Surgeons need to understand the effects of the nasal cartilage on facial morphology, the function of both soft tissues and hard tissues and nasal function when performing nasal surgery. In nasal cartilage-related surgery, the main goals for clinical research should include clarification of surgical goals, rationalization of surgical methods, precision and personalization of surgical design and preparation and improved convenience of doctor–patient communication. Computational technology has become an effective way to achieve these goals. Advances in three-dimensional (3D) imaging technology will promote nasal cartilage-related applications, including research on computational modelling technology, computational simulation technology, virtual surgery planning and 3D printing technology. These technologies are destined to revolutionize nasal surgery further. In this review, we summarize the advantages, latest findings and application progress of various computational technologies used in clinical nasal cartilage-related work and research. The application prospects of each technique are also discussed. The nasal cartilage system contains two alar cartilages, the nasal septum cartilage, two upper lateral cartilages , and some accessory cartilage components. The nasal cartilage is considered the most demanding element of nasal surgery, especially of rhinoplasty and facial plastic surgery. The surgeon should understand the association of the nasal cartilage to the facial morphology, the function of both soft tissues and hard tissues, and nasal function. Patient-specific characteristics may also impact the outcomes of nasal surgery. Nasal surgery involving the nasal cartilage can be roughly divided into cosmetic surgery , deformity reconstruction , functional reconstruction  and related operations such as tumour resection.2 Computational technology is one aspect of biomedical engineering that is used in clinical research, which forms the link between principle and practice. Computational technology can assist in exploring the role of physical factors and predict the results to guide the external conditions that should be applied in practice.3 The research on nasal cartilage-related surgery is conducted primarily to investigate the principles of surgical design and the changes in related physical factors  caused by the operation.7 It differs from basic research on nasal cartilage-related tissue engineering and should be verified by clinical operation and post-operative effect evaluation. Computational technology has become an important tool for nasal cartilage-related surgery and clinical application due to its high efficiency, low costs and ability to analyse and simulate organs and tissues independently.In recent years, biomedical engineering applications for the nasal cartilage has developed rapidly.10The workflow for implementing computational technology is as follows: (1) apply imaging and model reconstruction technologies to build accurate models, (2) use structural mechanics and fluid mechanics analysis to explore biomechanical mechanisms and (3) use three-dimensional (3D) printing and computer-aided design (CAD) to assist clinical treatment. Using computational technology, we can target individual patient characteristics, such as the patient’s tissue anatomy and surgical requirements, and combine them with surgical methods to predict or obtain information that would be helpful for clinical treatment. Therefore, computational technology, mainly related to surgical modelling and simulation, can assist maxillofacial plastic surgeons in better understanding the nasal cartilage.Three-dimensional imaging technologies should form the basis for all patient-specific 3D model-related studies and applications. However, imaging of the nasal cartilages is more difficult than imaging of other cartilage types because of its small and complex structural features. Computational technology, such as structural and fluid mechanics analysis, can provide a reliable method to form the theoretical foundation for surgical technique modification. It can also directly help improve medical care, such as with virtual surgical planning and 3D printing, which have definitely increased surgical accuracy. In this review, we mainly introduce computational technologies related to the clinical research of the nasal cartilages, aiming to provide clinicians with alternative analytical methods, theoretical foundations and application techniques when selecting reasonable and effective treatment options for patients. A brief guideline demonstrating how this review is structured and the items to consider when starting a nasal cartilage-related clinical study using computational technology is shown in Fig. 11 This discrepancy has led to limited planning and prediction of surgical outcomes, and it has also made it difficult to correlate the identified structures with functional outcomes.13 Conventional techniques currently used for 3D modelling of nasal cartilage include computerized tomography (CT) and magnetic resonance imaging (MRI). Since both methods of airway reconstruction can be applied, this section mainly discusses the 3D imaging methods used in the model reconstruction of nasal cartilage. Meanwhile, the 3D imaging of facial muscles is also discussed, as the facial muscles may also be included for a more complete nasal model.Three-dimensional imaging technology forms the basis of model reconstruction and is the foundation of the clinical patient-specific application of most computational technology. Precise and accurate 3D imaging of the nose structure is mandatory for completing a variety of subsequent computer processing steps. At present, one of the fundamental challenges in the preoperative evaluation of rhinoplasty is to distinguish the position and morphological characteristics of the nasal cartilage. Unlike articular cartilage, which is surrounded by synovial fluid, the nasal cartilage is surrounded by soft tissue, and articular cartilage is often larger than nasal cartilage.14 which is calculated based on the concentration of calcium hydroxyapatite or dipotassium hydrogen phosphate in the bone.15 Contrast-enhanced CT is an expanded form of CT that utilizes iodinated contrast media (ICM) to evaluate the soft tissue; specifically, intra-articular injection is frequently suggested for knee evaluation in a technique named CT arthrography.16 ICM is used to contact the soft tissue structure. CT arthrography is regarded as the gold standard to evaluate the surface morphology of the articular surface, but it may not be applied to nasal cartilage. Administration of ICM through intravascular routes may help to reveal the structures in the nasal area, but this needs to be demonstrated in future studies, and the ability to show nasal cartilage has never been shown. However, ICM may suggest a clue for nasal-related muscle reconstruction. Quantitative CT arthrography can be used to identify the glycosaminoglycan (GAG) content,17 which may have the potential to distinguish nasal cartilage. ICM administration is also a problem for quantitative CT arthrography if applied to nasal cartilage. Cone beam CT (CBCT) has also been used in arthrography, and it shows good ability to separate the articular cartilage from the surrounding tissue.18 However, the characteristics of nasal cartilage, including its surrounding tissues, size and shape, make its visualization difficult on CBCT imaging, which limits the application of this technique to model reconstruction of the nasal cartilage.CT scans make use of computer-processed combinations of numerous X-ray measurements taken from different angles to produce cross-sectional images of specific areas of the human body, allowing the user to obtain tomographic images of the corresponding tissues. Cartilage is not easily visible on CT because of its similar X-ray attenuation to soft tissues, and it may often require the administration of contrast media for visualization. In contrast, CT is the best imaging method to evaluate bone due to its greater contrast resolution than soft tissues. CT can be applied to illustrate bony characteristics and quantify biologically relevant information, such as bone mineral density,19 applied the method of stereorendering to CT scan results to show the morphological characteristics of nasal cartilage. Their study showed that this method could aid in improving the accuracy of the pathological diagnosis of the nose, but they did not verify that the reconstructed model could be applied to the nasal cartilage. The resolution of micro-CT is much higher than that of ordinary CT, with the cross-sectional pixel size reaching the micron level, which can improve the localization and morphological visualization of the nasal cartilage. Visscher et al.20 did not reconstruct the nasal cartilage structure with CT, but applied micro-CT to verify the effect of cartilage modelling  can directly help to measure the proteoglycan/GAG content of cartilage and can also effectively evaluate cartilage regeneration, but this technique suffers from issues related to the toxicity of gadolinium administration and wait time.25 T1ρ can also be used to assess the proteoglycan/GAG content, but the evaluation is not as specific as dGEMRIC, as it also reflects other cartilage changes.26 In T2 mapping, increased T2 values can reflect the degeneration of cartilage, and this sequence can be read on most scanners.27 Decreased ultrashort echo time (UTE)‐T2* values can reflect cartilage matrix degeneration, while acute elevations in UTE‐T2* after anterior cruciate ligament injury may indicate irreversible cartilage damage and can help in evaluating the deep zone of cartilage.28 Sodium imaging is mostly associated with assessment of the GAG content, but its disadvantages include a low signal-to-noise ratio and the need for coils and high field strengths.29 Diffusion-weighted imaging can be used to evaluate the collagen structure, but the sequences are long and require high field strength similar to sodium imaging.30 In diffusion-tensor imaging, the mean diffusivity is correlated to proteoglycan concentration and anisotropy represents the collagen structure, but the disadvantages of diffusion-tensor imaging are the same as those of diffusion-weight imaging.31 GAG chemical exchange saturation transfer MRI can non-invasively quantify GAG content in cartilage without coils, but requires high field strength.32MRI uses nuclear magnetic resonance to image body tissues. Compared with CT, MRI is more widely used for imaging soft tissues. MRI is also often applied to the detection and evaluation of cartilage in vivo. For MRI, the imaging sequences are important.34 The assessment of implanted tissue-engineered cartilage during rhinoplasty is also frequently examined by MRI.35 As early as 2001, Kleinheinz and Joosl36 used MRI to distinguish and evaluate cartilage and muscle tissue in patients with unilateral cleft lip and palate. The most significant advantage of MRI is that can be used to identify different soft tissues, and because of the various water and hydrocarbon contents of different kinds of tissue, MRI has also become the most potent tool for distinguishing cartilage.For nasal cartilage, MRI has been widely used in the diagnosis of diseases and effect evaluation of treatments. Nasal cartilage tumours are often clinically imaged using MRI.20 created a cartilage reconstruction model by scanning the nasal tissue of a corpse after fixation. Our team used MRI for the first time to scan the nasolabial part of healthy individuals and patients with unilateral cleft lip and nose deformities, reconstructed the cartilage structure of the nose and designed surgery based on the cartilage structure.6 Micro-MRI can also be used to scan smaller elements of the nasolabial tissues, resulting in higher resolution images. However, the very same small scanning range used in micro-CT also limits its scope for clinical application , OsiriX , Amira  and Avizo . Some domestic software, such as BioVision , ANYTHINK-GVCM  and Trandomed , can also help handle imaging data nicely.41 Multiple models can be assembled using CAD software, such as Creo Parametric .6Commonly used medical image processing software can often complete most of the reconstruction work. If further modification or design of the model is required, software such as Geomagic  and 3D Max  should be selected, and such software is also available for measurements.6 in which the nasal cartilage model and nasal model or airway model reconstruction are based on patient image data. The process of individual model reconstruction is as follows: (1) DICOM format data are obtained by CT or MRI scans of the patient’s nasolabial region; (2) DICOM data are imported into the model reconstruction software for modelling, and anatomy-based segmentation is performed based on the threshold set on each slice. Because the area of nasal cartilage in each slice is small, manual segmentation is often required to obtain a more accurate model. The solid model is then exported in STL format; (3) computer-aided software is selected to design, modify and measure the reconstructed model if needed and to assemble the model for later processing  DICOM format data are obtained by CT or MRI scans of the patient’s nasolabial region; (2) DICOM data are imported into the model reconstruction software for nasal soft tissue modelling, and the solid model is exported in STL format; (3) CAD software is used to reconstruct the nasal cartilage model based on the anatomical structure, and the output is exported in the STL format; and (4) the appropriate software is chosen to design, modify and measure the reconstructed model if needed and to assemble the model for later processing  the models to be derived from the imaging; (2) the software to be used; and (3) the imaging segmentation tools to be used. This may help to find the right set of software and hardware for good model reconstruction.The above three model reconstruction cases are typically encountered in nasal cartilage research. For those models derived from the patient’s imaging data, brightness thresholding, region growing and manual segmentation are the keys to successful modelling. CT is good at showing hard tissues and automatic thresholding may help to save time, but when considering a small region such as that for a bone fracture, manual editing should be used. For MRI, deriving medium brightness tissue such as cartilage or demonstrating the connection between different soft tissues can take the bulk of time. During model reconstruction, the following should be kept in mind:Computational simulation is designed to predict the behaviour of a real-world or physical system-based mathematical model by computer. Computational simulations of tissues and organs can help researchers understand the influence of different and complex factors, such as engineering, anatomy, physics and mechanics, on a particular biomedical problem and assist in finding possible solutions. The most significant advantage of computational simulation technology is that it can ignore complicated influencing factors, observe the trend of activity of a single factor and provide directional guidance for clinical observation and treatment. Model simulation technology originated from the field of engineering. As mentioned in the introduction, the influence of physical factors on experimental results in tissue engineering can be guided by computational simulation. In clinical research, the quality of the surgical outcome often requires sufficient economic and time costs to be verified. It is not advisable to choose or modify the surgical method blindly. With the application of computational simulation technology, the surgical results can be predicted in advance to guide surgical practice, and the validity of the simulated results will be verified by the surgical outcomes, thereby further improving the therapeutic effects by forming a virtuous circle and reducing costs. Structural mechanics analysis and fluid mechanics analysis are the two most commonly used areas of computational simulation technology for research on the nose. Structural biomechanics analysis focuses on the effect of surgery on nasal morphology, while air dynamics analysis can be used to study the impact of surgery on nasal ventilation and other functions.The finite element method is the most commonly used method for both structural mechanics analysis and fluid mechanics analysis and requires a software to complete four steps: mesh development, preprocessing, solving and post processing.42 and FEBio 45 have been used for mesh generation and preprocessing in nasal cartilage and nasal-related research. Hypermesh ,46 Trelis 47 and CATIA 48 have been used for other kinds of cartilage in mesh generation and preprocessing and can also be applied to nasal cartilage. In addition to its convenient model reconstruction function, Mimics has certain advantages in surface 3D meshing. FEBio can be used for preprocessing, such as the calculation of superelastic coefficients and the extraction of non-linear characteristics. Abaqus  has been widely used in finite element analysis,51 for example, in the analysis of porcine nasal cartilage by Chae et al.52 in 2001. Its advantage lies in structural mechanics analysis and performing non-linear calculations. Ansys Workbench contains a variety of analysis modules that are very convenient to use.7 COMSOL , FEBio and SolidWorks  have also been used for nasal cartilage-related finite element analysis.56Each step has a corresponding software or software module, and some software contains modules for all four steps, which can be selected according to the research requirements. Mimics , Ansys Workbench 57 Different approaches can be chosen. Tetrahedral mesh generation is most commonly used in patient-specific applications, as it can be generated automatically. It can be easily used if the information of the model is available as a closed surface. Quality control of tetrahedral meshes is challenging for this automatic approach, however, and the Delaunay triangulation method,58 modified-octree technique,59 and advancing front technique60 can be applied to help in this process. The computation (CPU) time is related to the choice of mesh generator. For this approach, the main portion of the time will be spent extracting information from the patient’s images, such as for model reconstruction, rather than mesh generation, as it may only take a few minutes to generate the tetrahedral elements for a well-reconstructed model. Hexahedral and hexa-dominant mesh generation are other common approaches. Although it is a more accurate method, the manual generation of hexahedral elements takes up the bulk of time when performing patient-specific tissue modelling. Every single element requires the operator’s effort to complete. In patient-specific applications, there are no completely automatic approaches that are suitable for hexahedral meshing when targeting tissues or organs. Structured and unstructured grid generations are two types of meshing.62 Structured grid generation is based on rules for geometrical grid subdivisions and mapping techniques. For two-dimensional analyses, triangular or quadrilateral grids are applied, and hexahedral elements are used for three-dimensional methods. Unstructured grid generation is based on an explicit definition of the connections between nodes to form elements, in addition to the coordinates of the nodes themselves. Isogeometric analysis is another meshing method, which eliminates the finite element polynomial representation of geometry and replaces it with the representation.63 Meshless methods are also promising tools for surgical simulation, in which field variable interpolation is performed without the use of a predefined mesh.64 To summarize, there are a variety of meshing methods, and one should be chosen that can solve the research problem and meet the study requirements.Finite element meshing is the most critical step for the finite element method. For complicated tissue or organ shapes, mesh generation is an extremely difficult and complicated process. Manual intervention for those structures is always needed.Structural biomechanics analysis can be used to quantitatively study the deformations, stresses, energy and so on, produced by the 3D model of tissue structure under different influencing factors. Model reconstruction for nasal cartilage-related finite element analysis is performed according to the purpose of the study. The whole nose, including bone, cartilage and soft tissue, is not always required. When only targeting the mechanical properties of one aspect of the cartilage, such as the nasal septum or alar cartilage, only the model of this cartilage instead of that of the whole nose may be needed to perform computer-based mechanical testing. However, when targeting the influence of changes in the cartilage on the entire nose, the cartilage and soft tissue should be included in the model construction at a minimum because the nasal cartilage should be considered as one complete system. The different nasal cartilages are connected in the nasal system of humans, so changing one part will affect the others. Thus, the selection of the correct modelling strategy is the key to successful nasal finite element analysis.The boundary conditions selected for the finite element analysis in structural biomechanics should be consistent with the actual research objectives. The constitutive equation can be set to be non-linear, linear, or an even more complicated system, but real human tissue cannot be simply defined. Appropriate simplification of the model is inevitable, and this is the reason why the boundary conditions of different studies are set differently.65 At the same time, the setting of the physical properties of different tissues is also important. Taking nasal cartilage as an example, the physical and mechanical properties of different nasal cartilages or different parts from one cartilage are different.56 Important literature related to the finite element analysis of nasal cartilage is listed in Supplementary Table The closer the computational simulation results are to reality, the richer the set environmental conditions and the more complicated the calculation process.50 obtained three types of deformation by loading forces on different parts of a simplified nasal septum model to correspond to nasal septum deflections observed in the clinic. Lee et al.51 explored the characteristics of stress distribution by changing conditions such as the angle and length of the nasal septum model and simulating the force on the nasal tip after trauma. A simplified nasal septum model was also applied in the analysis of the effect of laser treatment on the biomechanical properties of nasal cartilage.67Simplifying the multi-factor, multi-condition and complex structure to analyse the influence of a single variable is still the most common method for nasal cartilage finite element analysis, and the simplification methods are also varied. At present, the nasal septum and the septal L-strut are the most frequently studied parts of the nasal anatomy using simplified models. Computers are used to design both the nasal septum model and the L-strut model to be as similar to reality as possible without involving other cartilages or soft tissues. By applying certain external factors (mostly different loading forces) or changing the side length or angle of the model, simulations of structural biomechanical changes under different conditions can be performed. Liong et al.68 combined the analysis of the force on the septal L-strut dissected from human specimens and the finite element analysis of the simplified L-strut in one study. Lee et al.69 analysed the deformation and stress distribution of the entire L-strut by changing the material properties and the support of the nasal tip and proposed the importance of maintaining adequate cartilage support at the bone–cartilage junction and nasal condyle. This study also compared its outcomes with those of Mau’s study. They further applied this model to analyse the minimum width and structural characteristics of the L-strut, which stabilizes the nasal septum, and indicated that only 1 cm was needed to support 45% of the whole width of the nasal septum.70Simplified models of the septal L-strut have been studied many times. As early as 2007, Mau et al.54 established three simplified models of the alar cartilage with different widths to simulate various cartilage resections and proposed maintaining at least 6 mm of lateral crus of the alar cartilage to ensure adequate structural support, for which sufficient width may be able to resist the force caused by post-operative scarring. The stress distribution in the tissue caused by the scar left after inverse V incisions on the columella was also analysed by a finite element model containing partial cartilage and soft tissue, which was set under non-linear hyperelastic conditions.71 Chang et al.45 recently measured the mechanical properties of nasal cartilage under non-linear conditions for the first time and verified the outcomes with the finite element method.Simplified models of the alar cartilage are more complicated than those related to the nasal septum because the alar cartilage is a curved structure that supports the bilateral nasal alas and nasal columella. Oliaei et al.42 first included bone, cartilage and soft tissue in one finite element analysis to simulate the clinical problems encountered in functional rhinoplasty and pointed out that the nasal septum cartilage and most of the alar cartilage worked together to support the nasal tip. Based on Manuel’s model and research, Shamouelian et al.72 further investigated the two main mechanisms that support the nasal tip  and proposed that the second contact has a more significant effect on the nasal tip support. Leary et al.55 analysed the influence of different nasal cartilage resection widths on their strength and stability, using a model modification idea similar to that of Oliaei’s research.54 Tjoa et al.73 used Manuel’s model to simulate wound healing and surgical steps to explore their associations with inverted-V deformities. Gandy et al.41 analysed the effects of the size and shape of the columellar implant and its relationship with the medial crus of the alar cartilage on nasal tip support. From the series of studies by Manuel et al.,42 it was again shown that the same model can achieve the simulate different clinical problems through appropriate modification of the model and changes in the way that force is applied. At the same time, the model can also be used to analyse the function of each part of the structure. However, there are obvious problems in this series of studies. One is that the reconstruction of the nasal cartilage is not based on an individual patient’s image data, and the other is the lack of experimental or clinical data to further verify the results of the computer simulation.In 2014, Manuel et al.4 Next, we applied the finite element method to evaluate the effect of different alar cartilage suspension manoeuvres on a unilateral complete cleft lip nose model reconstructed from micro-MRI data and demonstrated the characteristics of different manoeuvres.7 Then, we explored the biomechanical forces that should be included during cleft lip rhinoplasty.5 We also used a secondary unilateral cleft lip nasal deformity model to simulate two suturing manoeuvres during unilateral cleft lip rhinoplasty, including the passive intercrural suture and a suture suspending the alar cartilage from the upper lateral cartilage. The functional biomechanical characteristics of the two sutures on the nasal structure were revealed, and clinical data were used to verify the finite element outcomes.6 This series of studies can be regarded as an example of “using finite element analysis to obtain a theoretical basis for guiding clinical practice”  determine the clinical problems and design the modifications or solutions; (2) use computational simulations to predict the changes, compare the results to the objectives, and change the solution if the results do not meet the expectations; (3) practice the solutions to the clinical work and collect the data; and (4) compare the clinical outcomes with the computational results to finally decide if the problems have been solved. This kind of combination of theory and practice should help to impact this computer-simulating clinical research area.76 and some measurement tools such as peak nasal rhinomanometry and acoustic rhinometry.78 Measurement of peak nasal inspiratory flow is also an effective method to assess nasal ventilation.79 Although these methods can help in determining the status of nasal ventilation function, they are unable to reveal the characteristics of nasal airflow and the causes of such airflows, such as local airflow and pressure changes and turbulence. Therefore, computational fluid dynamics (CFD) has become an effective method for analysing the characteristics of airway airflow. These computational techniques can not only quantify the various indexes of airflow in the airway, but can also be used to visualize the simulated airflow, which is impossible for other methods.83The ventilation function of the upper airway is critical, and the first step of airflow into the upper airway is through the nasal airway. There are many methods for assessing ventilation function, including patient-reported quality of life questionnaires and physical examinations,84 Computational fluid mechanics need to follow appropriate calculation methods. The most basic algorithm is to apply Euler equations under inviscid fluid conditions and to apply Navier–Stokes equations under viscous fluid conditions. The workflow of nose-related CFD analysis is as follows: (1) reconstruct the airway model based on CT or MRI image data; (2) set boundary conditions ; and (3) perform fluid mechanics calculations and analysis.86 Typically, CFD is based on the principle of finite elements; that is, the entire airway needs to be meshed.87 ANSYS provides a series of modules based on finite element analysis, such as ICEM-CFD and Fluent, which can be used for fluid dynamic analyses of airways. However, the finite element method takes a very long time to complete just a single fluid mechanics analysis,88 and if the computer is not sufficiently configured, it will cause the computer to freeze or the operation to fail. The ANSYS Discovery Live processor module for the fluid mechanics analysis of velopharyngeal function recently published by our team can solve this problem well. The calculations performed by this software no longer require meshing the model.90 Regardless of the type of software used, much information can be obtained from the simulation, which is impossible for the other methods. Visualizing and quantifying airway fluid can significantly improve researchers’ and doctors’ understanding of the physiological functions of the nose.CFD is a typical application of fluid mechanics, mathematics and computer science. Digital models are used to simulate the flow of liquids, particles and gasses in a flow field.84 For example, CFD showed that the magnitude and direction of the airflow pattern in an individual patient’s sinonasal anatomy after virtual endoscopic skull base surgery.91 However, the difficulty of sinus reconstruction is that it can only be observed if the sinus is connected to the nasal cavity after model reconstruction, and some small sinus models will cause the modelling process to be extremely complicated. The choice of whether to reconstruct the sinus should be based on the study purpose, but modelling should be as accurate as possible to simulate the real sinuses, so all the potential functional parts should be retained as best as possible.Airway model reconstruction is much easier than nasal cartilage model reconstruction, as the airway has a clear boundary with the respiratory tract. For airways including the nasal cavity, nasopharynx, oropharynx, laryngopharynx and trachea, choosing the appropriate part of the airway is vital for CFD analyses. However, in aiming to analyse the airflow in the nose, one should not only reconstruct the nasal cavity, as the air in an entire flow field cannot be separated, and even a small change in the field could induce a change in the entire airflow pattern. For example, when the cross-sectional area of one large portion equals the total area of two small portions, the airflow patterns under the two conditions are totally different. Herein, researchers should choose the right parts of the airway based on their study design. The airway from the nostrils to the start of the trachea is recommended, as the morphology of the trachea and the distance to the nasal cavity should make the trachea have little influence on the airflow in the nasal cavity. Another aspect that should be considered is the collection of data from the sinuses, including the frontal sinus, ethmoid sinus, sphenoid sinus and maxillary sinus. The sinuses will definitely influence the airflow in the nasal cavity.92 and (3) set the speed or pressure-inlet condition associated with the research needs. This is because the analysis processes of different studies may involve inhalation or exhalation, and the corresponding states of different diseases are not consistent. When simulating the inhalation process, the inlet should be set at the nostrils, while for the exhalation process, the inlet should be set at the other side of the model. Changes to the velocity, pressure and inlets as well as the outlets over time in one simulation should also be applied when the goal of the study is to understand the airflow in the entire respiration process. At the same time, such changes will also cause the different settings of the equations, algorithms and physical properties of gases used in the simulation to change.93The boundary conditions of the model need to be set before calculation. Common steps for setting the conditions for the nasal steady-state airflow field are as follows: (1) set a wall condition  at the airway walls, (2) set a pressure-outlet condition with gauge pressure to 094 established the first 3D model of the airway for dynamic airflow analysis, which was reconstructed based on CT data. Since then, CFD research has been widely employed in various studies related to the nose and airflow. In addition to the study of airflow, the use of CFD has also included changes in temperature and humidity97 and drug delivery through the respiratory tract.99 Of all the published CFD analyses of nasal airflow, the main direction has been to study nasal obstruction, the research of which mostly involves abnormal airway structure and surgical intervention , is used in orthognathic, cranio-orbital and traumatic surgeries and microsurgeries involving craniofacial–facial bones. By acquiring the patient’s 3D image data, a software is used to reconstruct patient-specific tissues, and the surgical design can be performed on the reconstructed 3D model. Virtual surgical planning in orthognathic surgery is one ideal example.117 The advancements in 3D imaging techniques guarantee better visualization of any preoperative, intraoperative and post-operative phenotypic changes of both bone and soft tissues, which can help improve the accuracy of diagnosis and treatment planning. Furthermore, virtual planning allows fabrication of custom cutting guides and fixation plates, which can help surgeons reproduce virtual surgical planning osteotomies and save time for placement and removal of intraoperative splints. Orbital and traumatic reconstructions are also ideally suited for virtual planning, as CT allows a good view of the bony anatomy and critical neurovascular structures, which can help in efficiently planning osteotomies, fracture reductions and orbital implant placement.119In the past few years, virtual surgical planning has gradually become an essential tool in the clinical work of craniofacial surgery.121 Some reports applied patient-specific data to the design of rhinoplasty, but the analyses focused on the soft tissue without describing the nasal cartilage , as CBCT or 3D photography cannot demonstrate clear cartilage information.125 In addition to only designing the external nasal shape, other studies used CFD to design the surgery, but these studies only extracted the patient’s airway model for analysis without involving the nasal cartilage.128 In virtual surgical planning for nasal airway obstruction, modification of the patient’s preoperative model was first performed, and CFD was applied to evaluate nasal patency.129 Zarrabi et al.130 reported the use of CAD/CAM to assist the reconstruction of the patient’s face. In this study, the designed scaffold was used to support a nasal prosthesis, which can be regarded as the prototype of the patient-specific design of the nasal cartilage.In the field of functional rhinoplasty, however, patient-specific virtual surgery planning has not been widely used, which may be due to the uniqueness of individual nasal structures. Appropriate digital modification of the patient’s computational models mimicking actual surgery and healing was proven to have the potential to predict post-operative outcomes and improve the success rates of surgery.131 started to use 3D computational animations to demonstrate cleft lip and palate surgery for teaching. These animations describe the process of cleft lip rhinoplasty in detail, including the characteristics of the nasal cartilage at the site of the cleft lip nasal deformity and ways to manipulate the nasal cartilage during surgery. These animations described the methods for performing incisions and sewing the cartilage well and can aid medical students or surgeons understand the surgical process better. Different manoeuvres for cartilage suturing during cleft lip rhinoplasty were also shown along with an explanation. In recent years, the technology has been further developed, yielding digital simulations involved in human–computer interactions, which enabled students to study each surgical step in great detail.134 Each step of cleft lip nasal deformity reconstruction was listed. The students and doctors can choose the step they want to learn and view the manoeuvre from different angles. Videos of actual surgery were included and could be watched at the same time as the simulator was manipulated.However, medical education on rhinoplasty using computational 3D technology and digital simulation has been carried out since the beginning of this century. In 2002, Cutting et al.As we mentioned in the section on nasal cartilage imaging, our team first performed MRI scans of patients to obtain patient-specific nasal cartilage information in 2018. As virtual surgery planning requires patient-specific data, the application of virtual surgery planning to nasal cartilage was delayed with respect to that for bone and soft tissue. Computational imaging technology further limits this application. There are two main problems with nasal cartilage reconstruction: (1) the resolution of ordinary MRI is low, and micro-MRI cannot be used for patient scanning; and (2) as a result of the poor image resolution, it always takes much time to perform artificial reconstruction of the nasal cartilage, which also limits its clinical application. However, it is believed that as the technology continues to be developed, these problems will be gradually solved, and virtual surgery planning will become well applied to nasal cartilage-related surgery.118 The function of 3D printing in current clinical applications is mostly to build patient-specific implants following the principles of precision medicine.135 In rhinoplasty, cartilage implantation is widely used, and the current sources of implanted bone are mostly from the patient’s auricle or rib cartilage.137 Commercial implants can also be chosen.139 The creation of appropriate implants is not only limited by the quality of the cartilage, but can also cause secondary trauma to the patient. 3D printing has now become the method of choice for the accurate design and construction of patient-specific implants.142 Tissue engineering cartilage is expected to be a solution to the above problem, and 3D bioprinting will become the leading force in the research of tissue engineering cartilage implants. 3D bioprinting is the construction of active tissues or organs in vitro based on the principles of 3D printing.143 The development of bioinks, which are biocompatible and can contain other biological components such as cells or bioactive factors, was essential in promoting the application of 3D printing to tissue engineering.118 Herein, 3D printing for the nasal cartilage area could encompass two kinds of targets: (1) based on tissue engineering, 3D bioprinting could be used to fabricate a scaffold for regenerating the biological cartilage, which would then be applied or implanted to the defect area; or (2) 3D printing could be used directly to build a biocompatible scaffold or implant to function as the cartilage itself or to fabricate the prosthesis, in which biological cartilage is not needed.3D printing is a manufacturing technique that can be used to build complex 3D geometric structures, which can be used as scaffolds for tissue engineering or patient-specific implantation. 3D printing technology was first developed in 1990 and after approximately a decade, was implemented in the medical field to perform bioprinting.144 The inkjet method creates a pressure change upstream of the nozzles to eject the material droplet. High-speed printability, low costs and the possibility of encapsulating cells in the material are the advantages of the inkjet method. The laser-assisted method does not require nozzles. During printing, a laser pulse is used to stimulate the target area, and the energy-absorbing layer is evaporated, leading to the formation of a droplet. The extrusion method is the most commonly used method, in which the material fuses to create a continuous structure after leaving the nozzles at room temperature. Affordability, high speed and the ability to print multiple materials at the same time with a multi-nozzle printer are the advantages of the extrusion method. 3D printing materials for tissue engineering can be summarized into four types: polymers, ceramics, composites and cell aggregates.Inkjet, laser assisted and extrusion are the three main 3D printing methodologies.145 Different cells,148 scaffolds from different materials,153 and different bioactive factors155 have been applied to the tissue engineering of nasal cartilage and have achieved good results, but tissue engineering related to physical factors is more common in other types of cartilage.157 Nevertheless, the 3D bioprinting of nasal cartilage remains in the experimental stage because it is limited by the clinical application of related bioactive factors. This method has the potential to improve cartilage engineering.160For the first nasal cartilage target, with the development of tissue engineering, four elements have gradually been developed: cells, scaffolds, bioactive factors and physical features.162 The 3D-printed nasal implant or stent can be regarded as a substitute for the nasal cartilage and has been gradually applied to rhinoplasty. In nasal septum perforation, 3D printing has been used to make a prosthesis that fits the size of the perforation and acts as the nasal septum cartilage.163 In nasal septum deviation, a stent to correct the deviation has also been accurately manufactured by 3D printing.164 A 3D-printed, porous titanium scaffold can also act as the nasal cartilage and was combined with a skin flap for nasal reconstruction  complete the patient-specific design on the computer; (2) select the appropriate materials for 3D printing; and (3) print the patient-specific nasal prosthesis Fig. .161,162 ion Fig. .165 The Computational technology has great potential for clinical application and research in the field of nasal cartilages. The rational use of these methods can lead to the clarification of surgical goals, rationalization of surgical approaches, increased precision and personalization of surgical design and preparation, and improved convenience of doctor–patient communication. Meanwhile, the application of computational technology will also reduce medical costs and improve medical efficiency. Advances in 3D imaging technology will promote nasal cartilage-related applications and research, including computational modelling technology, computational simulation technology, virtual surgery planning and 3D printing technology, which are destined to revolutionize nasal surgery further.Supplementary information


We present a 51-year-old male who sustained a traumatic amputation with a saw of the right thumb, index finger, and carpal bones back to the radius. The amputated digits were mangled and not suitable for replantation. We performed pollicization of the long finger which helped restore a more functional hand. In select situations, this reconstructive option has the advantages of being a single-stage procedure with limited donor site morbidity and no need for microsurgical anastomosis.  Pollicization means the transposition of an adjacent finger to reconstruct a missing thumb. This technique involves the transfer of a finger on a neurovascular bundle, with skeletal fixation, and muscular stabilization in a position which offers opposition and flexion. The reconstructed thumb should have normal sensibility, sufficient mobility, bony stability, proper length, and positioning for function. The indications for pollicization, regardless of the etiology , depends only on the level of traumatic amputation or aplasia and the availability of adjacent functional digits, usually the index finger.The first description of use of the long finger pollicization comes from the work of Guermonprez in 1887 . SittingThis article presents a challenging case of total thumb and index finger loss secondary to trauma, where we were able to use the long finger to restore a functional thumb. This case highlights several critical points in the surgical planning and evaluating possible options influenced by the patient’s desires and limitations, which resulted in the restoration of a functional thumb. We discuss all the salient features of this case that make it unique.This is a 51-year-old male who presented acutely after he sustained a mutilating injury to his dominant right hand while using a large tire saw at work. He had a complete avulsion of the thumb and near-complete amputation of the index finger at the metacarpophalangeal joint. The zone of injury extended proximally to the radius, and severe damage was sustained by the trapezium and scaphoid bones. There was significant soft tissue injury of the radial and dorsoradial aspect of the hand, but his third, fourth and fifth digits were not involved. He had intact sensory and motor function to the ulnar three digits. The amputated thumb was placed on ice and transported with the patient to the hospital.The patient was taken emergently to the operating room for possible replantation. Careful examination revealed bony amputation of the entire thumb, through the first metacarpal and trapezium. There was multilevel soft tissue injury of the thumb, and hence, it was not suitable for replantation. The second finger had multilevel injuries, with no appreciable blood supply. The index proximal phalanx and the second metacarpal had severely comminuted fractures rendering it nonsalvageable Figure . A revisMultiple reconstructive options were discussed with the patient, including simple soft tissue coverage with a skin graft, osteoplastic reconstruction with a toe-to-thumb transplant, and a single-stage pollicization of the middle finger to reconstruct the thumb. The patient had a significant medical and social history including his active tobacco and cocaine use, in combination with poor glycemic control, which put him at increased risk of wound complications with any surgical intervention. We discussed the utility of a great toe-to-hand transplant for thumb reconstruction, but being a laborer, the patient declined to sacrifice his foot function in addition to his already significant hand disability. The patient wished to proceed with the option that could optimize the function of his hand while requiring the fewest surgical interventions and the quickest return to work.InvestigationsSignificant labs on presentation included HbA1c of 11.0 , glucose of 269 , and albumin of 3.1 .Plain radiographs of the right hand demonstrated a complete avulsion of the thumb and severely comminuted fractures of the second metacarpal and second proximal phalanx, as well as injury to the trapezium and scaphoid Figure .TreatmentPrior to performing pollicization, management of the soft tissue injuries on the hand needed to be addressed. Three days after the initial injury, an additional surgical washout and exploration were undertaken. A ray amputation was performed of the remaining comminuted second metacarpal, and a repair of the extensor tendon laceration of the third finger was done. We injected 80 units of Botox at the base of the remaining digits and throughout the hand to optimize perfusion. The open wound was covered with a dermal matrix layer (Integra Template), and negative pressure wound vacuum-assisted closure (VAC) therapy was begun. The patient was discharged home.After extended discussions of the patient’s various reconstructive options, nine days later, the patient underwent pollicization of the long finger. Longitudinal skin incisions were placed on the dorsal and palmar surfaces of the hand just ulnar to the third metacarpal, taking care to incorporate the superficial veins of the middle finger. Given the extensive soft tissue injury, a carpal tunnel release was concomitantly performed. Sharp and blunt dissection was used to separate the third finger and intermetacarpal carpal ligaments from the fourth finger and metacarpal, ensuring to include the intact neurovascular bundle with the third finger into the palm. This combined volar/dorsal dissection was carried down to the midportion of the third metacarpal. Capillary refill was continuously checked during this dissection to ensure the third finger remained well perfused.An angled osteotomy was then performed through the midportion of the third metacarpal, and an attempt was made to transpose the long finger onto the base of the trapezoid. However, there was insufficient length on the pedicle, and the decision was made to transpose the long finger to the capitate instead. An oscillating saw was used to perform an osteotomy on the radial side of the capitate. The third finger was then transposed without tension on the pedicle. The neo-thumb and fourth/fifth fingers could easily be brought in opposition in this position. Two 0.62 K-wires were used to secure the third metacarpal to the capitate and showed excellent bony coaptation.With the neo-thumb in this transposed position, it was noted that the extensor tendon of the previous third finger was redundant, and since this tendon had been previously repaired at the second operation, the decision was made to excise the redundant portion of the tendon and perform a direct shortening repair. The wound was closed with a combination of local tissue rearrangement and full-thickness skin graft from the lower abdomen Figure . 100 uniOutcome and follow-upThere was no vascular compromise of the pollicized digit, and the patient reported sensibility almost immediately. He began physical therapy at two weeks post-operative. There was some superficial skin necrosis on the hand that required additional skin grafting approximately two months after pollicization. At 6 months follow-up, his wounds had completely healed. His pain level was 0 out of 10 at rest and with most exercises and activities. The right thumb’s metacarpophalangeal joint’s degree of flexion was 50, and the interphalangeal joint’s degree of flexion was 22. His right-hand grip strength was 30 pounds, compared to 74 pounds on the left. Three-point pinch strength was 5 pounds on the right and 18 pounds on the left. Lateral pinch strength was 5 pounds on the right and 19 pounds on the left. His initial QuickDASH  score was down to 48% from 68% initially at two weeks post-operative. He performed gross grasp, fine grip, key pinch, pen hold, and firm pinch (Figure Creation of a functional and aesthetically pleasing thumb presents a formidable challenge to a reconstructive surgeon. The default in thumb reconstruction is replantation. If replantation cannot be performed or fails, several other surgical methods can be used to reconstruct the thumb. The optimum technique depends on the level of amputation, age, comorbidities, patient occupation, and patient preference .The classic indication for thumb reconstruction using the pollicization technique is amputation at the carpometacarpal level or proximal, as shown in Figure If replantation is not an option and amputation is proximal to the metacarpophalangeal joint, then pollicization is the procedure of choice. Pollicization is the safest procedure, shortest to perform, and quickest to obtain results. With the reduced total rehabilitation period, swift restoration of thumb function, easy dissection in the absence of scar tissue, and cost-effectiveness are some of its other inherent advantages . SecondaSome of the technical pearls during the transfer of an intact adjacent digit for thumb reconstruction include preservation of the carpometacarpal joint and thenar muscles and maintenance of the first web space, either with inset of pollicized digit or by means of a flap later. Also, the segment being transferred must have sufficient length to allow opposition with the remaining fingers after the transfer and offer good distal sensibility. At least one digital artery must be intact, and the neighboring finger must retain at least one feeding artery after the transfer . In our The current literature is not clear about the optimum situation for thumb reconstruction with heterotopic replantation or injured long finger pollicization. Sallis described pollicization using the long finger, but the donor digit was an injured finger . WeinsweWe routinely acutely use botulinum A toxin injections in severe traumatic or crush injuries of the hand. Laarakker and Borah described dramatic improvements in digital survival in hand and finger injuries with early Botox injections into the affected fingers and adjacent to radial and ulnar arteries . Botox uAlthough there are not direct reports of functional outcomes following pollicization for trauma, functional outcomes after post-traumatic thumb reconstruction in comparison with non-reconstructed thumb have been studied. The findings favor improvement in hand function after thumb reconstruction relative to amputated non-reconstructed thumbs ,18. SimiCreation of a functional and aesthetically pleasing thumb in patients with hand trauma is a formidable challenge. Pollicization is the reconstructive technique of choice for thumb amputations at or proximal to the carpometacarpal joint. Adjacent finger pollicization is a safe and fast procedure that gives early functional results when done properly. However, if the index finger is also injured and unsalvageable, then one should not hesitate to use the long finger for pollicization.


As a kind of ultra-sensitive acceleration sensing platform, optical tweezers show a minimum measurable value inversely proportional to the square of the diameter of the levitated spherical particle. However, with increasing diameter, the coupling of the displacement measurement between the axes becomes noticeable. This paper analyzes the source of coupling in a forward-scattering far-field detection regime and proposes a novel method of suppression. We theoretically and experimentally demonstrated that when three variable irises are added into the detection optics without changing other parts of optical structures, the decoupling of triaxial displacement signals mixed with each other show significant improvement. A coupling detection ratio reduction of 49.1 dB and 22.9 dB was realized in radial and axial directions, respectively, which is principally in accord with the simulations. This low-cost and robust approach makes it possible to accurately measure three-dimensional mechanical quantities simultaneously and may be helpful to actively cool the particle motion in optical tweezers even to the quantum ground state in the future. Optical tweezers (OT), as an intriguing tool in various areas such as cell biology, weak mechanics sensing and quantum physics, enjoys increasingly attractive prospects ,2,3. A pThe minimum measurable force in a measurement of bandwidth b is 16P/πρνr . kB is Bis 14 μm  and 10 μOwing to its axial symmetry, the particle centroid is naturally on the optical axis in OT with a single beam and a spherical particle, but this is not truly a misaligned OT with multi-beams. Beam misalignment is defined as the incomplete coincidence of the focuses and optical axes of the multi-beams in OT. The distance between the particle centroid and the optical axis escribed . To a ceAlthough a spherical particle of three micrometers in diameter ,13 or 10Most mechanical quantities to be measured in OT are directly related to the levitated particle centroid displacement detection. The displacement detection methods mainly fall into two camps: recording far-field interference images directly ,15 with The typical QPD scheme of particle centroid displacement detection in OT is shown in As shown in  will be :(1){Vx=Vi-axis detection response resulting from the j-axis motion, i-axis detector can be expressed as:Assuming that j-axis motion detection sensitivity of i-axis detector is defined as:j-axis. The particle is on the optical axis and is 10 μm away from the focus of Beam No.1, along the beam propagation direction when The logarithmic form Assuming the detection response The random collision noise of gas molecules determines the standard deviation of j-axis displacement  cooling . kB is tWe used the same structure explained in Increasing detection information is a feasible way to coupling suppression. The QPD method can only obtain the total intensities of four parts of the far-field interference image, while image recording methods are defective in accuracy by getting intensities of many points. Herein we try to find out the characteristics of a far-field interference image, which are more closely related to the positional change of a particle by a combination of simulation of and experiment on the QPD detection regime.Triaxial QPD detection responses of OT with single Gaussian beam structure were calculated by means of Rayleigh scattering ,17, Mie For the OT structure we used, the derivation below shows that 253 instances of computation are needed if DFFT is chosen as the first Fresnel diffraction method compared with the SFFT. Furthermore, 4 instances of computation are required for the SFFT compared with the DFFT in the second diffraction. The SFFT and DFFT methods are both based on scalar diffraction. The intensity distribution of the image rather than the phase is concerned there. Paraxial approximations should therefore be taken into account , that isOnly the forward scattered field is considered above, while the backward field of the second beam is ignored in OT with counter-propagating beams. Simulation shows that backward field intensity is two orders of magnitude lower than that of the forward one because of the low refractive index and Mie scattering state.For the OT structure we used, the images in It can be seen from A difference in laser intensity between the two halves of the interference image corresponds to a radial signal in QPD. Neither the spot nor the ring in the image is divided equally by QPD when the particle is not on the optical axis as in Assuming that the two beams only have nonzero The coupling-detection ratios The experiments were performed as follows: First, a piezoelectric ceramics excited by high voltage signal was used to vibrate a glass substrate. The sphere originally stuck on the glass substrate fall into the laser focus and was trapped by the laser. Second, we recorded the triaxial QPD signals under two conditions. The first condition is that there are no irises before the triaxial QPD photosensitive surface, and the second one is that the diameters of the irises were adjusted carefully to optimize coupling suppression effect as good as possible. Lastly, the electronic signals of QPD output were collected by a signal acquisition card  and transmitted into PC. The PC computed the displacement power spectrum with the time domain data in real time for the convenience of adjusting irises. The laser beam profiler  and the adjustable irises  both came from USA.The far-field interference image was recorded by a beam profiler as in A variable iris was placed in front of QPD on each axis in modified QPD method in experiments, as close to it as possible to reduce the diffraction effect. The simulations in In theory, coupling-detection ratio between axes i-axis motion detector, according to Equation (2) and Equation (4), is determined as follows:In contrast, the displacement power spectrum (PSD) of the particle is a more convenient tool for checking the coupling ratio, as it is unnecessary to add devices of applying known forces into the OT and choosing the magnitude of the force carefully. Displacement PSD on the j-axis in OT can be described as :(9)Sxx,jAs a result, the reduction of gas pressure can lower the upper limit of PSD method for checking the coupling ratio. The reduction of gas pressure also wakens the collision thermal movement and improves the signal to noise ratio of the above exerting known force method. However, the reduction of gas pressure cannot go on all the time because the levitated particle is more likely to escape from the OT in lower gas pressure. In order to ensure the particle stably exist in OT under low pressure, and the mechanical energy of it is continuously reduced, we need to apply appropriate feedback force on the particle according to the position and velocity information of it. This is the so-called cooling.Coupling in detection may degrade the feedback cooling performance since the motions between axes are all random and uncorrelated to each other. Many application in ultra-weak mechanics sensing and quantum physics studies with OT also require cooling the particle motion in vacuum ,12. The When using modified QPD instead of conventional QPD, In generally, for particles whose sizes are relatively smaller, ranging from tens of nanometer to hundreds of nanometer, the resonance peaks in displacement power spectrum of all three axes are located at tens of kilohertz or even hundreds of kilohertz. Such high resonance frequencies make the main motion components of three axis of small-sized particle are separated in the frequency domain. In that case, coupling can be reduced to a low level by narrowband filter. For example, three different lock-in amplifiers were used to extract triaxial motions of particles of diameter ranging from 26 to 160 nm in reference . HoweverApart from misalignment, there are other factors that affect detection accuracy. When using conventional QPD methods, The voltages PSD of the red line in Overall, optical tweezers with counter-propagating beams and a large-sized particle is a technology with great potential, which is applicable in fields of research such as cell biology, weak mechanics sensing and quantum physics. However, its measurement accuracy faces challenges due to coupling of different axes. This paper proves that coupling is caused by misalignment from the perspective of the forward-scattering far-field.A new method of suppressing coupling is proposed herein, adding a variable iris in front of the QPD photodetector on each axis. Experiments show a reduction of 49.1 dB in coupling-detection ratio radially and that of 22.9 dB axially, which is basically in accord with simulations. These make it possible to accurately measure three-dimensional mechanical quantities with OT synchronously and may be helpful to actively cooling the particle even to quantum ground state in ultra-low gas pressure in basic physics research. The measurements of bandwidth and signal strength do not suffer a great loss in these methods as opposed to those such as increasing beam diameter. A laser beam profiler and three variable irises are added into OT without changing the original optical structures of levitation and detection. Thus, they provide simple operation at a low cost and structural compatibility.


Cyclophilin D (CypD) is a mitochondrial peptidyl-prolyl cis-trans isomerase, well-known for regulating the mitochondrial permeability transition pore (PTP), a nonspecific large conductance pore whose opening leads to cell death and has been implicated in ischemia/reperfusion injury in multiple organs, in neurodegenerative disorders, and in muscular dystrophies. While the main target of CypD is a matter of ongoing research, inhibiting CypD protects in models of those diseases making it an interesting therapeutic target. The present review focuses on post-translational modifications of CypD that have been identified by recent studies, which can alter the regulation of the PTP and contribute to understanding the mechanisms of action of CypD. Cyclophilin D (CypD) is a highly conserved peptidyl-prolyl cis-trans isomerase (PPIase) that plays an important role in mitochondrial biology. It is encoded by the genomic Ppif gene and contains a mitochondrial targeting sequence which is cleaved upon entering the mitochondrial matrix, reducing its size from 22 to 19 kDa. It was named, like all cyclophilins, after its ability to bind the drug cyclosporine A (CsA) . CyclophMitochondria are the power house of the cell; they create energy in the form of ATP through oxidative phosphorylation. The electron transport chain  uses reducing equivalents from fatty acid oxidation, glycolysis, and the Krebs cycle to transfer electrons ultimately to oxygen, pump protons from the matrix to the intermembrane space, and thus generate an electrochemical gradient across the inner mitochondrial membrane. The ATP synthase exploits this gradient to create ATP from ADP and inorganic phosphate. Inorganic phosphate is imported from the cytosol by the PiC. The newly produced ATP however is localized in the matrix and needs to be transferred to the cytosol for the cell to use it. This transport is mediated by the ANT, which also imports ADP from the cytosol. To increase the efficiency of ATP production and transportation to the cytosol, the ATP synthase can oligomerize with the ANT and PiC, forming synthasomes . FurtherCypD is a regulator of the PTP, and thus of mitochondrial coupling. It sensitizes PTP to calcium and oxidative stress. It can also directly bind to the ATP synthase and reduce ATP production while its displacement from the inner mitochondrial membrane by CsA increases ATP synthesis . In hear−/− fibroblasts are protected against oxidative stress; however, consistent with the previous study, the protection is lost in cells expressing a wild type (WT) CypD but not in cells expressing the R96G CypD mutant  has been reported to phosphorylate CypD and to enhance PTP opening and, consistent with this concept, GSK-3 inhibition (which would decrease CypD phosphorylation) protects from PTP opening in human cancer cell models . Similariability . Finallyiability . The kiniability , there ciability , 2002.−/− mice CypD is hyperacetylated at this residue, leading to sensitization of the PTP and increased cell death in a model of transaortic constriction  . Lysine triction  In addittriction . Of intetriction . In the it model . These dit model  and thisThere are a large number of studies showing that CypD is a regulator of the PTP, an activator of cell death in I/R injury and that cyclosporine A desensitizes PTP and confers cardioprotection . HoweverCypD can undergo multiple post-translational modifications and regulate mitochondrial bioenergetics and the PTP. However, most post-translational modifications of CypD have been studied in relation to the PTP. It is unclear how the majority of those post-translational modifications affect mitochondrial bioenergetics. In addition, although CypD sensitizes the opening of the PTP to stressful stimuli and possibly acts as an uncoupler by interacting directly with the ETC and the ATP synthase, its physiological role remains elusive.GA wrote initial draft of the manuscript. EM edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Automated Driving Systems (ADS) have received a considerable amount of attention in the last few decades, as part of the Intelligent Transportation Systems (ITS) field. However, this technology still lacks total automation capacities while keeping driving comfort and safety under risky scenarios, for example, overtaking, obstacle avoidance, or lane changing. Consequently, this work presents a novel method to resolve the obstacle avoidance and overtaking problems named Hybrid Planning. This solution combines the passenger’s comfort associated with the smoothness of Bézier curves and the reliable capacities of Model Predictive Control (MPC) to react against unexpected conditions, such as obstacles on the lane, overtaking and lane-change based maneuvers. A decoupled linear-model was used for the MPC formulation to ensure short computation times. The obstacles and other vehicles’ information are obtained via V2X (vehicle communications). The tests were performed in an automated Renault Twizy vehicle and they have shown good performance under complex scenarios involving static and moving obstacles at a maximum speed of 60 kph. Problems related to traffic have been of major concern in societies for many decades, especially those related to maximizing safety and traffic efficiency . The autThe National Highway Traffic Safety Administration (NHTSA) has calculated at least 1 person dies and more than 50 people are injured in a traffic accident every 100 million miles traveled , and 94%One key component of this technology is the software embedded in these intelligent systems. Accordingly, AV’s decision and control processes have been divided into three task levels: (i) strategic level associated with navigation, (ii) tactical with the trajectory generation, and (iii) operational level or tracking of the trajectory planned . Risky mThere are different approaches to solve the lane change-based problems. There are two general groups to tackle dynamic environment planning, which are: (i) sampling-based methods (trajectory candidates) and (ii) Optimal Control Problem (OCP) methods . A consiGenerally, sampling-based methods are good enough for tackling simple cases of lane change-based problems  departing from the original lane, (ii) cruising in the opposite lane to overtake the other vehicle, and (iii) returning to the original lane ,21,22. IThis knowledge of separation in stages has been brought to the ADS field since the early days, for example, works done in automated overtaking using fuzzy logic principles , path geNewer tendencies in ADS try to use the benefits of Machine Learning (ML) architectures in AV to simplify the process of imitating human driving-style. For example, ML approaches have been successfully deployed in the area of obstacle recognition and classification under real-time driving conditions.Another tendency is the use of real-time optimization methods because they have a good capacity to solve the problem without programming specific cases or using an extensive dataset . AnotherDynamic programming, indirect and direct methods are the three general classes mostly used to solve optimization problems. The first one is strong in non-convex problems but it demands a big amount of computational time, making real-time computation extremely difficult. The second one shows efficient results but with a trade-off of high difficulty in introducing constraints. In general, direct methods, for example, Sequential Quadratic Problems (SQP), are strong enough against non-linear problems and it is relatively easy to introduce constraints in them . Most ofA recent study has proved Bézier curves are a reliable solution for an optimal trajectory generation ,39. The The topic of real-time risk-assessment is of interest to design safe AV. The approach presented by  has estaAnalyzing the state-of-the-art, there are some gaps in the technology in terms of the generation of a real-time trajectory that can ensure safety while managing unexpected conditions without hard-coding a bunch of specific cases. A good solution is to propose a smooth trajectory generation method (Bézier curves) with the capacity of generating a real-time response in the case of unexpected conditions (MPC), which is safe by a binary-evaluation of the risk over the maneuver (collision checking).The approach presents a method to resolve the overtaking and obstacle avoidance maneuver. This hybrid planning method combines a nominal trajectory generated with Bézier curves (parametric curves) and the maneuver optimization provided by an MPC. No specific conditions have been considered, and the problem is completely solved using MPC constraints and reference manipulation.A general vision of the approach is presented in This nominal trajectory was inspired in a previous work . All theBézier curves are a type of parametric curves widely used in ADS in the last years ,42,43, dThe generated curve starts at control point The direction in the start and end of the trajectory are defined by Pn→=vn−1 .The curve will lay into a convex hull formed by the They are The amount of changes in curvature concavity is proportional to the changes of the vectors in These curves were used for the nominal trajectory planning as it is explained in . This prThe generated trajectory is fully contained in the path lane, keeping safety and feasible solutions for the vehicle. Additionally, the total distance of the generated trajectory is fixed considering a vision horizon. Nevertheless, in these experiments the nominal trajectory was pre-computed offline, in a newer version of this method, the nominal trajectory is computed online .In ADS, the use of MPC for decision and control have been mainly based on the kinematic bicycle model and the dynamic model of the vehicle, which includes forces over the tires . These mA linear model of the vehicle was selected to find an optimal solution, with a fast response time. The model used is a decoupled integrator chain model for longitudinal and lateral dynamics, which is mostly related to holonomic systems; nevertheless, the constraints were manipulated to provide non-holonomic properties . AdditioThe proposed model was a triple integrator chain based on jerk, as it is shown in:The output of the MPC longitudinal portion is a smooth speed profile. Nevertheless, it depends on the acceleration produced by the throttle and brake. Moreover, these acceleration changes must be smooth to avoid unexpected movement while the vehicle is cruising. The smoothness of its rate of change is the reason to include acceleration and jerk as part of the problem formulation.All the states and control variables are bounded constraints, which is a special case of inequality constraints. Those constraints are:ented in ). The acThe maximum permissible speed is calculated using the formula of total acceleration and an approximation for small variations in longitudinal  formulation, where it minimizes the function This problem will have linear bounded constraints due to the performances of other participants . In this sense, the convex optimization function and the inequality constraints result in a convex problem with a feasible and fast solution. In the case of varying the lateral (offset) and the longitudinal (distance and speed) constraints, the linear inequality constraints will be transformed into non-linear constraints, which could diverge in unfeasible solutions. Mechanisms for detection and mitigation of the unfeasible solutions have been implemented see .Nominal Trajectory Calculator.Both trajectories are combined considering the method described in , which iNominal Trajectory Calculator module uses this information from perception and communication modules to generate the control variables: lateral error, angular error, curvature, and the speed setpoint. The lateral error is the deviation of the vehicle front and the nominal trajectory. The angular error is the angle between the vehicle’s orientation and the nominal trajectory. The curvature is the inverse of the turning radius in each segment of the trajectory, as it is defined in [Nominal Trajectory Calculator. This modified trajectory is sent to the control blocks , and thEquation  is integThe system outputs consider the minimum speed setpoint between the one obtained from the MPC and the one provided by the nominal trajectory. This is a safety consideration avoiding rear-end collisions. In the case of the lateral domain, the lateral displacement of the first MPC state is added to the nominal lateral error, generating a possible lane-change maneuver.This combination of both approaches permits to lead the vehicle safely through intersections, roundabouts, and merging using the nominal trajectory; the MPC will be in charge of the dynamic speed adaption , overtaking, and obstacle avoidance maneuvers.Lane-change based maneuvers depend on situations that constantly change  and constraint satisfaction (safety) is a demand on vehicles . In these terms, the MPC calculator will be in charge of manipulating the MPC reference and constraints according to the nominal trajectory and obstacles on the road.This module collects the information generated in the MPC previous iteration, and future vehicle states are reconstructed with it . PropagaIn this approach, the obstacles are transmitted via communications (V2X) using a piece of third party equipment and connecting it to the control interfaces via a TCP socket . NeverthA collision evaluation is executed over each future vehicle state (propagated ones) and the propagation of other vehicle positions using a kinematic model. An evaluation of vehicles’ segments intersection is executed and in case of at least one intersection, that space and time will be tagged as collision a.In the case of a collision in the opposite lane, the lateral bounds move to the nominal-lane. In the case of a collision in the nominal-lane, the lateral bounds move to the opposite lane. The reference of the lane offset is considered the first bound change. An example is shown in In the case of detecting a blockage in the lanes, the vehicle will limit the longitudinal distance constraint up to the blockage distance. Another example is shown in In the case of verifying unfeasible conditions (states out of the bounds), the ego vehicle moves the reference speed to 0 from the moment of the detection of an unfeasible condition. This section explains the experimental set-up, which includes: the tracking controllers used during the tests, the MPC solver, the prototype AV, and the test tracks. Moreover, the control architecture was the one presented in .A control law, based on lateral and angular error and the curvature of the trajectory, was selected for the lateral control (vehicle steering) ,49. ThisIn this sense, the method used to calculate the control variables is presented in the bottom part of The distance k curvature and lateral error is defined as Considering the value of Longitudinal fuzzy logic controllers can be easily and intuitively designed using human experience, as in . A fuzzyThe ACADO Toolkit was the solver used for the MPC problem formulation. It is a software toolbox (library) based on C++ and it is used to solve OCP applications. It is a complete tool-chain that offers a great variety of possible configurations with efficient execution times. Some of its major characteristics are: (i) it is open-source, (ii) no external packages are needed to use this library, (iii) it is compatible with platforms such as Matlab/Simulink, and (iv) the learning process of this software is relatively fast and it has a great numbert of examples .This toolkit was used to solve three typical control problems, which are: (i) offline multi-objective control problems , (ii) it can be used for parameters and states estimations (model identification problem), and (iii) online OCP, where an optimal control output (subject to a constraint set in a prediction horizon) is given. The configuration of the solver was multiple shooting discretization, Runge–Kutta integration of discrete states, and the SQP method to solve the minimization problem .Finally, this toolbox can be used with a Matlab/Simulink interface where the AD architecture was developed .Some simulation results are presented in this work using the Dynacar simulator  top. It A closed test track was used for algorithm validation under a real platform. The dimensions are 20 m wide by 85 m long. It has two lanes, roundabouts, straight segments, and additionally bend segments overlapped in the middle. The scenario can manage speeds of around 30 kph without compromising safety during test execution.The lower part of This section presents the results obtained with the real vehicle at low-medium and at medium-high speeds in All the tests were performed considering 10 prediction samples of the MPC at a sample time of 0.5 s.The results of the overtaking at low-medium are presented in The vehicle speed is shown in The real vehicle has been tested on a different test track to increase the speed until 60 kph, which is a straight path of around 500 m long. In this case, the approach was tested in a scenario of moving vehicles in the same direction. The approach is capable of modeling the constraints around the free-collision space, which keeps safety during the execution of the overtaking maneuver. A simulated test case was evaluated and the results are presented in The returning process is demonstrated with the lateral offset in The algorithm has obtained reliable results under difficult situations like the one presented in this simulation test case. This type of scenario can be improved, in terms of safety, with a cooperation agreement among the vehicles. Nevertheless, more extensive tests under different situations will be performed in the future, along with multiple real platforms, to validate the statement.This work has presented a novel method to resolve overtaking and obstacle avoidance maneuvers. It considers a smooth and continuous Bézier trajectory combined with an MPC formulation. This hybrid trajectory is obtained in less than 10 milliseconds  while decoupling vehicle kinematics . The obstacles collision evaluation demands more than 100 milliseconds, depending on the number of obstacles. Our approach has presented good results under real scenarios, considering detection and/or communication of other participants’ information. Comfort and safety (collision avoidance) have been considered in this approach.Most of the tests have been performed with a real automated vehicle, validating the approach in a closed test track with virtual obstacles. For the bend segments, the automated vehicle has reached 30 kph in lane-change maneuver, but in longer paths, a maximum speed of around 60 kph has been reached, using communications with the other vehicles around.Obstacle avoidance and overtaking maneuvers are supported in curve segments considering static obstacles and moving ones. The approach reduces the ego-vehicle speed to 0 kph if a blockage of the path exists.In Additionally, the simulation test case was included to introduce some risky maneuvers that will be tested in future works. These planned tests will include a cooperation agreement method to avoid undesired conditions, i.e., returning to the lane in the middle of the maneuver due to perturbances during the prediction computation.


Introduction: Low back pain (LBP) is a very common pathology among pregnant women and various methods are used to reduce the pain. The aim of this study is to conduct an evidence-based systematic review and meta-analysis regarding the effectiveness of the interventions used to reduce low back pain related to pregnancy. 2 index as well as x2 test were used to determine the heterogeneity between studies. A random-effects meta-analysis was carried out. The aim was to compare the effectiveness between various methods and the typical care provided on low back pain during pregnancy. Methods and materials: The PEDro database, PubMed, and Cochrane Library were searched from January 2012 until December 2020 as well as the reference lists from identified articles. Studies of any non-pharmaceutical treatment to decrease low back pain were included but only randomized controlled trials were selected. The articles found were screened using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) question. Details about the type of intervention, sample size, outcome measures, results, and statistical significance were extracted from the selected studies. A meta-analysis for pain intensity was conducted and the IResults: From all the articles found in the mentioned databases only 13 studies met the criteria. In these studies, exercise, manipulation, ear acupuncture, Kinesio tape, transcutaneous electrical nerve stimulation (TENS), and neuroemotional technique were the interventions used. In the meta-analysis, six studies with 693 participants were included. The interventions were found to have in total a statistically significant effect on low back pain in comparison with the control group that included the typical care provided to pregnant women , p<0,01) and they had a high heterogeneity . Exercise and TENS were determined as more effective than the other types of interventions.Conclusions: TENS and progressive muscle relaxation exercises accompanied by music were found to be the most effective interventions. Although exercise decreased LBP it was not found to have a statistically significant result even though it seems to improve the disability and quality of life of pregnant women. Osteopathic manual treatment (OMT), Kinesio tape, and ear acupuncture affected the lumbar pain intensity but the difference compared to typical care or sham treatment was not statistically significant, while yoga did not improve pregnancy-related LBP. Further research is needed to determine the effectiveness of the interventions mentioned.  Low back pain (LBP) is a common pathology and affects both men and women of all ages. LBP is also very frequent amongst women during pregnancy and has a great impact on their daily lives . Other nSince antiquity LBP during pregnancy was known as well as identified for many centuries and described by Hippocrates, Vesalius, Pinean, Hunter, Velpeau, and many other scientists . The latThe biomechanics of the body has been transformed due to the increasing weight and width of the body, in particular of the abdomen, and can raise the action force exerted to the back . AlteratPennick et al. (2013) conducted a systematic review of the interventions aiming to reduce or treat pelvic as well as LBP during pregnancy . The preThis systematic review was developed in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines by Moher et al.  and it iSearch methodsThe search was conducted through PubMed, PEDro, and Cochrane Library databases as well as the reference lists from identified articles. Only randomised controlled trials (RCTs) published within a nine-year period, from January 2012 until December 2020, were included. The search strategy was performed with the use of the following Medical Search Heading (MeSH) terms: "low back pain" AND "pregnancy" AND " therapeutics".Study selectionThe selection of the studies was based on the Population Intervention Comparison Outcome (PICO) question Table . The priExclusion criteriaThe exclusion criteria were determined at the beginning of the search. Articles with a publication date before 2012 were not included as well as the ones written in other languages than English or Greek. Studies where neither the abstract nor the full text was not available were also excluded. A large number of the articles found referred to LBP after or during the delivery of the embryo or they explored the effect of the interventions on both low back and pelvic pain. They were also excluded.Methodological quality The assessment of the methodological quality of selected articles was conducted by four of the authors independently and was based on the criteria of the Physiotherapy Evidence Database (PEDro) scale  and CritData extractionData from each included article were extracted by each individual based on the following categories: interventions, sample size/group size, duration, follow-up, outcome measures, outcomes and statistical significance.Meta-analysisThe meta-analysis aimed to determine the effectiveness of various treatments on low back pain related to pregnancy in comparison with the Usual Obstetric Care (UOBC). Statistical analysis and meta-analysis were conducted using Review Manager 5.4 software . The level of statistical significance was set at p<0.05 and the odds ratios (OR) were calculated for all dichotomous outcomes. Analyses for the RCTs were conducted using a random-effects model to evaluate whether the effect of LBP was different when examining evidence from interventions versus UOBC. 2 test for heterogeneity and the I2 statistic   underlines the importance of developing effective treatment programs for this condition. Despite these figures, it is estimated that over 50% of women receive little or no intervention from healthcare providers . The aimIn total, 160 articles were found in the three databases searched, but only 13 of them with 2213 pregnant women participating and six different interventions examined were included in the systematic review. Eight articles were about exercise, two about OMT, and one of each of the following interventions: TENS, Kinesio tape, yoga, and ear acupuncture. From them, only six studies (n=693) meet the criteria for the meta-analysis and of them four examined the effect of exercise, one of TENS, one of OMT, and one of ear acupuncture.Exercise was found to be a very common practice used to decrease LBP and the majority of the relative studies were categorized as of «high methodological quality» Tables , 4. The The exercise components of the interventions included strength and stretching , enduraThe high quality of evidence from the meta-analysis has shown that OMT if received in addition to usual care, it has a greater impact on the decrease of LBP and functional disability than the usual care provided without OMT , nonspecific ear acupuncture (NSEAc), and placebo ear acupuncture (PEAc) in comparison to typical care, a single study carried out by Vas et al. . The metThe following studies were from the ones included in the systematic analysis but excluded from the meta-analysis. Kinesio tape additional to paracetamol was found to have better results on LBP compared to only paracetamol in a study conducted by Kaplan et al. . The resThe small number of related studies, as well as the small population of the participants in the majority of studies, resulted in limited conclusions from this review. In most of the articles included there was a long-term follow up so the results of this review will also represent the long-term effectiveness of the mentioned interventions. In addition, the high heterogeneity that was found was the result of the high difference of the participants in the studies as well as the high effectiveness of TENS, exercise, and muscle relaxation exercises accompanied by music and that consequently means that further research should be conducted in order to determine the effectiveness of the mentioned interventions on the LBP during pregnancy.This study was considered to be the updated version of the systematic review and meta-analysis of Liddle et al. (2015)  and inclLBP is a very common pathology that appears in all people but there is a very high prevalence of it during pregnancy so there is a need to determine effective interventions to reduce or better treat the problem better. In summary, TENS and muscle relaxation exercises accompanied by music were found to be the most effective interventions and they have a statistically important impact on lumbar pain. Various kinds of exercise were examined and they seem to reduce the pain intensity. Although most of the articles regarding exercise were of a high methodological standard, the results were not in total statistically significant but there was a great impact on the secondary outcomes such as disability and quality of life. Ear acupuncture and Kinesio tape, even though they were found effective in decreasing LBP, the results were not significant while yoga was neither effective nor statistically significant. Due to the high heterogeneity of the studies included in the meta-analysis the effectiveness of the described methods as well as the statistically significant interventions should be examined further in future studies.