Biomedical engineering advances最新文献

{"title":"Comparative analysis of a conventional cantilever abutment and innovative double abutment in dental implant prosthesis: A finite element analysis study","authors":"Luciana Silva Colepícolo ,&nbsp;Paulo Henrique Vieira Magalhães ,&nbsp;Maria Auxiliadora Mourão Martinez ,&nbsp;Luís Otávio Miranda Cota ,&nbsp;Rafael Paschoal Esteves Lima ,&nbsp;Lucas Fernandes Sousa Pessoa ,&nbsp;Guilherme Augusto Oliveira ,&nbsp;Fernando Oliveira Costa","doi":"10.1016/j.bea.2025.100151","DOIUrl":"10.1016/j.bea.2025.100151","url":null,"abstract":"<div><div>The innovative double paraboloid abutment (DA) in dental implant prosthesis is based on the new concept of Biodynamic Optimized Peri-implant Tissue (BOiT) and was introduced in a human case series report with follow-ups ranging from 3 to 12 years. This study aimed to evaluate the influence of two structural designs: the innovative DA and a distal conventional cantilever (CC) in fixed prostheses retained by a single dental implant. The evaluation focused on stress and strain distributions in bone tissue (cortical and medullary), as well as stress distribution in the abutments, UCLA, implants, and retaining screws under axial and oblique loading, using 3D finite element analysis. Each model consisted of a bone block representing the area from the right second premolar to the first molar, with one internal hexagon implant (4.0 × 10 mm) supporting a fixed dental prosthesis of two elements. Forces of 100 N were applied in both axial and oblique directions (at 30° in the Y direction). The von Mises criterion was used to assess maximum principal stress values and microstrain. Simulations were created using ANSYS mechanical software. After applying the loads and obtaining the stress results, using the same materials for each of the modeled parts, as well as bone and identical loads, it was observed that the DA design yielded more favorable results than the cantilever. The DA showed significantly lower stress levels and better strain distributions, indicating a more favorable biomechanical interaction between structures. These findings suggest that DA designs may reduce stress concentrations and potentially minimize the risk of clinical complications compared to traditional CC designs, leading to improved long-term implant stability and success rates in patients missing two adjacent dental elements, supported by a single osseointegrated implant.</div></div>","PeriodicalId":72384,"journal":{"name":"Biomedical engineering advances","volume":"9 ","pages":"Article 100151"},"PeriodicalIF":0.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143684258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Determining the optimal design parameters for gyroids using computational fluid dynamics analysis under a non-Newtonian perfusion system","authors":"Abhisek Gupta ,&nbsp;Masud Rana ,&nbsp;Nitesh Mondal","doi":"10.1016/j.bea.2025.100153","DOIUrl":"10.1016/j.bea.2025.100153","url":null,"abstract":"<div><div>A gyroid scaffold provides a biologically acceptable environment for tissue growth and regeneration of injured tissue and organs. The effective waste and nutrient transport between implanted scaffolds and surrounding tissue remains a key challenge in bone tissue engineering. Consequently, this study aims to assess the flow transport parameters of gyroid scaffolds, focusing on their porous structures, which are commonly used as scaffold units in recent times. In this study, a computational fluid dynamics analysis was done with the four types of gyroids to identify the optimum scaffold for the better growth or regeneration of tissue. The different hydrodynamics parameters were observed for both Newtonian and non-Newtonian fluids for different gyroid structures. The variation of wall shear stress (WSS) and permeability were studied and compared for both Newtonian and non-Newtonian fluids between gyroids. Later, a sinusoidal non-Newtonian flow was applied to the gyroids to examine the responses due to pulsatile flow. The results showed that non-Newtonian flow generates higher WSS and lower permeability than Newtonian flow within gyroids in each case. Furthermore, additional regions within the scaffold were found to fall within the favorable zone for bone growth under pulsatile flow conditions. The findings of this study hold promise for enhancing scaffold design in tissue engineering and identifying ways to promote optimal cell seeding areas within the scaffold in vitro.</div></div>","PeriodicalId":72384,"journal":{"name":"Biomedical engineering advances","volume":"9 ","pages":"Article 100153"},"PeriodicalIF":0.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143592493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding and generating synergy-based hand movements using electroencephalography during motor execution and motor imagery","authors":"Dingyi Pei,&nbsp;Ramana Vinjamuri","doi":"10.1016/j.bea.2025.100152","DOIUrl":"10.1016/j.bea.2025.100152","url":null,"abstract":"<div><div>Brain-machine interfaces (BMIs) have proven valuable in motor control and rehabilitation. Motor imagery (MI) is a key tool for developing BMIs, particularly for individuals with impaired limb function. Motor planning and internal programming are hypothesized to be similar during motor execution (ME) and motor imagination. The anatomical and functional similarity between motor execution and motor imagery suggests that synergy-based movement generation can be achieved by extracting neural correlates of synergies or movement primitives from motor imagery. This study explored the feasibility of synergy-based hand movement generation using electroencephalogram (EEG) from imagined hand movements. Ten subjects participated in an experiment to imagine and execute hand movement tasks while their hand kinematics and neural activity were recorded. Hand kinematic synergies derived from executed movements were correlated with EEG spectral features to create a neural decoding model. This model was used to decode the weights of kinematic synergies from motor imagery EEG. These decoded weights were then combined with kinematic synergies to generate hand movements. As a result, the decoding model successfully predicted hand joint angular velocity patterns associated with grasping different objects. This adaptability demonstrates the model's ability to capture the motor control characteristics of ME and MI, advancing our understanding of MI-based neural decoding. The results hold promise for potential applications in noninvasive synergy-based neuromotor control and rehabilitation for populations with upper limb motor disabilities.</div></div>","PeriodicalId":72384,"journal":{"name":"Biomedical engineering advances","volume":"9 ","pages":"Article 100152"},"PeriodicalIF":0.0,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143550883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Photosensitizer of phthalocyanine-conjugated chitosan-doped nano-silver for inactivation against bacteria and promote wound healing","authors":"Wenqing Lai ,&nbsp;Huanliang Liu ,&nbsp;Jun Yan,&nbsp;Lei Tian,&nbsp;Yue Shi,&nbsp;Zhuge Xi,&nbsp;Bencheng Lin","doi":"10.1016/j.bea.2025.100147","DOIUrl":"10.1016/j.bea.2025.100147","url":null,"abstract":"<div><div>Controlling microbial infection should receive more attention and research support against the rapidly growing phenomenon of bacterial resistance to antibiotics caused by the abuse and inappropriate use of antibiotics. Photodynamic antibacterial chemotherapy should be an alternative option to the antibiotic resistance problem. In this study, new photosensitive material of phthalocyanine-modified chitosan (Pc-CS) was synthesized and studied to effectively inactivate Gram-positive and Gram-negative bacteria, including drug-resistant strains, through photodynamic action. The new photosensitive material of Pc-CS@Ag which was synthesized by phthalocyanine-conjugated chitosan and doping nano-silver could photodynamically inactivate the Gram-positive and Gram-negative bacteria with 90 % maximum effect concentration (EC₉₀) of 3.12–6.25 µg/mL, and had the similar eradiation activity against drug-resistant bacteria (EC₉₀=6.25 µg/mL). Chitosan conjugation and nano-silver doping had less influence on the singlet oxygen yield of phthalocyanine. The material exhibited significant concentration and light intensity dependence in the photodynamic antibacterial mechanism and had a visible post-antibiotic effect. Moreover, the photosensitive material was effective in healing wounds in BALB/c mice. The healing wounds results suggest that the photosensitive material ameliorate excision wounds, and wound healing could be due to their effective antimicrobial activity and biocompatibility. Therefore, this photosensitive material has good potential for antibacterial applications.</div></div>","PeriodicalId":72384,"journal":{"name":"Biomedical engineering advances","volume":"9 ","pages":"Article 100147"},"PeriodicalIF":0.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143453096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanical and microstructural properties of additively manufactured porous titanium alloy constructs for orthopaedic and maxillofacial reconstruction","authors":"Khaled M. Hijazi ,&nbsp;Haojie Mao ,&nbsp;David W. Holdsworth ,&nbsp;S. Jeffrey Dixon ,&nbsp;Amin S. Rizkalla","doi":"10.1016/j.bea.2025.100148","DOIUrl":"10.1016/j.bea.2025.100148","url":null,"abstract":"<div><div>Porous intraosseous implants, fabricated from titanium alloy by selective laser melting (SLM), promote osseointegration and decrease stress shielding. Nevertheless, the application of such constructs in surgery has been restricted due to issues with their structural and mechanical properties. In addition, the flexural properties of porous constructs are not well known. Hence, this research aimed to investigate the mechanical and microstructural properties of porous constructs made from Ti6Al4V alloy for applications such as mandibular reconstruction. Computer models were created of dumbbell-shaped and square prism constructs with cubic pore structures. Five strut thicknesses between 250 and 650 µm with a constant 1 mm unit cell size were created, which gave rise to pores of sizes between 350 and 750 µm. Nonporous models were used as controls. Constructs were fabricated from these models using selective laser melting. Computed tomography was used to investigate internal defects and surface roughness. Internal defects made up &lt; 1.0 % of the total volume. Loose and partially melted particles caused a rough surface on the struts, with arithmetic mean height ranging between 2.0 and 9.5 µm. Finite element analysis (FEA) was performed to simulate tensile and flexural loadings and predict locations of mechanical weakness. Static tensile and three-point bend tests were performed on SLM-built constructs using an Instron screw-type testing machine. The FEA models incorporated mechanical properties of Ti6Al4V, which were sourced from the stress-strain curves from tensile tests on nonporous constructs produced via selective laser melting. There was close agreement between the FEA simulations and the actual tensile and flexural strengths and moduli of the constructs (deviations &lt; 11 %). The results of real-life mechanical tests and FEA tests demonstrated that the modulus and strength values are strongly correlated with strut thickness (R²&gt;0.95). Porous Ti6Al4V constructs with strut thicknesses ranging between 350 and 450 µm were found to have modulus and strength values that matched those of the mandible. This study demonstrated that FEA models can accurately predict the mechanical behaviour of SLM-built porous constructs. This will permit the rapid design of patient-specific porous devices that facilitate bone alignment, vascularization, tissue ingrowth, and skeletal function.</div></div>","PeriodicalId":72384,"journal":{"name":"Biomedical engineering advances","volume":"9 ","pages":"Article 100148"},"PeriodicalIF":0.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bio-based composite membranes from fish scales: A novel approach to harnessing collagen and hydroxyapatite for tissue engineering applications","authors":"Israel Núñez-Tapia ,&nbsp;Jimena Macouzet-Garduño ,&nbsp;Fernanda Ramírez-Ruiz ,&nbsp;Febe Carolina Vázquez-Vázquez ,&nbsp;Marco Antonio Álvarez-Pérez ,&nbsp;Lauro Bucio-Galindo ,&nbsp;María Cristina Piña-Barba","doi":"10.1016/j.bea.2025.100146","DOIUrl":"10.1016/j.bea.2025.100146","url":null,"abstract":"<div><div>Fish scales, a by-product of the fishing industry, have been identified as a potential source of hydroxyapatite and collagen due to their inherent composition. The present study aims to develop a bio-based membrane from fish scales as a raw material, evaluating its suitability for tissue engineering applications.</div><div>The characterisation of the resulting membranes was performed by infrared spectroscopy, which allowed the identification of peaks corresponding to the vibrational modes of the amides present in collagen. The presence of hydroxyapatite was confirmed by X-ray diffraction, the results of which were in agreement with the ICDD 009–0431 standard. The collagen denaturation temperature (70 °C) was determined using differential scanning calorimetry. Furthermore, the mechanical properties were evaluated by uniaxial tensile tests, following the standards of ASTM-D1708–96, and the Young's moduli were obtained as 7179 ± 77 kPa in dry conditions and 760 ± 133 kPa in wet conditions.</div><div>In tests with human gingival fibroblasts, the fish scale-derived membranes showed higher cell viability and significantly higher proliferation rates compared to the commercial type I collagen membrane used as a control (Matrixflex™, obtained from highly purified porcine peritoneum), highlighting the potential of fish scale-derived membranes as bio-based composite materials.</div></div>","PeriodicalId":72384,"journal":{"name":"Biomedical engineering advances","volume":"9 ","pages":"Article 100146"},"PeriodicalIF":0.0,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tissue engineering and biosensing applications of carbon-based nanomaterials","authors":"Seydanur Yücer ,&nbsp;Begüm Sarac ,&nbsp;Fatih Ciftci","doi":"10.1016/j.bea.2025.100145","DOIUrl":"10.1016/j.bea.2025.100145","url":null,"abstract":"<div><div>Carbon nanomaterials (CNMs) have emerged as a transformative class of materials in the biomedical field, offering exceptional versatility and efficacy. This study highlights the unique mechanical, electrical, and biocompatible properties of CNMs that make them indispensable for applications such as drug delivery, biosensing, tissue engineering, and medical implants. Specifically, graphene's remarkable conductivity and mechanical strength enhance biosensor sensitivity and scaffold durability, while the tubular structure and functional surface chemistry of carbon nanotubes (CNTs) improve cellular interactions and mechanical stability in implants. Carbon dots, with their tunable fluorescence and high biocompatibility, are proving to be powerful agents for bioimaging, enabling more precise diagnostics.</div><div>This review consolidates recent advancements in the synthesis, functionalization, and biomedical integration of CNMs, emphasizing their role in next-generation applications. Notably, it addresses challenges related to scalable production and clinical safety, offering insights into overcoming these obstacles. The findings underline the transformative potential of CNMs in revolutionizing therapeutic and diagnostic approaches, paving the way for innovative solutions in healthcare.</div></div>","PeriodicalId":72384,"journal":{"name":"Biomedical engineering advances","volume":"9 ","pages":"Article 100145"},"PeriodicalIF":0.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143161031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring therapeutic strategies for androgen-independent prostate cancer using a magnetic coculture platform","authors":"Anjani Chavali ,&nbsp;Giles Fitzwilliams ,&nbsp;Adam Germain ,&nbsp;Sandra Khuon ,&nbsp;Young-tae Kim","doi":"10.1016/j.bea.2025.100144","DOIUrl":"10.1016/j.bea.2025.100144","url":null,"abstract":"<div><div>Prostate cancer stands as the most diagnosed cancer in males and remains one of the leading causes of death among men in the United States. The progression of prostate cancer to a life-threatening state occurs upon metastasis, typically spreading to vital organs such as the liver, lungs, bones, and lymph nodes, where it sustains growth even in the absence of androgens. In this study, we employed a magnetic coculture device to investigate the interactions between androgen-independent prostate cancer (PC3) cells and healthy normal fibroblasts, aiming to discern their dynamics. Subsequently, the coculture was exposed to varying dosages of Fenbendazole to assess its efficacy differentially on healthy fibroblasts compared to androgen-independent prostate cells. Employing this straightforward coculture method, we observed significant growth, motility, and cluster formation of prostate cancer cells upon direct contact with surrounding fibroblasts. The impact of Fenbendazole was evident in its capacity to markedly diminish the growth and metastasis of prostate cancer cells relative to surrounding fibroblasts. Notably, our findings revealed that a dosage of 2.5 µM Fenbendazole significantly eradicated PC3 cells with minimal damage to surrounding fibroblasts, thus indicating its potential for prostate cancer treatment in-vivo models.</div></div>","PeriodicalId":72384,"journal":{"name":"Biomedical engineering advances","volume":"9 ","pages":"Article 100144"},"PeriodicalIF":0.0,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143161029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biochemical and biophysical cues of the extracellular matrix modulates stem cell fate: Progress and prospect in extracellular matrix mimicking biomaterials","authors":"Anuska Mishra ,&nbsp;Unnati Modi ,&nbsp;Rahul Sharma ,&nbsp;Dhiraj Bhatia ,&nbsp;Raghu Solanki","doi":"10.1016/j.bea.2024.100143","DOIUrl":"10.1016/j.bea.2024.100143","url":null,"abstract":"<div><div>Stem cell therapies hold immense promise for the treatment of a wide range of diseases; however, the full therapeutic potential remains untaped. This limitation arises primarily from our incomplete understanding of the complex mechanisms of stem cell niches. A promising avenue of research lies in the development of Extracellular Matrix (ECM)-based novel biomaterials, which closely mimic the natural microenvironment of stem cells. These biomaterials provide essential biophysical and biochemical cues necessary for mechanotransduction, thereby enhancing the efficacy and safety of stem cell therapies by precisely modulating stem cell fate. In this review, we discuss the critical role of the stem cell niche and its interplay with ECM, detailing its structural composition and functional significance. We further explore how the biophysical and biochemical factors of the ECM modulate specific transmembrane receptors, triggering intracellular signaling mechanisms that regulate cell morphology, cytoskeletal dynamics, viability, migration, and differentiation. Engineered biomaterials to replicate the properties of the ECM are discussed along with the incorporation of tailored biophysical and biochemical cues into scaffolds and biomaterials to modulate stem cell fate. Overall, this review underscores the innovative applications of ECM mimicking biomaterials in biomedical engineering, emphasizing their transformative potential to modulate stem cell fate and advance regenerative medicine.</div></div>","PeriodicalId":72384,"journal":{"name":"Biomedical engineering advances","volume":"9 ","pages":"Article 100143"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143161030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gingival fibroblast seeded bioengineered scaffolds for treatment of localized gingival recession","authors":"Rajul Chordia ,&nbsp;Aritri Ghosh ,&nbsp;Shalini Dasgupta ,&nbsp;Sayandeep Saha ,&nbsp;Tirthankar Debnath ,&nbsp;Ashit Kumar Pal ,&nbsp;Ananya Barui","doi":"10.1016/j.bea.2024.100142","DOIUrl":"10.1016/j.bea.2024.100142","url":null,"abstract":"<div><div>Gingival recession is a prevalent issue present in most of the Indian population, associated with interproximal tissue deficiency, leading to dental problems. Its treatment has remained a major problem in the field of periodontics due to autologous graft morbidity and limited healing associated with the current artificial grafts. The present study aims to is to develop bio-engineered chitosan-gelatin scaffolds seeded with primary gingival fibroblasts to address gingival recession as noninvasive grafts. Gingival fibroblasts were seeded on scaffolds with varying chitosan-gelatin ratios (1:1, 1:3) (v/v) and a chitosan control. Comprehensive characterization included morphological, mechanical, biochemical, and cellular analyses including cell viability, migration and transcriptomic studies. The chitosan-gelatin scaffolds (1:3) demonstrated a highly porous architecture with satisfactory biodegradation and swelling capacity. Furthermore, in vitro studies show significantly higher cellular compatibility, fibroblast migration, and F-actin expression. The upregulation of FGF-2 gene in this scaffold indicates its potential for promoting fibroblastic growth and improved wound healing potential. In addition, the antibacterial impact reflect its clinical potential of the fibroblast-seeded chitosan-gelatin (1:3) scaffold for potential tissue engineering applications in periodontal regeneration.</div></div>","PeriodicalId":72384,"journal":{"name":"Biomedical engineering advances","volume":"9 ","pages":"Article 100142"},"PeriodicalIF":0.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143161028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}