradient elements was applied in this region. Nevertheless, the remaining domain was modeled with relatively sparse elements. The first layer of thickness should satisfy y+ ≈ 1.
\nSchematic diagram of meshing system for the simulated corrugated tube.
Mathematical model should be constructed to numerically describe flow and heat transfer of corrugated tube. The Navier-Stokes equations generally are adopted to describe the laminar and turbulent flows, which could be solved by various kinds of simulation model including DNS, LES, and RANS. The direct numerical simulation (DNS) can solve accurately the turbulent fluctuation, but these models require huge computing power, which is many orders of magnitude higher than other models. Reynolds-averaged Navier-Stokes (RANS) is a high efficient model that can be used to approximate turbulence by time-averaged turbulent fluctuation, but the accuracy of the models is much less than DNS. The accuracy and efficient of LES are between the DNS and RANS.
\nThe k-ε (k-epsilon) model is one of the most prominent RANS models, which has been implemented in most CFD codes and is considered the most common industry model. The stability and robustness of the models have a well-established regime of predictive capability, satisfying general purpose simulation by offering a comparative good accuracy. In our research work for outward convex corrugated tube, we use standard k-ε model for numerical simulation research.
\nThe governing equations in a RANS (Reynolds Averaged Navier-Stokes) manner are given below.
\nContinuity equation:
\nMomentum equation:
\nEnergy equation:
\nThe standard k-ε model is adopted here to close governing equations:
\nwhere μt is the turbulent or eddy viscosity, and \n
The next step in preprocessing is setting up the boundary conditions. Boundary conditions refer to the conditions that the solution of the equations should satisfy at the boundary of the moving fluid. Boundary condition will be different for each type of problem. In our research work, the initial and boundary conditions of the outward convex corrugated tube heat exchangers are shown as follows:
The inlet conditions at the shell side are as follows: velocity inlet U = Uin, Tin = 563.15 K, and the inlet turbulence specifications are a turbulence intensity of I = 5% and hydraulic diameter D = 20 mm.
The outlet conditions at the shell side are as follows: pressure outlet, Po = 7 MPa, and the outlet turbulence specifications are a turbulence intensity of I = 5% and a viscosity ratio μt/μlam = 5%.
The wall conditions are as follows: the outer wall temperature boundary condition is constant, Tw = 700 K, and the inner wall-coupled boundary condition was set as a no-slip boundary, u = v = w = 0, T = Tw, and q = qw.
The final step in preprocessing is setting up the numerical procedure, which includes solver, discretization, and convergence criterion. In our work, the governing equations are discretized by the finite volume method and solved by the steady-state implicit format. The SIMPLE algorithm is used to couple the velocity and pressure fields. The second-order upwind scheme is applied herein. The convergence criterion for energy is set to be 10−7 relative error and 10−4 relative error for other variables.
\nThe variable distribution exhibits the opposite similar tendency at the shell side compared with that at the tube side. In this chapter, we mainly analyze the distribution of velocity, temperature, and turbulence kinetic energy.
\nFigure 9(a) shows the velocity vector distribution in the tube side of outward convex corrugation tube. As shown from this figure, when fluid flow starts to cross the corrugation section bended from the straight segment, the flow boundary layer separates into two parts: one is the wall boundary layer developed at the near wall region; the other is shear layer associated with an inflection point of large velocity gradient developed away from the wall, which moves away from the surface at the separation point and forms a free shear layer. When the fluid flows through the upstream of the corrugation, the flow velocity decreases and the pressure increases due to the narrowing of the flow cross section. The fluid layer near the wall is gradually difficult to overcome the rising pressure due to the small amount of momentum, resulting in a reflow of the original flow direction. The recirculating zone between the separating streamline and the free boundary streamline is generated at the upstream of the corrugation.
\nVelocity vector distribution at tube side and at shell side. (a) tube side; (b) shell side.
Figure 9(b) indicates the velocity vector distribution in the shell side of outward convex corrugation tube. As shown in this figure, the upstream side boundary of the corrugation is influenced by the accelerating outer-flow, that is, a favorable gradient. As the boundary layer thickens, instabilities occur when the near-wall fluid begins to decelerate as shown in Figure 7. The flow separates at the downgrade of the corrugation crest, which is associated with an inflection point of the large velocity gradient developed away the wall.
\nFigure 10(a) shows the temperature distribution in the tube side of outward convex corrugation tube. As shown in Figure 8, the wall velocity boundary layer becomes thicker at the upstream side of the corrugation accompany gradually, while the temperature boundary layer gets thicker along the flow direction, due to the eddy generating. Then it goes into thinner at the downstream side of the corrugation with the velocity boundary layer getting thinner, due to the scouring action of the fluid.
\nTemperature distribution at tube side and at shell side. (a) tube side; (b) shell side.
Figure 10(b) shows the temperature distribution in the tube side of outward convex corrugation tube. As shown in Figure 9, the wall velocity boundary layer becomes thicker at the downstream side of the corrugation accompany gradually, while the temperature boundary layer gets thicker along the flow direction, due to the eddy generating. Then, it goes into thinner at the upstream side of the corrugation with the velocity boundary layer getting thinner, due to the scouring action of the fluid. The thinnest temperature boundary layer occurs at the corrugation crest.
\nTurbulence kinetic energy (TKE) is one of the most important variables in boundary layer since it is a measure of the turbulence intensity, which is tightly related to the velocity profile. Figure 11(a) shows the turbulence kinetic energy distribution in the tube side of outward convex corrugation tube. As shown in this figure, the magnitude of the TKE gradient increases past upstream side section of corrugation with a noticed reduction after the flow reattaches as it enters downstream side section of corrugation. The location of the maximum turbulence kinetic energy extends over most of the corrugation, before descending when passing the downstream section of the wave trough.
\nTKE distribution at tube side and at shell side. (a) tube side; (b) shell side.
Figure 11(b) shows the turbulence kinetic energy distribution in the tube side of outward convex corrugation tube. As shown in this figure, the magnitude of the high TKE extends fairly constant past most of the corrugation with a noticed reduction after the flow reattaches. The location of the high TKE extends over most of corrugation at a height, which roughly equals to the maximum corrugation height, before subsiding toward the corrugation trough.
\nHeat transfer enhancement methods are classified into three classifications: active, passive, and compound. The active methods include electrostatic and magnetic fields, induced pulsation, mechanical aid, vibration, and jet impingement. These methods require external activating power to enhance the heat transfer [3, 4, 5, 6]. Passive methods modify the geometrical structure to expand the effective surface area to disturb the actual boundary layer. Compound methods combine the two heat transfer augmentation methods to increase heat transfer performance. In the above-mentioned methods, passive methods have attracted significant attention from researchers and engineers since they are user-friendly and affordable. Extensive research has been devoted to develop highly efficient heat transfer components to better understand the physical mechanisms and optimal parameters of passive heat transfer augmentation methods.
\nThe heat transfer enhancement mechanism in the corrugated tube is described as follows. The periodically corrugated structure on the tube wall arouses periodic alteration of velocity gradient, leading to adverse and favorable pressure gradient locally. The recurrent alternation of axial pressure gradient induces the secondary disturbance, and then the produced intensive eddy destroys the flow boundary layer. The eddy also increases the turbulence intensity of the flow. The disturbance caused by corrugated structures thus increases the heat transfer coefficient drastically.
\nFigure 12 shows the effect of Re on Nuc with various p/D and H/D. The Nuc tends to increase linearly with the increasing Re with a fixed structure of the corrugated tube. This behavior occurs because the increases of flow velocity break wall thermal boundary layer and could obtain higher convective heat transfer coefficient. Moreover, with the decreasing p/D and increasing H/D, the values of the Nuc increase.
\nEffect of Re on Nu with various p/D and H/D in the tube side. (a) various p/D (b) various H/D.
In order to compare the performance between corrugated tube and smooth tube, the ratio of Nu in the corrugated tube to that in the smooth tube (Nuc/Nus) is adopted to indicate the relative grow rate of heat transfer performance. Figure 13 shows the effect of Re on Nuc/Nus with various p/D and H/D, and the figure exhibits that with the increase of Re, Nuc/Nus declines deceleratedly. Moreover, the Nuc/Nus increases with the decreasing p/D and increasing H/D.
\nEffect of Re on Nuc/Nus with various p/D and H/D in the tube side. (a) various p/D (b) various H/D.
Figure 14 shows the effect of Re on Nuc with various p/D and H/D in the shell side. Compared with Figure 12, the changing tendency of Nuc along with Re, p/D, and H/D is consistent, but the Nuc in the shell side is obviously higher than in the tube side.
\nEffect of Re on Nu with various p/D and H/D in the shell side. (a) various p/D (b) various H/D.
Figure 15 shows the effect of Re on Nuc/Nus with various p/D and H/D in the shell side. It can be found when compared with Figure 13, the changing tendency of Nuc/Nus along with Re, p/D, and H/D is also consistent, but the Nuc/Nus in the shell side is obviously higher than in the tube side.
\nEffect of Re on Nu with various p/D and H/D in the shell side. (a) various p/D (b) various H/D.
Generally, heat transfer enhancement accompanies with a penalty of flow resistance when a heat transfer enhancement component (corrugated tube in this paper) is utilized in a heat exchanger compared to the smooth tube. Therefore, an assessment criterion needs to be constructed to evaluate the overall heat transfer performance for the investigated corrugated tube. The function of overall heat transfer performance is adopted as follows:
\nFigure 16 indicates the effect of Re on overall heat transfer performance (η) with various p/D and H/D in the tube side of outward convex corrugated tube. The figure displays that with the increase of Re, η declines deceleratedly. This is because the Nuc/Nus gradually decreases along with increasing Re. In addition, with the increase of p/D, η decreases when Re < 30,000, but increases when Re > 30,000. This can be explained from the fact that decreasing extent of Nuc/Nus is larger than that of fc/fs with increase in p/D when Re < 30,000, but lower when Re > 30,000. Moreover, the η decreases obviously with the increasing H/D, and the decreasing extent from H/D = 0.02 to H/D = 0.06 is more obvious than that from H/D = 0.06 to H/D = 0.10. This variation is quite intuitive because of the fact that increasing extent of Nuc/Nus is larger than that of fc/fs along with increasing H/D.
\nEffect of Re on η with various p/D and H/D in the tube side. (a) various p/D (b) various H/D.
It can be observed from Figure 17 that the changing trend of η with various p/D and H/D in the shell side is almost the same from the tube side. However, the values of η in the shell side are larger than in the tube side. Therefore, the overall heat transfer enhancement in the shell side is superior to the tube side.
\nEffect of Re on η with various p/D and H/D in the shell side. (a) various p/D (b) various H/D.
Response surface methodology (RSM) is composed of a series of statistical and mathematical method for analyzing empirical results, which can construct connection between effect factors and objective functions. The sensitivity of each effect factor and the interactions between two factors can also be analyzed to the objective functions. Recently, RSM has been extensively used to study on the optimal design of heat exchangers, which is able to efficiently and accurately provide the design consideration for heat exchangers [7, 8, 9].
\nRSM constructs the relationship between objective functions and design variables using a series of statistical and mathematical methodology. The function expression of the relationship could be written as follows:
\nwhere G represents the objective functions and X1, X2, …, Xk stand for design variables, f represents an approximate function, and ε is the residual error between the real value and the approximate value. The approximate functions are described as a quadratic polynomial, aiming to reflect the nonlinear characteristic between objective functions and design variables. In this study, the quadratic polynomial function, including the linear, square, and interaction terms, can be expressed as follows:
\nwhere bI represents the linear effect of design variable XI, bI,I represents the quadratic effect of XI, and bI,J represents the linear-linear interactions between XI and XJ.
\nIn our present work, we adopted the flow chart of optimization procedure as shown in Figure 18. Three objective functions including heat transfer, pressure drop, and overall heat transfer performance in a heat exchanger tube are selected for optimization. In this simulation plan, a most popular design method called the design of experiment (DOE) and central composite design (CCD) is applied. As shown in Figure 19, points including factorial points and center points augmented by axial points are set in CCD. The numerical results for DOE runs are utilized in reflecting the behavior of responses with geometrical and flow parameters.
\nFlow chart of optimization procedure.
CCD model. (a) Two factors. (b) Three factors.
Nondominated sorting genetic algorithm II (NSGA-II) combined with the multi-objective optimization is adopted in this study. The advantages of NSGA-II are a uniformly distributed Pareto-optimal front, which can suitably detect Pareto-optimal front for multi-objective problems, decrease time consuming, and present solutions with a single run.
\nFigure 20 shows the NSGA-II flowchart. As specified in Figure 18, the RSM has been employed to determine the fitness functions in the optimization algorithm. As well, cross over and mutation contained in genetic operators are used in order to generate a new population. Finally, the optimization process is wrapped up with condition of repetitions number.
\nNSGA-II flowchart.
This algorithm uses two functions including nondominated sorting function and crowding distance function, respectively. This subprogram takes population members as input, ranks them, and puts them into fronts in proportion to their ranks. Crowding distance function has been designed to avoid the accumulation of population members in a limited distance. On the other hand, there are no blank intervals in the domain by using crowding distance function. The function is applied for comparison between members of a front that has equal ranks. Compared to the previous and the next member and also the first and the last member of the population, the normalization Euclidean distance of each solution of the front is for each reference point. Normalization is applied to avoid the problem that the objectives are in the different scale.
\nANOVA is one statistical analysis method used to evaluate the fitness of regression models, perform significance testing, and construct simplified regression models between design factors and objective functions. Tables 1 and 2 are ANOVA for Nuc and fc. According to the values of R2, the fitting degree of the RSM is estimated. The F value and P value indicate the influencing significances of the model terms, judging the significant degree of each model term for the global sensitivity analysis. If the model term is the most significant, the corresponding P value is minimum, and F value is maximum. Generally, the terms having a P value >0.05 are considered insignificant and are removed from the models.
\nAnalysis of variable (ANOVA) for Nuc.
Analysis of variable (ANOVA) for fc.
The regression response surface models are described in quadratic polynomial form. Coefficients in the models are determined based on a series of statistical and mathematical methods. The models evaluate the objective functions G including Nuc/Nus, fc/fs, and η, which are expressed as:
\nIn our optimum work, the regression response surface models for evaluating Nuc and fc are expressed as:
\nWe applied 2D response surface contour plots to describe the regression response surface model, in order to display the interaction influence of each pair of design variables on the required responses. From the 2D response surface contour plots, the regulation of objective functions with changing design variables can be clearly observed, distinguished by contour plot color. Figures 21 and 22 show the 2D surface plots of the combined effects for the standard deviation of Nuc and fc. It can be observed that the decrease of p/D, the increase of H/D, the decrease of r/D, and the increase of Re result in the augment of Nu. Moreover, it can be also seen that the decrease of p/D, the decrease of H/D, the increase of r/D, and the decrease of Re result in the weak of fc.
\nResponse surfaces contour plots of combined effects for Nuc.
Response surfaces contour plots of combined effects for fc.
By inspecting the numerical results of Nuc/Nus and fc/fs, it is found that these two responses are varied with the changes of the design parameters. There must exist design parameters corresponding to the optimal objective functions. The goal of optimization for a corrugated tube subjected the design constrains of structural limitation in this study is to find the optimal values of designing parameters to maximize Nuc/Nus and minimize fc/fs. In this study, the multi-objective optimization is executed by NSGA-II. The results for Pareto-optimal curve are shown in Figure 23, which clearly reveal the conflict between the two responses, Nuc/Nus and fc/fs. Any changed design parameter that increases Nuc/Nus leads to an increase of fc/fs. It is worth noting that the minimum values of fc/fs with Nuc/Nus for various points on Pareto optimal front. Therefore, the reported results are applicable for a problem with one objective function (fc/fs) and specific constraint (the value of selected or input Nuc/Nus). This means that the presented multi-objective optimization method provides a general optimal solution in simplified form, and one may obtain an optimum design (minimum of fc/fs and maximum of η) with a specified Nuc/Nus.
\nPareto-optimal curve.
A deep investigation of the heat and mass transfer was given in outward convex corrugated tube heat exchangers in this chapter. The detailed structure of the novel tube has been introduced, in which the heat and mass transfer mechanism is different with the traditional tube type. A specific manufacturing procedure by hydraulic bulking system has been presented for the novel tube type. The experimental setup and measuring system for the novel tube type have been depicted. From obtained experimental data, we found that with the increase of Re, Nuc/Nus, fc/fs, and PEC decline. The decreasing rate of Nuc/Nus and PEC is almost linear, but fc/fs is decelerated. The numerical study on the heat and mass transfer at outward convex corrugated tube heat exchangers has been displayed. The distribution of velocity, temperature, and turbulence kinetic energy has been analyzed. The recirculating zone between the separating streamline and the free boundary streamline is generated, which breaks the thermal boundary layer to enhance the heat transfer performance. Turbulence kinetic energy is improved at the recirculating zone. Heat and mass transfer enhancement of outward convex corrugated tube heat exchangers has been revealed. Both on the tube side and shell side, with the decreasing p/D and increasing H/D, the values of Nuc and Nuc/Nus increase. Moreover, with the increase of p/D, η decreases when Re < 30,000, but increases when Re > 30,000; the η decreases obviously with the increasing H/D. The multi-objective optimization is executed by RSM combined with NSGA-II. ANOVA is used to evaluate the fitness of regression models, perform significance testing, and construct simplified regression models between design factors and objective functions. 2D response surface contour plots are applied to describe the regression response surface model. Multi-objective optimization method provides a general optimal solution in simplified form, and one may obtain an optimum design (minimum of fc/fs and maximum of η) with a specified Nuc/Nus.
\nThe authors gratefully acknowledge the support by the National Natural Science Fund (Grant No. 51506034).
\nThe article has not been previously published, is not currently submitted for review to any other journal, and will not be submitted elsewhere before one decision is made.
Orthodontic tooth movement is a biological process that requires the relay of mechanical loading to biological signals by periodontal ligament (PDL) and alveolar bone (AB) cells such as osteoblasts, osteocytes and osteoclasts. The mechanotransduction of signals involves dynamic cellular communication which allows for coordinated cellular response of alveolar bone remodeling and periodontal tissue homeostasis that occurs in response to orthodontic force. This complex process depends on adaptive tissue remodeling of periodontium for both anabolic and catabolic events. Compression and tension forces from orthodontic treatment create stress and strain to the PDL and AB cells and their surrounding extracellular matrices (ECM), which respond to the stress and strain from orthodontic forces by expressing and secreting biologic mediators and inflammatory cytokines, osteoclast differentiation factors and ECM proteins such as collagen I, III, V and their modifying enzymes and proteases. These biomolecules, in turn, initiate the activation of fibroblasts, osteoblasts, osteocytes and recruitment and differentiation of osteoclasts leading to anabolic activities on the tension side and increased osteoclastic activity and low bone density on the compression side of tooth movement. These cellular and molecular events are strictly controlled at transcriptional, posttranscriptional and translational levels and the interference of these events affects the rate of tooth movement. Therefore, understanding the mechanism of cellular and molecular events of tooth movement will allow us to apply the cutting edge knowledge to improve clinical orthodontic practice using gene therapy or molecular biology approaches.
\nSeveral models have been proposed for mechanism of initiation of orthodontic tooth movement as below.
Pressure-tension model: it was derived from the observation of experiments from animal models, in which a force of a given direction was applied to a tooth to create the tension and compression areas in periodontal tissues [1, 2, 3, 4]. The histological studies demonstrated that bone was deposited on the alveolar wall on the tension side of the tooth in the presence of both heavy and light forces, with newly formed bone spicules followed the orientation of the periodontal fiber bundles. On the compression side, with the light forces, alveolar bone was resorbed directly by numerous multinucleated osteoclasts in Howship’s lacunae (frontal resorption). In contrast, the periodontal tissues were compressed with heavy forces, leading to capillary thrombosis, cell death and the production of localized cell-free areas (hyalinization). Hyalinization phenomenon was later supported by several investigators [5, 6, 7]. At the hyalinization sites, osteoclastic resorption of the adjacent alveolar wall did not take place directly, but was initiated from the neighboring marrow spaces referred as ‘undermining resorption’ [8].
Bone bending/piezoelectric current model: it was observed that the deformation that occurred when an external load was applied to a long bone produced electrical current in the surface curvature of the bone. Increased bone concavity was shown to be associated with electronegativity and bone formation; while increased bone convexity was associated with electropositivity and bone resorption [9]. This model has major flaws given the fact that piezoelectricity does not require the presence of living cells. Dead bone produces the same effects, which appear to be generated by shearing forces acting on the collagen fibers of the bone matrix. Therefore, the stress-generated electrical potentials could be a by-product of deformation. In addition, the magnitude of the current is small and may not be sufficient to induce cellular changes [8, 10].
Neurogenic inflammation model: it was based on the assumption that orthodontic tooth movement was the result of inflammatory processes triggered by peripheral nerve fibers referred as neurogenic inflammation. This inflammation is characterized by the release of neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P upon the stimulation of afferent nerve endings [11]. A report showed that the nerve ending released the neuropeptides after periodontal ligament had been strained by the force applied to the tooth [12].
Fluid flow shear stress model: it was based on the concept that osteocytes respond to mechanical forces. Locally strain derived from the displacement of fluid in bony canaliculi of osteocytes is very important [13]. When loading occurs, interstitial fluid squeezes through the thin layer of the non-mineralized matrix surrounding the cell bodies and cell processes, resulting in local strain at the cell membrane and activation of the affected osteocytes [14]. With regard to orthodontic force, the force on the side of the tooth receiving orthodontic pressure creates shear stress and activates responses on osteocytes [15]. The shear stress on the osteocytes induces increased secretion of biological mediators from the osteocytes leading to activation of osteoclasts [16, 17]. At the same time, on the tension side, the increased pulling force on the periodontal ligament is transferred to the bone. The resulting deformation drives the fluid flow shear stress on the network of osteocytes. This shear stress induces osteocyte activation, and osteocytes respond by secreting signaling molecules that contribute to osteoclast recruitment and differentiation.
In addition, it has been shown that compressive force induces bone matrix deformation and microcracks; and the accumulation of microscopic cracks in the bone matrix may induce additional damage to osteocytes in the microcrack region [18]. Microcracks are more prevalent on the pressure-side than on the tension-side of the tooth, and it has been hypothesized that microcracks were the first damage induced by the orthodontic force to induce osteocyte apoptosis and bone remodeling. Osteocyte apoptosis has been observed at the pressure side in an experimental tooth movement model in animal models, which may be associated with the subsequent bone resorption [19, 20]. Therefore, the microcracks may play a role in the initiation of bone resorption on the pressure side of the tooth under the compressive force of orthodontic loading [21].
\nAlthough there are several models proposed to explain the events of orthodontic tooth movement, no single model could directly and comprehensively explain this process. The evidence from histological and animal studies has shown that this complex biological process is initiated from the application of mechanical forces onto the orthodontic appliances, which converts into the biological signals to stimulate mechanosensitive cells. (Figure 1) [22] Literatures showed that orthodontic force application induced physiologic adaptation of alveolar bone with small magnitude of reversible injury to periodontium [23]. Significant evidence suggests that when mechanical loading forces are relayed from the orthodontic appliances to the PDL and bone tissues, the mechanoreceptor cells percept the loading forces as shear stress and strain [24] as the tooth shifts its position in the PDL space resulting in compression and tension areas in PDL and bone tissues [25].
\nIllustration of cellular events of periodontal ligament and alveolar bone at non-loading state. Blood vessels and periodontal fibroblasts reside in between the periodontal ligament collagen fibers. Inactive osteoblasts line along the alveolar bone surface and quiescent osteocytes reside in their bony lacunae. Modified from Hatch [25].
The sequence of biological events after loading of orthodontic force occurs as (1) fluid flow changes and matrix strain (Figure 2); (2) strain on mechanoreceptor cells (Figure 2); (3) cell activation (Figure 3); and (4) tissue remodeling leading to tooth movement (Figure 4) [15]. The mechanoreceptor cells in periodontal tissue include osteocytes and bone lining osteoblasts in alveolar bone and fibroblasts in PDL. The final result as tissue remodeling occurs in both mineralized and non-mineralized ECM during the tooth movement [26]. Recent studies have indicated that osteocytes are capable of sensing strain in their bone lacunae following mechanical loading of the bone [21]. The mechanism of how osteocytes sense, transfer, and respond to mechanical strain remains unclear. Osteocyte processes have been shown to utilize integrins, gap junctions and ion channels to respond to mechanosensing external physical stimuli [27, 28]. Fluid flow-induced shear stress is the strain resulted from an immediate change in fluid flow in the lacunar-canalicular system leading to an increasing strain on the osteocytes. This shear stress can amplify the mechanical signals to the osteocytes [14, 29]. Several proteins such as integrins, connexin 43, osteopontin, and vitronectin, and several transcriptional factors such as c-Fos expression in the osteocytes are affected by loading forces [30, 31, 32]. In addition, the reduced number of primary cilia of osteocytes could affect their secretion of prostaglandins (PGs) and increased cyclooxygenase-2 (COX2) and RANKL/OPG ratio in osteocytes in response to fluid flow shear stress [33, 34]. Recent studies showed that osteocytes can induce both anabolic and catabolic bone signals in response to loading [35, 36, 37], yet the mechanism of how osteocytes switch from catabolic activity to anabolic activity is unclear. Under compression, osteocytes undergo apoptosis and are coupled with bone resorption [19, 38]. However, fluid flow shear stress may induce osteocytes to secrete anabolic bone proteins such as prostaglandin-E2 (PGE2) or nitric oxide (NO) [39, 40]. Several recent evidence demonstrated the significance of osteocytes during osteoclast differentiation and activation [41, 42, 43]. The osteocyte ablation in vivo caused a significant reduction in osteoclastogenesis and osteoclastic activity under loading forces, suggesting the important roles of osteocytes during orthodontic tooth movement [44]. Increased evidence supported the close association between osteocytes and osteoclasts during tooth movement. Experimental tooth movement in mice demonstrated increased expression of osteopontin [45], matrix extracellular phosphoglycoprotein (MEPE) [46], and receptor activator of nuclear factor-kB ligand (RANKL) [43, 47] in osteocytes. These proteins play important roles in osteoclastic activity and osteoclastogenesis because deficiency of these proteins results in significant reduction or absence of the osteoclasts and increased bone mass in the animals [43, 48]. Osteocyte apoptosis occurred abundantly on the compression side of tooth movement in 1 day after loading, and then an increased number of osteoclasts were observed until day 3, resulting increased tooth movement by day 10 [49]. It is speculated that apoptotic osteocytes may release signaling proteins such as RANKL and interleukin (IL), to osteoclast precursors, and initiate osteoclastogenesis. In contrast, when subjected to fluid flow sheer stress, osteocytes secrete NO and PGE2, which these proteins have potent, anabolic, and direct effects on osteoblasts [40, 50, 51]. PGE2 expression increased in loaded bone tissue [52]. NO secreted from osteocytes promotes osteoblast differentiation, and plays an important role in bone formation during loading [40, 53]. NO can influence bone mass and simultaneously inhibit osteoclast activity [54]. Increased NO production by osteocytes after mechanical stimulation by fluid flow modulates apoptosis-related gene expression suggesting that NO maintains osteocyte viability [55].
\nInitial cellular events in periodontal ligament after force loading during tooth movement. The blood vessels are squeezed then local hypoxia and fluid flow change are initiated from the loading force. The mechanical strain affects the periodontal fibroblasts and osteoblasts in the periodontal ligament space. The strain creates fluid flow shear stress and strain on the osteocytes in their bone lacunae. The mechanical strain induces secretion of inflammatory cytokines and biological signaling mediators including interleukins, prostaglandins, tumor necrosis factors, nitric oxide, growth factors, proteinases and cell differentiation factors. These mediators, in turn, activate the periodontal fibroblasts, osteoblasts and osteocytes. Modified from Hatch [25].
Intermediate cellular events in periodontal ligament during tooth movement. The blood vessels dilate due to the response to the released mediators and cytokines. The activated fibroblasts, osteoblasts and osteocytes are ready to secrete M-CSF and RANKL to activate preosteoclasts from blood and bone marrow. In addition, the activated osteoblasts release OPG to act as competitive decoys for RANKL. The PDL fibroblasts release MMPs to degrade collagen fibers in the periodontal ligaments. Modified from Hatch [25].
Late cellular events in periodontal ligament and alveolar bone front during tooth movement. The activated osteoclast is derived from the fusion of preosteoclasts, creates ruffle border to seal the bone surface area and releases MMP9, TRAP and acid to resorb bone matrix and minerals. Apoptotic osteocytes also release the biomolecules and mediators to activate osteoclast recruitment for bone resorption leading to tooth movement. Modified from Hatch [25].
Beside osteocytes, preosteoblasts are also responsive to mechanical force. Mechanical force loading triggers several cell signaling pathways in osteoblasts such as calcium (Ca2+), NO, IL1β and adenosine triphosphate (ATP) in a short period of time [24, 56, 57]. NO and IL are potent mediators secreted during orthodontic tooth movement [58, 59]. Preosteoblast differentiation can be induced on the tension side of tooth movement via integrin/focal adhesion kinase signaling and Ca2+ channels [60, 61]. Fluid shear stress can trigger Ca2+ signaling pathway and promotes ATP release, PGE2 secretion and proliferation of osteoblasts [24, 57]. While on the compression side, reduced blood flow in PDL and localized hypoxia occurs. The reduction in O2 tension stabilizes hypoxia inducible factor-1 (HIF-1), a transcription factor that activates vascular endothelial growth factor (VEGF) and RANKL expression in PDL fibroblasts and osteoblasts leading to osteoclast differentiation and favoring bone resorption in areas of compression [62, 63, 64]. As mentioned above, inflammatory cascade is important for orthodontic tooth movement. During the process, inflammatory cytokine such as IL-1β, PGE2, tumor necrosis factor-alpha (TNF-α) and NO are secreted from preosteoblast in PDL and osteocytes in bone lacunae during the orthodontic tooth movement [59, 65, 66]. Compression is associated with elevated COX-2 which catalyzes production of PG, including PGE2, from arachidonic acid [67, 68]. Administration of PGE2 into alveolar bone of mice induces both osteoclasts and osteoblasts [26]. During orthodontic tooth movement, pain sensation occurs and, coincidentally, substance P and calcitonin gene related peptide (CGRP) are induced to be secreted during the tooth movement. These neuropeptides can enhance cellular secretion of inflammatory cytokine and in turn increase vasodilation and permeability of surrounding blood vessels [69, 70, 71, 72]. Several evidence showed that the inhibition of inflammation hindered tooth movement [73, 74], while inflammation in the alveolar bone promoted tooth movement [75, 76].
\nOsteoclasts are the major key cells that play significant roles during tooth movement. Osteoclasts are multinucleated giant cells which are formed by the fusion of mononucleated osteoclast precursors derived from hematopoietic origin and function to resorb the alveolar bone during tooth movement. The osteoclast progenitor cells require macrophage colony stimulating factors (M-CSF) for their proliferation and survival. M-CSF is a secreted cytokine by osteoblasts and affects osteoclast progenitors. The RANK/RANKL/OPG system has been a crucial mechanism in osteoclastogenesis during bone resorption and tooth movement [77, 78, 79]. Receptor activator for nuclear factor κB (RANK) is a transmembrane protein and a member of tumor necrosis factor receptor family that is expressed on osteoclastic precursors, preosteoclasts and osteoclasts. Receptor activator for nuclear factor κB ligand (RANKL) is a transmembrane protein and is a member of the tumor necrosis factor superfamily that is expressed on preosteoblasts, osteoblasts and osteocytes [80]. RANK is the receptor for RANKL and the binding between both of them stimulates the differentiation of preosteoclasts into mature osteoclasts. Osteoprotegerin (OPG) is a soluble extracellular tumor necrosis receptor protein that is secreted by preosteoblasts and osteoblasts. OPG is a decoy receptor for RANKL in regulating bone metabolism and inhibiting osteoclastogenesis and bone resorption. RANKL/OPG ratio is an important determinant of bone mass and skeletal integrity and also an indicator for the osteoclast function [78, 79]. Increased evidence demonstrated the direct association of tooth movement and activities of osteoclasts. Accelerated osteoclast resorption in alveolar bone of OPG deficient mice was observed during tooth movement [81] while inhibition of RANKL or deletion of RANKL in mice resulted in suppression of tooth movement [47]. In addition, local administration of M-CSF resulted in modulation of rate of tooth movement in animals [82].
\nOverall, the mechanism of tooth movement is complex and need strictly coordinated regulation of PDL, osteoclasts, osteocytes and osteoblasts. It is very challenging clinically to apply optimal force onto the tooth to avoid hyalinization. Clinically, tooth movement in patients is a result of combination of undermining and frontal resorption [83]. Compression sides involve increased expression of PGE2, TNF-α and IL-1β. PGE2 promotes osteoblast and osteoclast differentiation and activity. Activated osteoblasts secrete RANKL and OPG to trigger osteoclast differentiation and activity. TNF-α and IL-1β promote osteoclast differentiation and activity. In addition, matrix metalloproteinases (MMPs) expression is increased as well as the expression of M-CSF [84]. Loading compressive force affects osteocytes to upregulate the expression of connexin 43 [85], endothelial nitric oxide synthase (iNOS) [50], osteopontin [45], SOST [86] and RANKL [47]. These molecules recruit osteoclast precursors and activate osteoclasts to resorb the alveolar bone on the compression side. While on the tension side, increased expression of transforming growth factor-β (TGF-β), a potent ECM growth factor, was detected [87]. Several anabolic molecules such as bone sialoprotein (BSP) [88], collagen I (ColI) [89], vascular endothelial growth factor (VEGF) [84, 90], tissue inhibitors of metalloproteinases (TIMPs) [91], insulin-like growth factor (IGF) and its related receptor [92], heat shock protein 27 (HSP 27) [93] and ATP [94] were increasingly expressed on tension side during tooth movement. IL-6 around the osteocytes under loading can promote its signaling toward osteoblast pathway [53]. The presence of TIMPs around tension side is speculated to control the activity of MMP and remodeling pattern in alveolar bone. The anabolic events such as increased osteoblast activity and decreased osteoclast activity occur on the tension side of tooth movement.
\nAdministration of proteins that affect or activate osteoclasts could be a direct approach to modulate tooth movement though the dosage and side effects such as root resorption are factors of consideration. With modern advanced technology, the manufacturer can generate a large amount of human recombinant proteins for therapeutic purposes. However, the life span of these proteins once administered in human body is short and may not reach therapeutic level [95]. Gene therapy is a therapeutic approach that uses genes to treat or prevent diseases. Gene therapy is designed to introduce nucleotides into the cells to compensate for mutated genes or to restore the normal protein. If a mutation causes a crucial protein to be defective or missing, gene therapy may be able to introduce a normal copy of the gene to restore the function of the protein. After integration of the genes that encoded the target protein into the patient’s genetic machinery, gene therapy can allow the body to produce the required protein constantly so the level of protein will be constantly high at therapeutic level [96]. The concept of gene therapy includes cloning of selected DNA/RNA fragments into a delivery system in order to administer into the host or patient. The delivery system could be viral vectors or non-viral vectors such as liposomes, peptides, polymer particles, gene gun and electric perforation [97]. The clinical application of gene therapy can be achieved with in vivo or ex vivo approaches. The in vivo gene therapy will include injection of vectors into the patient directly while the ex vivo approach includes the introduction of vector into the cells then the transfected cells are transplanted back into the patient [98, 99, 100].
\nRecently gene therapy has been approved to be implemented in medicine. The U.S. Food and Drug Administration (FDA) regulates all gene therapy products in the United States and oversees research in this area. In medicine, the FDA recently approved gene therapy for the treatment of some types of leukemia and inherited blindness [101]. Several experiments of gene therapy in dentistry involved orofacial pain, squamous cell carcinoma, tooth and bone regeneration, salivary gland disease and orthodontic treatment [102].
\nThe gene therapy experiments in orthodontic treatment are still limited to cell cultures or animal experiments [103]. The purposes of previous gene therapy in orthodontic treatment were to investigate the possibility of acceleration of tooth movement or reduction of root resorption by modification of osteoclast differentiation factors such as RANKL or OPG [104, 105, 106, 107, 108, 109]. The first attempt for gene therapy in orthodontic treatment aimed to transfer OPG gene into periodontal tissue to reduce osteoclast activity and inhibit tooth movement. The gene transfer approach using a hemagglutinating virus of Japan (HVJ) envelope vector carrying mouse OPG messenger RNA (mRNA) was performed in rats for 21 days of tooth movement. The vector solution was administered into rat’s palatal gingiva by infiltration injection. The result showed that local OPG gene transfer reduced the number of osteoclasts and decreased tooth movement by 50% in rats in the experimental group compared to the ones in the control group. The effect of OPG gene transfer was local and did not affect bone mineral density of tibia of the animals [105]. The same group of investigators performed another experiment using the same system to transfer mouse RANKL mRNA to periodontal tissue to activate osteoclastogenesis and accelerate tooth movement in rats. The results showed that local RANKL gene transfer induced increased numbers of osteoclasts and accelerated tooth movement by approximately 150% in the rats in the experimental group compared to the control group. The effect of RANKL gene transfer was local and did not elicit any systemic effects. Interestingly, the number of osteoclasts was reduced time dependently after gene transfer [104]. Another group of investigators compared corticotomy with gene therapy using a hemagglutinating virus of Japan envelope vector containing mouse RANKL mRNA in rats for 32 days. The results showed increased level of RANKL protein 3 folds in the gene therapy group and 2 folds in the corticotomy group after 10 days; however, the level of RANKL protein was maintained in the gene therapy group but not in the corticotomy group. The number of osteoclasts in the RANKL gene therapy group was significantly higher at day 10 with or without tooth movement compared to the tooth movement only group. The tooth movement distance was 2 times more in the RANKL gene therapy group and 1.5 times in the corticotomy group; however, the rate of tooth movement slowed down in the corticotomy and controls groups but was constant in the RANKL gene therapy group. It was concluded that gene therapy was an alternative treatment for corticotomy to accelerate tooth movement and the efficacy of treatment was higher than corticotomy to accelerate tooth movement [106]. The OPG gene transfer experiment was performed by another group of investigators using the same viral envelope packaging and delivery system to investigate the inhibition of orthodontic relapse in rats. The first molars in the rats were moved mesially for 3 weeks then the springs were removed to generate orthodontic relapse in the rats. The rats received OPG gene therapy then were observed for 2 weeks. The results showed that relapse was significantly inhibited 2 times compared to the mock and control groups. The bone mineral density and bone volume fraction of alveolar bone were significantly increased in the gene therapy group compared to the mock and control groups. No difference of bone mineral density and bone volume fraction of tibia was found among groups. The investigators stated that local OPG gene therapy to periodontal tissues could inhibit relapse after orthodontic tooth movement via osteoclastogenesis inhibition [110]. The same group of investigators further investigated the effect of local OPG gene therapy on orthodontic root resorption with the same design of experiment. They utilized a microcomputed tomogram and histological analyses. The result showed no difference between root resorption at the beginning and the end of tooth movement in the OPG gene therapy group. However, the repair of root resorption in the gene therapy group was higher than other control groups [107]. Another study investigated the effect of local OPG gene therapy using mesenchymal stem cells as carriers for plasmid containing OPG mRNA. This cell mediated OPG gene transfer was generated by insertion of plasmid containing OPG mRNA into the mesenchymal stem cells and the cells were injected into the animals. The result showed that the cells containing OPG package grew in the animals’ PDL and the number of osteoclasts, level of RANKL and bone resorption were reduced significantly after single injection. The level of OPG was highest in the gene therapy group [108].
\nGene therapy is a promising treatment option for a number of diseases (including inherited disorders, some types of cancer, and certain viral infections). This approach is still in the developing process as an alternative approach to treat deformity or disease that conventional method could not achieved. Although many clinical trials have shown the efficacy of the treatment, the technique remains risky and is still under processes of investigation to make sure that it will be safe and do not elicit any systemic or hereditary effects for the patients.
\nWith the rise of advanced technology in biomedical engineering and medicine, gene therapy is no longer a science fiction. Several gene therapies have been approved to treat many conditions and deformities not only in the United States but worldwide [111]. In the past decade, gene targeting using endogenous microRNA (miRNA) has emerged as a powerful tool for targeted gene delivery. miRNAs are short, noncoding and highly conserved RNA sequences that tightly regulate the expression of genes by binding to their target sequence in the corresponding mRNAs [112, 113]. Majority of miRNA biogenesis involves transcription by RNA polymerase II to generate primary microRNA (pri-miRNA) followed by Drosha (RNase III enzyme) processing, which produces precursor miRNA (pre-miRNA). The pre-miRNA is transported to the cytoplasm via exportins/RanGTP complex. In the cytoplasm, the pre-miRNA is cleaved by another RNase III enzyme called Dicer to generate mature miRNA. The mature miRNA then forms a microRNA associated RNA-induced silencing complex (miRISC) with Argonaute proteins. The complex is steered to the target mRNA via base pairing with the target sequence of the miRNA. The degree of perfect complementarity at nucleotides 2–8 (binding sequence) in the 5′-end of the miRNA is essential for a successful action of the RISC complex. Depending on the extent of complementarity with the target sequence, gene expression is repressed either by inhibition of translation or by cleavage of the corresponding mRNA [114]. The process of gene therapy using endogenous miRNAs involves selection process of miRNA candidates, design of expression cassettes if constant expression is needed, selection of delivery carrier, and evaluation of system in cells, animal models and clinical trials [114]. Several miRNAs have been reported for their expression and roles in PDL and alveolar bones [115, 116, 117, 118]. Under loading, several miRNAs in PDL and alveolar bone respond to the loading force and orientation of forces in different pattern of expression [119, 120, 121]. miRNA-21 has been shown to have critical roles in PDL, osteoblasts and osteoclasts [120, 122, 123, 124, 125, 126, 127]. In addition, miRNA-21 deficient mouse demonstrated delayed tooth movement compared to the control mice via inhibition of osteoclastogenesis [127]. miRNA-29 was reported as a crucial miRNA for alveolar bone remodeling during tooth movement due to its expression under different orientation of loading forces and its expression profile in crevicular fluid during tooth movement in human [121, 128]. miRNA-29 expression in human PDL was up-regulated under compression but down-regulated under stretch force orientation [121] and its expression on crevicular fluid increased along the course of tooth movement [128]. Moreover, miRNA-29 sponge transgenic mice demonstrated delayed tooth movement due to the decreased numbers of osteoclasts [129]. These microRNAs could be a target candidate for gene therapy for orthodontic tooth movement. There are viral and nonviral delivery systems in clinical trials for gene therapy. Among viral vector system, lentiviral vector-based system has been developed and tested for its safety for more than 10 years. Non-integrating lentiviral vector have been investigated as a means of avoiding insertional mutagenesis. However, there is a disadvantage of this approach regarding the short-lived of the vectors in dividing cells [130]. Nonviral gene delivery systems (nVGDS) have great potential for therapeutic purposes and have several advantages over viral delivery including lower immunogenicity and toxicity, better cell specificity, better modifiability, and higher productivity. However, there is no ideal nVGDS; hence, there is widespread research to improve their properties [97]. The nVGDS system includes chemicals, peptides, liposomes, and polymers [97]. Exosomes are small (30–150 nm in diameter) extracellular vesicles that are formed in multivesicular bodies and are released from cells as the multivesicular bodies fuse with the plasma membrane. The exosomes were proposed to be used for delivery of miRNAs, protein and oligonucleotide complex [131], and were found to be cell secreted from osteoclasts [131] and in gingival crevicular fluid during the course of tooth movement [128].
\nAnother genome editing system that has recently gained attention in research and clinical application is CRISPR/Cas9 system. The CRISPR/Cas9 system is based on CRISPR (clustered regularly interspaced short palindromic repeats) sequence and CRISPR associated (Cas) gene mechanism that are crucial for innate defense mechanism in bacteria and archaea enabling the organisms to respond to and eliminate invading genetic materials from their phages [132]. The CRISPR/Cas9 system consists of two key molecules that introduce a mutation into the DNA. First, Cas9 is an enzyme that acts as a pair of DNA scissor. It cuts the two strands of DNA at a specific location in the genome so the genome editing could be performed either addition or removal. The other molecule is guide RNA (gRNA) which consists of a small piece of predesigned RNA sequence (∼20 bases long) located within a long RNA scaffold. The long RNA scaffold binds to DNA and the gRNA sequence guides Cas9 to edit the specific part of genome. gRNA sequence is designed to be complementary to the target DNA sequence in the target gene in the genome. gRNA sequence consists of short palindromic repeats and the sequences that complement with the target genes. The target sequences should be present close to protospacer adjacent motif (PAM) sequence which increases the specificity of Cas9. After Cas9 nuclease enzyme site specifically cleaves double stranded DNA activating double-strand break repair machinery. If the DNA repair template is provided, the piece of DNA repair template will be inserted into the sequence of target genes [133, 134]. With this mechanism, the plasmid containing gRNA, Cas9 sequences, TracrRNA (transactivating CRISP RNA) and DNA repair template sequence can be introduced into cells or embryo of the animals by viral or nonviral delivery system [135]. Until now, there is no CRISPR/Cas9 experiment involving orthodontic tooth movement, however, this technology has been implemented in recent mineralized tissue research [136, 137, 138, 139]. Future directions of gene therapy include the enhancement of the lentiviral vector-based approaches, fine tuning of the conditioning regimen, and the design of safer vectors or nonviral vector delivery system. In orthodontic field, the gene therapy approach will need several fundamental cell culture and animal experiments to demonstrate the safety and efficacy of the treatment concept. Clinical trials are required as the next step to ascertain the clinicians and patients for efficacy of the treatments.
\nWe would like to acknowledge Ms. Pornpasdchanok Asawasuwan for all artworks in the manuscript. This manuscript was supported by ROAAP fund, the University of Illinois at Chicago, Brodie Craniofacial Endowment fund, and the National Institute of Dental and Craniofacial Research (DE024531).
\nThe authors declare no conflict of interest.
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\\n\\nThe Author, on his or her own behalf and on behalf of any Co-Authors, will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Work as a consequence of IntechOpen's changes to the Work arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits as determined by IntechOpen.
\\n\\nAUTHOR'S DUTIES
\\n\\nWhen distributing or re-publishing the Work, the Author agrees to credit the Publication in which the Work has been published as the source of first publication, as well as IntechOpen. The Author guarantees that Co-Authors will also credit the Publication in which the Work has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Work.
\\n\\nThe Author agrees to:
\\n\\nThe Author is responsible for the payment of the Open Access Publishing Fees.
\\n\\nAll payments shall be due 30 days from the date of issue of the invoice. The Author or whoever is paying on behalf of the Author and Co-Authors will bear all banking and similar charges incurred.
\\n\\nThe Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Work worldwide for the full term of the above licenses, and shall provide to IntechOpen, at its request, the original copies of such consents for inspection or photocopies of such consents.
\\n\\nThe Author shall obtain written informed consent for publication from those who might recognize themselves or be identified by others, for example, from case reports or photographs.
\\n\\nThe Author shall respect confidentiality during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Authors and Co-Authors are confidential and are intended only for the recipients. The contents of any communication may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\\n\\nAUTHOR'S WARRANTY
\\n\\nThe Author and Co-Authors confirm and warrant that the Work does not and will not breach any applicable law or the rights of any third party and, specifically, that the Work contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy.
\\n\\nThe Author and Co-Authors confirm and warrant that: (i) the Work is their original work and is not copied wholly or substantially from any other work or material or any other source; (ii) the Work has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) Authors and any applicable Co-Authors are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) Authors and any applicable Co-Authors have not assigned, and will not during the term of this Publication Agreement, or purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Author and Co-Authors also confirm and warrant that: (i) he/she has the power to enter into this Publication Agreement on his or her own behalf and on behalf of each Co-Author; and (ii) has the necessary rights and/or title in and to the Work to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses granted in this Publication Agreement. If the Work was prepared jointly by the Author and Co-Authors, the Author and Co-Authors confirm and warrant that: (i) all Co-Authors agree to the submission, license and publication of the Work on the terms of this Publication Agreement; and (ii) they have the authority to enter into this binding Publication Agreement on behalf of each Co-Author. The Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each Co-Author.
\\n\\nThe Author agrees to indemnify IntechOpen for all liabilities, costs, expenses, damages and losses, as well as all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of, or in connection with, any breach of the agreed confirmations and warranties. This indemnity shall not apply in a situation in which a claim results from IntechOpen's negligence or willful misconduct.
\\n\\nNothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\nTERMINATION
\\n\\nIntechOpen has the right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including, without limitation: (i) if the Author and/or any Co-Author materially breaches this Publication Agreement; (ii) if the Author and/or any individual Co-Author is the subject of a bankruptcy petition, application or order; or (iii) if the Author and/or any corporate Co-Author commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for, or enters into, any compromise or arrangement with any of its creditors.
\\n\\nIn the event of termination, IntechOpen will notify the Author of the decision in writing.
\\n\\nINTECHOPEN’S DUTIES AND RIGHTS
\\n\\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen, at its discretion, agrees to publish the Work attributing it to the Author and Co-Authors.
\\n\\nIntechOpen has the right to include/use the Author and Co-Authors´ names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion, and marketing of the Work and has the right to contact the Author and Co-Authors until, and while, the Work is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\nIntechOpen is granted the authority to enforce the rights from this Publication Agreement on behalf of the Author and Co-Authors against third parties, for example in cases of plagiarism or copyright infringements. In respect of any such infringement or suspected infringement of the copyright in the Work, IntechOpen shall have absolute discretion in addressing any such infringement that is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the alleged infringer.
\\n\\nMISCELLANEOUS
\\n\\nFurther Assurance: The Author shall ensure that any relevant third party, including any Co-Author, shall execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of providing IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\nThird Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\nEntire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (known as the "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of any fraudulent pre-contract misrepresentation or concealment.
\\n\\nWaiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement, or by law, shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\nVariation: No variation of this Publication Agreement shall have effect unless it is in writing and signed by the parties, or by their duly authorized representatives.
\\n\\nSeverance: If any provision, or part-provision, of this Publication Agreement is, or becomes, invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\\n\\nAny modification to, or deletion of, a provision or part-provision under this clause shall not affect the validity and enforceability of the remainder of this Publication Agreement.
\\n\\nNo partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Author or any Co-Author, nor authorize any party to make or enter into any commitments for, or on behalf of, any other party.
\\n\\nGoverning law: This Publication Agreement and any dispute or claim, including non-contractual disputes or claims arising out of, or in connection with it, or its subject matter or formation, shall be governed by, and construed in accordance with, the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of, or in connection with, this Publication Agreement, including any non-contractual disputes or claims.
\\n\\nPolicy last updated: 2018-09-11
\\n"}]'},components:[{type:"htmlEditorComponent",content:'When submitting a manuscript, the Author is required to accept the Terms and Conditions set out in our Publication Agreement – Chapters below:
\n\nAUTHOR'S GRANT OF RIGHTS
\n\nSubject to the following Article, the Author grants, and shall ensure that each Co-Author grants, to IntechOpen during the full term of copyright, and any extensions or renewals of that term, the following rights:
\n\nThe foregoing licenses shall survive the expiry or termination of this Publication Agreement for any reason.
\n\nThe Author, on his or her own behalf and on behalf of any Co-Authors, reserves the following rights in the Work but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Work as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Author, and any Co-Author, confirms that they are, and will remain, a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Work and all versions of it created during IntechOpen's editing process, including the published version is retained by the Author and any Co-Authors.
\n\nSubject to the license granted above, the Author and Co-Authors retain patent, trademark and other intellectual property rights to the Work.
\n\nAll rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the specific approval of the Author or Co-Authors.
\n\nThe Author, on his or her own behalf and on behalf of any Co-Authors, will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Work as a consequence of IntechOpen's changes to the Work arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits as determined by IntechOpen.
\n\nAUTHOR'S DUTIES
\n\nWhen distributing or re-publishing the Work, the Author agrees to credit the Publication in which the Work has been published as the source of first publication, as well as IntechOpen. The Author guarantees that Co-Authors will also credit the Publication in which the Work has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Work.
\n\nThe Author agrees to:
\n\nThe Author is responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of issue of the invoice. The Author or whoever is paying on behalf of the Author and Co-Authors will bear all banking and similar charges incurred.
\n\nThe Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Work worldwide for the full term of the above licenses, and shall provide to IntechOpen, at its request, the original copies of such consents for inspection or photocopies of such consents.
\n\nThe Author shall obtain written informed consent for publication from those who might recognize themselves or be identified by others, for example, from case reports or photographs.
\n\nThe Author shall respect confidentiality during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Authors and Co-Authors are confidential and are intended only for the recipients. The contents of any communication may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\nAUTHOR'S WARRANTY
\n\nThe Author and Co-Authors confirm and warrant that the Work does not and will not breach any applicable law or the rights of any third party and, specifically, that the Work contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy.
\n\nThe Author and Co-Authors confirm and warrant that: (i) the Work is their original work and is not copied wholly or substantially from any other work or material or any other source; (ii) the Work has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) Authors and any applicable Co-Authors are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) Authors and any applicable Co-Authors have not assigned, and will not during the term of this Publication Agreement, or purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Author and Co-Authors also confirm and warrant that: (i) he/she has the power to enter into this Publication Agreement on his or her own behalf and on behalf of each Co-Author; and (ii) has the necessary rights and/or title in and to the Work to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses granted in this Publication Agreement. If the Work was prepared jointly by the Author and Co-Authors, the Author and Co-Authors confirm and warrant that: (i) all Co-Authors agree to the submission, license and publication of the Work on the terms of this Publication Agreement; and (ii) they have the authority to enter into this binding Publication Agreement on behalf of each Co-Author. The Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each Co-Author.
\n\nThe Author agrees to indemnify IntechOpen for all liabilities, costs, expenses, damages and losses, as well as all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of, or in connection with, any breach of the agreed confirmations and warranties. This indemnity shall not apply in a situation in which a claim results from IntechOpen's negligence or willful misconduct.
\n\nNothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\nTERMINATION
\n\nIntechOpen has the right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including, without limitation: (i) if the Author and/or any Co-Author materially breaches this Publication Agreement; (ii) if the Author and/or any individual Co-Author is the subject of a bankruptcy petition, application or order; or (iii) if the Author and/or any corporate Co-Author commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for, or enters into, any compromise or arrangement with any of its creditors.
\n\nIn the event of termination, IntechOpen will notify the Author of the decision in writing.
\n\nINTECHOPEN’S DUTIES AND RIGHTS
\n\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen, at its discretion, agrees to publish the Work attributing it to the Author and Co-Authors.
\n\nIntechOpen has the right to include/use the Author and Co-Authors´ names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion, and marketing of the Work and has the right to contact the Author and Co-Authors until, and while, the Work is publicly available on any platform owned and/or operated by IntechOpen.
\n\nIntechOpen is granted the authority to enforce the rights from this Publication Agreement on behalf of the Author and Co-Authors against third parties, for example in cases of plagiarism or copyright infringements. In respect of any such infringement or suspected infringement of the copyright in the Work, IntechOpen shall have absolute discretion in addressing any such infringement that is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the alleged infringer.
\n\nMISCELLANEOUS
\n\nFurther Assurance: The Author shall ensure that any relevant third party, including any Co-Author, shall execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of providing IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\nThird Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\nEntire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (known as the "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of any fraudulent pre-contract misrepresentation or concealment.
\n\nWaiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement, or by law, shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\nVariation: No variation of this Publication Agreement shall have effect unless it is in writing and signed by the parties, or by their duly authorized representatives.
\n\nSeverance: If any provision, or part-provision, of this Publication Agreement is, or becomes, invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to, or deletion of, a provision or part-provision under this clause shall not affect the validity and enforceability of the remainder of this Publication Agreement.
\n\nNo partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Author or any Co-Author, nor authorize any party to make or enter into any commitments for, or on behalf of, any other party.
\n\nGoverning law: This Publication Agreement and any dispute or claim, including non-contractual disputes or claims arising out of, or in connection with it, or its subject matter or formation, shall be governed by, and construed in accordance with, the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of, or in connection with, this Publication Agreement, including any non-contractual disputes or claims.
\n\nPolicy last updated: 2018-09-11
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:null},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). 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