牙髓再生的临床应用与未来

旨在修复牙髓牙本质复合体的牙髓再生治疗是近年来的研究热点,目前仅有牙髓血运重建技术已实现临床初步应用,而干细胞移植和细胞归巢等技术尚处于临床前阶段。经过多年的基础研究和临床实践,牙髓再生特别是牙髓血运重建技术在取得进展的同时也暴露出不少问题,包括概念混淆、适应证选择不当、评价标准不完善等。为此,本综述从牙髓血运重建技术出发,对牙髓再生临床应用的现状、存在的问题和未来的临床实践路径等进行分析和探讨。     

再生性牙髓治疗方法的前景

再生性牙髓治疗是基于生物学基础治疗的一种方法,目的是替换受损的部分牙髓组织或允许牙髓样组织形成以完全替代原牙髓组织。针对牙髓炎或牙髓坏死的年轻恒牙的治疗,研究者们利用口腔来源干细胞或根尖周组织的干细胞建立各种利于修复的微环境,提出了如牙髓血运重建术/干细胞归巢治疗等充满前景的新治疗技术,从而为牙髓的再生提供了大量研究资料及可选治疗手段。该文对再生性牙髓治疗方法的现状及其发展前景作一综述。     

牙髓炎的活髓保存及再生治疗新进展:从基础到临床

近年关于牙髓炎治疗的研究取得了较大进展,这主要得益于牙髓炎治疗的基础和临床研究的飞速进展,一些基础研究已转化为临床实践。牙髓炎检测方法的研究进展可以帮助临床医师更准确地诊断牙髓炎的状态,并采取相应的治疗手段,包括间接或直接盖髓术、牙髓切断术、牙髓再生术和根管治疗术等。针对牙髓炎的诊断理念、牙髓免疫防御和修复功能研究以及新型盖髓剂材料研究均有了较大进展,牙髓炎的活髓保存治疗成功率显著提高。对于难以实现活髓保存治疗的弥漫性冠髓炎或根髓炎,除根管治疗术外,牙髓血运重建、细胞归巢和牙髓干细胞移植牙髓再生等牙髓再生术也可作为一种治疗选择。本文重点阐述牙髓炎治疗研究进展和相关的临床转化实践,旨在为牙髓炎的活髓保存和牙髓再生治疗提供参考。     

牙髓炎的活髓保存及再生治疗新进展：从基础到临床

近年关于牙髓炎治疗的研究取得了较大进展, 这主要得益于牙髓炎治疗的基础和临床研究的飞速进展, 一些基础研究已转化为临床实践。牙髓炎检测方法的研究进展可以帮助临床医师更准确地诊断牙髓炎的状态, 并采取相应的治疗手段, 包括间接或直接盖髓术、牙髓切断术、牙髓再生术和根管治疗术等。针对牙髓炎的诊断理念、牙髓免疫防御和修复功能研究以及新型盖髓剂材料研究均有了较大进展, 牙髓炎的活髓保存治疗成功率显著提高。对于难以实现活髓保存治疗的弥漫性冠髓炎或根髓炎, 除根管治疗术外, 牙髓血运重建、细胞归巢和牙髓干细胞移植牙髓再生等牙髓再生术也可作为一种治疗选择。本文重点阐述牙髓炎治疗研究进展和相关的临床转化实践, 旨在为牙髓炎的活髓保存和牙髓再生治疗提供参考。     

再血管化和牙组织工程化牙髓再生的研究进展

牙髓再生一是通过刺激根尖部出血,诱导根尖部宿主细胞迁移和分化,共同实现牙髓的再血管化,使牙髓腔中再生长出活性组织实现牙根的继续发育,即再血管化治疗;再是利用工程学原理将干细胞辅以支架移植到根管,诱导分化新生牙髓,实现牙本质牙髓再生。本文就再血管化及其牙髓再生,牙组织工程及其牙髓再生研究进展以及存在的问题等作一综述。     

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提要：牙髓血运重建术通过彻底有效的根管消毒,尽量保护牙髓干细胞和牙乳头间充质干细胞,并为这些干细胞的增殖和分化提供良好的环境,使其在信号分子和盖髓剂矿物三氧化物凝聚体的诱导下,分化为成牙本质细胞和成牙骨质细胞等,从而使牙根在长度和厚度上得以继续发育。在不久的将来,牙髓血运重建术有可能成为年轻恒牙牙髓病变和部分根尖周病变的首选治疗方法。本文就近年来有关牙髓血运重建的实验室和临床研究进展做一综述。     

年轻恒牙牙髓再生性治疗的研究进展

个体患牙髓病或根尖周病后,年轻恒牙牙根的继续生长发育受阻,因此,如何保证患牙根尖的正常形成和继续生长发育对口腔医生而言极具挑战。近年来报道的牙髓再生治疗病例,其利用根管内残余牙髓组织、根尖周或牙周组织中干细胞的再生分化能力,在合适的条件诱导下再生出新的高度血管化并富含结缔组织的活髓,促使牙根继续生长发育,牙根长度增加、根管壁增厚、根尖孔缩窄闭合,而且临床检查和影像学辅助检查的结果均较理想,这具有划时代的意义。牙髓再生基于组织工程学,以达到用新生牙髓组织代替原有病变牙髓组织目的。其包括两种理念：一是牙髓血运重建,诱导根尖部干细胞迁移和分化,在患牙根管内新生出有活力的牙髓样组织,完成牙根继续生长发育;二是运用组织工程技术,将具有增殖分化潜能的干细胞和适宜的生物活性支架物质置入患牙根管内,在一定的生长因子诱导下,产生新的牙本质牙髓复合体（den?tin?pulp complex,DPC）,实现牙髓再生。笔者就这两部分的研究进展作一阐述。     

载细胞微球在牙髓再生研究中的进展及展望

高效的细胞培养和递送载体对于基于干细胞的组织再生具有重要作用.近年来,载细胞微球作为一种新型的干细胞培养和递送支架在再生医学领域颇受关注,它们具有尺寸小、比表面积大、可微创注射、能为细胞提供3D生长环境、可一体化体外扩增和体内移植等诸多优点.由于根管系统狭窄且不规则,且血管系统的重建较为困难,具有可注射、快速物质扩散能力的载细胞微球成为牙髓再生应用的理想选择.载细胞微球可以进一步功能优化设计以解决牙髓再生中面临的难题,如增强干细胞的成牙分化,或促进血管系统在根管中的重构再生等.目前尚无中文文献就该主题进行综述总结,因此,本文拟概述载细胞微球的性质和特点,重点介绍并评述其在牙髓再生中的研究现状,对今后的研究方向做总结展望.     

牙髓血运重建术治疗年轻恒牙根尖周病的研究进展

根管内血运重建术是1waya在2001年首次提出的一种牙髓再生方法,主要通过彻底有效的根管消毒。为牙髓干细胞、牙乳头间充质干细胞等增殖和分化提供良好的环境,从而促使牙根继续发育,多用于治疗年轻恒牙根尖周炎。至今,已有多位学者报道采用该方法取得了令人满意的结果．即患牙的根尖周损害影像消失、牙根继续发育。本文将从根管内血运重建术的发生原理、组织学来源、抗菌剂的应用及组织支架等方面的研究进展做一述评。     

基因强化组织工程在牙髓牙本质复合体和牙周组织再生中的应用研究进展

基因强化组织工程(gene-enhanced tissue engineering)是利用基因转染技术将编码蛋白因子的目的基因转染种子细胞或生物活性基质材料,使转染的细胞或基质表达目的基因,最终在体内促进靶细胞的增殖、分化及发挥正常的生理功能,从而促进组织的修复和重建的一种方法。其目的是通过传导局部的细胞信号再生丧失的组织。具体包括种子细胞(多潜能干细胞)、生长因子、修饰基因、支架材料等。本文对近年来基因强化组织工程在牙髓牙本质复合体和牙周组织再生方面的研究作一综述。1.基因强化组织工程在牙髓牙本质复合体再生中的应用研究目前很多研究证明不管是否牙源性干细胞,都可以诱导牙齿的发育和牙本质的形成[1]。成人牙髓的很多细胞拥有干细胞样功能,它们可以自我更新,有横向分化成神经样细胞、成骨细胞、成脂肪细胞、成肌细胞和成软骨细胞的能力[2]。将大鼠牙胚单个细胞接种于聚羟基乙酸支架,移植于Lew is大鼠大网膜内,12周后培育出了比较完整的牙齿组织,但目前这些技术尚无法控制再生组织的大小和形状[3]。Mod ino和Sharpe[4]证实E10d鼠口腔上皮与成体骨髓来源干细胞重组培养,体内种植后可分化为成牙本质细胞。Nak...     

Dental pulp regeneration via cell homing

The typical treatment for irreversibly inflamed/necrotic pulp tissue is root canal treatment. As an alternative approach, regenerative endodontics aims to regenerate dental pulp‐like tissues using two possible strategies: cell transplantation and cell homing. The former requires exogenously transplanted stem cells, complex procedures and high costs; the latter employs the host's endogenous cells to achieve tissue repair/regeneration, which is more clinically translatable. This systematic review examines cell homing for dental pulp regeneration, selecting articles on in vitro experiments, in vivo ectopic transplantation models and in situ pulp revascularization. MEDLINE/PubMed and Scopus databases were electronically searched for articles without limits in publication date. Two reviewers independently screened and included papers according to the predefined selection criteria. The electronic searches identified 46 studies. After title, abstract and full‐text examination, 10 articles met the inclusion criteria. In vitro data highlighted that multiple cytokines have the capacity to induce migration, proliferation and differentiation of dental pulp stem/progenitor cells. The majority of the in vivo studies obtained regenerated connective pulp‐like tissues with neovascularization. In some cases, the samples showed new innervation and new dentine deposition. The in situ pulp revascularization regenerated intracanal pulp‐like tissues with neovascularization, innervation and dentine formation. Cell homing strategies for pulp regeneration need further understanding and improvement if they are to become a reliable and effective approach in endodontics. Nevertheless, cell homing currently represents the most clinically viable pathway for dental pulp regeneration.     

Dentin and dental pulp regeneration by the patient's endogenous cells

The goal of regenerative endodontics is to restore the functions of the dental pulp–dentin complex. Two approaches are being applied toward dental pulp–dentin regeneration: cell transplantation and cell homing. The majority of previous approaches are based on cell transplantation by delivering ex vivo cultivated cells toward dental pulp or dentin regeneration. Many hurdles limit the clinical translation of cell transplantation such as the difficulty of acquiring and isolating viable cells, uncertainty of what cells or what fractions of cells to use, excessive cost of cell manipulation and transportation, and the risk of immune rejection, pathogen transmission, and tumorigenesis is associated with ex vivo cell manipulation. In contrast, cell homing relies on induced chemotaxis of endogenous cells and therefore circumvents many of the difficulties that are associated with cell transplantation. An array of proteins, peptides, and chemical compounds that are yet to be identified may orchestrate endogenous cells to regenerate the dental pulp–dentin complex. Both cell transplantation and cell homing are scientifically valid approaches; however, cell homing offers a number of advantages that are compatible with the development of clinical therapies for dental pulp–dentin regeneration.     

年轻恒牙牙髓血管再生治疗

牙髓血管再生治疗是一种以生物学为基础、生理性取代受损牙齿结构（包括牙本质、牙根以及牙髓牙本质复合体）为目的的治疗技术,是牙髓病学最令人激动的新进展之一。牙髓血管再生治疗是年轻恒牙感染牙髓的治疗新选择,其是通过使用大量的药物冲洗根管并行根管封药控制炎症后,刺激根尖周组织引起出血,使血液进入根管中形成血凝块,然后使用矿物三氧化物凝聚体（MTA）封闭根管口。经过治疗的年轻恒牙能够获得与生理性发育相似的牙根发育。     

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?? Dental pulp revascularization is defined as biologically-based procedures designed to physiogically replace damaged tooth structures including dentin and root structures?? as well as cells of the pulp-dentin complex. Regenerative endodontics is one of the most exciting new developments in endodontics. It is a new treatment option for inflamed pulp in immature permanent teeth. After irrigation and disinfection of the root canal?? the periapical tissues are induced bleeding to fill the canal space to form blood clot. The tooth is then restored with a coronal seal of MTA. The immature tooth could attain continued root development similar to physiological root development after dental pulp revascularization treatment.      

Regenerative endodontics: barriers and strategies for clinical translation

Regenerative endodontics has encountered substantial challenges toward clinical translation. The adoption by the American Dental Association of evoked pulp bleeding in immature permanent teeth is an important step for regenerative endodontics. However, there is no regenerative therapy for most endodontic diseases. Simple recapitulation of cell therapy and tissue engineering strategies that are under development for other organ systems has not led to clinical translation in regeneration endodontics. Recent work using novel biomaterial scaffolds and growth factors that orchestrate the homing of host endogenous cells represents a departure from traditional cell transplantation approaches and may accelerate clinical translation.     

牙髓根尖周病的治疗新方法：再生牙髓病学之路

为促进牙髓牙本质复合体的再生,学者们将组织工程学技术应用于牙髓治疗中,并提出了再生牙髓病学的概念。作为口腔医学的新兴学科,再生牙髓病学运用牙源性干细胞、生物支架以及生长因子等因素促进牙根继续发育和牙髓组织再生。临床上,牙髓再生技术已应用于治疗年轻恒牙牙髓坏死及根尖周炎,越来越多的病例报道或研究结果显示牙髓再生的可能性,牙髓再生治疗将成为口腔医生治疗牙髓病的新选择。本文就再生牙髓病学的现状和发展进行总结分析。     

Challenges of stem cell‐based pulp and dentin regeneration: a clinical perspective

There are two types of approaches to regenerate tissues: cell‐based and cell‐free. The former approach is to introduce exogenous cells into the host to regenerate tissues, and the latter is to use materials other than cells in an attempt to regenerate tissues. There has been a significant advancement in stem cell‐based pulp and dentin regeneration research in the past few years. Studies in small and large animals have demonstrated that pulp/dentin‐like tissues can be regenerated partially or completely in the root canal space with apical openings of 0.7–3.0 mm using dental pulp stem cells, including stem cells from apical papilla (SCAP) and subpopulations of pulp stem cells. Bone marrow mesenchymal stem cells (BMMSCs) and adipose tissue‐derived MSCs (AdMSCs) have also been shown to regenerate pulp‐like tissue. In contrast, the cell‐free approach has not produced convincing evidence on pulp regeneration. However, one crucial concept has not been considered nor defined in the field of pulp/dentin regeneration and that is the critical size defect of dentin and pulp. Without such consideration and definition, it is difficult to predict or anticipate the extent of cell‐free pulp regeneration that would occur. By reasoning, cell‐free therapy is unlikely to regenerate an organ/tissue after total loss. Similarly, after a total loss of pulp, it is unlikely to regenerate without using exogenously introduced cells. A cell homing approach may provide a limited amount of tissue regeneration. Although stem cell‐based pulp/dentin regeneration has shown great promise, clinical trials are difficult to launch at present. This article will address several issues that challenge and hinder the clinical applications of pulp/dentin regeneration which need to be overcome before stem cell‐based pulp/dentin regeneration can occur in the clinic.     

Dental regenerative therapy targeting sphingosine-1-phosphate (S1P) signaling pathway in endodontics

The establishment of regenerative therapy in endodontics targeting the dentin-pulp complex, cementum, periodontal ligament tissue, and alveolar bone will provide valuable information to preserve teeth. It is well known that the application of stem cells such as induced pluripotent stem cells, embryonic stem cells, and somatic stem cells is effective in regenerative medicine. There are many somatic stem cells in teeth and periodontal tissues including dental pulp stem cells (DPSCs), stem cells from the apical papilla, and periodontal ligament stem cells. Particularly, several studies have reported the regeneration of clinical pulp tissue and alveolar bone by DPSCs transplantation. However, further scientific issues for practical implementation remain to be addressed. Sphingosine-1-phosphate (S1P) acts as a bioactive signaling molecule that has multiple biological functions including cellular differentiation, and has been shown to be responsible for bone resorption and formation. Here we discuss a strategy for bone regeneration and a possibility for regenerative endodontics targeting S1P signaling pathway as one of approaches for induction of regeneration by improving the regenerative capacity of endogenous cells.Scientific field of dental scienceEndodontology