本文關(guān)鍵詞：富含α2巨球蛋白血清的分子生物學(xué)研究及其在創(chuàng)傷性關(guān)節(jié)炎早期干預(yù)治療中的作用　出處：《山西醫(yī)科大學(xué)》2017年博士論文　論文類(lèi)型：學(xué)位論文

  更多相關(guān)文章： a2巨球蛋白 富含α2巨球蛋白血清 創(chuàng)傷性關(guān)節(jié)炎 超濾離心法 熒光分子斷層成像

【摘要】：研究背景:前交叉韌帶(Anterior cruciate ligament,ACL)損傷是青壯年尤其是競(jìng)技體育運(yùn)動(dòng)者中最常見(jiàn)的膝關(guān)節(jié)韌帶損傷之一。臨床上以ACL重建術(shù)為其治療的主要方法。但ACL重建術(shù)并不能降低ACL損傷所繼發(fā)的創(chuàng)傷性關(guān)節(jié)炎(Post-traumatic osteoarthritis,PTOA)發(fā)生的風(fēng)險(xiǎn)和進(jìn)程。最新的研究表明,在關(guān)節(jié)創(chuàng)傷后一周內(nèi)關(guān)節(jié)腔即出現(xiàn)大量的炎癥因子及氧自由基等,促使大量的軟骨細(xì)胞凋亡,成為啟動(dòng)PTOA關(guān)節(jié)軟骨退變和損傷的始動(dòng)因素。因此及早抑制這些炎性因子的活性對(duì)阻止或者減緩PTOA的發(fā)展至為關(guān)鍵。α-2巨球蛋白(Alpha-2-macroglobulin,A2M)作為一種廣譜的蛋白酶抑制劑在關(guān)節(jié)軟骨損傷時(shí)被合成和分泌到關(guān)節(jié)液中,可有效地抑制IL-1誘導(dǎo)軟骨基質(zhì)降解的基質(zhì)金屬蛋白酶(MMP-3、9、13)和多種炎癥因子(IL-1β、6、8,TNF-a和GM-CSF)的活性,但其在關(guān)節(jié)軟骨損傷后血清和關(guān)節(jié)液中分泌情況卻一直未見(jiàn)相關(guān)研究。本課題組在前期研究中也已經(jīng)證實(shí)采用前交叉韌帶切斷術(shù)(Anterior cruciate ligament transection,ACLT)制作的SD大鼠的創(chuàng)傷性關(guān)節(jié)炎(PTOA)模型中,適量的補(bǔ)充外源性的A2M可以明顯的減緩關(guān)節(jié)軟骨的退變進(jìn)程,具有非常顯著的正性關(guān)節(jié)軟骨保護(hù)作用。但所使用的A2M為大分子量蛋白質(zhì),免疫原性強(qiáng),異種A2M長(zhǎng)期關(guān)節(jié)腔注射極有可能引起免疫反應(yīng),因此尋求一種更加簡(jiǎn)單的提純或富含A2M血清的方法并觀(guān)察其對(duì)創(chuàng)傷性關(guān)節(jié)炎(PTOA)的治療效果具有非常重要臨床價(jià)值。研究目的:1)分析A2M在A(yíng)CL損傷時(shí)血清、關(guān)節(jié)液中的分布變化,明確與關(guān)節(jié)軟骨退化存在的關(guān)聯(lián),為外源性補(bǔ)充A2M提供理論依據(jù);2)采用超濾離心法制備富含A2M血清(A2M-Rich Serum,A2MRS),檢測(cè)A2MRS中的A2M的蛋白濃度及蛋白活性,并分析其分子生物學(xué)特性;3)觀(guān)察富含A2M血清(A2M-Rich Serum,A2MRS)對(duì)創(chuàng)傷性關(guān)節(jié)炎(PTOA)的關(guān)節(jié)軟骨是否具有明顯的治療效果或減緩關(guān)節(jié)軟骨退化的作用。研究方法:1)首先以2月齡96只SD大鼠為實(shí)驗(yàn)對(duì)象,分為兩組,每組48只。實(shí)驗(yàn)組通過(guò)前交叉韌帶切斷術(shù)(Anterior cruciate ligament transection,ACLT)建立PTOA動(dòng)物模型,對(duì)照組采取假手術(shù)切開(kāi),不行ACLT。術(shù)后3天及1、2、4、8及12周每個(gè)時(shí)間點(diǎn)各組處死8只大鼠,收集血清及膝關(guān)節(jié)盥洗液。采用酶聯(lián)免疫吸附試驗(yàn)(ELISA)檢測(cè)大鼠ACL損傷后不同時(shí)間點(diǎn)的關(guān)節(jié)盥洗液、血清中A2M的濃度變化規(guī)律,同時(shí)采用番紅O固綠染色觀(guān)察PTOA隨著時(shí)間的延長(zhǎng)其關(guān)節(jié)軟骨退化的病理進(jìn)程與體液中A2M的含量變化是否存在某種關(guān)聯(lián),探討A2M是否可以作為關(guān)節(jié)軟骨退變?cè)缙谠\斷及監(jiān)測(cè)病理進(jìn)程的生物標(biāo)記物,為外源性補(bǔ)充A2M提供理論依據(jù)。2)采用超濾離心法制備富含A2M血清(A2M-Rich Serum,A2MRS),采用酶聯(lián)免疫吸附試驗(yàn)(ELISA)、蛋白免疫印跡法(Western Blot)等方法檢測(cè)其分子生物學(xué)性質(zhì)。3)選取80只健康成年SD大鼠,分為4組,每組20只:Sham+Saline(空白對(duì)照組)、ACLT+HA2MRS(高劑量組)、ACLT+LA2MRS(低劑量組)、ACLT+Saline(陽(yáng)性對(duì)照組)。手術(shù)后3天、2周、4周依據(jù)分組的不同關(guān)節(jié)腔定時(shí)注射30ul生理鹽水或30ul不同濃度A2MRS(高劑量組A2M為20ug/ul,低劑量組A2M為10ug/ul)。每個(gè)時(shí)間點(diǎn)治療后24小時(shí)關(guān)節(jié)腔注射MMP680免疫熒光探針,采用熒光分子斷層成像系統(tǒng)(Fluorescence Molecular Tomography,FMT)動(dòng)態(tài)檢測(cè)基質(zhì)金屬蛋白酶(Matrix metalloproteinase,MMP)在關(guān)節(jié)液中濃度的變化,觀(guān)察A2MRS對(duì)基質(zhì)金屬蛋白酶是否具有抑制作用。術(shù)后8周統(tǒng)一處死動(dòng)物,小動(dòng)物X線(xiàn)片觀(guān)察膝關(guān)節(jié)退變的影像學(xué)表現(xiàn),印度墨水染色評(píng)估關(guān)節(jié)軟骨大體損傷情況,并行Mankin’s評(píng)分;脛骨平臺(tái)關(guān)節(jié)軟骨采用甲苯胺藍(lán)、番紅O固綠染色、蘇木精-伊紅染色(HE染色)和免疫組化法觀(guān)察A2MRS對(duì)PTOA軟骨病理退變是否具有減緩或者修復(fù)作用,采用OARIS評(píng)分系統(tǒng)評(píng)估關(guān)節(jié)軟骨的病理變化并作統(tǒng)計(jì)學(xué)分析;股骨髁關(guān)節(jié)軟骨采用實(shí)時(shí)熒光定量PCR法(RTPCR)對(duì)軟骨組織中II型膠原(COL-II)、X型膠原(COL-X)、基質(zhì)金屬蛋白酶3、13(Matrix metalloproteinase,MMP-3、13)、軟骨聚集蛋白聚糖(Aggrecan)、Runt蛋白相關(guān)轉(zhuǎn)錄因子-2(Runt-related transcription factor,Runx2)等指標(biāo)進(jìn)行檢測(cè),評(píng)估富含A2M血清對(duì)關(guān)節(jié)軟骨損傷在基因?qū)用嫔系恼{(diào)控作用。采用ELISA檢測(cè)關(guān)節(jié)液中基質(zhì)金屬蛋白酶(Matrix metalloproteinase,MMP-13)濃度。結(jié)果:1)ACLT術(shù)后實(shí)驗(yàn)組與對(duì)照組的關(guān)節(jié)軟骨早期大體觀(guān)察與組織病理學(xué)觀(guān)察并無(wú)明顯的區(qū)別,但術(shù)后8周開(kāi)始,實(shí)驗(yàn)組的關(guān)節(jié)軟骨退化明顯加重。實(shí)驗(yàn)組術(shù)后3天、1周、8周關(guān)節(jié)盥洗液中A2M的濃度較血清中的濃度明顯增高。并且實(shí)驗(yàn)組術(shù)后3天關(guān)節(jié)液盥洗液中的A2M的濃度與對(duì)照組關(guān)節(jié)盥洗液中A2M濃度相比較明顯增高,術(shù)后1周開(kāi)始迅速降低與對(duì)照組無(wú)差別。2)采用超濾離心法制備的富含A2M血清(A2M-Rich Serum,A2MRS)經(jīng)ELISA檢測(cè)結(jié)果為:人的血清中A2M的濃度為2.43±0.66mg/ml,富含A2M血清(A2MRS)中A2M的濃度為19.52±4.37mg/ml,A2MRS中的A2M的濃度較正常血清中的濃度提高了8.04倍。蛋白免疫印跡(Western Blot)結(jié)果顯示:富含A2M血清(A2MRS)相比正常血清在180k D處有非常明顯的蛋白濃聚現(xiàn)象。A2M蛋白活性檢測(cè)表明:富含A2M血清(A2MRS)的A2M蛋白活性較正常血清A2M的活性提高2.13倍。3)動(dòng)物體內(nèi)實(shí)驗(yàn)觀(guān)察A2MRS對(duì)PTOA關(guān)節(jié)軟骨退化的治療作用,通過(guò)熒光分子斷層成像系統(tǒng)(Fluorescence Molecular Tomography,FMT)檢測(cè)結(jié)果表明:富含A2M血清(A2MRS)早期可以明顯抑制創(chuàng)傷性關(guān)節(jié)炎關(guān)節(jié)液中基質(zhì)金屬蛋白酶3、13(Matrix metalloproteinase,MMP-3、13)。膝關(guān)節(jié)的X光片的影像學(xué)表現(xiàn):ACLT+Saline組的髕骨下緣有明顯的骨贅增生,其余三組在影像學(xué)表現(xiàn)上均沒(méi)有觀(guān)察到明顯的退行性改變。印度墨水染色表明:Sham+Saline組中軟骨表面未見(jiàn)明顯損傷,ACLT+Saline組軟骨表面損傷最為嚴(yán)重,而ACLT+A2MRS組關(guān)節(jié)面損傷明顯減輕,其中ACLT+HA2MRS組中軟骨損傷在A(yíng)CL切斷組中最小,改良Mankin's評(píng)分顯示:ACLT+HA2MRS組和ACLT+LA2MRS與ACLT+Saline組相比較均有明顯統(tǒng)計(jì)學(xué)意義,但ACLT+HA2MRS組與ACLT+LA2MRS組相比較無(wú)統(tǒng)計(jì)學(xué)意義。脛骨平臺(tái)番紅O固綠染色、HE染色及甲苯胺藍(lán)染色結(jié)果均顯示:ACLT+Saline組軟骨厚度明顯變薄,軟骨表面有較多小的裂隙,軟骨細(xì)胞分布紊亂,糖胺多糖染色較差。ACLT+LA2MRS組軟骨細(xì)胞聚集成團(tuán),軟骨厚度降低,ACLT+HA2MRS組中軟骨表面較為平滑,細(xì)胞排列較整齊,Sham+Saline組軟骨表面完整,結(jié)構(gòu)良好,細(xì)胞分布均勻,糖胺多糖染色良好。OARIS評(píng)分顯示:ACLT+Saline組為10.15±2.88,ACLT+HA2MRS組為5.54±2.61,ACLT+LA2MRS組為4.87±2.74,Sham+Saline為3.05±1.39,統(tǒng)計(jì)學(xué)分析表明:兩個(gè)實(shí)驗(yàn)組(ACLT+HA2MRS和ACLT+LA2MRS)與陽(yáng)性對(duì)照組(ACLT+Saline)均有顯著性差異(p0.0001),兩個(gè)實(shí)驗(yàn)組(ACLT+HA2MRS和ACLT+LA2MRS)與空白對(duì)照組(Sham+Saline)均有顯著性差異。而ACLT+HA2MRS組與ACLT+LA2MRS組之間經(jīng)統(tǒng)計(jì)學(xué)分析不具有顯著性差異(p=0.22)。在II型膠原的免疫組化染色上,ACLT+HA2MRS組和ACLT+LA2MRS組的陽(yáng)性細(xì)胞明顯比ACLT+Saline組染色強(qiáng),即ACLT+HA2MRS組較ACLT+LA2MRS組陽(yáng)性細(xì)胞要強(qiáng),但兩組II型膠原的免疫組化染色均低于Sham+Saline組。在X型膠原和MMP-13的免疫組化染色上,ACLT+Saline組陽(yáng)性細(xì)胞在四組中表達(dá)最強(qiáng),Sham+Saline組的陽(yáng)性細(xì)胞表達(dá)最弱,而兩個(gè)治療組ACLT+HA2MRS組及ACLT+LA2MRS組在X型膠原表達(dá)上介于A(yíng)CLT+Saline組與Sham+Saline組之間,并且同樣存在劑量依賴(lài)性,即ACLT+HA2MRS的X型膠原的表達(dá)比ACLT+LA2MRS組弱。RT-PCR結(jié)果表明A2MRS具有較為明顯的抑制負(fù)性基因X型膠原(COL-X)、基質(zhì)金屬蛋白酶3、13(Matrix metalloproteinase 3、13,MMP-3、13)、Runt蛋白相關(guān)轉(zhuǎn)錄因子-2(Runt-related transcription factor,Runxn2)的m RNA表達(dá)。關(guān)節(jié)液中MMP-13的ELISA測(cè)定結(jié)果表明:ACLT+HA2MRS組、ACLT+LA2MRS組與Sham+Saline組中關(guān)節(jié)液中MMP-13濃度均顯著低于A(yíng)CLT+Saline,統(tǒng)計(jì)學(xué)分析有顯著性差異,但前三組之間組相比均無(wú)統(tǒng)計(jì)學(xué)差異。結(jié)論:1.關(guān)節(jié)液中A2M可以作為生物標(biāo)記物早期診斷創(chuàng)傷性關(guān)節(jié)炎,術(shù)后一周關(guān)節(jié)液中A2M的迅速降低提示外源性的補(bǔ)充至關(guān)重要。2.超濾離心法可高效便捷的制備具有較高蛋白濃度和蛋白活性的富含A2M血清。3.富含A2M血清(A2MRS)具有較為明顯減緩關(guān)節(jié)軟骨退化的正性治療作用。
[Abstract]:Background: anterior cruciate ligament (Anterior cruciate, ligament, ACL) in young adults especially injury is one of the most common knee ligament injury in sports. In clinical ACL reconstruction is the main treatment. But ACL reconstruction can not reduce ACL damage secondary to traumatic arthritis (Post-traumatic osteoarthritis PTOA), and the risk of the occurrence process. The latest research shows that in a week after trauma in joint articular cavity is the emergence of a large number of inflammatory cytokines and oxygen free radicals, promote the apoptosis of chondrocytes in great quantities, become the initiating factors start PTOA articular cartilage degeneration and injury. Therefore to inhibit these inflammatory cytokines activity is the key to the development of prevent or slow PTOA. Alpha -2 macroglobulin (Alpha-2-macroglobulin, A2M) as a broad-spectrum protease inhibitor in cartilage was synthesized and secreted The joint fluid, matrix metalloproteinases can effectively inhibit IL-1 induced cartilage matrix degradation (MMP-3,9,13) and a variety of inflammatory cytokines (IL-1 beta, 6,8, TNF-a and GM-CSF) activity in serum, but the articular cartilage and synovial fluid secretion but has no related research. The research group in the early stage research has also confirmed that the anterior cruciate ligament transection (Anterior cruciate ligament transection, ACLT) of traumatic arthritis in rats of the SD (PTOA) model, the amount of exogenous A2M can significantly reduce the articular cartilage degeneration process, has a significant protective effects of articular cartilage but. The use of A2M as a high molecular weight protein, immunogenicity, long-term intra-articular injection of xenogeneic A2M is likely to cause immune reactions, thus seeking a more simple purification or rich A2M serum and observe The traumatic arthritis (PTOA) treatment has very important clinical value. The purpose of the study: 1) analysis of A2M in ACL injury serum distribution in synovial fluid, clear associated with articular cartilage degeneration, and provide a theoretical basis for the exogenous A2M; 2) were rich in A2M serum by centrifugal ultrafiltration legal (A2M-Rich Serum, A2MRS, A2MRS) detection of A2M protein concentration and protein activity, and to analyze its molecular biological characteristics; 3) were rich in A2M serum (A2M-Rich Serum, A2MRS) of traumatic arthritis (PTOA) whether the articular cartilage has obvious therapeutic effect or reduce articular cartilage degradation effect. Methods: 1) first in February at the age of 96 SD rats were divided into two groups, 48 rats in each group. The experimental group by anterior cruciate ligament transection (Anterior cruciate ligament transection, ACLT) to establish an animal model of PTOA, the control group took The sham operation incision, no ACLT. and 1,2,4,8 after 3 days and 12 weeks each time point were sacrificed 8 rats, collect serum and knee joint lavage. Using enzyme-linked immunosorbent assay (ELISA) detection of joint lavage at different time points after ACL injury in rats, the concentration changes of serum A2M, at the same time using safranin O fast green staining of PTOA with the extension of time and the content changes of pathological process of humoral articular cartilage degradation in A2M if there is any connection, to investigate whether A2M can be used as biomarkers of articular cartilage degeneration in the early diagnosis and monitoring of pathological process, and provide a theoretical basis for.2 of exogenous A2M in preparation) A2M serum by centrifugal ultrafiltration method (A2M-Rich, Serum, A2MRS) by enzyme linked immunosorbent assay (ELISA), Western blotting (Western Blot) were used to detect the molecular biological properties of.3) select 80 healthy SD rats were divided into 4 groups, 20 rats in each group: Sham+Saline (control group), ACLT+HA2MRS (high dose group), ACLT+LA2MRS (low dose group), ACLT+Saline (positive control group). 3 days after surgery, 2 weeks, intra-articular injection of 30ul in different time saline or 30ul of different concentration of A2MRS on the basis of 4 weeks group (high dose group A2M 20ug/ul, low dose group A2M 10ug/ul). For each time point of 24 hours after intra-articular injection of MMP680 immuno fluorescence probe by fluorescence molecular tomography systems (Fluorescence Molecular Tomography, FMT) dynamic detection of matrix metalloproteinases (Matrix metalloproteinase, MMP) concentration changes in joint in the solution, to observe whether A2MRS has inhibitory effect on matrix metalloproteinases. 8 weeks after operation were unified animal performance, small animal X-ray observation of knee joint degeneration imaging, India ink staining in the assessment of articular cartilage damage, and Mankin 's score; articular cartilage by toluidine blue and safranin O fast green staining, hematoxylin eosin staining (HE staining) and immunohistochemistry method to observe the effect of A2MRS on PTOA cartilage pathological degeneration is slow or repair, OARIS was applied to evaluate the pathological changes of articular cartilage of the femoral and statistical analysis; condylar articular cartilage by using real-time fluorescence quantitative PCR method (RTPCR) for type II cartilage collagen (COL-II), type X collagen (COL-X), matrix metalloproteinase 3,13 (Matrix metalloproteinase MMP-3,13), cartilage proteoglycan aggregate (Aggrecan), Runt protein transcription factor -2 (Runt-related transcription factor, Runx2). The evaluation indexes were detected, A2M rich serum injury role in regulation of gene level of articular cartilage. ELISA was used to detect the matrix in the joint fluid metal protease (Matrix metalloproteinase, MMP-13). . results: 1) ACLT early after operation in experimental group and control group of articular cartilage gross observation and histological observation had no obvious difference, but at 8 week after operation, the experimental group of articular cartilage degeneration was significantly increased. The experimental group after 3 days, 1 weeks, 8 weeks of wash liquid A2M the concentration in serum concentration was significantly higher than the experimental group. And after 3 days of joint lavage fluid concentrations of A2M in the control group and the concentration of A2M in the joint lavage compared significantly increased, 1 weeks after the operation began to rapidly reduce differences between the two groups.2) were prepared by ultrafiltration (A2M in serum A2M-Rich Serum, A2MRS) by ELISA test results: the concentration of serum A2M was 2.43 + 0.66mg/ml, A2M in serum (A2MRS) concentration in A2M was 19.52 + 4.37mg/ml, the concentration of A2MRS in A2M compared with normal serum concentrations increased 8.04 times. Protein immunoblotting (Western Blot). The results show that the A2M rich serum (A2MRS) compared with normal serum 180K in D has very obvious protein concentration phenomenon of.A2M protein activity detection showed that A2M (A2MRS) in serum A2M protein activity compared with normal serum A2M activity increased 2.13 times.3) therapeutic effect of A2MRS in vivo animal experimental observation on articular cartilage degradation PTOA and by fluorescence molecular tomography system (Fluorescence Molecular Tomography, FMT) test results showed that the serum containing A2M (A2MRS) can inhibit matrix metalloproteinase early traumatic arthritis synovial fluid 3,13 (Matrix metalloproteinase MMP-3,13). The expression of X of the knee X-ray imaging: group ACLT+Saline significantly lower edge of patella the osteophyma, the other three groups showed in the image were observed no degenerative changes obviously. India ink staining showed that Sham+Saline group had no obvious loss of cartilage surface Group ACLT+Saline cartilage injury, surface damage is most serious, while in ACLT+A2MRS group, the articular surface was reduced, the cartilage injury in the ACL group ACLT+HA2MRS group in the minimum cut, the modified Mankin's score showed that group ACLT+HA2MRS and ACLT+LA2MRS compared with the ACLT+Saline group had significant statistical significance, but the ACLT+HA2MRS group and ACLT+LA2MRS group comparison was statistically significant tibial plateau. Safranin O fast green staining, HE staining and toluidine blue staining showed that the cartilage thickness was significantly thinner in group ACLT+Saline, the cartilage surface has many small cracks, the distribution of cartilage cell disorder, glycosaminoglycan poor staining of chondrocytes of.ACLT+LA2MRS group were clustered into groups, the thickness of articular cartilage in ACLT+HA2MRS group decreased, the cartilage surface is smooth, cells arranged was group Sham+Saline cartilage surface integrity, good structure, uniform cell distribution and glycosarninoglycan staining good.OARIS score Display: ACLT+Saline group is 10.15 + 2.88, 5.54 + 2.61 ACLT+HA2MRS group, ACLT+LA2MRS group is 4.87 + 2.74, 3.05 + 1.39 Sham+Saline, statistical analysis showed: two experimental groups (ACLT+HA2MRS and ACLT+LA2MRS) and positive control group (ACLT+Saline) had significant difference (P0.0001), two experimental groups (ACLT+HA2MRS and ACLT+LA2MRS) and control group (Sham+Saline). There were significant differences between ACLT+HA2MRS group and ACLT+LA2MRS group were analyzed statistically no significant difference (p=0.22). The immunohistochemistry of collagen II staining, positive cells of ACLT+HA2MRS group and ACLT+LA2MRS group were significantly higher than in group ACLT+Saline or ACLT+HA2MRS staining, compared with group ACLT+LA2MRS that group of positive cells, but the immune group of two groups of type II collagen staining were lower than those of Sham+Saline group. In the immunohistochemistry of collagen X and MMP-13 staining, ACLT+ positive cells in the Saline group in the four groups The expression of Sham+Saline positive cells were the strongest, the expression of the weakest, while the two treatment group ACLT+HA2MRS group and ACLT+LA2MRS group in the expression of type X collagen between ACLT+Saline group and Sham+Saline group, and the same is dose dependent, i.e. type X collagen ACLT+HA2MRS expression in ACLT+LA2MRS group than in the weak.RT-PCR results show that A2MRS has obvious inhibition negative type X collagen gene (COL-X), matrix metalloproteinase 3,13 (Matrix metalloproteinase 3,13, MMP-3,13), Runt protein transcription factor -2 (Runt-related transcription factor, Runxn2) expression of M RNA. The testing results of MMP-13 in synovial fluid ELISA showed that: ACLT+HA2MRS group, ACLT+LA2MRS group and Sham+Saline group in MMP-13 synovial fluid concentration were significantly lower than that of ACLT+Saline, has statistically significant difference between the three groups before, but there was no significant difference between the groups. Conclusion: 1. in synovial fluid A2M Can be used as a biomarker for early diagnosis of traumatic arthritis, one week after operation in the synovial fluid of A2M rapidly decreased vital.2. suggesting that the supplement of exogenous centrifugal ultrafiltration can be efficient and convenient preparation with high protein concentration and protein activity of A2M rich serum.3. A2M rich serum (A2MRS) has obvious positive effect to slow the degradation of articular cartilage.

【學(xué)位授予單位】：山西醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R687.4

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