【摘要】：研究背景:肌腱粘連是指肌腱損傷修復(fù)過程中周圍組織的增生和侵入,造成肌腱運(yùn)動(dòng)功能障礙。外傷術(shù)后肌腱粘連是肌腱損傷后常見問題之一,迄今為止仍無有效的解決方法,仍大概有30～40%的病人術(shù)后有關(guān)節(jié)活動(dòng)度不佳,手功能受限等并發(fā)癥[1]。我們希望通過深入肌腱粘連機(jī)制的研究來解決這一問題。肌腱粘連發(fā)生的原因可能為機(jī)械性和化學(xué)性的損傷。損傷誘發(fā)間質(zhì)細(xì)胞和肥大細(xì)胞釋放多種活性物質(zhì),使組織產(chǎn)生炎性反應(yīng),毛細(xì)血管通透性增加,大量漿液滲出。這些滲出物如不能被分解吸收,則促使纖維蛋白積聚,繼而發(fā)生纖維細(xì)胞浸潤(rùn)和新生毛細(xì)血管的長(zhǎng)入,最后形成纖維粘連[2]。目前認(rèn)為肌腱的愈合由內(nèi)、外兩種修復(fù)機(jī)制完成。內(nèi)源性修復(fù)機(jī)制指通過肌腱細(xì)胞增生修復(fù)損傷肌腱;外源性修復(fù)機(jī)制指通過腱周組織增生,纖維母細(xì)胞,炎癥細(xì)胞的增生修復(fù)損傷肌腱。肌腱自身的強(qiáng)度主要取決于內(nèi)源性修復(fù)機(jī)制;而外源性修復(fù)則主要形成粘連[3,4]。由于炎性反應(yīng)導(dǎo)致局部組織滲出增多,炎性后的機(jī)化后更加重肌腱的粘連,這就是肌腱外源性修復(fù)容易廣泛粘連的主要問題[5]。TGF-β1/Smad3是創(chuàng)傷修復(fù)過程中的重要信號(hào)通路。TGF-β1是各種損傷后組織發(fā)生病理性纖維化的因素之一。目前實(shí)驗(yàn)發(fā)現(xiàn)在肌腱損傷時(shí)TGF-β1可刺激腱細(xì)胞DNA合成,促進(jìn)腱細(xì)胞增殖參與肌腱的修復(fù),促使成纖維細(xì)胞和巨噬細(xì)胞的募集、血管的生成、刺激膠原的產(chǎn)生[6]。丹參酮ⅡA,TanshinoneⅡA,為唇形科鼠尾草屬植物丹參(Salviamiltior-rhizabunge)的有效成份具有抗菌、消炎、擴(kuò)張血管、抗血小板凝集等作用來治療冠心病等心血管疾病[7-9]。我們研究TSA是否可以有效的防止肌腱粘連和其可能作用機(jī)制,包括微小RNA(miRNA)及通過TGF-β/Smad信號(hào)通路的蛋白表達(dá),并且進(jìn)一步驗(yàn)證并運(yùn)用于臨床。本研究的成功實(shí)施將為肌腱功能修復(fù)提供了新的理論和途徑。第一部分丹參酮ⅡA治療肌腱粘連的動(dòng)物實(shí)驗(yàn)研究背景:肌腱表面和腱鞘之間的肌腱粘連是一種常見的臨床問題。雖然骨科修復(fù)技術(shù)和康復(fù)治療進(jìn)步使肌腱粘連得到一定的改善,但仍然無法徹底根治。丹參酮ⅡA(TSA)是因?yàn)樗目寡谆钚宰鳛橹饕δ芑钚缘闹参锘瘜W(xué)物質(zhì)之一。我們用丹參酮ⅡA(TSA)在大鼠的跟腱損傷模型中來防止肌腱粘連的和通過TGF-β/Smad信號(hào)通路研究可能的作用機(jī)制,包括微RNA(miRNA)的表達(dá)和蛋白質(zhì)表達(dá)。方法:建立SD大鼠的跟腱損傷模型,肌腱損傷處通過改良Kessler的技術(shù)縫合,隨機(jī)分為TSA和對(duì)照組。肌腱斷端用TSA進(jìn)行干預(yù),并用生理鹽水作為對(duì)照。6周后對(duì)肌腱組織進(jìn)行大體觀察和組織學(xué)評(píng)價(jià)。我們通過顯微鏡觀察,大體觀察肌腱的粘連情況,根據(jù)瘢痕量來評(píng)價(jià)膠原纖維的重塑的程度。通過實(shí)時(shí)PCR檢測(cè)microRNA的表達(dá)和通過western blotting來檢測(cè)蛋白表達(dá)。結(jié)果:根據(jù)肌腱粘連的評(píng)價(jià)標(biāo)準(zhǔn),發(fā)現(xiàn)TSA組比對(duì)照組粘連形成少。兩組中均未觀察到肌腱斷裂或局部感染的情況。TSA組中肌腱組織中的膠原纖維的含量降低,與對(duì)照組相比有顯著的統(tǒng)計(jì)學(xué)差異,P=0.0004。在TSA組中在修復(fù)肌腱組織中進(jìn)行檢測(cè) miRNA 的檢測(cè)包括的 miR-155,miR-29b,miR-21,miR-133B 和 let7 的表達(dá),僅觀察到miR-29b的表達(dá)比對(duì)照組有增高,P0.0001,有顯著的統(tǒng)計(jì)學(xué)差異。western blotting來檢測(cè)TSA組中TGF-β1和p-Smad3蛋白的表達(dá)低于對(duì)照組。結(jié)論:在大鼠粘連模型中使用TSA可能是防止肌腱粘連的有效方法。第二部分丹參酮ⅡA治療肌腱粘連的臨床研究背景:手外傷容易造成術(shù)后掌指關(guān)節(jié)粘連和關(guān)節(jié)活動(dòng)受限。特別是創(chuàng)傷術(shù)后掌指關(guān)節(jié)僵硬的患者,由于掌指關(guān)節(jié)的活動(dòng)度對(duì)手指功能影響較大,所以如何恢復(fù)手部掌指粘連患者術(shù)后手部功能及提高生活質(zhì)量具有重要意義。2015年9月～2016年3月,我們對(duì)80例掌指關(guān)節(jié)粘連的病人進(jìn)行臨床研究,隨機(jī)雙盲分成兩組�，F(xiàn)通過回顧分析患者臨床資料,討論丹參酮ⅡA(TSA)防治掌指關(guān)節(jié)粘連的臨床療效。目的:探討丹參防治創(chuàng)傷后掌指關(guān)節(jié)粘連的臨床療效。方法:2015年9月～2016年3月,對(duì)80例掌指關(guān)節(jié)粘連的病人進(jìn)行研究。隨機(jī)雙盲分成兩組,TSA組40例和空白組40例。男58例,女22例;年齡20～55歲,平均38歲。其中拇指掌指關(guān)節(jié)16例,示指24例,環(huán)指22例,中指11例,小指7例。致傷原因:機(jī)器傷33例,運(yùn)動(dòng)傷21例,車禍傷17例,刀砍傷9例。治療前、治療后3個(gè)月和6個(gè)月進(jìn)行影像學(xué)評(píng)估,功能評(píng)定采用手部關(guān)節(jié)活動(dòng)度TAM系統(tǒng)評(píng)價(jià)法(total active movement,TAM),日常生活手功能評(píng)定采用Michigan手功能評(píng)價(jià)(Michigan Hand Outcome Questionnaire,MHQ),評(píng)分?jǐn)?shù)據(jù)采用獨(dú)立樣本t檢驗(yàn)。結(jié)果:患者術(shù)后切口均Ⅰ期愈合,術(shù)后均無內(nèi)固定松動(dòng)、斷裂,骨折不愈合等并發(fā)癥�；颊呔@隨訪,隨訪6個(gè)月時(shí)TAM評(píng)分丹參組優(yōu)27例,良10例,可3例,差0例,優(yōu)良率93%;空白組優(yōu)15例,良16例,可9例,差0例,優(yōu)良率78%,組間比較差異有統(tǒng)計(jì)學(xué)意義(P0.05);MHQ評(píng)分丹參組60.0±14.2分,空白組50.1±15.7分。組間比較差異有統(tǒng)計(jì)學(xué)意義(t=2.96,P0.05)。結(jié)論:運(yùn)用丹參酮ⅡA可以減少術(shù)后掌指關(guān)節(jié)粘連程度,臨床療效滿意。第三部分丹參酮ⅡA聯(lián)合Swanson人工關(guān)節(jié)置換治療嚴(yán)重掌指關(guān)節(jié)粘連的初期療效研究Swanson人工關(guān)節(jié)最初并用于近端指間關(guān)節(jié)(proximal interphalangeal joint,PIP)和掌指關(guān)節(jié)(metacarpophalangealjoint,MCP)的關(guān)節(jié)置換。既往研究主要集中在Swanson人工關(guān)節(jié)置換治療類風(fēng)濕MCP關(guān)節(jié)的臨床療效[10-12]。對(duì)于創(chuàng)傷后掌指關(guān)節(jié)僵硬患者的治療缺乏系統(tǒng)的臨床研究�？紤]到目前創(chuàng)傷后重度掌指關(guān)節(jié)粘連及僵硬的患者臨床療效不佳,我們選擇使用丹參酮ⅡA聯(lián)合Swanson人工關(guān)節(jié)置換來解決這個(gè)問題。評(píng)估其近期臨床療效和患者的主觀評(píng)價(jià)。目的:探討丹參酮ⅡA聯(lián)合Swanson人工關(guān)節(jié)置治療創(chuàng)傷后重度掌指關(guān)節(jié)粘連及僵硬患者的初期療效。方法:從2014年9月至2015年7月在就診的屬于創(chuàng)傷后重度掌指關(guān)節(jié)粘連及僵硬患者,使用丹參酮ⅡA聯(lián)合Swanson人工關(guān)節(jié)置換治療掌指關(guān)節(jié)嚴(yán)重粘連僵硬患者的回顧性研究。其中男3例,女1例。示指為2例,中指為1例,同時(shí)涉及示指和中指1例。掌指關(guān)節(jié)離斷3人,掌指關(guān)機(jī)擠壓傷1人�；颊咂骄挲g為52.15±2.6歲(范圍41歲～67歲)。數(shù)據(jù)統(tǒng)計(jì)包括術(shù)前和術(shù)后6個(gè)月的評(píng)分(握力,關(guān)節(jié)活動(dòng)范圍,Sollerman 手功能測(cè)定和 Michigan 手功能評(píng)價(jià)(Michigan Hand Outcome Questionnaire,MHQ)"。結(jié)果:隨訪時(shí)間為術(shù)后6個(gè)月。握力較術(shù)前顯著增加(術(shù)前4.2±2.2公斤,術(shù)后6.7±2.8公斤,P=0.027)。關(guān)節(jié)運(yùn)動(dòng)度范圍已顯著增加(術(shù)前24.6±9.0度,術(shù)后47.0±10.7度,P0.001)。Sollerman評(píng)分顯示前和操作后,無統(tǒng)計(jì)學(xué)顯著差異。MHQ總得分較術(shù)前顯著增加(術(shù)前50±15,術(shù)后57±15,P=0.002)。功能方面,日常生活,外觀和滿病人滿意度等術(shù)后評(píng)分也顯著增加了。然而日常工作和疼痛的術(shù)后評(píng)分沒有改善。所有患者對(duì)術(shù)后外觀,自身滿意度改善。結(jié)論:丹參酮ⅡA聯(lián)合Swanson人工關(guān)節(jié)置換可明顯改善掌指關(guān)節(jié)僵硬患者的運(yùn)動(dòng)范圍�；颊呤植棵烙^性功能及都得到了提高。今后的長(zhǎng)期隨訪將有助于更好地確定該方法的功效。我們建議外傷后掌指關(guān)節(jié)僵硬患者可以選擇丹參酮ⅡA聯(lián)合Swanson人工關(guān)節(jié)置換這個(gè)手術(shù)方式。
[Abstract]:BACKGROUND: Tendon adhesion refers to the proliferation and invasion of surrounding tissues during tendon repair, resulting in tendon dysfunction. Postoperative tendon adhesion is one of the common problems after tendon injury. Up to now, there is no effective solution to this problem. There are still about 30-40% patients with poor joint mobility and limited hand function. Complications [1]. We hope to solve this problem through in-depth study of the mechanism of tendon adhesion. The causes of tendon adhesion may be mechanical and chemical injuries. Injury induces the release of a variety of active substances in stromal cells and mast cells, resulting in inflammation of tissues, increased capillary permeability, and massive serous exudation. If the exudate can not be absorbed, it will promote the accumulation of fibrin, then the infiltration of fibrocytes and the growth of new capillaries, and finally the formation of fiber adhesion [2]. The strength of the tendon itself mainly depends on the endogenous repair mechanism, whereas the exogenous repair mainly forms adhesion [3,4]. Because of the inflammation reaction, the local tissue exudates more, and the inflammation after the mechanization of tendon adhesion, this is the muscle. TGF-beta 1 is one of the important signaling pathways in the process of wound repair. TGF-beta 1 is one of the factors causing pathological fibrosis after various injuries. Promote the recruitment of fibroblasts and macrophages, angiogenesis, stimulation of collagen production [6].Tanshinone II A, Tanshinone II A, an effective ingredient of Salvia miltior-rhizabunge, has the effects of antibacterial, anti-inflammatory, vasodilation, anti-platelet aggregation and other cardiovascular diseases [7-9]. To investigate whether TSA can effectively prevent tendon adhesion and its possible mechanisms, including the expression of microRNA (microRNA) and protein via TGF-beta/Smad signaling pathway, and further validate and apply to clinical practice. The successful implementation of this study will provide a new theory and approach for tendon functional repair. Background: Tendon adhesion between the tendon sheath and the tendon surface is a common clinical problem. Although advances in orthopaedic repair and rehabilitation have improved tendon adhesion to some extent, it is still not completely cured. Tanshinone II A (TSA) is a plant whose anti-inflammatory activity is the main functional activity. One of the chemicals. We used tanshinone II A (TSA) to prevent tendon adhesion in the rat Achilles tendon injury model and investigated possible mechanisms of action, including microRNA (microRNA) expression and protein expression, through the TGF-beta/Smad signaling pathway. METHODS: SD rat Achilles tendon injury model was established. The tendon injury site was modified by Kessler's technique suture. After 6 weeks, the tendon tissue was observed and histologically evaluated. We observed the tendon adhesion by microscope and evaluated the degree of collagen remodeling by scar size. MicroRNA was detected by real-time PCR. Results: According to the evaluation criteria of tendon adhesion, there were fewer adhesion formation in TSA group than in control group. No tendon rupture or local infection was observed in both groups. In TSA group, the expression of microRNAs including microRNAs-155, microRNAs-29b, microRNAs-21, microRNAs-133B and let7 was detected in repaired tendon tissues. The expression of microRNAs-29b was significantly higher than that in control group (P 0.0001). The expression of TGF-beta 1 and p-Smad3 protein in TSA group was lower than that in control group. Conclusion: TSA may be an effective method to prevent tendon adhesion in rat adhesions model. Part 2: Clinical research background of tanshinone II A in the treatment of tendon adhesion: Hand trauma is liable to cause postoperative metacarpophalangeal joint adhesion and limitation of joint movement, especially in patients with metacarpophalangeal joint stiffness after trauma due to the mobility of metacarpophalangeal joint. From September 2015 to March 2016, 80 patients with metacarpophalangeal joint adhesion were randomly divided into two groups. The clinical data of the patients were analyzed retrospectively to discuss tanshinone II A (Tanshinone II A). Objective: To investigate the clinical effect of Salvia miltiorrhiza on the prevention and treatment of metacarpophalangeal joint adhesion after trauma. Methods: 80 patients with metacarpophalangeal joint adhesion were studied from September 2015 to March 2016. They were randomly divided into two groups, 40 cases in TSA group and 40 cases in blank group. There were 16 cases of metacarpophalangeal joint, 24 cases of index finger, 22 cases of ring finger, 11 cases of middle finger and 7 cases of small finger. Michigan Hand Outcome Questionnaire (MHQ) and independent sample t test were used to evaluate the hand function. Results: All the incisions healed in the first stage, and there were no complications such as loosening of internal fixation, rupture and nonunion. All the patients were followed up. The TAM score of Danshen group was excellent in 27 cases and good in 10 cases. There were 3 cases, fair 3 cases, poor 0 cases, excellent and good rate 93%; the blank group 15 cases, good 16 cases, fair 9 cases, poor 0 cases, excellent and good rate 78%. There was significant difference between the two groups (P 0.05); MHQ score of Danshen group 60.0 (+ 14.2), blank group 50.1 (+ 15.7). There was significant difference between the two groups (t = 2.96, P 0.05). Conclusion: Tanshinone II A can reduce postoperative metacarpophalangeal joint adhesion. The third part is the preliminary study of Tanshinone II A combined with Swanson artificial joint replacement in the treatment of severe metacarpophalangeal joint adhesion. Swanson artificial joint was initially used in proximal interphalangeal joint (PIP) and metacarpophalangeal joint (MCP). There is no systematic clinical study on the treatment of metacarpophalangeal joint stiffness after trauma. Considering the poor clinical efficacy of severe metacarpophalangeal joint adhesion and stiffness after trauma, we choose tanshinone II A combined with Swanson artificial joint. Objective: To investigate the initial efficacy of tanshinone II A combined with Swanson arthroplasty in the treatment of severe metacarpophalangeal joint adhesion and stiffness after trauma. A retrospective study of patients with severe adhesion and stiffness of metacarpophalangeal joints treated with tanshinone II A combined with Swanson arthroplasty was conducted. There were 3 males and 1 females. The index finger was 2 cases, the middle finger was 1 case, and the index finger and the middle finger were 1 case. Data included preoperative and postoperative scores (grip strength, range of motion, Sollerman hand function, and Michigan Hand Outcome Questionnaire, MHQ). "Results: Follow-up time was 6 months after surgery. Grip strength increased significantly (4.2 The range of motion of the joints was significantly increased (24.6 [9.0], 47.0 [10.7], P 0.001). Sollerman score showed no significant difference between before and after operation. The total score of MHQ was significantly increased (50 [15], 57 [15], P = 0.002) compared with that before operation. Conclusion: Tanshinone II A combined with Swanson arthroplasty can significantly improve the range of motion in patients with metacarpophalangeal joint stiffness. The aesthetic function of the hand and the postoperative scores of the patients have been improved. Long-term follow-up will be helpful. We suggest that patients with traumatic metacarpophalangeal joint stiffness may choose tanshinone II A combined with Swanson arthroplasty.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R686.1

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