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Gastric cardia adenocarcinoma (GCA) and esophageal squamous cell carcinoma (ESCC) present significant health challenges in China, often diagnosed at advanced stages with poor prognoses. However, effective biomarkers for early detection remain elusive. This study aimed to integrate methylome and transcriptome data to identify DNA methylation markers for the early detection of GCA and ESCC. In the discovery stage, we conducted Infinium MethylationEPIC array analysis on 36 paired GCA and non-tumor adjacent tissues (NAT), identifying differentially methylated CpG sites (DMCs) between GCA/ESCC and NAT through combined analyses of in-house and publicly available data. In the validation stage, targeted pyrosequencing and quantitative real-time RT-PCR were performed on paired tumor and NAT samples from 50 GCA and 50 ESCC patients. In the application stage, an independent set of 438 samples, including GCA, ESCC, high- and low-grade dysplasia (HGD/LGD), and normal controls, was tested for selected DMCs using pyrosequencing. Our analysis validated three GCA-specific, two ESCC-specific, and one tumor-shared DMCs, exhibiting significant hypermethylation and decreased expression of target genes in tumor samples compared with NAT. Leveraging these DMCs, we developed a GCA-specific 4-marker panel (cg27284428, cg11798358, cg07880787, and cg00585116) with an area under the receiver operating characteristic curve (AUC) of 0.917, effectively distinguishing between cardia HGD/GCA patients and cardia LGD/normal controls. Similarly, an ESCC-specific 3-marker panel (cg14633892, cg04415798, and cg00585116) achieved an AUC of 0.865 in distinguishing esophageal HGD/ESCC cases. Furthermore, integrating cg00585116, age, and alcohol consumption yielded a tumor-shared logistic model with good discrimination for two cancer/HGD (AUC, 0.767; 95% confidence interval, 0.720-0.813). The mean AUC of the model after 5-fold cross-validation was 0.764. In summary, our study identifies novel DNA methylation markers capable of accurately distinguishing GCA/ESCC and HGD from LGD and normal controls. These findings offer promising prospects for targeted DNA methylation assays in future minimally invasive cancer screening methods.

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Diabetic wound healing including diabetic foot ulcers is a major clinical challenge, which could bring an increased level of mortality and morbidity. However, conventional wound dressings exhibit limited healing efficacy due to their lack of active modulation for the healing process. Here, a near-infrared (NIR) stimuli-responsive composite hydrogel dressing with the synergistic effect of both mechanical contraction and epithelial-mesenchymal transition (EMT) was developed to facilitate cell migration and vascularization for diabetic wound healing. In the methacrylated gelatin-based composite hydrogel, N-isopropylacrylamide and polydopamine nanoparticles were incorporated to endow the composite hydrogel with thermosensitive and photothermal properties. Linagliptin (LIN) was loaded into the composite hydrogel, and the drug release rate could be controlled by NIR laser irradiation. NIR-triggered on-demand active contraction of wound area and LIN release for biological stimulation were potentially realized in this responsive system due to the thermally induced sol-gel transition of the composite hydrogel. The release of loaded LIN could effectively promote cell migration by activating EMT and enhancing angiogenesis. In the full-thickness skin defect model, the LIN-loaded composite hydrogel with NIR laser irradiation had the highest wound closure rate as compared with the pure hydrogel and LIN-loaded hydrogel groups. Therefore, this composite hydrogel can serve as an excellent platform for promoting wound healing and will find more practical value in clinical treatment.

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An efficient gene transfer and expression tool is lacking for shrimps and shrimp cells. To solve this, this study has developed a shrimp DNA virus-mediated gene transfer and expression system, consisting of insect Sf9 cells for viral packaging, the shrimp viral vector of pUC19-IHHNV-PH-GUS and the baculoviral vector of Bacmid or Bacmid-VP28 encoding the shrimp WSSV envelope protein VP28. The pUC19-IHHNV-PH-GUS vector was constructed by assembling the genomic DNA of shrimp infectious hypodermal and hematopoietic necrosis virus (IHHNV), which has shortened inverted terminal repeats, into a pUC19 backbone, and then an expression cassette of baculoviral polyhedron (PH) promoter-driven GUS (ß-glucuronidase) reporter gene was inserted immediately downstream of IHHNV for proof-of-concept. It was found that the viral vector of pUC19-IHHNV-PH-GUS could be successfully packaged into IHHNV-like infective virions in the Sf9 cells, and the gene transfer efficiency of this system was evaluated and verified in three systems of Sf9 cells, shrimp hemolymph cells and tissues of infected shrimps, but the GUS expression could only be detected in cases where the viral vector was co-transfected or co-infected with a baculovirus of Bacmid or Bacmid-VP28 due to the Bacmid-dependence of the PH promoter. Moreover, the packaging and infection efficiencies could be significantly improved when Bacmid-VP28 was used instead of Bacmid.

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Chemoresistance remains the main obstacle limiting the treatment of osteosarcoma, seriously affecting the prognosis of adolescent patients with osteosarcoma. Recently, long non-coding RNAs (lncRNAs) were reported to be involved in chemoresistance, while the mechanisms of lncRNAs underlying osteosarcoma resistance to chemotherapy remain elusive. Here, LINC00520 was identified as a novel cisplatin resistance-related lncRNA in osteosarcoma, and its high expression was associated with poor prognosis of osteosarcoma patients. Functionally, LINC00520 could potentiate osteosarcoma resistance to cisplatin in vitro and in vivo. Mechanistically, LINC00520 bound to ENO1 and upregulated ENO1 protein expression by blocking FBXW7-mediated ENO1 ubiquitination and proteasomal degradation, thereby promoting glycolysis and ultimately inducing cisplatin resistance in osteosarcoma. Furthermore, METTL3 could stabilize and upregulate LINC00520 in an m6A-YTHDF2-dependent manner in osteosarcoma. This study proposes a novel lncRNA-driven mechanism for cisplatin resistance in osteosarcoma, and offers a promising therapeutic strategy for reversing chemoresistance in osteosarcoma by targeting the METTL3/LINC00520/ENO1/glycolysis axis.

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A vast amount of knowledge has been acquired through human activities such as farming, hunting, and fishing. Throughout history, humans have utilized living creatures for disease treatment, relying on the natural world's healing powers. The special "healers" may be able to treat patients via the power of nature. However, there was no systematic introduction or summary of these treatments. Therefore, we conducted a literature review based on PubMed, Google Scholar, Web of Science, Scopus, CNKI and WanFang DATA. Here, we defined this unique method as "animal healer" and six common kinds of animal healers were reviewed. These are fish therapy, pet therapy, worm therapy, leech therapy, maggot therapy, and bee therapy. According to the different characteristics of healers, treatment methods mainly included bite, parasitism, contact and communication. With the advantages of green and effectiveness, animal healers have great therapy potential against a variety of refractory diseases. The main purpose of this review is to draw people's attention to animal healer, promote it to become a possible clinical treatment strategy, and make further exploration in species cultivation, mechanism research, animal welfare, standard setting, safety evaluation and other aspects. In the future, animal healers will play an increasingly important role in medicine and hopefully solve more medical problems and dilemmas.

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The aim of this study was to develop a three-dimensional (3D) cell model in order to evaluate the effectiveness of a traditional Chinese medicine decoction in the treatment of arthritis. Chondrocytes (ATDC5) and osteoblasts (MC3T3-E1) were 3D printed separately using methacryloyl gelatin (GelMA) hydrogel bioinks to mimic the natural 3D cell environment. Both cell types showed good biocompatibility in GelMA. Lipopolysaccharide (LPS) was added to the cell models to create inflammation models, which resulted in increased expression of inflammatory factors IL-1ß, TNF-α, iNOS, and IL-6, and decreased expression of cell functional genes such as Collagen II (COLII), transcription factor SOX-9 (Sox9), Aggrecan, alkaline phosphatase (ALP), RUNX family transcription factor 2 (Runx2), Collagen I (COLI), Osteopontin (OPN), and bone morphogenetic protein-2 (BMP-2). The created inflammation model was then used to evaluate the effectiveness of Dangguiniantongtang (DGNT) decoctions. The results showed that DGNT reduced the expression of inflammatory factors and increased the expression of functional genes in the cell model. In summary, this study established a 3D cell model to assess the effectiveness of traditional Chinese medicine (TCM) decoctions, characterized the gene expression profile of the inflammatory state model, and provided a practical reference for future research on TCM efficacy evaluation for arthritis treatment.

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Standalone cellulose nanofibril (CNF) films have a natural tendency to shrink upon drying from wet conditions due to capillary drying stresses. This shrinkage happens in both the radial direction, and the vertical direction. In this study, we prepared two types of CNF films- one in a restrained condition that did not allow shrinkage in the radial direction but enabled it in the vertical direction and another with 11 % radial shrinkage but limited vertical shrinkage. The radial shrinkage led to a more porous structure than the vertical shrinkage, which brought about poorer oxygen/moisture barrier performance. However, the density and oxygen permeability of the films converged to a similar value upon a simple thermocompression process. Radial shrinkage resulted in 140 % and 90 % higher strain at break and toughness in films with a significant sacrifice in strength and modulus. Scanning electron microscopy revealed that radial shrinkage formed wavy layers in the core structure leaving more free space, whereas vertical shrinkage formed flatter layers. Radial shrinkage is likely to produce a thicker individual layer in the core structure of CNF films than vertical shrinkage. The insight from this study will help tune the mechanical and barrier performance of CNF films and their composites.

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Membranes are a selective barrier that allows certain species (molecules and ions) to pass through while blocking others. Some rely on size exclusion, where larger molecules get stuck while smaller ones permeate through. Others use differences in charge or polarity to attract and repel specific species. Membranes can purify air and water by allowing only air and water molecules to pass through, while preventing contaminants such as microorganisms and particles, or to separate a target gas or vapor, such as H2 and CO2, from other gases. The higher the flux and selectivity, the better a material is for membranes. The desirable performance can be tuned through material type (polymers, ceramics, and biobased materials), microstructure (porosity and tortuosity), and surface chemistry. Most membranes are made from plastic from petroleum-based resources, contributing to global climate change and plastic pollution. Cellulose can be an alternative sustainable resource for making renewable membranes. Cellulose exists in plant cell walls as natural fibers, which can be broken down into smaller components such as cellulose fibrils, nanofibrils, nanocrystals, and cellulose macromolecules through mechanical and chemical processing. Membranes made from reassembling these particles and molecules have variable pore architecture, porosity, and separation properties and, therefore, have a wide range of applications in nano-, micro-, and ultrafiltration and forward osmosis. Despite their advantages, cellulose membranes face some challenges. Improving the selectivity of membranes for specific molecules often comes at the expense of permeability. The stability of cellulose membranes in harsh environments or under continuous operation needs further improvement. Research is ongoing to address these challenges and develop advanced cellulose membranes with enhanced performance. This article reviews the microstructures, fabrication methods, and potential applications of cellulose membranes, providing some critical insights into processing-structure-property relationships for current state-of-the-art cellulosic membranes that could be used to improve their performance.

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Objective: This study analyzes the risk points in the quality control of bioink and the main processes of bioprinting, clarifies and explores the quality control and supervision model for bioprinting medical devices, and provides theoretical and practical guidance to ensure the safety and effectiveness of bioprinting medical devices. Methods: The quality control risk points throughout the bioprinting process were comprehensively analyzed, with a particular focus on bioprinting materials and key processes. The regulatory model and methods for bioprinting medical devices were examined. This research concentrated on critical technologies such as extrusion, laser-assisted, and in situ bioprinting, assessing their potential for clinical applications and regulatory challenges. Results: Bioink from different sources should meet regulatory requirements. It is essential to ensure aseptic handling of raw materials and to validate sterilization under "worst-case" conditions. Conclusion: As bioprinting technology advances rapidly, corresponding research into materials, processes, and quality risk control should be conducted to ensure the concurrent development of the regulatory system. This will continuously contribute to the orderly progression of the entire industry and human health.

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Esophageal squamous cell carcinoma (ESCC) is the predominant form of esophageal cancer and is characterized by an unfavorable prognosis. To elucidate the distinct molecular alterations in ESCC and investigate therapeutic targets, we performed a comprehensive analysis of transcriptomics, proteomics, and phosphoproteomics data derived from 60 paired treatment-naive ESCC and adjacent nontumor tissue samples. Additionally, we conducted a correlation analysis to describe the regulatory relationship between transcriptomic and proteomic processes, revealing alterations in key metabolic pathways. Unsupervised clustering analysis of the proteomics data stratified patients with ESCC into 3 subtypes with different molecular characteristics and clinical outcomes. Notably, subtype III exhibited the worst prognosis and enrichment in proteins associated with malignant processes, including glycolysis and DNA repair pathways. Furthermore, translocase of inner mitochondrial membrane domain containing 1 (TIMMDC1) was validated as a potential prognostic molecule for ESCC. Moreover, integrated kinase-substrate network analysis using the phosphoproteome nominated candidate kinases as potential targets. In vitro and in vivo experiments further confirmed casein kinase II subunit α (CSNK2A1) as a potential kinase target for ESCC. These underlying data represent a valuable resource for researchers that may provide better insights into the biology and treatment of ESCC.

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Osteoporotic fractures are the most severe complications of osteoporosis, characterized by poor bone quality, difficult realignment and fixation, slow fracture healing, and a high risk of recurrence. Clinically managing these fractures is relatively challenging, and in the context of rapid aging, they pose significant social hazards. The rapid advancement of disciplines such as biophysics and biochemistry brings new opportunities for future medical diagnosis and treatment. However, there has been limited attention to precision diagnosis and treatment strategies for osteoporotic fractures both domestically and internationally. In response to this, the Chinese Medical Association Orthopaedic Branch Youth Osteoporosis Group, Chinese Geriatrics Society Geriatric Orthopaedics Committee, Chinese Medical Doctor Association Orthopaedic Physicians Branch Youth Committee Osteoporosis Group, and Shanghai Association of Integrated Traditional Chinese and Western Medicine Osteoporosis Professional Committee have collaborated to develop this consensus. It aims to elucidate emerging technologies that may play a pivotal role in both diagnosis and treatment, advocating for clinicians to embrace interdisciplinary approaches and incorporate these new technologies into their practice. Ultimately, the goal is to improve the prognosis and quality of life for elderly patients with osteoporotic fractures.

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[This corrects the article DOI: 10.1016/j.bioactmat.2023.07.004.].

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PURPOSE: Pelvic bone segmentation and landmark definition from computed tomography (CT) images are prerequisite steps for the preoperative planning of total hip arthroplasty. In clinical applications, the diseased pelvic anatomy usually degrades the accuracies of bone segmentation and landmark detection, leading to improper surgery planning and potential operative complications. METHODS: This work proposes a two-stage multi-task algorithm to improve the accuracy of pelvic bone segmentation and landmark detection, especially for the diseased cases. The two-stage framework uses a coarse-to-fine strategy which first conducts global-scale bone segmentation and landmark detection and then focuses on the important local region to further refine the accuracy. For the global stage, a dual-task network is designed to share the common features between the segmentation and detection tasks, so that the two tasks mutually reinforce each other's performance. For the local-scale segmentation, an edge-enhanced dual-task network is designed for simultaneous bone segmentation and edge detection, leading to the more accurate delineation of the acetabulum boundary. RESULTS: This method was evaluated via threefold cross-validation based on 81 CT images (including 31 diseased and 50 healthy cases). The first stage achieved DSC scores of 0.94, 0.97, and 0.97 for the sacrum, left and right hips, respectively, and an average distance error of 3.24 mm for the bone landmarks. The second stage further improved the DSC of the acetabulum by 5.42%, and this accuracy outperforms the state-of-the-arts (SOTA) methods by 0.63%. Our method also accurately segmented the diseased acetabulum boundaries. The entire workflow took ~ 10 s, which was only half of the U-Net run time. CONCLUSION: Using the multi-task networks and the coarse-to-fine strategy, this method achieved more accurate bone segmentation and landmark detection than the SOTA method, especially for diseased hip images. Our work contributes to accurate and rapid design of acetabular cup prostheses.

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With the discovery of the intrinsic enzyme-like activity of metal oxides, nanozymes garner significant attention due to their superior characteristics, such as low cost, high stability, multi-enzyme activity, and facile preparation. Notably, in the field of biomedicine, nanozymes primarily focus on disease detection, antibacterial properties, antitumor effects, and treatment of inflammatory conditions. However, the potential for application in regenerative medicine, which primarily addresses wound healing, nerve defect repair, bone regeneration, and cardiovascular disease treatment, is garnering interest as well. This review introduces nanozymes as an innovative strategy within the realm of bone regenerative medicine. The primary focus of this approach lies in the facilitation of osteochondral regeneration through the modulation of the pathological microenvironment. The catalytic mechanisms of four types of representative nanozymes are first discussed. The pathological microenvironment inhibiting osteochondral regeneration, followed by summarizing the therapy mechanism of nanozymes to osteochondral regeneration barriers is introduced. Further, the therapeutic potential of nanozymes for bone diseases is included. To improve the therapeutic efficiency of nanozymes and facilitate their clinical translation, future potential applications in osteochondral diseases are also discussed and some significant challenges addressed.

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The number of patients with bone defects caused by trauma, bone tumors, and osteoporosis has increased considerably. The repair of irregular, recurring, and large bone defects poses a great challenge to clinicians. Bone tissue engineering is emerging as an appropriate strategy to replace autologous bone grafting in the repair of critically sized bone defects. However, the suitability of bone tissue engineering scaffolds in terms of structure, mechanics, degradation, and the microenvironment is inadequate. Three-dimensional (3D) printing is an advanced additive-manufacturing technology widely used for bone repair. 3D printing constructs personalized structurally adapted scaffolds based on 3D models reconstructed from CT images. The contradiction between the mechanics and degradation is resolved by altering the stacking structure. The local microenvironment of the implant is improved by designing an internal pore structure and a spatiotemporal factor release system. Therefore, there has been a boom in the 3D printing of personalized bone repair scaffolds. In this review, successful research on the preparation of highly bioadaptive bone tissue engineering scaffolds using 3D printing is presented. The mechanisms of structural, mechanical, degradation, and microenvironmental adaptations of bone prostheses and their interactions were elucidated to provide a feasible strategy for constructing highly bioadaptive bone tissue engineering scaffolds.

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The resection of malignant osteosarcoma often results in large segmental bone defects, and the residual cells can facilitate recurrence. Consequently, the treatment of osteosarcoma is a major challenge in clinical practice. The ideal goal of treatment for osteosarcoma is to eliminate it thoroughly, and repair the resultant bone defects as well as avoid bacterial infections. Herein, we fabricated a selenium/strontium/zinc-doped hydroxyapatite (Se/Sr/Zn-HA) powder by hydrothermal method, and then employed it with polycaprolactone (PCL) as ink to construct composite scaffolds through 3D printing, and finally introduced them in bone defect repair induced by malignant osteosarcoma. The resultant composite scaffolds integrated multiple functions involving anti-tumor, osteogenic, and antibacterial potentials, mainly attributed to the anti-tumor effects of SeO32-, osteogenic effects of Sr2+ and Zn2+, and antibacterial effects of SeO32- and Zn2+. In vitro studies confirmed that Se/Sr/Zn-HA leaching solution could induce apoptosis of osteosarcoma cells, differentiation of MSCs, and proliferation of MC3T3-E1 while showing excellent antibacterial properties. In vivo tests demonstrated that Se/Sr/Zn-HA could significantly suppress tumors after 8 days of injection, and the Se/Sr/Zn-HA-PCLs scaffold repaired femoral defects effectively after 3 months of implantation. Summarily, the Se/Sr/Zn-HA-PCLs composite scaffolds developed in this study were effective for tumor treatment, bone defect repair, and post-operative anti-infection, which provided a great potential to be a facile therapeutic material for osteosarcoma resection.

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Despite the large demand for dental restoration each year, the design of crown restorations is mainly performed via manual software operation, which is tedious and subjective. Moreover, the current design process lacks biomechanics optimization, leading to localized stress concentration and reduced working life. To tackle these challenges, we develop a fully automated algorithm for crown restoration based on deformable model fitting and biomechanical optimization. From a library of dental oral scans, a conditional shape model (CSM) is constructed to represent the inter-teeth shape correlation. By matching the CSM to the patient's oral scan, the optimal crown shape is estimated to coincide with the surrounding teeth. Next, the crown is seamlessly integrated into the finish line of preparation via a surface warping step. Finally, porous internal supporting structures of the crown are generated to avoid excessive localized stresses. This algorithm is validated on clinical oral scan data and achieved less than 2 mm mean surface distance as compared to the manual designs of experienced human operators. The mechanical simulation was conducted to prove that the internal supporting structures lead to uniform stress distribution all over the model.

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To address the rehabilitation needs of upper limb hemiplegic patients in various stages of recovery, streamline the workload of rehabilitation professionals, and provide data visualization, our research team designed a six-degree-of-freedom upper limb exoskeleton rehabilitation robot inspired by the human upper limb's structure. We also developed an eight-channel synchronized signal acquisition system for capturing surface electromyography (sEMG) signals and elbow joint angle data. Utilizing Solidworks, we modeled the robot with a focus on modularity, and conducted structural and kinematic analyses. To predict the elbow joint angles, we employed a back propagation neural network (BPNN). We introduced three training modes: a PID control, bilateral control, and active control, each tailored to different phases of the rehabilitation process. Our experimental results demonstrated a strong linear regression relationship between the predicted reference values and the actual elbow joint angles, with an R-squared value of 94.41% and an average error of four degrees. Furthermore, these results validated the increased stability of our model and addressed issues related to the size and single-mode limitations of upper limb rehabilitation robots. This work lays the theoretical foundation for future model enhancements and further research in the field of rehabilitation.

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Osteoarthritis may result in both cartilage and subchondral bone damage. It is a significant challenge to simultaneously repair cartilage due to the distinct biological properties between cartilage and bone. Here, strontium copper tetrasilicate/ß-tricalcium phosphate (Wesselsite[SrCuSi4O10]/Ca3(PO4)2, WES-TCP) composite scaffolds with different WES contents (1, 2, and 4 wt %) were fabricated via a three-dimensional (3D) printing method for the osteochondral regeneration. The physicochemical properties and biological activities of the scaffolds were systematically investigated. 2WES-TCP (WES-TCP with 2 wt % WES) composite scaffolds not only improved the compressive strength but also enhanced the proliferation of both rabbit bone mesenchymal stem cells (rBMSCs) and chondrocytes, as well as their differentiation. The in vivo study further confirmed that WES-TCP scaffolds significantly promoted the regeneration of both bone and cartilage tissue in rabbit osteochondral defects compared with pure TCP scaffolds owing to the sustained and controlled release of bioactive ions (Si, Cu, and Sr) from bioactive scaffolds. These results show that 3D-printed WES-TCP scaffolds with bilineage bioactivities take full advantage of the bifunctional properties of bioceramics to reconstruct the complex osteochondral interface, which broadens the approach to engineering therapeutic platforms for biomedical applications.

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Objective.Precise hip joint morphometry measurement from CT images is crucial for successful preoperative arthroplasty planning and biomechanical simulations. Although deep learning approaches have been applied to clinical bone surgery planning, there is still a lack of relevant research on quantifying hip joint morphometric parameters from CT images.Approach.This paper proposes a deep learning workflow for CT-based hip morphometry measurement. For the first step, a coarse-to-fine deep learning model is designed for accurate reconstruction of the hip geometry (3D bone models and key landmark points). Based on the geometric models, a robust measurement method is developed to calculate a full set of morphometric parameters, including the acetabular anteversion and inclination, the femoral neck shaft angle and the inclination, etc. Our methods were validated on two datasets with different imaging protocol parameters and further compared with the conventional 2D x-ray-based measurement method.Main results. The proposed method yields high bone segmentation accuracies (Dice coefficients of 98.18% and 97.85%, respectively) and low landmark prediction errors (1.55 mm and 1.65 mm) on both datasets. The automated measurements agree well with the radiologists' manual measurements (Pearson correlation coefficients between 0.47 and 0.99 and intraclass correlation coefficients between 0.46 and 0.98). This method provides more accurate measurements than the conventional 2D x-ray-based measurement method, reducing the error of acetabular cup size from over 2 mm to less than 1 mm. Moreover, our morphometry measurement method is robust against the error of the previous bone segmentation step. As we tested different deep learning methods for the prerequisite bone segmentation, our method produced consistent final measurement results, with only a 0.37 mm maximum inter-method difference in the cup size.Significance. This study proposes a deep learning approach with improved robustness and accuracy for pelvis arthroplasty planning.

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