在前一篇科普文章中，我們揭示了髖關(guān)節(jié)疼痛的基本情況。在這一篇文章里，我們將更系統(tǒng)地總結(jié)髖關(guān)節(jié)疼痛的不同病因，以便為大家提供全面參考。了解髖關(guān)節(jié)疼痛的潛在原因?qū)τ诰_診斷和有效治療是至關(guān)重要的。專業(yè)的骨科醫(yī)生和康復(fù)治療師通常會(huì)依據(jù)疼痛的性質(zhì)、發(fā)生位置、伴隨的癥狀等多方面因素，進(jìn)行全面的評(píng)估和診斷。在好大夫平臺(tái)上，我們致力于為您提供豐富而深入的關(guān)于髖關(guān)節(jié)疼痛的信息和資源。若您或您的親人正在面臨這一問題，請(qǐng)不要猶豫，及時(shí)與我們的醫(yī)療專家取得聯(lián)系，共同探尋適合您的解決方案。

干細(xì)胞治療股骨頭壞死：最新進(jìn)展及未來研究發(fā)展趨勢(shì)作者：LeiZhao,AlanDavidKaye,AaronJKaye,AlaaAbd-Elsayed.作者單位:DepartmentofOrthopedics,ShandongProvincialHospitalAffiliatedwithShandongUniversity,Jinan,250021,China.譯者：陶可（北京大學(xué)人民醫(yī)院骨關(guān)節(jié)科）摘要綜述目的：股骨頭壞死（ONFH）是一種常見病、多發(fā)病。它是由不同病因?qū)е碌难汗?yīng)中斷引起的。股骨頭壞死（ONFH）導(dǎo)致股骨頭軟骨下骨變性、壞死，最終導(dǎo)致股骨頭塌陷。股骨頭壞死（ONFH）致殘率較高，嚴(yán)重影響患者生活質(zhì)量，且常累及中青年人群。最新發(fā)現(xiàn)：近年來，干細(xì)胞和再生醫(yī)學(xué)的技術(shù)和理解不斷發(fā)展。許多研究報(bào)告了干細(xì)胞移植治療股骨頭壞死（ONFH）的成功結(jié)果。因此，干細(xì)胞移植有望成為治療股骨頭壞死（ONFH）的新方法。因此，在本報(bào)告中，我們?cè)u(píng)估了利用干細(xì)胞治療股骨頭壞死（ONFH）的現(xiàn)有技術(shù)和結(jié)果。通過計(jì)算機(jī)在線檢索2006年1月至2017年6月期間的PubMed和Cochrane圖書館數(shù)據(jù)庫，使用英文關(guān)鍵詞“治療、干細(xì)胞、股骨頭壞死”檢索相關(guān)文章。選取與股骨頭壞死（ONFH）治療相關(guān)的文獻(xiàn)。我們的檢索共獲得161篇文章，但只有9篇文章符合我們的納入標(biāo)準(zhǔn)并被納入我們的報(bào)告中。本綜述表明，細(xì)胞技術(shù)在治療股骨頭壞死（ONFH）方面已顯示出良好的證據(jù)。然而，這項(xiàng)技術(shù)還需要進(jìn)一步深入研究，以更好地探索和解決更理想的方法來克服與細(xì)胞來源相關(guān)的困難。圖示：干細(xì)胞技術(shù)被廣泛用于治療股骨頭壞死（ONFH）、骨缺損、神經(jīng)退行性病變等相關(guān)疾病手術(shù)治療如果股骨頭壞死(ONFH)進(jìn)展迅速且非手術(shù)治療無效，則需要手術(shù)治療。外科手術(shù)主要包括兩大類：股骨頭本身重建和全髖關(guān)節(jié)置換術(shù)(THA)。保留股骨頭的手術(shù)技術(shù)包括：髓芯減壓、截骨術(shù)以及有或無血供的植骨[36]。髓芯減壓是治療早期股骨頭壞死(ONFH)的重要手術(shù)方法之一。主要是通過髓芯減壓突破硬化區(qū)，導(dǎo)致骨內(nèi)壓降低、血液供應(yīng)改善[37]。髓芯減壓更適合早期股骨頭壞死(ONFH)患者。一些臨床醫(yī)生發(fā)明了血管化和非血管化骨移植物，或設(shè)計(jì)了用其他材料（例如鉭棒）支撐的支架治療股骨頭壞死(ONFH)[38]。目前植骨治療股骨頭壞死(ONFH)的適應(yīng)癥有：（1）帶血管腓骨移植；(2)帶血管蒂髂骨移植術(shù)；(3)游離腓骨移植；(4)骨瓣移植；(5)病灶清除、打壓植骨手術(shù)；(6)病灶切除、記憶合金網(wǎng)植入；(7)病灶切除、打壓植骨、多孔鉭釘支撐手術(shù)。各種植骨都存在問題，因此多孔鉭棒得到了廣泛的應(yīng)用。與傳統(tǒng)的單一打壓植骨相比，多孔鉭棒支撐組合在I-II期股骨頭壞死(ONFH)中具有明顯優(yōu)勢(shì)。一項(xiàng)研究發(fā)現(xiàn)，股骨頭髓芯減壓聯(lián)合植骨、2mm打壓植骨加多孔鉭棒支撐等手術(shù)方法對(duì)股骨頭壞死(ONFH)患者，可延長股骨頭壽命，推遲全髖關(guān)節(jié)置換術(shù)(THA)時(shí)間[39]。截骨術(shù)的目的是去除股骨頭承重區(qū)的壞死區(qū)。截骨術(shù)包括股骨轉(zhuǎn)子旋轉(zhuǎn)的內(nèi)翻或外翻截骨術(shù)等，以不改變股骨髓腔為原則[40,41]。如果股骨頭塌陷嚴(yán)重（ARCO分期、IIIC和IV），并且關(guān)節(jié)功能嚴(yán)重喪失或中度疼痛，應(yīng)選擇全髖關(guān)節(jié)置換術(shù)(THA)。傳統(tǒng)治療結(jié)合干細(xì)胞治療股骨頭壞死(ONFH)干細(xì)胞MSCs來源于中胚層間充質(zhì)，廣泛分布于骨髓、骨膜、肌肉、滑膜、滑液、肝臟、外周組織、臍帶血、脂肪、胎盤、胎肺、胎腎、臍帶等組織中[42,43]。從這些組織中分離提取出具有多向分化能力的間充質(zhì)干細(xì)胞，細(xì)胞具有很強(qiáng)的自我更新和增殖能力[44]。它們?cè)谔囟ǖ恼T導(dǎo)條件下可以分化為骨、軟骨、脂肪組織、肌肉、肌腱和血管內(nèi)皮細(xì)胞，甚至可以分化為神經(jīng)細(xì)胞[45]。相關(guān)研究表明干細(xì)胞MSC同種異體移植不會(huì)發(fā)生排斥反應(yīng)[46]。它已廣泛應(yīng)用于干細(xì)胞移植、基因治療、組織工程和其他研究工作。對(duì)于許多難治性疾病，細(xì)胞移植似乎是一種相對(duì)有效的療法。移植的自體細(xì)胞通常具有特定的功能，包括修復(fù)受損區(qū)域，避免使用傳統(tǒng)藥物對(duì)身體產(chǎn)生的毒性作用或副作用[47]。間充質(zhì)干細(xì)胞已廣泛應(yīng)用于骨缺損、軟骨缺損、組織損傷、骨關(guān)節(jié)炎、股骨頭壞死等修復(fù)。間充質(zhì)干細(xì)胞也已應(yīng)用于臨床實(shí)踐的其他領(lǐng)域[48]。干細(xì)胞治療股骨頭壞死(ONFH)是當(dāng)前研究的熱點(diǎn)，研究表明干細(xì)胞在特定條件下可以分化為成骨細(xì)胞。成骨細(xì)胞在骨壞死修復(fù)過程中發(fā)揮著重要作用，研究表明，使用骨髓干細(xì)胞移植到壞死股骨頭中可以使股骨頭壞死(ONFH)的發(fā)生率降低至0%[49]。髓芯減壓聯(lián)合干細(xì)胞MSC移植髓芯減壓后的干細(xì)胞MSC移植可以為壞死股骨頭的修復(fù)和重建提供種子細(xì)胞[16]。Tabatabaee等的一項(xiàng)研究中[14]，在髓芯減壓的基礎(chǔ)上，對(duì)18例28髖的股骨頭壞死(ONFH)患者進(jìn)行自體骨髓移植，所有患者平均隨訪2年。所有患者的西安大略大學(xué)和麥克馬斯特大學(xué)平均骨關(guān)節(jié)炎指數(shù)(WOMAC)和視覺模擬量表(VAS)評(píng)分均顯著改善。磁共振成像（MRI）顯示聯(lián)合治療組有顯著改善。研究人員認(rèn)為，這項(xiàng)技術(shù)可用于改善股骨頭壞死區(qū)域的修復(fù)，至少在股骨頭壞死(ONFH)的早期階段是這樣。Rastogi等[13]也得出結(jié)論，髓芯減壓聯(lián)合自體骨髓干細(xì)胞植入是一種安全有效的方法。Sen等進(jìn)行了一項(xiàng)臨床對(duì)照研究，表明在髓芯減壓后將自體骨髓單核細(xì)胞注入核心道可以為治療股骨頭壞死(ONFH)帶來更好的臨床結(jié)果和髖關(guān)節(jié)存活率[15]。Ma等[18]評(píng)價(jià)基于髓芯減壓的骨髓血沉棕黃層（BBC）植入治療股骨頭壞死的效果。作者得出結(jié)論，在治療的第二年，92%的股骨頭壞死(ONFH)患者的髖關(guān)節(jié)功能得到改善。更重要的是，治療組ARCO分期I/II期髖部無進(jìn)展率為100%，對(duì)照組為66.7%[18]。Zhang等等[17]指出，髓芯減壓聯(lián)合自體骨髓間充質(zhì)干細(xì)胞移植可以減輕疼痛，延緩或避免股骨頭塌陷。MRI評(píng)估發(fā)現(xiàn)軟骨病變面積顯著縮小，軟骨質(zhì)量顯著改善。Gangji等[19]比較了核心減壓聯(lián)合含有間充質(zhì)干細(xì)胞（MSCs）或自體成骨細(xì)胞（OB）的骨髓濃縮物（BMC）治療股骨頭壞死(ONFH)的效果。他們發(fā)現(xiàn)，除了減輕股骨頭壞死(ONFH)的疼痛之外，自體成骨細(xì)胞（OB）植入在延緩骨循環(huán)協(xié)會(huì)(ARCO)III期進(jìn)展方面比干細(xì)胞BMC治療更有效。然而，其他研究人員卻得出了不同的結(jié)論。Lim等[11]進(jìn)行了一項(xiàng)對(duì)照試驗(yàn)，比較了兩組治療股骨頭壞死的臨床效果和影像學(xué)結(jié)果：一組采用多次鉆孔減壓聯(lián)合干細(xì)胞移植，另一組采用干細(xì)胞移植聯(lián)合其他髓芯減壓方法：刮除術(shù)、植骨術(shù)等。結(jié)論是兩組之間沒有統(tǒng)計(jì)學(xué)上的顯著差異。從本研究來看，對(duì)于ARCOI-II期塌陷期的股骨頭壞死(ONFH)，髓核減壓聯(lián)合干細(xì)胞MSC移植獲得了良好的手術(shù)效果，但對(duì)于塌陷后的ARCOIII-IV期患者，這種手術(shù)方式效果不佳。生物力學(xué)支持和干細(xì)胞MSC動(dòng)脈輸注股骨頭壞死(ONFH)發(fā)生后，盡管進(jìn)行了髖關(guān)節(jié)挽救治療，改善股骨頭內(nèi)的血液供應(yīng)始終是該疾病的主要治療方法之一。自體干細(xì)胞移植和血管再生技術(shù)可以在治療中發(fā)揮重要作用。Kocher等[50]證實(shí)干細(xì)胞MSCs和內(nèi)皮祖細(xì)胞可以促進(jìn)缺血血流恢復(fù)。Kinnaird等[51]發(fā)現(xiàn)，將骨源干細(xì)胞肌肉注射到大鼠缺血后肢后，骨源干細(xì)胞可以促進(jìn)側(cè)支循環(huán)和肢體功能恢復(fù)。此外，與血管生成相關(guān)的細(xì)胞因子基因表達(dá)水平增加。Mao等[12]進(jìn)行了一項(xiàng)對(duì)照試驗(yàn)，其中55例89髖的股骨頭壞死(ONFH)患者接受鉭棒植入聯(lián)合間充質(zhì)干細(xì)胞靶向動(dòng)脈內(nèi)灌注，所有患者均隨訪36個(gè)月。隨訪36個(gè)月時(shí)，聯(lián)合治療組中有3個(gè)髖關(guān)節(jié)（6.25%）被發(fā)現(xiàn)臨床失敗，需要進(jìn)行全髖關(guān)節(jié)置換術(shù)THA；相比之下，對(duì)照組中有9個(gè)髖關(guān)節(jié)（21.95%）接受了全髖關(guān)節(jié)置換術(shù)THA。與對(duì)照組相比，聯(lián)合治療在36個(gè)月時(shí)顯著改善了Harris髖關(guān)節(jié)評(píng)分(HHS)。他們的結(jié)論是，干細(xì)胞MSC動(dòng)脈輸注是治療早期股骨頭壞死(ONFH)的有效且安全的方法。與開放式股骨頭干細(xì)胞移植相比，干細(xì)胞MSC選擇性動(dòng)脈輸注具有干細(xì)胞存活更好、分化更好、操作創(chuàng)傷小、不良反應(yīng)少、患者依從性好等優(yōu)點(diǎn)。手術(shù)可達(dá)到以下效果：（1）疏通病變股骨頭，改善靜脈回流，降低骨內(nèi)壓，恢復(fù)或改善股骨頭的血液供應(yīng)。(2)改善或增加股骨頭壞死區(qū)及髖關(guān)節(jié)周圍組織的血液循環(huán)，為壞死股骨頭提供良好的局部血液供應(yīng)。(3)干細(xì)胞MSCs可以保護(hù)局部血管內(nèi)皮，促進(jìn)血管內(nèi)皮細(xì)胞的修復(fù)、再生和血管生成。隨著干細(xì)胞干預(yù)的進(jìn)一步研究，這種方法似乎對(duì)未來的股骨頭壞死(ONFH)患者有積極作用。骨組織工程和間充質(zhì)干細(xì)胞組織工程是應(yīng)用細(xì)胞生物學(xué)，在體外培養(yǎng)功能相關(guān)的活細(xì)胞，復(fù)合移植體內(nèi)組織缺損并完成修復(fù)和重建。干細(xì)胞MSCs具有較強(qiáng)的分化潛能和增殖能力，細(xì)胞在來源、分離方式、分化組織類型等方面對(duì)于修復(fù)股骨頭壞死(ONFH)骨缺損具有獨(dú)特的優(yōu)勢(shì)。因此，它是骨組織工程種子細(xì)胞最理想的選擇。干細(xì)胞MSCs制成的復(fù)合支架可用于加強(qiáng)股骨頭壞死區(qū)域的修復(fù)，但也可以用作細(xì)胞、基因和生長因子的生物載體。此外，間充質(zhì)干細(xì)胞可以整合細(xì)胞和受體來調(diào)節(jié)細(xì)胞功能。Kang等[52]報(bào)道采用自體髂骨松質(zhì)骨移植聯(lián)合間充質(zhì)干細(xì)胞移植治療股骨頭壞死(ONFH)患者，隨訪32個(gè)月，臨床療效良好。Kawate等[53]采用β-磷酸三鈣作為載體承載自體骨髓干細(xì)胞BMSCs植入股骨頭壞死部位聯(lián)合血管化腓骨移植治療股骨頭壞死(ONFH)，長期隨訪發(fā)現(xiàn)大部分股骨頭壞死部位患者緩解至影像學(xué)觀察不同程度的局部高密度新骨形成。該疾病已得到控制，表明組織工程方法具有更好的治療股骨頭壞死(ONFH)的潛力。Yamasaki等[54]報(bào)道22例（30髖）股骨頭壞死(ONFH)患者接受單核細(xì)胞聯(lián)合磷酸鈣治療，8例（9髖）股骨頭壞死(ONFH)患者僅接受磷酸鈣治療。平均隨訪時(shí)間為29個(gè)月。治療組股骨頭壞死面積減少，僅3髖（3/30）出現(xiàn)股骨頭塌陷，而對(duì)照組6髖（6/8）出現(xiàn)嚴(yán)重股骨頭塌陷。Xiao等[55]在復(fù)合骨上用自體骨髓間充質(zhì)干細(xì)胞結(jié)合重組人骨形態(tài)發(fā)生蛋白2修復(fù)了兔股骨頭壞死(ONFH)缺損，他們發(fā)現(xiàn)這種方法可以防止塌陷并能形成新的骨組織。骨組織工程的興起為干細(xì)胞MSCs治療股骨頭壞死(ONFH)提供了有力支持。干細(xì)胞MSC移植聯(lián)合細(xì)胞因子隨著更多研究確定股骨頭壞死(ONFH)病因和發(fā)病機(jī)制，細(xì)胞因子已成為股骨頭壞死(ONFH)治療的焦點(diǎn)。目前已發(fā)現(xiàn)多種細(xì)胞因子可促進(jìn)干細(xì)胞MSCs分化為骨細(xì)胞和軟骨細(xì)胞[56]。股骨頭壞死(ONFH)基礎(chǔ)實(shí)驗(yàn)中使用的細(xì)胞因子包括骨形態(tài)發(fā)生蛋白（BMP）、血管內(nèi)皮生長因子（VEGF）、堿性成纖維細(xì)胞生長因子（BFGF）、腫瘤壞死因子（TNF）等。這些因子可以誘導(dǎo)干細(xì)胞MSC不可逆地分化為成骨細(xì)胞，有的可以誘導(dǎo)新生血管形成并參與股骨頭壞死(ONFH)的修復(fù)[57]。Reddi等[58]得出結(jié)論，骨形態(tài)發(fā)生蛋白（BMP）可以使間充質(zhì)細(xì)胞首先分化為軟骨細(xì)胞，然后分化為成骨細(xì)胞。成骨細(xì)胞可用于治療股骨頭壞死，這與它們?cè)诖龠M(jìn)新骨形成、血運(yùn)重建和促進(jìn)關(guān)節(jié)軟骨生長方面的作用有關(guān)。堿性成纖維細(xì)胞生長因子（BFGF）具有較強(qiáng)的成骨和誘導(dǎo)血管生成作用，與骨形態(tài)發(fā)生蛋白（BMP）聯(lián)合應(yīng)用效果優(yōu)于單獨(dú)應(yīng)用骨形態(tài)發(fā)生蛋白（BMP）。Jin等[59]通過堿性成纖維細(xì)胞生長因子（BFGF）和骨形態(tài)發(fā)生蛋白（BMP）作用于兔股骨頭壞死(ONFH)，觀察到壞死區(qū)域新生骨小梁的形成，由此，作者得出結(jié)論，堿性成纖維細(xì)胞生長因子（BFGF）和骨形態(tài)發(fā)生蛋白（BMP）可以顯著促進(jìn)骨細(xì)胞和成纖維細(xì)胞的生長和增殖。血管生成因子促進(jìn)股骨頭壞死區(qū)域相對(duì)于正常區(qū)域的血運(yùn)重建。血管生成因子可以維持壞死區(qū)域的血液供應(yīng)，可能作為治療股骨頭壞死(ONFH)的有效手段。血管內(nèi)皮生長因子（VEGF）具有很強(qiáng)的促進(jìn)內(nèi)皮生長和血管生成的作用，其他血管生成因子通過增強(qiáng)血管內(nèi)皮生長因子（VEGF）的表達(dá)和產(chǎn)生來全部或部分促進(jìn)血管生成[60]。盡管許多研究證明生長和分化因子在骨壞死的治療中發(fā)揮著重要作用，但這些研究都是在體外或動(dòng)物實(shí)驗(yàn)中進(jìn)行的，并沒有直接證據(jù)證明它們?cè)谌梭w中的有效用途。在這方面，較新的治療方法通?；趯?duì)病理過程的更好理解。隨著對(duì)股骨頭壞死(ONFH)過程了解的加深，各種生長和分化因子的作用將逐漸變得清晰，這種類型的治療可能會(huì)在未來出現(xiàn)[61]。?SurgicalTreatmentSurgicaltreatmentisindicatedifONFHprogressesrapidlyandnon-surgicaltreatmentisnoteffective.Thesurgicalproceduresincludetwomaincategories:thereconstructionofthefemoralheaditselfandTHA.Theoperationtopreservethefemoralheadincludescoredecompression,osteotomy,andbonegraftingwithorwithoutbloodsupply[36].CoredecompressionisoneoftheimportantsurgicalmethodsforthetreatmentofearlyONFH.Itismainlythroughcoredecompressiontobreakthroughthehardeningzone,leadingtoareductioninintraosseouspressureandimprovementofbloodsupply[37].Coredecompressionismoresuitableforearly-stagepatientswithONFH.Someclinicianshaveinventedvascularizedandnon-vascularizedbonegrafts,ordesignedasupportwithothermaterials,suchastantalumrods[38].Atpresent,theindicationsforbonegraftingare(1)vascularizedfibulargrafting;(2)withvascularpediclediliacbonegraft;(3)freefibulagrafting;(4)withboneflaptransplantation;(5)lesionremoval,compressionofbonegraftsurgery;(6)lesionremoval,memoryalloymeshimplantation;and(7)lesionremoval,impactionbonegraft,andporoustantalumnailsupportsurgery.Allkindsofbonegraftinghaveissues,andthus,poroustantalumrodiswidelyused.Comparedwithtraditionalsinglecompressionosteogenesis,thecombinationofporoustantalumrodsupporthasobviousadvantagesinstageI–IIONFH.Astudyfoundthatthecoredecompressionandboneimplant,2mmimpactionbonegraftingplusporoustantalumrodsupportingmethodsofoperationinONFHpatients,canprolongthelifeofthefemoralheadandpostponeTHAtime[39].Thepurposeofosteotomyistoremovethenecroticzonefromtheweight-bearingareaofthefemoralhead.Osteotomyincludesvarusorvalgusosteotomybythefemoralrotorrotationosteotomy,andsoon,withtheprincipleofnotchangingthemedullarycavityofthefemur[40,41].Ifthefemoralheadcollapseisserious(ARCO,IIICandIV),andthereisaseverelossofjointfunctionormoremoderatepain,THAshouldbechosen.?TraditionalTreatmentCombinedwithStemCellTherapyforONFHMSCsarederivedfrommesodermalmesenchymeandarewidelydistributedinthebonemarrow,bonemembrane,muscle,synovium,synovialfluid,liver,peripheraltissue,umbilicalcordblood,fat,placenta,fetallung,fetalkidney,umbilicalcord,andothertissues[42,43].MSCswithmulti-directionaldifferentiationabilityhavebeenisolatedandextractedfromthesetissues,andthecellshavestrongself-renewalandproliferationability[44].Theycandifferentiateintobone,cartilage,adiposetissue,muscle,tendon,andvascularendothelialcellsunderspecificconditionsofinductionandcanevendifferentiateintonervecells[45].RelatedstudieshaverevealedthatMSCallogeneictransplantationdoesnotundergorejection[46].Ithasbeenwidelyusedinstemcelltransplantation,genetherapy,tissueengineering,andotherresearchendeavors.Formanyrefractorydiseases,celltransplantationappearstobearelativelyeffectivetherapy.Transplantedautologouscellsusuallyhavespecificfunctions,includingrepairingdamagedregions,avoidingtoxiceffectsonthebodyorsideeffectscausedbytheuseoftraditionaldrugs[47].MSCshavebeenwidelyusedintherepairofbonedefects,cartilagedefects,tissueinjuries,osteoarthritis,andosteonecrosisofthefemoralhead.MSCshavealsobeenappliedinotherfieldsofclinicalpractice[48].StemcellsinthetreatmentofONFHarethefocusofcurrentresearch,whichhasdemonstratedthatstemcellscandifferentiateintoosteoblastsunderspecificconditions.Osteoblastsplayanimportantroleintheprocessofrepairingbonenecrosis,andstudieshaveshownthatusingbonemarrowstemcellstransplantationintoanecroticfemoralheadleadstoadecreaseintheincidencerateofONFHto0%[49].?CoreDecompressionCombinedwithMSCTransplantationMSCtransplantationaftercoredecompressioncanprovideseedcellsfortherepairandreconstructionofanecroticfemoralhead[16].InastudybyTabatabaeeetal.[14],basedoncoredecompression,autologousbonemarrowtransplantationwasperformedonONFHin18patientswith28hips,andallpatientswerefollowedupforanaverageof2years.ThemeanWesternOntarioandMcMasterUniversitiesOsteoarthritisIndex(WOMAC)andvisualanalogscale(VAS)scoresinallpatientsimprovedsignificantly.Magneticresonanceimaging(MRI)showedasignificantimprovementinthecombinationtreatmentgroup.Theresearchersbelievethatthistechniquecanbeusedtoimprovetherepairoffemoralheadnecroticarea,atleastintheearlystagesofONFH.Rastogietal.[13]alsoconcludedthatcoredecompressioncombinedwithautologousbonemarrowstemcellimplantationisasafeandeffectivemethod.Senetal.conductedaclinicalcontrolledstudy,whichshowedautologousbonemarrowmononuclearcellinstillationintothecoretractaftercoredecompressioncanresultinbetterclinicaloutcomesandhipsurvivalfortreatingONFH[15].Maetal.[18]evaluatedtheeffectofbonemarrowbuffycoat(BBC)implantationbasedoncoredecompressionfortreatmentofosteonecrosisofthefemoralhead.Authorsconcludedthatduringthesecondyearoftreatment,improvementinhipfunctionwasnoticedin92%ofpatientswithONFH.Moreimportantly,thenon-progressionrateforstageI/IIhipswas100%inthetreatmentgroupand66.7%inthecontrolgroup[18].Changetal.[17]indicatedthatthecoredecompressioncombinedwithautologousbonemarrowMSCstransplantationcanreducepainanddelayoravoidfemoralheadcollapse.AssessmentbyMRIfoundthatthecartilagelesionareawassignificantlyreducedandthecartilagequalitywasimprovedsignificantly.Gangjietal.[19]comparedcoredecompressioncombinedwithbonemarrowconcentrate(BMC)containingmesenchymalstemcells(MSCs)orautologousosteoblasticcells(OB)totreatONFH.TheyfoundthatOBcellimplantationwasmoreefficaciousthanBMCtreatmentindelayingtheprogressiontoAssociationResearchCirculationOsseous(ARCO)stageIIIinadditiontoreducingpaininONFH.However,otherresearchershavehaddifferentconclusions.Limetal.[11]conductedacontrolledtrialinwhichtheclinicaleffectsandradiologicalresultsoftwogroupsoftreatmentforosteonecrosisofthefemoralheadwerecompared:Onegrouputilizedtheuseofmultipledrillingcoredecompressioncombinedwithstemcelltransplantation,andtheothergrouputilizedtheapplicationofothercoredecompressionmethod,curettage,andbonegrafting.Theconclusionwasthattherewasnostatisticallysignificantdifferencebetweenthetwogroups.Fromthisstudy,forthecollapseoftheARCOstageI–IIperiodofONFH,coredecompressionandMSCtransplantationobtainedagoodsurgicaloutcome,butforpost-collapseoftheARCOstageIII–IVpatients,thissurgicalapproachwasineffective.?BiomechanicalSupportandMSCsArterialInfusionAfterONFHanddespitehipsalvagetreatment,improvingbloodsupplywithinthefemoralheadisalwaysoneofthemaintreatmentsofthedisease.Autologousstemcelltransplantationandvascularregenerationtechnologiescanplayanimportantroleinmanagement.Kocheretal.[50]confirmedthatMSCsandendothelialprogenitorcellscanpromoteischemicbloodflowrecovery.Kinnairdetal.[51]foundthatafterintramuscularinjectionofbone-derivedstemcellsintotheischemichindlimbsofrat,bone-derivedstemcellscouldpromotecollateralcirculationandlimbfunctionrecovery.Inaddition,thelevelofcytokinegeneexpressionassociatedwithangiogenesiswasincreased.Maoetal.[12]conductedacontrolledtrialinwhich55patientswith89hipsofONFHunderwenttantalumrodimplantationincombinationwithtargetedintra-arterialinfusionofMSCs,andallpatientswerefollowedupfor36months.At36monthsoffollow-up,threehipsinthecombinedtreatmentgroup(6.25%)werefoundtobeclinicallyfailedandrequiredTHA;incontrast,ninehips(21.95%)receivedTHAinthecontrolgroup.Comparedtothecontrolgroup,combinationtreatmentsignificantlyimprovedtheHarrishipscore(HHS)at36months.TheyconcludedthatMSCarterialinfusionisaneffectiveandsafemethodforearlyONFH.Comparedwithopenfemoralheadstemcelltransplantation,MSCselectivearterialinfusionhastheadvantagesofbetterstemcellsurvival,betterdifferentiation,lessinvasiveoperation,lessadversereaction,andgoodpatientcompliance.Theoperationmayachievethefollowingeffects:(1)Dredgethediseasedfemoralhead,improvethevenousreturn,decreasetheintraosseouspressure,andrestoreorimprovethebloodsupplyofthefemoralhead.(2)Improveorincreasethebloodcirculationofthetissuesaroundthefemoralheadnecroticregionandthehip,providingagoodlocalbloodsupplyforthenecroticfemoralhead.(3)MSCscanprotectthelocalvascularendotheliumandpromotetherepair,regeneration,andangiogenesisofvascularendothelialcells.Withadditionalresearchusingstemcellintervention,itappearsthismethodwillbepositiveforfutureONFHpatients.?BoneTissueEngineeringandMSCsTissueengineeringistheapplicationofcellbiology,functionallyrelatedlivingcells,whichculturedinvitro,compositetransplantationinvivotissuedefectandcompleterestorationandreconstruction.MSCshavestrongdifferentiationpotentialandproliferationability,andthecellshaveuniqueadvantagesforrepairingONFHbonedefectsintermsofsource,separationmode,anddifferentiatedtissuetype.Thus,itisthemostidealchoiceforbonetissueengineeringseedcells.ThecompositescaffoldsmadeofMSCscanbeusedtoreinforcetherepairofnecroticdefectsinthestructurebutcanalsobeusedasabiologicalcarrierforcells,genes,andgrowthfactors.Inaddition,MSCscanintegratecellsandreceptorstoregulatecellularfunction.Kangetal.[52]reportedusingautoiliaccancellousbonegraftcombinedwithMSCtransplantationforONFHpatientswithfollow-upfor32monthsdemonstratinggoodclinicalefficacy.Kawateetal.[53]usedbeta-tricalciumphosphateasthecarrierloadbearingautologousBMSCsimplantedintotheareaoftheheadnecrosiscombinedwithvascularizedfibulargraftingfortreatmentofONFH,andlong-termfollow-upfoundthatmostpatientswithosteonecroticsiteswererelievedtovaryingdegrees,imagingobservedlocalhighdensityofnewboneformation.ThediseasewasundercontrolandindicatedthatthetissueengineeringapproachhadabetterpotentialforthetreatmentofONFH.Yamasakietal.[54]reportedthat22cases(30hips)ofONFHpatientsweretreatedwithmononuclearcellscombinedwithcalciumphosphateandeightcases(ninehips)ofONFHpatientsweretreatedwithcalciumphosphateonly.Theaveragefollow-upwas29months.Inthetreatmentgroup,thefemoralheadnecroticareawasreduced,andonlythreehips(3/30)developedfemoralheadcollapse,whilesixhips(6/8)inthecontrolgroupdevelopedseriousfemoralheadcollapse.Xiaoetal.[55]repairedrabbitONFHdefectswithautologousbonemarrowMSCsoncompositebonecombinedwithrecombinanthumanbonemorphogeneticprotein2.Theyfoundthatthismethodpreventedthecollapseandcanformnewbonetissue.TheriseofbonetissueengineeringprovidesastrongsupportforthetreatmentofONFHbyMSCs.?MSCTransplantationCombinedCytokineWithadditionalresearchidentifyingONFHetiologyandpathogenesis,cytokineshavebecomeafocusofONFHtherapy.Atpresent,manycytokineshavebeenfoundtopromotethedifferentiationofMSCsintobonecellsandchondrocytes[56].ThecytokinesusedinbasicexperimentsinONFHincludebonemorphogeneticproteins(BMP),vascularendothelialgrowthfactor(VEGF),basicfibroblastgrowthfactor(BFGF),tumornecrosisfactor(TNF),andothers.ThesefactorscaninduceMSCsirreversiblytodifferentiateintoosteoblasts,andsomecaninduceneovascularizationandparticipateinrepairofONFH[57].Reddietal.[58]concludedthatBMPcancausemesenchymalcellstofirstdifferentiateintochondrocytesandthendifferentiateintoosteoblasts.Osteoblastsmaybeusedinthetreatmentoffemoralheadnecrosisrelatedtotheirroleinpromotingnewboneformation,revascularization,andpromotingarticularcartilagegrowth.BFGFhasastrongroleinosteogenesisandinducedangiogenesis,combinedwithBMPeffectisbetterthantheapplicationofBMPalone.Jinetal.[59]throughtheBFGFandBMProleinrabbitONFH,observedinnecroticregionsnewbonetrabeculaeandthus,authorsconcludedthatBFGFcombinedwithBMPcansignificantlypromotegrowthandproliferationofbonecellsandfibroblasts.Angiogenicfactorspromoterevascularizationoffemoralheadnecroticarearelativetothenormalregions.AngiogenicfactorscanmaintainbloodsupplytonecroticregionsandmaybeusedasaneffectivemeansoftreatmentforONFH.VEGFhasastrongroleinpromotingendothelialgrowthandangiogenesis,andotherangiogenicfactorspromotingangiogenesisinwholeorinpartbyenhancingtheexpressionandproductionofVEGF[60].Althoughmanystudieshavedemonstratedthatgrowthanddifferentiationfactorsplayasignificantroleinthetreatmentofbonenecrosis,thesestudieswereinvitroorinanimalexperiments,andthereisnodirectevidencetoprovetheireffectiveuseinhumans.Inthisregard,newermethodsoftreatmentaretypicallybasedonimprovedunderstandingofpathologyprocesses.WithimprovedunderstandingoftheONFHprocess,theeffectsofvariousgrowthanddifferentiationfactorswillgraduallybecomeclearerandthistypeoftreatmentmaybeseeninthefuture[61].StemCellTherapyforOsteonecrosisoftheFemoralHead:CurrentTrendsandComprehensiveReviewAbstractPurposeofreview:Osteonecrosisofthefemoralhead(ONFH)isacommonandfrequentlyoccurringdisease.Itiscausedbyinterruptionofbloodsupplywithdifferentetiologies.ONFHleadstodegenerationandnecrosisofthesubchondralboneofthefemoralheadandeventuallycollapseofthefemoralhead.ONFHhasahighdisabilityrate,seriouslyaffectingthequalityoflivingofpatients,andofteninvolvesmiddle-agedandyoungerpeople.Recentfindings:Inrecentyears,thetechnologyandunderstandingofstemcellsandregenerativemedicinehavebeendevelopingrapidly.NumerousstudieshavereportedsuccessfulresultsinthetreatmentofONFHbystemcelltransplantation.Thus,stemcelltransplantationisexpectedtoserveasanewmethodinthetreatmentofONFH.Inthepresentreport,therefore,weevaluatedcurrenttechniquesandoutcomesutilizingstemcellsinthetreatmentofONFH.Acomputer-basedonlinesearchofPubMedandCochraneLibrarydatabasesbetweenJanuary2006andJune2017wasperformedtosearchrelatedarticlesusingthekeywordsof"treatment,stemcell,osteonecrosisofthefemoralhead"inEnglishlanguage.LiteraturerelatedtothetreatmentofONFHwasselected.Oursearchobtainedatotalof161articles,butonly9articlesmetourinclusioncriteriaandwereincludedinourreport.ThepresentreviewrevealsthatcelltechnologyhasdemonstratedgoodevidenceinthetreatmentofONFH.However,thistechnologyneedsadditionalin-depthstudytobetterexploreandappreciatemoreidealwaystoovercomedifficultiesassociatedwithsourceofcells.文獻(xiàn)出處：LeiZhao,AlanDavidKaye,AaronJKaye,AlaaAbd-Elsayed.StemCellTherapyforOsteonecrosisoftheFemoralHead:CurrentTrendsandComprehensiveReview.Review,CurrPainHeadacheRep.2018May3;22(6):41.doi:10.1007/s11916-018-0700-x.