Research progress in stem cell-based tissue engineering technology assisting mandibular distraction osteogenesis

doi:10.3969/j.issn.2095-4344.1795

Abstract

Abstract:

BACKGROUND: Since mandibular distraction osteogenesis has achieved significant repercussions in clinical practice, many scholars have been working on studies that enhancing osteogenesis and shortening the course of treatment. Among them, stem cell transplantation has attracted much attention as a hotspot.
OBJECTIVE: To summarize the current progress and deficiency of stem cell-based tissue engineering technology assisting mandibular distraction osteogenesis.
METHODS: Following the PRISMA guidelines, a computer-based search of PubMed, WOS, CNKI and WanFang databases was performed by the first author for relevant articles with the keywords of “distraction osteogenesis,mandibular, mandible, stem cells” in English and Chinese, respectively. Animal models, types of stem cells and routes of transplantation in the selected literature were extracted and counted up. The results were tabulated and introduced briefly.
RESULTS AND CONCLUSION: Fifty-one articles were strictly selected as per the eligibility criteria, analyzed and summarized. In the selected literature, the timing, methods and types of stem cell transplantation vary greatly. The majority of animal experimental studies have confirmed that stem cell-based tissue engineering technology can enhance bone and blood vessel regeneration in mandibular distraction osteogenesis. Explorations on the selection and application of stem cells in mandibular distraction osteogenesis assisted by stem cell-based tissue engineering technology cannot only provide ideas for future treatment, but also lay the foundation for clinical trials.

Key words: mandibular distraction osteogenesis, tissue engineering, stem cells, bone regeneration, angiogenesis, stem cell transplantation, National Natural Science Foundation of China

CLC Number:

Han Zhiqi, Jiang Weidong, Zhou Nuo. Research progress in stem cell-based tissue engineering technology assisting mandibular distraction osteogenesis[J]. Chinese Journal of Tissue Engineering Research, 2019, 23(25): 4031-4036.

Figures/Tables 4

(1)骨髓间充质干细胞：自1970年Freidenstein等[40]发现在塑料培养皿上骨髓间充质干细胞可以分化成为骨及软骨后，骨髓间充质干细胞做为一种具有自我更新能力和多向分化潜能的细胞，逐渐被学界所熟悉，成为近年来干细胞辅助下颌牵张成骨的研究热点。大量研究表明局部应用骨髓间充质干细胞可以促进骨折愈合、缩短骨折愈合时间。由于骨髓间充质干细胞具有显著的成骨分化潜能，目前是组织工程中最常用的骨再生细胞[41]。在下颌牵张成骨的应用中，23篇文献全部证实骨髓间充质干细胞可以促进下颌牵张成骨的成骨速度，缩短固定期时间。陈燕等[42]将骨髓间充质干细胞注入实验组兔下颌牵张成骨处，生理盐水注入对照组，通过免疫组化法进行检测发现新生骨痂处骨保护素的表达显著高于对照组，这可能说明骨髓间充质干细胞促进下颌牵张成骨的作用可能是通过骨保护素的高表达来实现的。 (2)内皮祖细胞：内皮祖细胞是血管内皮细胞的前体细胞，在生理或病理因素刺激下，可从骨髓中动员到损伤处进行损伤修复。自1997年Asahara等[43]首次证明了循环外周血中存在能分化为血管内皮细胞的前体细胞，将其命名为内皮祖细胞以来，因其具有促血管新生的作用，越来越多的学者将其作为种子细胞用于骨组织工程学。Rozen等[44]将内皮祖细胞等移植于山羊胫骨骨缺损动物模型中，发现其修复缺损能力明显增强。王亚茜[19]首次使用内皮祖细胞移植辅助下颌牵张成骨，证实内皮祖细胞可以通过促进血管新生的方式增强下颌牵张成骨中的血管新生与血管生成，从而缩短治疗时间。然而有关内皮祖细胞辅助下颌牵张成骨的实验研究极少，体内外实验探究内皮祖细胞与下颌牵张成骨的关系将会成为一个研究热点。 (3)脂肪间充质干细胞：近年来，由于脂肪间充质干细胞数量丰富且易于提取的原因，逐渐受到学者们的大量关注。相比骨髓间充质干细胞的提取需要对患者髂骨、胫骨等骨髓进行穿刺，造成患者极大痛苦，脂肪间充质干细胞的提取则相对简单易行，且对患者创伤小。Halvorsen等[45]观测到脂肪间充质干细胞可以诱导分化为成骨细胞、成软骨细胞等多种细胞。骨髓间充质干细胞的成骨能力大于脂肪间充质干细胞，因为骨髓间充质干细胞具有固有的成骨特性，而脂肪间充质干细胞需要外部环境的刺激来诱导分化为成骨细胞。Mahmoudifar等[46]向培养脂肪间充质干细胞的培养基中添加地塞米松、骨形态发生蛋白等成功将脂肪间充质干细胞诱导为成骨细胞，但是这些体外诱导方式无法运用于干细胞体内移植。Lai等[20]将Osterix转染于脂肪间充质干细胞并移植于下颌牵张成骨处，证明Osterix转染的脂肪间充质干细胞可以增强下颌牵张成骨的成骨速度与质量，而未转染的脂肪间充质干细胞则与普通下颌牵张成骨无明显差别。 (4)牙髓干细胞：牙髓干细胞由Gronthos等[47]在2000年时首次发现并正式提出，并指出牙髓干细胞具有多向分化潜能，不仅可以分化为成牙本质细胞，而且可以在特殊刺激下诱导分化为成骨细胞。这可能是由于牙髓干细胞来源于颅面神经嵴，对颅面骨骼的发育具有促进作用。在提取方式上，相对于骨髓间充质干细胞、内皮祖细胞、脂肪间充质干细胞等需要对患者进行有创操作造成患者痛苦，牙髓干细胞可在脱落乳牙内提取，方便易行，且对患者无损伤。越来越多的国家已经建立了乳牙牙髓干细胞库[48]，为日后治疗机体创伤及病变提供了一个很好的组织工程学种子细胞来源。在下颌牵张成骨研究方面，Alkaisi等[21]首次将人牙髓干细胞移植于兔下颌牵张成骨处，结果不仅证实牙髓干细胞显著增强兔下颌牵张成骨的质量与速度，而且发现在未使用免疫抑制剂的情况下向兔体内移植人牙髓干细胞并未造成免疫排斥反应，这为临床上使用同种或异种牙髓干细胞进行下颌牵张成骨的治疗打下了一定的基础。尽管上述研究证实脂肪间充质干细胞、牙髓干细胞等细胞在下颌牵张成骨应用中取得了积极的成果，但也有报道指出，这些细胞与骨髓间充质干细胞相比具有较低的成骨能力[49-50]。接下来需要将这些细胞与骨髓间充质干细胞辅助下颌牵张成骨进行对比，从成骨效率与方便易行两方面确定最适合进行干细胞治疗的细胞种类。 2.4.2 细胞移植方式如表4所示，在26篇文献中，通过注射方式将干细胞悬液注射入下颌牵张成骨间隙的文献共有16篇，通过生物支架将干细胞放入下颌牵张成骨间隙的文献有8篇，通过细胞膜片将干细胞植入下颌牵张成骨间隙的文献有2篇(2篇同时使用了细胞膜片+生物支架)，另有2篇未提及移植方式。Ma等[22]研究发现细胞膜片移植促进下颌牵张成骨的成骨作用要优于注射干细胞悬液，见图3，这可能得益于细胞膜片可以将干细胞更好地保留并固定在牵张成骨区，使得牵张成骨区的干细胞数量与浓度显著增加，一次性较大数量细胞移植得以实现。但相对于简单快捷的注射操作，使用细胞膜片或生物支架的方式不得不进行下颌牵张成骨区的二次开创手术，这会增加感染等并发症的风险。周诺等[27]使用一种注射型生物支架对氧化聚乙烯和聚丙烯共聚物(PluronicF-127)成功解决了使用生物支架需要二次植入的问题，并证实使用PluronicF-127要优于注射细胞悬液。细胞移植的最佳时机是截骨时植入细胞膜片或生物支架，牵张期、固定期注射干细胞悬液。这都说明了下颌牵张成骨区干细胞固定并保留的重要性，将来仍需进一步研究移植方法与移植时机的选择是否通过增加下颌牵张成骨区细胞数量影响成骨质量与速度。"

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