【作者】 张勇；

【导师】 杨惠林；

【作者基本信息】 苏州大学 ， 骨外科学（专业学位）， 2022， 博士

【摘要】 第一部分美多芭治疗早期非创伤性股骨头坏死的非随机回顾性临床研究目的:本研究拟分析评估使用美多芭药物保守治疗早期非创伤性股骨头坏死患者的临床疗效。方法:经本院伦理委员会批准及患者同意,回顾性分析了我院2002年10月至2013年5月所收治的49例(85髋)非外伤性股骨头坏死患者口服美多芭治疗的临床疗效。作为同期对照组,37例(67髋)非创伤性股骨头坏死患者因各种原因未接受美多芭治疗,给予减少髋关节负重及钙剂治疗。随访期间,使用Charnley改良Merle d’Aubigne临床评分系统检查髋关节的功能。所有患者在治疗前和每次就诊期间均需评估疼痛程度、行走能力和髋关节活动总范围,间隔3月行X线,6月行MRI检查。结果:所有完成治疗的患者平均随访时间为71.67个月。治疗组和非治疗组在治疗前患者基本情况以及股骨头坏死分期方面没有显著性差异。末次随访,治疗组的Ficat分期仍较初次随访时加重,然而治疗组的平均Charnley评分为16.02±2.73,非治疗组则为10.36±2.99,差异具有统计学差异(P<0.05)。治疗组Charnley评分较初诊时有所改善(P<0.05),未治疗组Charnley临床评分较初诊明显恶化(P<0.05)。而治疗组在Ficat分期临床进展率和平均临床评分方面均优于非治疗组。结论:本研究发现美多芭在延缓患者股骨头塌陷方面有一定疗效。治疗组在Ficat分期和平均临床评分方面均优于非治疗组。在股骨头坏死修复过程中,美多芭可能通过增加新骨形成的速度,从而增加股骨头的机械强度,防止其塌陷。美多芭可以改善患者的临床症状,并在大多数情况下避免或至少延迟对关节置换术的需要,这对于改善较年轻患者的生存质量显得尤其重要。第二部分基于网络药理学探讨人参治疗股骨头坏死的药理学机制和潜在药用价值目的:本研究旨在进行系统分析并基于网络药理学方法预测人参在股骨头坏死中的潜在作用机制。方法:以网络药理学为基础,利用中药系统药理学数据库和分析平台数据库对药材的活性成分及相应靶点进行鉴定,利用Gene Cards和在线孟德尔遗传对股骨头坏死相关基因进行筛选。此外,使用STRING和Cytoscape、基因本体论(GO)术语和京都基因和基因组百科全书(KEGG)通路富集分析构建了成分-靶标(I-T)和蛋白质-蛋白质相互作用(PPI)网络,以揭示人参活性成分治疗股骨头坏死的药理机制。结果:从人参中鉴定出28种活性草药成分,共有88个与股骨头坏死相关的共同靶基因。I-T网络分析显示,Dianthramine(蒽胺)和Frutinone A(果酮)结合的靶基因最多,节点度数高达58。ALOX15可以和高达16种活性成分作用,MIF可以和13种成分作用,CA6,DUSP3,ESR1可以分别和12种成分相作用。此外,ESR1的自由度为37,明显高于其他蛋白,说明ESR1(雌激素受体1)在蛋白质相互作用网格中发挥了重要的作用。进行GO富集分析以阐明88个基因参与的生物学过程。通过KEGG通路富集分析阐明了人参活性成分参与股骨头坏死治疗过程中可能激活的信号通路。其中信号通路富集最多的条目重要集中于神经活性配体-受体相互作用(hsa04080),化学致癌作用-受体激活(hsa05207),钙信号通路(hsa04020),类固醇激素生物合成(hsa00140),血清素突触(hsa04726)等。结论:网络药理学提示多种人参活性成分可能通过多靶点和多种信号通路治疗股骨头坏死。第三部分通过建立股骨近端有限元模型探讨软骨下骨厚度和股骨头囊性变坏死的位置对于股骨头塌陷的影响目的:通过有限元分析建模技术,探讨不同软骨下骨厚度与股骨头负重区形变和应力集中的关系,以及比较不同部位囊性变所承受的应力情况。旨在有效评估影响股骨头塌陷的因素,从而评价股骨头塌陷的风险,为临床医生在诊疗过程中诊断和治疗提供一定的理论基础。方法:建立股骨近端有限元模型。将患者的CT图像数据导入mimics中,重建股骨近端三维模型,并导入Geomagic软件进行修饰。在3-matic软件中重新划分面网格,在hypermesh软件中划分体网格。导入Mimics软件中基于CT值行材料赋值,最后导入hypermesh中加载边界条件。模拟单足站立位进行载荷设定和静态分析,施加压力以人体质量的2.5倍,即1500N的加载,进行模拟计算。股骨远端平面所有节点的自由度均约束固定,使得股骨远端固定。导入ABAQUS软件进行模型的计算和有限元后处理。结果:随着软骨下骨厚度的降低,股骨头负重区的最大位移增加,而股骨头负重区的最大应力值同样增加。在下降到2mm以下后,模型的力学性能会出现迅速的衰减。分别建立了四个股骨近端有限元模型(囊性变分别位于前外侧、前内、后外和后内)。位于股骨头外侧区域的囊性变的应力要明显大于内侧囊性变所受到的应力。位于股骨头靠前侧位置的囊性变所受应力要高于位于股骨头靠后位置的应力。结论:当坏死的股骨头软骨下骨的厚度低于2mm时,其塌陷的风险会显著增高,因此需要临床医生及时进行干预和治疗。股骨头前外侧囊性变所受应力峰值最大。在前外侧出现囊性变的股骨头坏死的患者往往更容易出现股骨头塌陷。第四部分经头颈开窗减压病灶清除打压植骨术治疗股骨头坏死的临床疗效分析目的:本研究的目的是为了评价经头颈开窗减压病灶清除打压植骨术治疗股骨头坏死的临床疗效。方法:本研究搜集和纳入了2019年3月至2020年10月的经诊断为股骨头无菌性坏死,同时接受经头颈开窗打压植骨手术的病例。比较了术前和术后的髋关节功能改善情况,以及患者髋关节疼痛的改善情况。结果:所有18例患者均未有失访,随访时间为12-18个月,平均16.5个月。所有患者经头颈开窗减压病灶清除打压植骨术均顺利完成。术后1年随访期间拍摄X平片检查打压植骨融合情况,发现所有18例患者人工骨移植物均融合完毕。术后最后一次随访Harris评分为82.52±12.51分,与术前65.85±9.65对比有统计学显著性差异。在18例患者(共20例患髋)中,患者的良好及以上的占比为83.33%,其中Harris评分优秀的病例有6髋,良好的病例有9髋,合格的病例有4髋,差的病例有1髋。单因素Logistics回归分析发现,患者术后Harris评分的改善与术前ARCO分期相关,而与病因,年龄,临床症状没有明显相关性。结论:所有患者经头颈开窗减压病灶清除打压植骨术均顺利完成,术中未出现明显异常。术后最后一次随访Harris评分与术前相比有所改善。患者术后Harris评分的改善与术前ARCO分期相关,而与病因,年龄,临床症状没有明显相关性。更多还原

【Abstract】 PART Ⅰ A non-randomized retrospective clinical study of Madopar in the treatment of early stage non-traumatic femoral head necrosisObjective:The purpose of this study was to retrospectively analyze the clinical efficacy of Madopar in the treatment of early stage non-traumatic femoral head necrosis.Methods:The efficacy of oral administration of Madopar in 49 patients(85 hips)with non-traumatic femoral head necrosis which were admitted by our hospital from October 2002 to May 2013 was retrospectively analyzed.During follow-up,hip function was examined using the Charnley modified clinical scoring system.37 patients(67 hips)who did not receive Madopar treatment were chosen as the control group.All patients were assessed in terms of pain level,ability to walk,and total range of motion about the hip joint.The X-ray examination was performed 3 months apart and MRI examination was performed every 6 months.Results:The mean follow-up time of all patients was 71.67 months.There was no significant difference between the treatment group and the non-treatment group in terms of patient demographics and the stage of femoral head necrosis before treatment.At the last follow-up,Ficat staging was worse in the treatment group than that of the initial follow-up,but the mean clinical score was better than that of the initial follow-up.In addition,treatment group showed better performance in terms of Ficat staging and mean clinical score than non-treatment group.Conclusions:Preliminary results suggest that it is effective in delaying femoral head collapse after the oral administration of Madopar.Ficat staging and mean clinical score were better in the treatment group than that in the non-treatment group.It may increase the rate of new bone formation during repair of femoral head necrosis,thereby increasing mechanical strength and preventing femoral head collapse.PART Ⅱ Pharmacological mechanism of ginseng in the treatment of femoral head necrosis based on network pharmacologyObjective:This study aims to conduct a systematic analysis and predict the potential mechanism of ginseng in the treatment of femoral head necrosis based on a network pharmacology approach.Methods:Based on network pharmacology analysis,the active components and corresponding targets were identified using the databases of traditional Chinese medicine.The related genes of femoral head necrosis were screened by Gene Cards and online Mendelian genetics database.Furthermore,component-target(IT)and protein-protein interaction(PPI)networks were constructed using STRING database,Cytoscape software,Gene Ontology(GO)terminology and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis.Results:Twenty-eight active herbal components were identified in ginseng,with a total of 88 common target genes associated with femoral head necrosis.I-T network analysis showed that Dianthramine and Frutinone A have the most binding target genes,and the node degree is as high as 58.ALOX15 can bind up to 16 active components.MIF can bind 13 components.CA6,DUSP3,and ESR1 can interact with 12components,respectively.In addition,the degree of freedom of ESR1 is 37,which is significantly higher than that of other proteins.The result indicates that ESR1(estrogen receptor 1)may play an important role in the protein interaction grid.GO enrichment analysis was performed to elucidate the biological processes involved in 88 overlapped genes.Through KEGG pathway enrichment analysis,the most enriched entries in signaling pathways are mainly concentrated in neuroactive ligand-receptor interaction(hsa04080),chemical carcinogenesis-receptor activation(hsa05207),calcium signaling pathway(hsa04020),steroid hormone biosynthesis(hsa00140),Serotonin Synapse(hsa04726).Conclusion:The active components of ginseng may treat femoral head necrosis through multiple targets and various signaling pathways.PART Ⅲ To investigate the influence of subchondral thickness and cystic position on femoral head collapse using finite element analysisObjective:The purpose is to effectively evaluate the factors including subchondral thickness and cystic position which affect the collapse of the femoral head,so as to evaluate the risk of collapse of the femoral head,and to provide a certain theoretical basis about the diagnosis and treatment for clinicians in the process of diagnosis and treatment.Methods:A finite element model of proximal femur was established.The patient CT image datas were imported into mimics.The 3D model of the proximal femur was then reconstructed,and imported into Geomagic software for further modification.The surface meshes were re-meshed in 3-matic software and the volume meshes were meshed in hypermesh software.The load setting and static analysis were carried out by simulating the standing position on one foot,and the pressure was 2.5 times the body mass,that was the load of 1500N.The degrees of freedom of all nodes in the plane of the distal femur were constrained and fixed.Results:With the decrease of subchondral thickness,the peak displacement of the femoral head weight-bearing area increased,and the peak stress value of the femoral head weight-bearing area also increased.After dropped below 2mm,the mechanical properties of the model would decay rapidly.Besides,four finite element models of proximal femurs were established respectively(the cystic degenerations were located in the anterolateral,anteromedial,posterolateral,and posteromedial regions,respectively).The stress of cystic degeneration in the lateral area of the femoral head was significantly greater than that of medial cystic degeneration.The stress of cystic degeneration located anterior to the femoral head was higher than that located posterior to the femoral head.Conclusion:When the thickness of the subchondral layer of the necrotic femoral head was less than 2 mm,the risk of its collapse significantly increased.The anterolateral cystic degeneration of the femoral head suffered the largest stress peak.It could be inferred that patients with anterolateral femoral head necrosis with cystic degeneration tend to be more prone to collapse of femoral head.PART Ⅳ Analysis of the clinical efficacy of decompression and bone grafting through head and neck fenestration in the treatment of femoral head necrosisObjective:The purpose of this study is to evaluate the clinical efficacy of decompression and bone grafting through head and neck fenestration in the treatment of femoral head necrosis.Methods:Patients who were diagnosed as aseptic necrosis of the femoral head from March 2019 to October 2020 and underwent transcephalic fenestration for bone grafting were included in this study.Preoperative and postoperative hip function,as well as hip pain level were compared.Results:All 18 patients were not lost during follow-up,and the follow-up time was12-18 months,with an average of 16.5 months.All patients underwent head and neck decompression and bone grafting were successfully completed.During the 1-year follow-up period,X-ray films were taken to check the fusion of the compressed bone graft,and it was found that the artificial bone graft was fused in all 18 patients.The Harris score at the last follow-up after operation was 82.52±12.51 points,which was significantly different from that before operation,which was 65.85±9.65.Among 18patients(20 hips in total),the proportion of patients with good or above was 83.33%,including 6 hips with excellent Harris score,9 good hips,4 qualified hips,and 1 poor hip.Logistics univariate regression analysis found that the improvement of postoperative Harris score was associated with preoperative ARCO stage,but not with etiology,age,and clinical symptoms.Conclusion:All patients underwent head and neck fenestration decompression and bone grafting were successfully completed,and no obvious abnormality occurred during the operation.The Harris score at the last follow-up after operation was 82.52±12.51points,which was significantly different from that before operation,which was65.85±9.65.The improvement of postoperative Harris score was related to preoperative ARCO stage,but not to etiology,age,and clinical symptoms.更多还原