Effects of time delays in a mathematical bone model

In this paper we propose a mathematical model of bone remodeling with time delays of both osteoclast-derived paracrine signaling of tumor and tumor-derived paracrine signaling of osteoclast. The effects of time delays on the growth of tumor cells and bone system are studied in multiple myeloma-induced bone disease. In the case of small osteoclast-derived paracrine signaling, it is found that the growth of tumor cells slows down, the oscillation period of the ratio of osteoclasts to osteoblasts is extended with increasing time delay, and there is a competition between the delay and osteoclast-derived paracrine signaling. In the ease of large tumor-derived paraerine signaling, the tumor-derived paracrine signaling can induce a more significant decline in tumor growth for long time delay, and thus slowing down the progression of bone disease. There is an optimal coupling between the tumor-derived paracrine signaling of osteoclasts and time delay during the progressions of bone diseases, which suppresses the tumor growth and the regression of bone disease.

Anti-Interference Study on Radiographic Bone Age Estimation Based on Artificial Intelligence Model

In this paper, the interferences of X-ray image noise on a bone age model, Xception model, were studied. We conduct a comparative experiment test according to the output performance of the neural network model using both the original image training and noise-added (Gaussian noise plus salt-pepper noise) training, and analyze the anti-interference ability of the Xception model, hoping to improve it through noise enhancement training and generalize the application ability of the model. The results show that the model trained with noise-added (Gaussian noise plussalt-pepper noise) images can make predictions that are more robust and less affected by the image disturbances, such as image noise.

Geometric Bone Modeling:From Macro to Micro Structures

There is major interest within the bio-engineering community in developing accurate and non-invasive means for visualizing, modeling and analyzing bone micro-structures. Bones are composed of hierarchical bio-composite materials characterized by complex multi-scale structural geometry. The process of reconstructing a volumetric bone model is usually based upon CT/MRI scanned images. Meshes generated by current commercial CAD systems cannot be used for further modeling or analysis. Moreover, recently developed methods are only capable of capturing the micro-structure for small volumes （biopsy samples）. This paper examines the problem of re-meshing a 3D computerized model of bone micro- structure. The proposed method is based on the following phases： defining sub-meshes of the original model in a grid-based structure, remeshing each sub-mesh using the neural network （NN） method, and merging the sub-meshes into a global mesh. Applying the NN method to micro-structures proved to be quite time consuming. Therefore, a parallel, grid-based approach was applied, yielding a simpler structure in each grid cell. The performance of this method is analyzed, and the method is demonstrated on real bone micro-structures. Furthermore, the method may be used as the basis for generating a multi-resolution bone geometric model.

Selective serotonin re-uptake inhibitor sertraline inhibits bone healing in a calvarial defect model

Bone wound healing is a highly dynamic and precisely controlled process through which damaged bone undergoes repair and complete regeneration. External factors can alter this process, leading to delayed or failed bone wound healing. The findings of recent studies suggest that the use of selective serotonin reuptake inhibitors(SSRIs) can reduce bone mass, precipitate osteoporotic fractures and increase the rate of dental implant failure. With 10% of Americans prescribed antidepressants, the potential of SSRIs to impair bone healing may adversely affect millions of patients’ ability to heal after sustaining trauma. Here, we investigate the effect of the SSRI sertraline on bone healing through pre-treatment with(10 mg·kg-1sertraline in drinking water, n = 26) or without(control, n = 30) SSRI followed by the creation of a 5-mm calvarial defect. Animals were randomized into three surgical groups:(a) empty/sham,(b) implanted with a DermaMatrix scaffold soak-loaded with sterile PBS or(c) DermaMatrix soak-loaded with542.5 ng BMP2. SSRI exposure continued until sacrifice in the exposed groups at 4 weeks after surgery. Sertraline exposure resulted in decreased bone healing with significant decreases in trabecular thickness, trabecular number and osteoclast dysfunction while significantly increasing mature collagen fiber formation. These findings indicate that sertraline exposure can impair bone wound healing through disruption of bone repair and regeneration while promoting or defaulting to scar formation within the defect site.

Ultrasonic backscatter characterization of cancellous bone using a general Nakagami statistical model

The goal of this study is to analyze the statistics of the backscatter signal from bovine cancellous bone using a Nakagami model and to evaluate the feasibility of Nakagami-model parameters for cancellous bone characterization. Ultrasonic backscatter measurements were performed on 24 bovine cancellous bone specimens in vitro and the backscatter signals were compensated for the frequency-dependent attenuation prior to the envelope detection. The statistics of the backscatter envelope were modeled using the Nakagami distribution. Our results reveal that the backscatter envelope mainly followed pre-Rayleigh distributions, and the deviations of the backscatter envelope from Rayleigh distribution decreased with increasing bone density. The Nakagami shape parameter(i.e., m) was significantly correlated with bone densities(R = 0.78–0.81, p < 0.001) and trabecular microstructures(|R| = 0.46–0.78, p < 0.05). The scale parameter(i.e.,?) and signal-to-noise ratio(SNR) also yielded significant correlations with bone density and structural features. Multiple linear regressions showed that bone volume fraction(BV/TV) was the main predictor of the Nakagami parameters,and microstructure produced significantly independent contribution to the prediction of Nakagami distribution parameters,explaining an additional 10.2% of the variance at most. The in vitro study showed that statistical parameters derived with Nakagami model might be useful for cancellous bone characterization, and statistical analysis has potential for ultrasonic backscatter bone evaluation.

The pinhole SPECT for animal model of bone metastasis with SPC-A-1BM human pulmonary adenocarcinoma bone metastasis cell line

The study was to investigate the role of pinhole single photon emission computed tomography (SPECT), the human pulmonary adenocarcinoma bone-seeking metastasis cell line SPC-A-1BM was used.These cells form typical osteolytic bone metastases when inoculated into the arterial circulation of NIH-Beige-Nude-XD (BNX) mice via the left ventricle.In order to evaluate the irradiation impact of ^(99m)Tc-MDP versus X-ray on cells growth,we used six groups of SPC-A-1BM cells in our imaging scheme and irradiated by various doses of ^(99m)Tc-MDP (37,74,111, 370,740 MBq) and X-ray(40 kV,2 mA,6 s) respectively.The cell's number of each group was well recorded in different exposure time(4,8,12,24,48,72,96 hours).After that,SPC-A-1BM cells(1×106) were inoculated into the mice via left ventricle.We compared the results obtained with those different doses of ^(99m)Tc-MDP using pinhole SPECT and conventional X-ray skeletal surveys.The data show that the cell-survival number of 111 MBq group has insignificant difference with that of X-ray and the dose is adequate to have an ideal image.Besides,it is important that the chromosome of the cells in the group of 111 MBq showed no irradiation-related damages in our test.These results implied that ^(99m)Tc-MDP pinhole SPECT may provide another way other than conventional X-ray skeletal surveys in detecting bone metastasis of pulmonary adenocarcinoma in BNX mice.

Administration of soluble activin receptor 2B increases bone and muscle mass in a mouse model of osteogenesis imperfecta

Osteogenesis imperfecta（OI） comprises a group of heritable connective tissue disorders generally defined by recurrent fractures, low bone mass, short stature and skeletal fragility. Beyond the skeletal complications of OI,many patients also report intolerance to physical activity, fatigue and muscle weakness. Indeed, recent studies have demonstrated that skeletal muscle is also negatively affected by OI, both directly and indirectly. Given the well-established interdependence of bone and skeletal muscle in both physiology and pathophysiology and the observations of skeletal muscle pathology in patients with OI, we investigated the therapeutic potential of simultaneous anabolic targeting of both bone and skeletal muscle using a soluble activin receptor 2B（ACVR2B） in a mouse model of type Ⅲ OI（oim）. Treatment of 12-week-old oim mice with ACVR2 B for 4 weeks resulted in significant increases in both bone and muscle that were similar to those observed in healthy,wild-type littermates. This proof of concept study provides encouraging evidence for a holistic approach to treating the deleterious consequences of OI in the musculoskeletal system.

New simulation model for bone formation markers in osteoporosis patients treated with once-weekly teriparatide

Daily 20-mg and once-weekly 56.5-mg teriparatide（parathyroid hormone 1–34） treatment regimens increase bone mineral density（BMD） and prevent fractures, but changes in bone turnover markers differ between the two regimens. The aim of the present study was to explain changes in bone turnover markers using once-weekly teriparatide with a simulation model. Temporary increases in bone formation markers and subsequent decreases were observed during once-weekly teriparatide treatment for 72 weeks. These observations support the hypothesis that repeated weekly teriparatide administration stimulates bone remodeling, replacing old bone with new bone and leading to a reduction in the active remodeling surface. A simulation model was developed based on the iterative remodeling cycle that occurs on residual old bone. An increase in bone formation and a subsequent decrease were observed in the preliminary simulation. For each fitted time point, the predicted value was compared to the absolute values of the bone formation and resorption markers and lumbar BMD. The simulation model strongly matched actual changes in bone turnover markers and BMD. This simulation model indicates increased bone formation marker levels in the early stage and a subsequent decrease. It is therefore concluded that remodeling-based bone formation persisted during the entire treatment period with once-weekly teriparatide.

Postnatal ex vivo rat model for longitudinal bone growth investigations

Background: Chondrocytes in the growth plate(GP) undergo increases in volume during different cascades of cell differentiation during longitudinal bone growth. The volume increase is reported to be the most significant variable in understanding the mechanism of long bone growth.Methods: Forty-five postnatal Sprague-Dawley rat pups, 7-15 days old were divided into nine age groups(P7-P15). Five pups were allocated to each group. The rats were sacrificed and tibia and metatarsal bones were harvested. Bone lengths were measured after 0, 24, 48, and 72 hours of ex vivo incubation. Histology of bones was carried out, and GP lengths and chondrocyte densities were determined.Results: There were significant differences in bone length among the age groups after 0 and 72 hours of incubation. Histological sectioning was possible in metatarsal bone from all age groups, and in tibia from 7-to 13-day-old rats. No significant differences in tibia and metatarsal GP lengths were seen among different age groups at 0 and 72 hours of incubation. Significant differences in chondrocyte densities along the epiphyseal GP of the bones between 0 and 72 hours of incubation were observed in most of the age groups.Conclusion: Ex vivo growth of tibia and metatarsal bones of rats aged 7-15 days old is possible, with percentage growth rates of 23.87 ± 0.80% and 40.38 ± 0.95%measured in tibia and metatarsal bone, respectively. Histological sectioning of bones was carried out without the need for decalcification in P7-P13 tibia and P7-P15 metatarsal bone. Increases in chondrocyte density along the GP influence overall bone elongation.

In vivo testing of a bone graft containing chitosan, calcium sulfate and osteoblasts in a paste form in a critical size defect model in rats

Bone loss associated with musculoskeletal trauma or metabolic diseases often require bone grafting. The supply of allograft and auto-graft bones is limited. Hence, development of synthetic bone grafting materials is an active area of research. Chitosan, extracted from chitin present in crawfish shells, was tested as a de-livery vehicle for osteoblasts in a 2-3 mm size defect model in rats. Twenty-seven male Lewis rats, divided into three groups with sacrifice intervals of 3, 6 &amp;amp;9 months were used. In the experimental samples, a critical size defect was filled with chitosan bone graft paste and fixed with a plate, while in the operated control group, a critical size defect was repaired only by a plate (no paste was applied). An unoperated control group was also included. Bone growth was evaluated histologically by examining undecal-cified and decalcified stained sections. The fe-murs were also examined non-destructively by micro-computed tomography (礐T). Defects filled with chitosan bone graft paste demon-strated superior healing across all time periods compared to unfilled defects as examined by histology and micro-computed tomography. Crawfish chitosan has successfully been used as a cell delivery system for osteoblasts for use as a synthetic bone graft material.

On a Constitutive Material Model to Capture Time Dependent Behavior of Cortical Bone

It is commonly known that cortical bone exhibits viscoelastic-viscoplastic behavior which affects the biomechanical response when an implant is subjected to an external load. In addition, long term effects such as creep, relaxation and remodeling affect the success of the implant over time. Constitutive material models are commonly derived from data obtained in in vitro experiments. However during function, remodeling of bone greatly affects the bone material over time. Hence it is essential to include long term in vivo effects in a constitutive model of bone. This paper proposes a constitutive material model for cortical bone incorporating viscoelasticity, viscoplasticity, creep and remodeling to predict stress-strain at various strain rates as well as the behavior of bone over time in vivo. The rheological model and its parameters explain the behavior of bone subjected to longitudinal loading. By a proper set of model parameters, for a specific cortical bone, the present model can be used for prediction of the behavior of this bone under specific loading conditions. In addition simulation with the proposed model demonstrates excellent agreement to in vitro and in vivo experimental results in the literature.

From Sméagol to Gollum: Mechanical Stress and Bone Remodelling

This imaginary transformation from Sméagol to Gollum is a dramatization of the illusive repercussions of mechanical stress affecting bone. This paper presents the main ideas of mechanical stress and bone remodelling from a novel’s perspective. The object of this study is to provide evidence for new ways to explore bone’s functional adaptation to mechanical stress made through the copious interpretation and integration of new and existing literature. It tackles the underlying biology of bone cells and how they detect and react to strain stimuli. The different types of mechanical demands in daily activities are sifted through and any misconceptions found fallible in literature are refined. A personal experience of a stress fracture is reviewed to parallel the implications that lead to the incident with the findings on the link between mechanical stress and bone remodelling. Some factors regarding age, gender and ethnicity and the interplay with mechanical stress influencing bone remodelling are considered. Brief overviews of three new medical novelties in bone healing are outlined, hoping that these interventions of proper medical techniques can be a change for the better: one from Gollum to Sméagol rather than vice versa.

Microstructure-based Finite Element Modelling and Characterisation of Bovine Trabecular Bone

The mechanical behaviour of trabecular bone is dependent on both the properties of individual trabeculae as well as their three-dimensional arrangement in space. In this study, nanoindentation was used to determine trabecular stiffness of bovine bone, both dehydrated and rehydrated. Values of 18.3 GPa and 14.3 GPa were obtained for dehydrated and rehydrated trabeculae respectively. These values were then used for finite element analysis where the mesh was generated directly from an X-ray microtomography dataset. The relationship between intrinsic tissue properties and apparent stiffness was explored. Moreover, the important role of collagen in bone micromechanics was demonstrated by complementing the study with Raman spectroscopy.

皮质悬吊装置和股骨间微动磨损有限元分析

研究了皮质悬吊装置的钛板和股骨表面的皮质骨承受交变载荷发生的微动行为.基于钛/皮质骨材料建立了球/平面微动磨损有限元模型,通过与Hertz接触理论和已有试验结果进行对比,验证了有限元方法的正确性;同时研究了位移幅值、摩擦系数和法向力对钛球/皮质骨接触面间微动磨损行为的影响.最后把已验证的模型和方法用于研究前交叉韧带(ACL)重建手术中的皮质悬吊装置和股骨间的微动磨损情况.发现随着微动位移幅值从2μm增大至10μm,磨损状态由部分滑移向完全滑移转变,最大磨损深度由0.195μm逐渐增大至14.13μm,磨损体积由5.69×10^(4)μm^(3)增大至1.41×10^(6)μm^(3);在位移幅值为5和10μm时,磨损深度、磨损面积和磨损体积都表现出随摩擦系数增大而减小的趋势;在位移幅值为5μm时,磨损深度随法向力的增加逐渐减小,在位移幅值为10μm时,磨损深度随法向力的增加逐渐增大.通过研究交变载荷下皮质悬吊装置/皮质骨微动磨损模型的微动磨损行为发现:磨损深度最大值在皮质骨隧道孔边缘的应力最大值处,并且与球/平面微动磨损模型预测趋势相同,可以通过增加皮质悬吊装置和皮质骨隧道孔边缘接触面间的摩擦系数来提高皮质骨的抗微动磨损能力,提高ACL重建手术成功率.

基于医学CT与SLM技术的踝关节骨骼逆向建模与制备

基于医学CT与3D打印技术实现了骨骼重建与制造。通过对病人踝关节骨骼原始CT数据的采集,运用医学逆向工程软件Mimics及Geomagic软件对骨骼分别进行三维模型重建和骨骼曲面修复、优化,得到了骨面较为光滑平整的踝关节模型。通过对骨骼模型进行静力学分析,说明在人体结构生物力学条件下,所建立的踝关节三维模型满足力学要求。通过实验获得了TC4钛合金激光选区熔化(SLM)技术的优化工艺参数为激光功率240 W,扫描速度800 mm/s,扫描间距为0.12 mm,铺粉厚度为0.05 mm。采用该工艺参数和所建立的踝关节模型,实现了TC4钛合金踝关节3D打印逆向制造,所得制品的形状与组织成分优,满足医学使用要求。

Computational Simulations of Bone Remodeling under Natural Mechanical Loading or Muscle Malfunction Using Evolutionary Structural Optimization Method

Live bone inherently responds to applied mechanical stimulus by altering its internal tissue composition and ultimately biomechanical properties, structure and function. The final formation may structurally appear inferior by design but complete by function. To understand the loading response, this paper numerically investigated structural remodeling of mature sheep femur using evolutionary structural optimization method (ESO). Femur images from Computed Tomography scanner were used to determine the elastic modulus variation and subsequently construct finite element model of the femur with stiffest elasticity measured. Major muscle forces on dominant phases of healthy sheep gait were imposed on the femur under static mode. ESO was applied to progressively alter the remodeling of numerically simulated femur from its initial to final design by iteratively removing elements with low strain energy density (SED). The computations were repeated with two different mesh sizes to test the convergence. The elements within the medullary canal had low SEDs and therefore were removed during the optimization. The SEDs in the remaining elements varied with angle around the circumference of the shaft. Those elements with low SED were inefficient in supporting the load and thus fundamentally explained how bone remodels itself with less stiff inferior tissue to meet load demand. This was in line with the Wolff’s law of transformation of bone. Tissue growth and remodeling process was found to shape the sheep femur to a mechanically optimized structure and this was initiated by SED in macro-scale according to traditional principle of Wolff’s law.

基于机器学习构建肺腺癌骨转移自动化模型

目的采用机器学习算法对关键变量进行识别,并对肺腺癌(LUAD)患者骨转移风险进行预测。方法回顾性分析2019年1月至2022年6月淮南东方医院集团附属肿瘤医院收治的132例确诊非小细胞肺癌(NSCLC)患者的临床资料,包括是否发生骨转移、年龄、性别、病理类型、吸烟状况、T分期、N分期、骨转移前是否有其他部位的转移,以及癌胚抗原(CEA)、碱性磷酸酶(ALP)、鳞状细胞癌抗原(SCCA)、糖类抗原125(CA125)、细胞角蛋白19片段抗原21-1(CYFRA21-1)、神经元特异性烯醇化酶(NSE)、钙(CA)水平。采用LASSO回归分析方法来筛选与骨转移相关的关键特征,并将其用于构建6种机器学习模型,另收集63例NSCLC患者的临床数据用于模型的外部验证。不同模型的预测性能通过受试者工作特征曲线(ROC曲线)来评估。校准曲线和DCA曲线用于验证所建模型的准确性和获益能力。使用SHAP包对logistic模型进行解释。结果LASSO回归分析最终筛选了4个重要变量,包括性别、N分期、CEA水平和糖类抗原CA125水平。在6种机器学习模型中,logistic模型在训练集(AUC=0.710)、测试集(AUC=0.705)和外部验证集(AUC=0.655)均具有最佳的预测效能和稳定性。SHAP图显示在logistic模型中4个变量的权重从高到低依次为CEA、性别、T分期和CA125。成功构建了LUAD骨转移的机器学习模型和网页计算器。结论logistic预测模型可以识别LUAD骨转移高风险患者,这有助于临床医生指导高危患者做出适当预防措施。

维持性血液透析患者甲状旁腺切除术后早期骨饥饿综合征风险预测模型的构建与验证

目的:甲状旁腺切除术(parathyroidectomy,PTX)是治疗难治性继发性甲状旁腺功能亢进(secondary hyperparathyroidism,SHPT)的有效方法,但PTX后极易出现骨饥饿综合征(hungry bone syndrome,HBS),严重威胁维持性血液透析(maintenance hemodialysis,MHD)患者的生命健康。目前已有研究分析PTX后并发HBS的风险因素,但风险预测模型的预测性能和临床适用性仍待进一步验证。本研究旨在构建MHD伴SHPT患者PTX后并发HBS的风险预测模型,并验证其预测效果。方法:回顾性收集2020年1月至2021年12月在长沙捷奥肾病医院行PTX的MHD伴SHPT的368例患者为训练集,按照是否发生HBS分为HBS组和non-HBS组,对2组的一般资料、手术相关信息、生化指标等进行比较,应用多因素logistic回归筛选HBS的影响因素,建立风险预测模型。采用受试者操作特征(receiver operator characteristic,ROC)曲线、决策曲线、校准曲线对模型进行评价。收集2022年1至12月在中南大学湘雅三医院行PTX的MHD伴SHPT的170例患者为验证集进行外部验证。结果:MHD伴SHPT患者PTX后HBS发生率为60.60%,logistic回归分析结果显示:术前骨骼受累(OR=3.908,95%CI 2.179~7.171)、术前血钙(OR=7.174,95%CI 2.291~24.015)、术前全段甲状旁腺激素(intact parathyroid hormone,i PTH)(OR=1.001,95%CI 1.001~1.001)、术前碱性磷酸酶(alkaline phosphatase,ALP)(OR=1.001,95%CI 1.000~1.001)、术后第1天血钙(OR=0.006,95%CI0.001~0.038)是MHD患者伴SHPT行PTX后并发HBS的独立危险因素(均P<0.01)。构建的风险预测模型在内部训练集和外部验证集中均表现出良好的预测结果,内部验证集的准确度为0.821,灵敏度为0.890,特异度为0.776,约登指数为0.666,曲线下面积(area under curve,AUC)为0.882(95%CI 0.845~0.919);外部验证集的准确度为0.800,灵敏度为0.806,特异度为0.799,约登指数为0.605,AUC为0.863(95%CI 0.795~0.932)。结论:术前骨骼受累、术前血钙、术前iPTH、术前ALP、术后第1天血钙水平是MHD伴SHPT患者行PTX后并发HBS的影响因素,基于上述因素构建的风险预测模型可靠。

辅助治疗股骨干骨折缺损数值模拟分析

针对股骨干断裂骨折患者手术治疗康复治疗问题,使用医学影像处理和逆向工程技术,依据股骨CT扫描数据,重构股骨干2mm横断缺损和股骨干10°楔形缺损断裂模型。为了分析接骨板、螺钉应力、应变变化规律及股骨整体应力集中状况,在700N轴向载荷和15N·m扭转载荷条件下,建立锁定型和锁定加压型接骨板数值模拟系统进行数值模拟分析。结果发现:锁定加压型内固定系统适用于股骨干2mm横断模型,螺钉不易发生失效断裂;锁定型内固定系统适用于股骨干10°楔形缺模型,螺钉未出现失效断裂现象,便于患者康复。