Chinese Journal of Tissue Engineering Research ›› 2022, Vol. 26 ›› Issue (10): 1631-1640.doi: 10.12307/2022.215
Zhou Yi, Liu Xiaoyan, Xiang Bingyan
Received:
2021-04-23
Revised:
2021-04-24
Accepted:
2021-05-21
Online:
2022-04-08
Published:
2021-10-27
Contact:
Xiang Bingyan, MD, Professor, Chief physician, Master’s supervisor, Department of Joint Surgery, Third Affiliated Hospital of Zunyi Medical University (Zunyi First People’s Hospital), Zunyi 563000, Guizhou Province, China
About author:
Zhou Yi, Master candidate, Department of Joint Surgery, Third Affiliated Hospital of Zunyi Medical University (Zunyi First People’s Hospital), Zunyi 563000, Guizhou Province, China
Supported by:
CLC Number:
Zhou Yi, Liu Xiaoyan, Xiang Bingyan. Application advantages of concentrated growth factors in the field of tissue repair and regeneration[J]. Chinese Journal of Tissue Engineering Research, 2022, 26(10): 1631-1640.
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2.1 浓缩生长因子的研究脉 见图3。 血小板浓缩物发展至今,主要分为以下3类:第1代为富血小板血浆,第2代为富血小板纤维蛋白,第3代为浓缩生长因子。20世纪80年代以来,富血小板血浆作为第1代血小板浓缩产物,逐渐应用于软硬组织的修复和再生等领域[2-3]。富血小板血浆的制备需要加入凝血酶等生物制剂,对人体健康有潜在威胁,且制备的富血小板血浆有效成分含量较少,生长因子作用时间短,富血小板血浆的实际疗效和安全性存在一定争议。富血小板纤维蛋白在富血小板血浆的基础上进一步改进和简化,通过模拟生理性的凝血过程,仅对全血进行匀速离心而制备,制备过程中无需添加任何生物制剂[4-5]。有研究表明富血小板纤维蛋白较富血小板血浆释放的生长因子量更大且持续时间更长,富血小板纤维蛋白更利于组织缺损的修复与再生[6-7]。因此富血小板纤维蛋白更多的被广泛应用于颌面外科,整形外科等领域[8-9]。2006年,SACCO首次运用特定的差速离心方法制备出第3代血小板浓缩物浓缩生长因子。与富血小板血浆和富血小板纤维蛋白不同,浓缩生长因子制备采用特定的变速离心,形成了更具韧性的三维纤维蛋白网络,为细胞的黏附、增殖提供了三维空间,变速离心也能够释放出更高浓度的生长因子[10-11],并将白细胞、血小板更为稳定地聚合在浓缩生长因子内[12],使浓缩生长因子的有效成分提取和分离更加完全。此外,浓缩生长因子具有良好的可塑性和兼容性,能被制备成提取液、冻干材料和浓缩生长因子膜等,也可加入培养基中,还能与组织工程的材料结合应用。近年来越来越多的研究对浓缩生长因子的应用价值进行探索。但目前大部分综述仅着重关注浓缩生长因子在促进骨组织修复方面的研究进展,尤其是在口腔种植体修复领域[13],颌面骨修复领域[14-15],然而浓缩生长因子在促进其他组织的修复与再生中仍具有相当的潜力,最近的研究也开始关注浓缩生长因子除促进骨修复以外的作用。"
2.2 浓缩生长因子的制备和应用形式 浓缩生长因子的制备和应用方法如图4所示。 浓缩生长因子的制备是将静脉血装入无菌玻璃专用试管中,不加入任何添加剂,通过Medifuge专用离心机离心,其离心程序:加速30 s,以2 700 r/min离心2 min,2 400 r/min 离心4 min,2 700 r/min 离心4 min, 3 000 r/min 离心3 min,减速36 s 至停止。血液经过浓缩生长因子离心程序离心后分为3 层:中间层为浓缩生长因子凝胶层,上层为血浆层,下层为红细胞层[16]。用注射器将管顶部的去血小板血浆抽出,并将浓缩生长因子层和红细胞层从试管上取下。然后用剪刀将两层分离,得到浓缩生长因子层,过程中保留浓缩生长因子层和红细胞层的交界部分,因为这个部分富含血小板、白细胞及各种生长因子。"
2.3 浓缩生长因子的应用形式 主要包括4种,见表1。 2.3.1 浓缩生长因子凝胶 通过上述方法制备的浓缩生长因子凝胶切成碎片后可以直接植入体内,用于促进体内软硬组织缺损的愈合,效果良好[17-18]。在体外也可以将浓缩生长因子放入条件培养基中,例如直接将浓缩生长因子凝胶加入培养基,再加入体积分数1%胎牛血清,50 μmol/L抗坏血酸盐, 100 nmol/L地塞米松和10 mmol/L β-甘油磷酸酯制作成成骨条件诱导培养基,在体外已被证明有良好的诱导成骨作用。 2.3.2 冻干浓缩生长因子 浓缩生长因子可在-80 ℃下冻干24 h,制作成冻干浓缩生长因子,或者冷冻干燥后进一步研磨,制作成浓缩生长因子粉末直接使用。浓缩生长因子经过冻干后,方便使用和保存,有研究表明冻干的浓缩生长因子粉末,生长因子在浓缩生长因子中处于自由扩散状态,可持续释放胰岛素样生长因子1、血管内皮生长因子、转化生长因子β1和血小板衍生生长因子AB等生长因子[19]。 2.3.3 浓缩生长因子提取物 浓缩生长因子提取物,是浓缩生长因子的另一种应用形式,制作原理是通过将完整的浓缩生长因子机械压缩,或者匀速离心,将浓缩生长因子富含纤维蛋白的部分和富含生长因子的液态浓缩生长因子提取物分离。因浓缩生长因子提取物多成液态或者半凝胶状,在体外加入培养基后,相比直接放入整体的浓缩生长因子,不仅能充分释放各种生长因子,还可以做到定量加入浓缩生长因子提取物,根据浓缩生长因子提取物的浓度制作成不同浓缩生长因子提取物浓度的条件培养基,目前一些研究支持体积分数10%的浓缩生长因子提取物培养基对成骨诱导作用最 大[20-21],高浓度的浓缩生长因子提取物反而抑制细胞的增殖和分化[22]。同样直接植入体内损伤部位可以促进愈合作用,但由于浓缩生长因子提取物失去了纤维蛋白三维结构的缓释作用,可能导致各种生长因子在损伤局部原位过快释放[23]。目前对于浓缩生长因子提取物的最佳浓度和生长因子释放动力学相关研究较少,还需要进一步探究。 2.3.4 浓缩生长因子膜 由于浓缩生长因子富含纤维蛋白成分,运用压缩器均匀地机械压缩后,可以制备成浓缩生长因子膜。有研究表明经过压缩后的浓缩生长因子膜,原有的纤维蛋白三维结构在一定程度上被改变,释放生长因子相较浓缩生长因子凝胶缓慢[24-25],这可能为延长生长因子缓释时间提供了参考。由于薄膜浓缩生长因子植入更加便捷,且浓缩生长因子膜增大了和损伤部位的接触面积,使各种生长因子能大面积释放到损伤局部的各个部位。一些研究借鉴了Masqulet技术生成诱导膜的原理,将浓缩生长因子膜原位覆盖于骨缺损部位的表面,取得了良好的骨缺损修复效果[26-27]。浓缩生长因子膜的发明,确实为临床治疗提供了很大便利,对于慢性皮肤溃疡缺损,浓缩生长因子膜直接覆盖于创面表面,也有良好的愈合效果[28]。 2.4 浓缩生长因子的生物学特性 浓缩生长因子具备生物学活性的两大核心结构是天然的纤维蛋白支架和各种内源性生长因子,此外还有含有少量的白细胞、CD34+免疫细胞、白细胞介素6细胞因子等,使浓缩生长因子还具备一定的抗炎和免疫调节作用[16]。 天然的纤维蛋白支架是在浓缩生长因子特定变速离心过程中不断交联形成的,由于为包含加速和减速过程,大幅度增加了纤维蛋白互相重叠交联的程度,更有利于纤维蛋白原转化为纤维蛋白,相比富血小板纤维蛋白,浓缩生长因子的纤维蛋白网络更加致密和坚固[29]。变速离心过程相比单一匀速离心,能将各沉降系数不同的成分更加完全地分离,因此浓缩生长因子相比富血小板纤维蛋白有更多种类的生长因子和细胞因子[30]。在交替离心力的作用下,各种生长因子和血小板在纤维蛋白网络中嵌入的概率显著增加,这可能有助于生长因子的缓释时间的延长[31]。纤维蛋白支架天然的三维结构本身具有一定的机械支撑作用,同时可与纳米羟基磷灰石等组织工程材料联合形成更为稳定的三维支架结构[32]。这种空间结构为细胞聚集、黏附、分化及增殖提供了适宜的环境,在一定程度上充当了细胞外基质的作用[33]。致密的纤维蛋白网络为浓缩生长因子中的生长因子提供保护,避免被纤溶酶溶解[10]。具备一定孔隙率和孔径的三维纤维蛋白网络支架,避免了各种内源性生长因子爆发性释放,具有一定的缓释作用,更符合生理性释放过程[30]。不同于人工合成的支架材料,天然的纤维蛋白网络自行降解,并且在降解过程中释放出更多的生长因子和血小板,进一步促进损伤组织愈合[34]。 浓缩生长因子在离心过程中因血小板从各个方向相互碰撞破裂,释放出a颗粒,a颗粒中蕴含有大量生长因子,其中主要包括血小板衍生生长因子、转化生长因子β1、血管内皮生长因子、胰岛素样生长因子1、表皮生长因子及骨形成发生蛋白。血小板衍生生长因子作为一种生物趋化因子,也能促进细胞的有丝分裂。 有研究显示,血小板衍生生长因子是启动细胞分化级联反应的关键因子[35-36],能促进口腔黏膜成纤维细胞有丝分裂进而转化成肌成纤维细胞,并促进细胞增殖、趋化和胶原合成[37];骨髓间充质干细胞的趋化,以及向成骨分化过程中,血小板衍生生长因子表达也明显增加[38];因血小板衍生生长因子的趋化作用,在干细胞生物疗法中,可诱导间充质干细胞定向迁移,实现靶向治疗[39]。血小板衍生生长因子促进血管内皮细胞有丝分裂,调控细胞增殖和凋亡,减少血管内皮损伤,可能是动脉粥样硬化治疗的新靶点[40]。转化生长因子β1是属于一组调节细胞生长和分化的转化生长因子β超家族成员,主要作用是促进成纤维细胞的增殖和分化以及调节细胞免疫表型[41-42],目前有研究表明转化生长因子β1还能通过促进间充质细胞的转化加速伤口愈合[43]。血管内皮生长因子一种高度特异性的促血管内皮细胞生长因子,其主要作用是促进血管生长和调节血管通透性。浓缩生长因子中的血管内皮生长因子在感染性骨缺损模型中表达增加,局部血管化作用增强,在骨组织愈合中有关键作用[44]。血管内皮生长因子可联合间充质干细胞促进血管生成和重建,实现早期修复创面[45]。胰岛素样生长因子1是一种多功能细胞增殖调控因子。有研究证实,浓缩生长因子中释放的胰岛素样生长因子1通过胰岛素样生长因子1R/PI3K/AKT信号通路促进耳郭软骨细胞增殖。此外,胰岛素样生长因子1是一种神经营养因子,能保护运动神经元,抑制神经炎症反应,可能对神经损伤的再生有积极作用[46]。表皮生长因子的主要作用是调控上皮细胞增殖和迁移,促进各种表皮组织生长[47]。骨形成发生蛋白能刺激DNA的合成和细胞的复制,促进间充质细胞定向分化为成骨细胞,是骨缺损修复和骨代谢调控的重要因子[48]。在骨组织工程中各种生物材料联合骨形态发生蛋白,通过促进成骨细胞的增殖和分化,能明显增强各种骨缺损模型的修复效果,加速骨组织重建和再生[49-50]。骨形态发生蛋白对软骨的再生也有促进作用,有研究将骨形态发生蛋白用于关节软骨的修复,治疗骨性关节 炎[51],此外骨形态发生蛋白在未成熟软骨发育阶段中有重要调控作用,骨形态发生蛋白2和6在生长板软骨中表达梯度明显增加[52]。"
目前的一些研究致力于比较富血小板血浆、富血小板纤维蛋白、浓缩生长因子中有效生长因子的浓度和释放。LEE等[33]的研究发现浓缩生长因子中血小板衍生生长因子和表皮生长因子的浓度和含量均高于富血小板纤维蛋白,且浓缩生长因子在体外成骨作用大于富血小板纤维蛋白。LEI等[34]的研究中表明,富血小板纤维蛋白和浓缩生长因子 14 d持续稳定释放血小板衍生的生长因子、血管内皮生长因子、骨形态发生蛋白2和转化生长因子β1,生长因子浓度基本相似。MASUKI等[10]的研究发现,与富血小板血浆制剂相比,富血小板纤维蛋白和浓缩生长因子提取液中血小板和血小板衍生生长因子含量均较高,而富血小板纤维蛋白中转化生长因子β1、血小板衍生生长因子BB、血管内皮生长因子浓度大于浓缩生长因子。大多数研究认为富血小板纤维蛋白和浓缩生长因子中内源性生长因子浓度明显高于富血小板血浆,但对于富血小板纤维蛋白和浓缩生长因子中生长因子浓度的差异目前无统一定论。大量内源性生长因子的释放和活化,多信号通路激活,多个作用靶点相互调节,互相协同,是浓缩生长因子促进组织修复和重塑的主要机制,相比单一的某一种生长因子,浓缩生长因子形成综合的生长因子缓释储存库,是其主要优势之一。浓缩生长因子中主要生长因子的生物学作用,见表2。"
2.5 浓缩生长因子在体外对细胞的作用 由于含有大量促进成骨的活性细胞因子,浓缩生长因子在体外的成骨作用被广泛研究。多项研究评价了浓缩生长因子在体外对细胞的成骨作用。浓缩生长因子体外诱导干细胞成骨的研究6项,包括人牙髓干细胞(hDPSCs)、人骨髓间充质干细胞(hBMSCs)、人牙周膜干细胞(hPDLSCs)及人根尖乳头干细胞(hSCAP);非干细胞研究6项,包括牙髓细胞(DPCs)、牙周膜成纤维细胞(PDLFs)、MC3T3-E1细胞、兔骨膜衍生细胞(PDCs)、SAOS-2成骨样细胞及人牙周膜细胞(hPDLCs)。几乎所有研究都集中于浓缩生长因子体外对细胞的增殖、迁移和成骨分化,成骨分化检测包括碱性磷酸酶活性,茜素红染色评估矿化面积,以及Runx2、骨形态发生蛋白2及BSP等成骨相关基因表达水平,见表3。有3项研究设置了不同的浓缩生长因子提取物浓度[22-23,53],JIN等[23]的研究表明,低于50%浓缩生长因子促进人牙髓干细胞增殖、迁移及成骨分化,高于50%浓度则表现为抑制作用。但AGHAMOHAMADI等[22]的研究却表明:90%浓缩生长因子对牙周膜干细胞增殖仍有显著促进作用,这说明浓缩生长因子对于不同干细胞的增殖分化可能存在不同的最适浓度。有5项研究设置了阳性对照组,以比较浓缩生长因子、LPF、A-LPF、成骨诱导培养基、以及基因修饰后的生长因子对细胞的成骨分化作用。有研究认为富血小板纤维蛋白体外成骨作用强于浓缩生长因子[54],有研究认为富血小板纤维蛋白和浓缩生长因子体外成骨作用无明显差异[55],有研究表明浓缩生长因子体外诱导成骨分化强于单纯成骨诱导培养基[18]。有研究认为浓缩生长因子体外诱导成骨分化强于人重组转化生长因子β1联合人重组血小板衍生生长因子AB[24]。有2项研究涉及浓缩生长因子对PI3K/Akt信号通路和Wnt3a信号通路的影响[24,56]。"
多项研究探讨了浓缩生长因子体外对神经细胞、脂肪细胞、成纤维细胞、血管内皮细胞的影响。其中2项研究表明浓缩生长因子能减轻紫外线照射对人皮肤成纤维细胞的损伤,并减少氧自由基的生成,这可能对皮肤抗老化作用产生积极影响[57-58];此外另一项研究表明浓缩生长因子能提高脂肪移植存活率[59],这表明浓缩生长因子在皮肤美容领域的一定潜力。有3项研究对神经细胞的研究中发现,浓缩生长因子能分泌神经营养因子以及促进神经细胞部分再生,这可能对神经损伤后再修复有积极作用[60-62]。有4项研究表明浓缩生长因子在体外促进了血管内皮生长因子的表 达[59,63-65],这表明浓缩生长因子体外确切的促血管生成作用,局部促血管化作用是组织修复再生过程中的关键之 一,如表4所示。"
2.6 浓缩生长因子在体内对组织修复和再生的研究 浓缩生长因子在体外的成骨作用已经在大量研究中获得肯定,所以近年有许多研究致力于评估浓缩生长因子在体内对骨缺损修复的作用。在文章的报告中,包括了多项将浓缩生长因子应用于体内骨缺损修复的基础研究和临床研究。骨缺损的类型包括颅骨临界骨缺损、上下颌骨、牙种植体周围骨缺损,以及四肢长骨骨缺损(包括桡骨、股骨和胫骨)。植入的方式多采用浓缩生长因子凝胶或浓缩生长因子凝胶膜。几乎所有研究都肯定了浓缩生长因子在体内对于骨缺损修复的积极作用,仅有1项研究否定浓缩生长因子的效果[17],此研究将浓缩生长因子凝胶植入药物相关性颌骨坏死骨质疏松患者的骨缺损部位,术后6个月的随访结果显示,浓缩生长因子治疗手术组与单纯手术组在骨缺损愈合率上无显著性差异。有4项研究将浓缩生长因子与自体或同种异体骨联合植入体内[66-69],用于修复骨缺损,均表明联合组在骨缺损面积的缩小和骨密度改善方面的显著优势。此外,有4项研究将浓缩生长因子与骨组织工程材料联合用于骨的修复和重建,包括浓缩生长因子联合纳米羟基磷灰石、Bio-Oss骨粉和矿化胶原[32,70-72],这几种联合方式均表现出浓缩生长因子与材料良好的兼容性,以及确切的骨缺损修复效果。 有研究将浓缩生长因子作为支架,搭载骨髓间充质干细胞共同植入[73],在鼠的临界颅骨缺损相比单纯植入浓缩生长因子或胶原,取得更好的骨缺损修复效果,以及观察到这种联合方式可能促进缺损局部血管形成的现象。有研究创新性地将Masquelet膜诱导技术与浓缩生长因子凝胶膜结合,并表明在术后12周时,这种创新性地结合治疗方式比对照组有更多的新骨生成[26]。 浓缩生长因子的体内研究不仅仅局限在骨组织等硬组织的修复作用,由于含有多种内源性生长因子以及多种灵活可变的应用形式,浓缩生长因子也被应用于修复多种软组织缺损。CHEN等[28]的Meta分析中,包括578例患者,8项随机对照试验,表明浓缩生长因子对于修复皮肤慢性溃疡创面的积极效果。ZHAO等[74]的研究中,将自体浓缩生长因子膜植入鼻中隔黏膜缺损部位,术后6个月黏膜完全修复,且无并发症发生。有研究将浓缩生长因子凝胶植入干槽症患者牙槽周围软组织缺损中,在术后第7天浓缩生长因子治疗组的新生肉芽组织数量显著高于单纯手术 组[75]。与促进骨修复不同的是,浓缩生长因子修复软组织的效果存在一些争议。在牙龈退缩的修复2项研究中,一项研究认为浓缩生长因子仅能改善牙龈角化宽度和龈厚,修复效果有限[76];另一项研究则认为结缔组织比浓缩生长因子凝胶更有利于治疗牙龈萎缩[77]。此外,有研究在治疗种植体周围炎的研究中也表明,胶原膜植入在治疗牙龈愈合及骨再生方面优于浓缩生长因子膜[78]。 有2项关于浓缩生长因子和拔牙术后并发症的研究中,一项研究表示浓缩生长因子可降低下颌第三磨牙拔除术后牙槽骨炎发生率[79],另一项研究却认为浓缩生长因子和A-富血小板纤维蛋白对下颌第三磨牙拔除术后患者的疼痛、局部肿胀程度的缓解没有作用[80]。另外2项关于皮肤的研究中表明,浓缩生长因子能够改善皮肤光老化损伤程度以及在治疗面部凹陷瘢痕的良好效果[81-82]。此外,有研究发现浓缩生长因子联合米诺地尔能治疗雄激素性脱发,且效果优于单独米诺地尔治疗[83]。还有研究将浓缩生长因子与Masquelet技术结合[27],发现浓缩生长因子治疗组形成的诱导膜厚度、炎症程度、膜血管化程度、膜增殖率、干细胞比例均优于对照组,可见浓缩生长因子可能为优化Masquelet技术提供了一种参考,如表5所示。"
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