Chinese Journal of Tissue Engineering Research ›› 2022, Vol. 26 ›› Issue (22): 3580-3585.doi: 10.12307/2022.288
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Lu Haiping1, Lang Xuemei2, Zhang Cheng1, Ju Songli1, Zhang Yi3, Wang Xin1
Received:
2021-02-25
Revised:
2021-03-19
Accepted:
2021-06-11
Online:
2022-08-08
Published:
2022-01-12
Contact:
Zhang Yi, PhD, Associate professor, Master’s supervisor, School of Public Health, Zunyi Medical University, Zunyi 563000, Guizhou Province, China
Wang Xin, PhD, Chief physician, Doctoral supervisor, Department of Orthopedics, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
About author:
Lu Haiping, Master candidate, Department of Orthopedics, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
Lang Xuemei, Attending physician, Pre-hospital Emergency Department of Chongqing Emergency Center, Chongqing 400010, China
Lu Haiping and Lang Xuemei contributed equally to this article.
Supported by:
CLC Number:
Lu Haiping, Lang Xuemei, Zhang Cheng, Ju Songli, Zhang Yi, Wang Xin. Application of polycaprolactone modified biological barrier membrane in bone tissue engineering[J]. Chinese Journal of Tissue Engineering Research, 2022, 26(22): 3580-3585.
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2.1 聚己内酯屏障膜物理结构的改良 植入屏障膜的微观结构和结构表面物理化学特性对细胞附着、排列和增殖有着深远的影响。在植入骨缺损后,聚己内酯屏障膜除了发挥屏障功能外,还应允许一些小分子如营养物质和氧气分子滤过,以保证组织正常的生命活动,这就需要聚己内酯屏障膜具有一定的孔隙率及适宜的孔径大小。有研究认为,组织只能在直径大小超过100 μm的孔径生长,且孔径的大小和内部相互连通性还可以决定组织生长的类型[8]。此外,材料表面较高的孔隙率有助于间充质干细胞及成骨细胞的黏附增殖[9]。在屏障膜顶面(结缔组织面),大小约10 nm的纳米孔径结构被认为可以有效防止纤维结缔组织和上皮组织侵入骨缺损,还可允许营养物质和其他小分子滤过;而在屏障膜的底面(骨缺损面),孔径约200 μm的微孔结构被认为有助于骨组织的黏附再生[10]。KIM等[11]制备了顶部为纳米孔结构,底部为叶堆积结构(增加孔径大小)的聚己内酯屏障膜,并将骨形态发生蛋白2固定在膜上,检测发现该屏障膜在体外促进骨形态发生蛋白2释放的能力明显大于正常结构的聚己内酯屏障膜(大约是其2倍),且在体内具有更佳的促进成骨基因Runx2表达的能力。 除了孔径大小外,屏障膜的其他物理性能也能影响其成骨活性。DAS等[12]采用3D打印技术制造了具有不同有效表面积的聚己内酯-壳聚糖复合屏障膜,并在该复合屏障膜上接种人间充质干细胞培养20 d,发现随着4个组聚己内酯-壳聚糖复合屏障膜有效表面积的增加[依次为(69.0±2.0)%,(74.0±2.0)%,(84.0±1.0)%,(88.0±1.0)%],聚己内酯-壳聚糖复合屏障膜上的人间充质干细胞活力也相应增强[用耗氧比表示,相应的分别为(10±2),(15±3),(33±2),(38±7) μmol/(L?min)],且后两组耗氧比显著大于前两组(P < 0.05)。这表明聚己内酯-壳聚糖屏障膜的有效表面积能够影响人间充质干细胞的存活能力,对骨再生过程发挥着不可忽略的影响。 2.2 聚己内酯与骨替代材料复合 2.2.1 与磷酸钙材料复合 羟基磷灰石是常用的骨替代材料之一,具有良好的成骨诱导及成血管性能[13]。聚己内酯本身具有较强的疏水性,使得其在植入骨缺损后不利于间充质干细胞的黏附增殖[14]。聚己内酯与羟基磷灰石复合既能够发挥聚己内酯生物膜的屏障功能,又能体现羟基磷灰石促进成骨的能力,还能提升聚己内酯材料的亲水性能,为复合材料发挥良好的成骨功能提供了研究基础[14]。聚己内酯-羟基磷灰石复合屏障膜已被证明在体内、外具有促进人间充质干细胞和成骨细胞增殖和分化的能力[15]。有研究者用肝素改善聚己内酯的疏水性,采用电纺丝技术制得聚己内酯-明胶-纳米羟基磷灰石复合屏障膜,该膜在体外具有良好促进兔间充质干细胞增殖分化的能力[16]。此外,GROPPO等[17]采用电纺丝技术将聚己内酯与羟基磷灰石混合制得聚己内酯-羟基磷灰石复合屏障膜,植入大鼠3.3 mm亚临界颅骨缺损模型中,90 d后观察到聚己内酯-羟基磷灰石屏障膜组骨缺损几乎完全愈合,而对照组的骨缺损体积仍>5 mm3(P < 0.05)。 近年来,磷酸三钙由于在体内具有适宜的降解度及良好的成骨诱导活性成为了理想的骨替代材料,其可分为高温相的β-磷酸三钙和低温相的α-磷酸三钙[18-19]。有研究者采用电纺丝技术制备了含不同比重纳米β-磷酸三钙颗粒(5%,10%和15%)的聚己内酯-纳米β-磷酸三钙复合屏障膜,在体外发现聚己内酯-10%纳米β-磷酸三钙复合屏障膜组具有最佳的细胞相容性及促进人胎儿成骨细胞增殖能力(大约是聚己内酯-5%纳米β-磷酸三钙复合屏障膜组的1.3倍,是聚己内酯-15%纳米β-磷酸三钙复合屏障膜组的1.2倍, P < 0.05)[20]。SHIM等[21]采用3D打印技术打印出了聚己内酯与β-磷酸三钙复合屏障膜并植入犬下颌骨模型8周,测得聚己内酯与β-磷酸三钙组的新骨形成量显著大于单独聚己内酯屏障膜组、胶原膜组[(29.22±3.11),(27.29±2.19),(25.92±6.97) mm3,P < 0.05]。这表明磷酸三钙的加入显著增强了聚己内酯屏障膜在体内外的成骨活性。 双相磷酸钙是羟基磷灰石与磷酸三钙组成的复合物,其生物活性高于羟基磷灰石,并具有良好的成骨诱导活性[22-23]。有研究者采用电纺丝技术制得聚己内酯-双向磷酸钙复合屏障膜,在植入5 mm大鼠颅骨缺损模型2个月后,聚己内酯-双向磷酸钙屏障膜组再生骨量显著高于单独应用聚己内酯屏障膜组[(12.12±1.75),(6.85±0.23)mm3,P < 0.05][24]。此外,有报道30%比重的双向磷酸钙加入聚己内酯复合屏障膜可使该膜具有更高的吸水能力和溶解能力,这使得该屏障膜不仅具有优越的成骨活性,还适合应用于一些药物的释放(如盐酸四环素等)[25]。 2.2.2 与生物活性玻璃复合 生物活性玻璃是一种由二氧化硅、氧化钠、氧化钙和五氧化二磷等基本成分组成的硅酸盐,已被证明在体内、外具有良好的抗菌活性及诱导血管组织生长的能力,已被广泛应用于牙科和矫形外科[26-27]。有研究者采用电纺丝技术制备了含纳米生物活性玻璃比重为20%、厚度约为260 μm的聚己内酯-生物活性玻璃复合屏障膜,该复合膜在体外展现出良好的细胞相容性,在接种小鼠来源的成骨前体细胞MC3T3-E1培养14 d后,检测到聚己内酯-生物活性玻璃复合屏障膜组(实验组)的细胞生长水平显著优于纯聚己内酯膜组(对照组),实验组碱性磷酸酶活性约是对照组2倍(P < 0.05)[28]。另有研究者采用电纺丝技术在聚己内酯屏障膜中添加了两种成分不同的介孔生物活性玻璃(成分分别为二氧化硅-氧化钙-五氧化二磷和二氧化硅-氧化锶-五氧化二磷)制得了两种不同的复合屏障膜,并接种具有向成骨方向分化能力的人脐带沃顿胶间充质干细胞,培养28 d后发现含二氧化硅-氧化钙-五氧化二磷复合屏障膜组人脐带沃顿胶间充质干细胞的分化能力是单独聚己内酯屏障膜组的1.5倍(P < 0.05),二氧化硅-氧化锶-五氧化二磷复合屏障膜组人脐带沃顿胶间充质干细胞分化能力是单独聚己内酯屏障膜组的1.7倍(P < 0.05)[29]。以上数据表明,生物活性玻璃的加入使得聚己内酯屏障膜在体外具有良好的成骨性能。 此外,有报道双层复合屏障膜(聚氨酯作为上层,发挥隔离纤维组织和上皮组织作用;而多孔的聚己内酯-生物活性玻璃复合生物膜作为下层,发挥诱导成骨功能)在植入大鼠背侧皮下切口6周后,除了正常的异物反应外,该复合屏障膜不会诱发宿主免疫细胞炎症[30]。另有研究报道,将聚乙二醇作为连接剂采用电纺丝技术制备的聚己内酯-聚乙二醇-生物活性玻璃复合屏障膜,在植入新西兰大白兔颅骨缺损10周后,复合屏障膜组平均新骨形成量约是对照组(不含生物活性玻璃组)的2倍(P < 0.05)[31]。这提示生物活性玻璃的加入使得聚己内酯屏障膜在体内也具有良好的成骨能力。值得注意的是,聚己内酯屏障膜在与纳米生物活性玻璃颗粒复合后,复合屏障膜的拉伸强度会随着纳米生物活性玻璃颗粒比重的增加而降低,这会影响复合屏障膜发挥正常生物功能,其解决的办法是在复合屏障膜中进一步加入银离子和钴离子增强其机械性能[32]。 2.2.3 与天然高分子材料复合 壳聚糖是一种具有良好生物相容性、生物活性、生物降解性、低免疫反应等特性的天然高分子聚合物[33-34]。在骨再生修复过程中,壳聚糖还具有显著的骨诱导性,它能促进成骨细胞和间充质干细胞的增殖分化,并能促进新血管生成[35-36]。有报道将大鼠间充质干细胞分别接种在电纺丝制得的含不同比例壳聚糖和聚己内酯组成的复合屏障膜上共培养7 d,发现70聚己内酯-30壳聚糖屏障膜组具有最佳促进大鼠间充质干细胞增殖的能力(约是纯聚己内酯复合屏障膜组的1.5倍,约是50聚己内酯-50壳聚糖复合屏障膜组的1.9倍,P < 0.05);且与单独应用聚己内酯纳米纤维膜相比,70聚己内酯-30壳聚糖及50聚己内酯-50壳聚糖复合纳米纤维屏障膜上成骨相关基因骨钙蛋白和Runx2的表达也显著升高(P < 0.05)[37]。这表明,比重为70∶30左右的聚己内酯-壳聚糖复合生物屏障膜在体外对于间充质干细胞的增殖分化具有最佳的促进能力。 胶原是体内正常存在的蛋白,而明胶是胶原部分水解后的产物,两者均是天然组织工程支架材料之一,具有良好的生物相容性和生物安全性,已被广泛应用于多种组织的再生研究[38]。有研究表明,电纺丝技术得到的70聚己内酯-30胶原复合生物膜在体外具有促进骨髓内皮祖细胞增殖的能力,并可通过促进骨缺损处血管再生进一步促进骨愈合过程[39]。另有报道将不同比例的聚己内酯-胶原复合屏障膜植入大鼠皮下组织3 d后,测得50聚己内酯-50胶原复合屏障膜组的碱性磷酸酶活性是单独应用聚己内酯屏障膜的9倍,成骨相关基因骨桥蛋白的表达约是单独应用聚己内酯屏障膜的2.5倍(P < 0.05)[40]。 有研究者采用电纺丝技术制备了含10%明胶的聚己内酯-明胶复合屏障膜,并接种兔来源的骨髓间充质干细胞,培养7 d后发现,聚己内酯-明胶复合屏障膜间充质干细胞长入深度为纯聚己内酯屏障膜的2.5倍(P < 0.05)[41]。此外,REN等[42]证明了70聚己内酯-30明胶复合屏障膜相比其他比例(聚己内酯∶明胶分别为50∶50、30∶70)在体外其具有更佳的促进成骨细胞系MC3T3-E1增殖的能力(P < 0.05)。然而,有研究认为聚己内酯-明胶复合屏障膜中的高聚己内酯含量并不利于软骨的再生,尤其是形状复杂的软骨,复合屏障膜中聚己内酯与明胶的最佳促进软骨再生比例可能在 30∶70左右,但具体比例仍待进一步研究[43]。 2.2.4 与人工高分子材料复合 目前应用在聚己内酯生物膜中的人工高分子聚合物主要是聚酯类,如聚乳酸、聚乳酸-羟基乙酸共聚物、聚乙醇酸等。其中聚乳酸应用最为广泛,聚乳酸可分为左旋聚乳酸、右旋聚乳酸和外消旋聚乳酸3种异构体,左旋聚乳酸和右旋聚乳酸由于拉伸强度高、降解速度适宜,成为了外科整形、骨科和口腔替代的理想的材料[44]。有研究采用电纺丝技术制备了不同比例的聚己内酯-左旋聚乳酸复合屏障膜,通过测量其机械性能,发现90聚己内酯-10左旋聚乳酸复合屏障膜具有最佳的断裂应变(应用于外科手术的先决条件之一),而纯聚己内酯组和70聚己内酯-30左旋聚乳酸组的断裂应变显著降低[(43.98±10.00),(37.17±10.00),(39.30±12.00) mm,P < 0.05];此外,在聚己内酯-左旋聚乳酸复合屏障膜上接种大鼠来源的成骨细胞培养24 h后发现,90聚己内酯-10左旋聚乳酸复合屏障膜组成骨细胞黏附能力与纯聚己内酯组相似,均大于70聚己内酯-30左旋聚乳酸复合屏障膜组(P < 0.05)[45]。这表明,尽管左旋聚乳酸的掺入没有使聚己内酯-左旋聚乳酸复合屏障膜表面的细胞黏附能力大幅提升,但是其机械性能明显提高,这使得该复合材料有望应用于外科。此外在体内实验中,有研究证明了将电纺丝制得的聚己内酯-聚乳酸复合屏障膜植入大鼠腰椎缺损模型可以防止修复过程中瘢痕粘连,利于腰椎缺损的修复[46]。 有报道显示,采用电纺丝技术制备的80∶20聚己内酯-聚乳酸-羟基乙酸共聚物复合屏障膜相比于90∶10和70∶30聚己内酯-聚乳酸-羟基乙酸共聚物复合屏障膜具有更佳的机械性能及表面孔径结构,这有助于成骨细胞的生长[47]。另有研究者采用同样的方法制备了不同比例的聚己内酯-聚乳酸-羟基乙酸共聚物复合屏障膜,通过检测其机械性能和体外促进人脂肪来源干细胞(具有向软骨、成骨分化潜能)增殖分化能力,发现相比于50∶50和70∶30聚己内酯-聚乳酸-羟基乙酸共聚物复合屏障膜组,85∶15聚己内酯-聚乳酸-羟基乙酸共聚物复合屏障膜具有更佳的拉伸性能及促进人脂肪来源干细胞增殖分化的能力(P < 0.05)[48]。 2.2.5 加入金属离子 屏障膜在植入骨缺损后导致其植入失败的原因之一是感染[49]。金属离子(如锌离子、镁离子、铜离子等)已被证明在体内、外不仅具有良好的抗菌性能,还有成骨诱导活性及诱导血管再生能力,从而得到研究者们的关注[50-51]。目前,金属离子在骨替代材料中已得到广泛应用,而在聚己内酯膜中的应用也逐渐成为研究热点[52-53]。 氧化锌已被美国食品和药物管理局列为安全的锌基化合物之一,尽管其作用机制尚不明确,但已被应用作为食品包装中的抗菌剂、修复性牙科材料、伤口敷料以及组织工程原料等[54-55]。有研究者采用电纺丝技术在聚己内酯-胶原屏障膜中分别引入1%,3%和5%的氧化锌纳米颗粒,并接种人成骨细胞培养7 d后发现,聚己内酯-胶原-1% 氧化锌屏障膜细胞活力最高,约是聚己内酯-胶原-3%氧化锌屏障膜组的4.5倍(P < 0.05),约是聚己内酯-胶原-6%氧化锌屏障膜组的5倍(P < 0.05)[49]。此外在口腔修复研究领域,有研究者比较了含不同比重(分别为5%,15%和30%)氧化锌纳米颗粒的聚己内酯-胶原-氧化锌复合屏障膜的抗菌性能及细胞相容性,发现相比于其他组,聚己内酯-胶原-15%氧化锌组拥有较好的抗菌性能(仅次于聚己内酯-胶原-30%氧化锌屏障膜组)及最佳的促进人牙髓干细胞增殖分化的能力[56]。 有报道采用电纺丝技术将20%比重的锶-磷酸钙纳米颗粒加入聚己内酯-壳聚糖复合屏障膜,并接种大鼠骨髓间充质干细胞培养,第11天时,聚己内酯-锶-磷酸钙-壳聚糖膜上的骨髓间充质干细胞碱性磷酸酶活性显著高于聚己内酯-壳聚糖膜组及聚己内酯-磷酸钙-壳聚糖膜组(P < 0.05);此外,他们还发现聚己内酯-锶-磷酸钙-壳聚糖屏障膜释放的Sr2+和Ca2+还可以协同作用增强骨髓间充质干细胞的血管生成分化,引起大量的血管内皮生长因子分泌,可通过血管-成骨偶联促进成骨[57]。另有研究报道,用电纺丝技术将不同比例的二氧化硅纳米颗粒掺入聚己内酯屏障膜,发现尽管3组复合膜(50聚己内酯-50二氧化硅、纯聚己内酯和25聚己内酯-75二氧化硅膜)之间并没有表现出差异的成骨分化能力,但50聚己内酯-50二氧化硅屏障膜具有最佳的拉伸模量(13.5±1.27) MPa,而纯聚己内酯组的拉伸模量为(9.5±1.75) MPa,25聚己内酯-75二氧化硅复合膜组的拉伸模量仅为(8.9±1.32) MPa,这提示50聚己内酯-50二氧化硅复合膜更具有应用于外科的潜力(P < 0.05)[58]。 2.2.6 加入生长因子 骨形态发生蛋白是转化生长因子家族中的一种具有分泌功能的蛋白质,它具有诱导骨髓间充质干细胞定向分化为成骨细胞、促使细胞外基质钙化等功能。骨形态发生蛋白可通过丝氨酸/苏氨酸激酶受体发挥多种功能如促进成骨发育、诱导交感神经肾上腺素的表达等[59-60]。 骨形态发生蛋白2已被证明能在体内、外促进间充质干细胞和成骨细胞的增殖分化,从而加速骨缺损的愈合进 程[61-62]。据此,有研究者用电纺丝技术制得聚苯乙烯(作为黏附剂)-聚己内酯复合屏障膜,并将制得的复合屏障膜放在含人来源的骨形态发生蛋白2溶液中孵育,添加骨形态发生蛋白2涂层,最终得到聚己内酯-聚苯乙烯-骨形态发生蛋白2复合屏障膜,该复合屏障膜不仅在体外促进人成骨细胞MG-63的黏附和增殖,而且在植入大鼠颅骨缺损模型8周后,聚己内酯-聚苯乙烯-骨形态发生蛋白2复合屏障膜的骨缺损基本完全愈合,而不含骨形态发生蛋白2组骨缺损面积仍大于30%(P < 0.05)[63]。另有研究采用电纺丝技术制得聚己内酯膜,并采用胶原(带正电荷)将带负电荷的骨形态发生蛋白2引入聚己内酯屏障膜上,制得聚己内酯-胶原-骨形态发生蛋白2复合屏障膜,在植入小鼠上颌骨缺损模型90 d后,聚己内酯-胶原-骨形态发生蛋白2复合屏障组的新骨形成量大约是不含骨形态发生蛋白2屏障膜组的4倍(P < 0.05)[64]。有报道称,聚己内酯-骨形态发生蛋白2复合屏障膜在体外还具有促进人骨膜细胞分化的能力,将聚己内酯-骨形态发生蛋白2复合屏障膜植入8 mm大鼠颅骨缺损模型8周后,实验组骨缺损几乎完全愈合,而对照组愈合面积不足50%,且实验组新骨形成量显著高于对照组(约是对照组3倍)[11]。 骨形态发生蛋白6是骨形态发生蛋白的另一种亚型,循环血液中的骨形态发生蛋白6是由骨髓间充质干细胞和造血干细胞产生的,已被证明可通过Smad信号通路将成骨信号转导至骨髓间充质干细胞,可定向诱导其向成骨、成软骨方向分化[65]。除此之外,破骨细胞也能释放骨形态发生蛋白6,它可将成骨细胞招募到骨再吸收部位影响骨愈合进程[66]。有研究者证明,小鼠前体成骨细胞MC3T3-E1在聚己内酯-胶原-骨形态发生蛋白6复合屏障膜中具有良好的细胞活性;此外在共培养21 d时,聚己内酯-胶原-骨形态发生蛋白6复合屏障膜组成骨相关基因骨钙蛋白和骨桥蛋白表达分别是不含骨形态发生蛋白6组的1.8倍和1.5倍(P < 0.05)[67]。 MIN等[68]采用肝素固定法将血小板衍生生长因子β和骨形态发生蛋白2固定在聚己内酯屏障膜上,在体外接种人骨髓间充质干细胞共培养2周后,发现含较高血小板衍生生长因子β浓度和较低骨形态发生蛋白2浓度的复合膜更有利于肌腱的成长,而含较高骨形态发生蛋白2浓度和较低血小板衍生生长因子β浓度的复合膜更有利于促进成骨。另有报道采用肝素固定法在聚己内酯膜中引入β-转化生长因子并将所得复合膜植入小鼠临界大小颅骨缺损模型2周,发现加入100 μg/L β-转化生长因子复合屏障膜组的新骨形成量显著高于含50 μg/L β-转化生长因子复合屏障膜组,及空白对照组[(17.55±6.08)%,(10.82±2.20)%,(5.36±3.40)%,P < 0.05][69]。 2.2.7 加入干细胞及干细胞来源物质 干细胞(如间充质干细胞,脂肪来源干细胞等)具有一定的向成骨分化的能力,将干细胞引入聚己内酯屏障膜已被证明具有良好的成骨效应[70]。将人尿源性干细胞引入聚己内酯-明胶复合屏障膜中所得的复合屏障膜,可通过分泌血管内皮生长因子和β-转化生长因子促进内皮细胞的迁移、增殖,从而形成新生血管,最终通过血管-成骨偶联促进骨愈合进程[71-72]。但是,将干细胞直接引入屏障膜的方法被繁琐的细胞培养及加工过程限制,而外泌体的应用很好地解决了这个问题。 外泌体是一种由细胞分泌且可以通过向受体细胞输送生物活性分子(如种蛋白质和核酸)来介导细胞间通讯的直径为30-100 nm的膜性微型囊泡,其具有活跃的生物学功能如促进血管再生、骨在生等[73-75]。有研究证明,从人诱导多能干细胞来源间充质干细胞中分离出的外泌体,可以通过PI3K/Akt信号通路增强成骨诱导活性[76]。WANG等[77]用多巴胺作为连接桥梁,采用电纺丝技术将人间充质干细胞来源的外泌体及具有抗炎作用的亚硝基谷胱甘肽加入聚己内酯生物膜中,并接种小鼠巨噬细胞系RAW264.7培养,7 d后发现聚己内酯-多巴胺(对照组)炎性因子白细胞介素6、肿瘤坏死因子α、一氧化氮合酶和白细胞介素1β的基因表达分别是聚己内酯-多巴胺+亚硝基谷胱甘肽+外泌体(实验组)的5,2.5,1.6和2.3倍,而对照组碱性磷酸酶相关基因表达约是实验组的1/2,骨形态发生蛋白相关基因表达约是对照组1/3。这说明该复合支架不仅能够降低炎症水平,还具有诱导成骨分化的作用。 另有研究者将间充质干细胞和成骨细胞来源的细胞外基质掺入聚己内酯组成聚己内酯-细胞外基质复合屏障膜中,该复合屏障膜在体外具有良好的促进成骨前体细胞增殖的能力(约是未加入细胞外基质复合屏障膜组的1.1倍);在植入8 mm大鼠颅骨缺损模型2个月后,聚己内酯-细胞外基质复合屏障膜组新骨形成量约是单独应用聚己内酯屏障膜组的1.7倍(P < 0.05)[78]。"
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