Horizontal bone augmentation by means of guided bone regeneration 通过引导骨再生技术进行横向骨质增生
Goran I. Benic & Christoph H. F. Hämmerle
Oral implants are a means to anchor dental prostheses in situations of partial or complete edentulism. Over the years, implant dentistry has developed into a field supported by a sound preclinical and clinical evidence base. Through the evolved clinical concepts and treatment strategies, patients may now benefit from excellent solutions for improving quality of life. Furthermore, the medium- and long-term results of properly executed dental-implant treatments yield high survival and success rates of dental prostheses. A number of factors critical for the long-term survival of implants and implant-supported reconstructions have been identified over time. One prerequisite is a sufficient amount of bone at the implant recipient site to allow osseointegration of the endosseous implant surface. Following the introduction of oral implants into the dental field, implants were usually placed in areas of sufficient bone to improve the predictability of osseointegration of the implant. More recently, implants have been placed in positions that are optimal for fabrication of the planned reconstruction. One key factor responsible for such adaptation of the clinical procedures is the high predictability and the success of the bone regeneration procedures. Currently, the most appropriate approach for treatment with dental implants is first of all to plan the desired prosthetic reconstruction and then to place the implants in the three-dimensional position optimal for achieving the planned treatment result and the regeneration of bone necessary to osseointegrate the implants. 口腔种植体是在部分或完全缺牙的情况下固定义齿的一种手段。多年来，种植牙学已发展成为一个拥有完善的临床前和临床证据基础的领域。通过不断发展的临床概念和治疗策略，患者现在可以从改善生活质量的优秀解决方案中获益。此外，正确实施牙科种植治疗的中长期结果显示，牙科修复体的存活率和成功率都很高。随着时间的推移，人们发现了一些对种植体和种植体支持的重建的长期存活至关重要的因素。其中一个先决条件是种植体受体部位有足够的骨量，以保证骨内种植体表面的骨结合。在将口腔种植体引入牙科领域后，种植体通常被植入有足够骨量的区域，以提高种植体骨结合的可预测性。最近，种植体被植入到了最适合计划重建的位置。临床程序之所以要进行这样的调整，一个关键因素是骨再生程序的高可预测性和成功率。目前，使用种植牙进行治疗的最合适方法首先是规划所需的修复重建，然后将种植体植入最佳的三维位置，以实现计划的治疗效果和骨结合所需的骨再生。
The best documented and most widely used method to augment bone in localized alveolar defects is guided bone regeneration. Based on a series of experimental studies, a biological principle of healing was discovered by Nyman & Karring in the early 1980s. The work of these investigators was aimed at regener- ating lost periodontal tissues (116, 158, 160). They found that the cells which first populate a wound area determine the type of tissue that ultimately occupies the original space. From this knowledge, they developed a technique, utilizing barrier membranes, which prevented undesired cells from accessing the wound and, at the same time, allowed cells with the capacity to form the desired tissue to access the wound space. This technique was termed guided tissue regeneration and it led to novel possibilities to regenerate periodontal tissues, including new root cementum, periodontal ligament and alveolar bone (81, 82, 157, 161). 对局部牙槽骨缺损进行骨增量的最有效和最广泛使用的方法是引导骨再生。在一系列实验研究的基础上，Nyman 和 Karring 在 20 世纪 80 年代初发现了一种生物愈合原理。这些研究人员的工作旨在使丧失的牙周组织再生（116、158、160）。他们发现，首先出现在伤口区域的细胞决定了最终占据原始空间的组织类型。根据这一知识，他们开发出一种利用屏障膜的技术，既能阻止不需要的细胞进入伤口，又能让有能力形成所需组织的细胞进入伤口空间。这种技术被称为引导组织再生，它为牙周组织的再生带来了新的可能性，包括新的牙根骨水泥、牙周韧带和牙槽骨（81、82、157、161）。
Soon thereafter, guided tissue regeneration was applied for the regeneration of bone tissue (for review see . A large series of animal experiments and human clinical studies , 128, 129, 159, 229) have documented guided bone regeneration to be a successful method for augmenting bone in situations where there is inadequate bone volume for the placement of endosseous dental implants. Furthermore, when implants are placed and a bone defect results, leaving part of the endosseous surface of the implant exposed, a large body of literature documents guided bone regeneration to be successful for predictable bone formation (16, 51, 53, . 此后不久，引导组织再生技术被应用于骨组织再生（综述见 。大量的动物实验 和人类临床研究 、128、129、159、229）证明，引导骨再生是一种成功的方法，可在骨量不足的情况下增加骨量，从而植入骨内种植体。此外，当种植体植入后出现骨缺损，导致部分种植体的骨内面暴露在外时，大量文献记载引导骨再生可成功实现可预测的骨形成（16、51、53、 .
In clinical practice the development of guided bone regeneration has substantially influenced the possibility of implant use. Bone augmentation procedures have allowed the placement of implants in jaw bone areas lacking an amount of bone sufficient for standard implant placement. Therefore, the indications for implants have broadened to include jaw regions with bone defects and those with a bone anatomy that is unfavorable for implant anchorage. Such situations occur as a result of congenital, post-traumatic 在临床实践中，引导骨再生技术的发展极大地影响了种植体的使用。通过骨增量手术，可以在骨量不足以植入标准种植体的颌骨区域植入种植体。因此，种植体的适应症已扩大到骨缺损的颌骨区域和骨解剖结构不利于种植体固定的颌骨区域。出现这种情况的原因有先天性的、创伤后的
or postsurgical defects, or may be caused by disease processes. 或手术后的缺陷，也可能是由疾病过程引起的。
The aim of this review is to present the scientific and clinical basis of guided bone regeneration and the accepted clinical procedures, and to provide an outlook into possible future options related to bone augmentation. 本综述旨在介绍引导性骨再生的科学和临床基础以及公认的临床程序，并展望与骨质增生相关的未来可能选择。
Membranes 薄膜
Over the past three decades, a large variety of barrier membranes have been used for guided bone regeneration procedures. The criteria required to select appropriate barrier membranes for guided bone regeneration encompass biocompatibility, integration by the host tissue, cell occlusiveness, space-making ability and adequate clinical manageability (95). Additionally, documentation on the procedures and materials regarding clinical safety and long-term effectiveness needs to be available to recommend their use in humans. The barrier membranes used for guided bone regeneration procedures can be classified as nonresorbable or resorbable (Table 1). In turn, resorbable membranes can be classified as natural or synthetic, depending on their origin. 在过去的三十年中，有大量不同的屏障膜被用于引导骨再生手术。为引导骨再生选择合适的屏障膜所需的标准包括生物相容性、与宿主组织的整合性、细胞包容性、空间制造能力和足够的临床可管理性（95）。此外，还需要提供有关程序和材料的临床安全性和长期有效性的文件，以便推荐在人体中使用。用于引导骨再生程序的屏障膜可分为不可吸收膜和可吸收膜（表 1）。而可吸收膜根据其来源可分为天然膜和合成膜。
Nonresorbable membranes 非吸收膜
Expanded polytetrafluoroethylene (e-PTFE) membranes were the first generation of clinically well-documented barrier membranes used for guided boneregeneration procedures (53, 76, 238). e-PTFE is a synthetic polymer with a porous structure, which does not induce immunologic reactions and resists enzymatic degradation by host tissues and microbes. Integration of titanium reinforcement within e-PTFE membranes increases their mechanical stability and allows the membranes to be individually shaped. 膨体聚四氟乙烯（e-PTFE）膜是第一代用于引导性骨再生手术的临床记录良好的屏障膜（53、76、238）。e-PTFE 是一种具有多孔结构的合成聚合物，不会引起免疫反应，并能抵抗宿主组织和微生物的酶降解。在 e-PTFE 膜中加入钛加固材料可增加其机械稳定性，并使膜可单独成型。
These characteristics have been claimed to be advantageous for the successful treatment of challenging defects that lack the support of the membrane by the adjacent bone walls. Successful treatment outcomes following large lateral and vertical augmentations by means of e-PTFE membranes have been clinically documented (29, 37, 199). 据称，这些特性有利于成功治疗缺乏邻近骨壁支撑膜的高难度缺损。临床记录显示，使用 e-PTFE 膜进行大面积横向和纵向增量后，治疗效果非常成功（29、37、199）。
An increased rate of soft-tissue complications after premature membrane exposure has been reported as a disadvantage of the use of e-PTFE membranes (38). Once exposed to the oral cavity, the porous surface of e-PTFE membranes is rapidly colonized by oral microbes . This often leads to infections of the adjacent tissues and to the subsequent need for early membrane removal, resulting in impaired bone regeneration (80, 85, 149, 193, 198, 238). Another disadvantage of e-PTFE membranes is the need for re-entry surgery and membrane removal, which is associated with patient morbidity and the risk of tissue damage. To overcome such drawbacks and to simplify the surgical protocols, resorbable membranes have been developed. 据报道，过早暴露膜后软组织并发症的发生率增加是使用 e-PTFE 膜的一个缺点（38）。一旦暴露于口腔，e-PTFE 膜的多孔表面会迅速被口腔微生物 定植。这通常会导致邻近组织感染，随后需要尽早去除膜，从而影响骨再生（80、85、149、193、198、238）。e-PTFE 膜的另一个缺点是需要再次进入手术和移除膜，这与患者的发病率和组织损伤的风险有关。为了克服这些缺点并简化手术方案，人们开发了可吸收膜。
Resorbable membranes 可吸收膜
A variety of resorbable membranes have been evaluated for use in guided bone regeneration procedures (138, 200, 238) (Table 1). Resorbable membranes have the following advantages: no need for membrane-removal surgery and thus elimination of the need to expose the regenerated bone; a wider range of surgical techniques possible at abutment connection; better cost-effectiveness; and decreased patient morbidity. However, the difficulty of maintaining the barrier function for an appropriate length of time is considered a major drawback of resorbable membranes. In addition, depending on the material, the resorption process of the membrane may interfere with wound healing and 在引导骨再生手术中使用的可吸收膜种类繁多（138、200、238）（表 1）。可吸收膜具有以下优点：无需进行膜去除手术，因此无需暴露再生骨；在基台连接处可使用更多的手术技术；成本效益更高；降低患者发病率。不过，可吸收膜的一个主要缺点是难以在适当的时间内保持屏障功能。此外，根据材料的不同，可吸收膜的吸收过程可能会影响伤口愈合，并导致牙龈感染。
Table 1. Membranes used for guided bone regeneration procedures 表 1.用于引导骨再生程序的薄膜
e-PTFE, expanded polytetrafluoroethylene; d-PTFE, dense polytetrafluoroethylene. e-PTFE：膨体聚四氟乙烯；d-PTFE：致密聚四氟乙烯。
bone formation. Finally, the lack of stability of the material makes the use of membrane-supporting materials mandatory. 骨形成。最后，由于这种材料缺乏稳定性，因此必须使用膜支撑材料。
Membranes made of native collagen exhibit good tissue integration, fast vascularization and biodegradation without a foreign-body reaction (163, 180, 181). Native collagen membranes are well documented and have been shown to render good results and low complication rates in both animal and human (93, 111, 149, 238) studies. Currently, native collagen membranes are the standard treatment for the majority of guided bone regeneration indications (88). Another advantage of the use of native collagen membranes for guided bone regeneration is spontaneous healing in the presence of mucosal dehiscence. In contrast to nonresorbable membranes, epithelialization of the exposed collagen achieving secondary wound closure is spontaneous ( ). This is a significant clinical advantage because, in the case of soft-tissue complications, the membrane does not require any surgical interventions and can be left in place. 由原生胶原蛋白制成的膜具有良好的组织整合性、快速血管化和生物降解性，不会产生异物反应（163、180、181）。在动物 和人体（93、111、149、238）研究中，原生胶原蛋白膜都被证明具有良好的效果和较低的并发症发生率。目前，原生胶原膜是大多数引导骨再生适应症的标准治疗方法（88）。使用原生胶原蛋白膜进行引导骨再生的另一个优势是在粘膜开裂的情况下可自发愈合。与不可吸收膜相比，暴露的胶原蛋白上皮化实现二次伤口闭合是自发的（ ）。这是一个显著的临床优势，因为在软组织并发症的情况下，膜不需要任何手术干预，可以留在原位。
The major drawbacks of native collagen membranes may be caused by their unfavorable mechanical properties, such as poor resistance to collapse (101, 190, 207, 236), and by the fast degradation, resulting in an early loss of barrier function (143, 163, 237). The rapid biodegradation of native collagen by the enzymatic activity of host tissues and microbes has been demonstrated in animal models (181, 193, 195). However, it is important to emphasize that the degradation time of native collagen may vary considerably, depending on its source and its original structure (180). 原生胶原蛋白膜的主要缺点可能是其不利的机械特性，如抗塌陷性差（101、190、207、236），以及降解速度快，导致屏障功能早期丧失（143、163、237）。宿主组织和微生物的酶活性已在动物模型中证实了原生胶原蛋白的快速生物降解（181、193、195）。不过，必须强调的是，原生胶原蛋白的降解时间可能会有很大差异，这取决于其来源和原始结构（180）。
Several physical, chemical and enzymatic processes for cross-linking collagen fibrils have been developed, in order to prolong the degradation time of the membranes (25, 122, 144, 172, 235). A recent study on a rat model evaluated eight different collagen membranes and found the increased degree of cross-linking to be directly related to prolonged biodegradation time, decreased tissue integration and foreign body reaction (181). Histological investigations showed that inflammatory cells are involved in the resorption process of cross-linked collagen membranes (21, 181). This may explain the increased frequency of mucosal dehiscence with impaired soft-tissue healing and wound infections that occurred in clinical trials (3, 14). In contrast, other preclinical and clinical studies showed promising results for cross-linked collagen membranes, exhibiting adequate tissue integration and successful bone regeneration that were similar, or even superior, to those achieved when using native collagen membranes (72, 149, 193, 223). Furthermore, several studies revealed that the premature exposure of a cross-linked collagen membrane was followed by complete spontaneous secondary epithelialization without impaired bone regeneration (72, 74, 149). These contrasting findings indicate differences in the biological behaviors among the different types of cross-linked membranes. 为了延长胶原蛋白膜的降解时间，人们开发了几种物理、化学和酶交联胶原蛋白纤维的工艺（25、122、144、172、235）。最近一项针对大鼠模型的研究评估了八种不同的胶原蛋白膜，发现交联程度的增加与生物降解时间延长、组织整合度降低和异物反应直接相关（181）。组织学调查显示，炎症细胞参与了交联胶原蛋白膜的吸收过程（21，181）。这可能是临床试验中出现粘膜开裂、软组织愈合受损和伤口感染的频率增加的原因（3、14）。与此相反，其他临床前和临床研究显示交联胶原蛋白膜具有良好的效果，表现出充分的组织整合和成功的骨再生，与使用原生胶原蛋白膜时的效果相似甚至更好（72、149、193、223）。此外，有几项研究显示，交联胶原膜过早暴露后会出现完全自发的继发性上皮化，而不会影响骨再生（72、74、149）。这些截然不同的研究结果表明，不同类型的交联膜在生物学行为上存在差异。
The use of synthetic resorbable membranes made out of aliphatic polyesters such as polylactic acid, polyglycolic acid, trimethylcarbonate and their copolymers has been reported to be effective for guided bone regeneration procedures in experimental (60, , as well as in clinical studies. However, the use of these membranes may be subject to drawbacks such as inflammatory foreign-body reactions associated with their degradation products (223, 226). Some studies found a reduced defect fill when applying polylactic acid and polyglycolic acid membranes as opposed to e-PTFE membranes (132, 200, 204). 据报道，在实验（60、 以及临床 研究中，使用脂肪族聚酯（如聚乳酸、聚乙醇酸、三甲基碳酸酯及其共聚物）制成的合成可吸收膜可有效引导骨再生程序。然而，这些膜的使用可能存在一些缺陷，如与其降解产物相关的炎性异物反应（223，226）。一些研究发现，与 e-PTFE 膜相比，使用聚乳酸和聚乙醇酸膜可减少缺损填充（132、200、204）。
Form-stable polylactic acid/polyglycolic acid copolymer (PLGA) membranes, modified with N -methyl-2-pyrrolidone as a plasticizer, were recently evaluated in preclinical and clinical (242) studies. PLGA membranes used for guided bone regeneration of large peri-implant defects appear susceptible to fracture when they are not supported by grafting material, indicating that the mechanical stability of the membrane is insufficient for this type of application (112). In combination with grafting material, PLGA performed similarly to native collagen. In a recent multicenter, randomized controlled trial, including 40 patients with peri-implant dehiscences, guided bone regeneration was performed using either PLGA membranes or titanium-reinforced e-PTFE membranes (187). At 6 months re-entry surgery, the mean vertical defect fill was within the PLGA group and within the e-PTFE group. Titaniumreinforced e-PTFE membranes were able to maintain the horizontal thickness of the regenerated region more effectively and developed fewer soft-tissue complications compared with PLGA membranes. 最近在临床前 和临床（242）研究中评估了用N-甲基-2-吡咯烷酮作为增塑剂改性的形式稳定的聚乳酸/聚乙二醇酸共聚物（PLGA）膜。用于引导种植体周围大面积缺损骨再生的 PLGA 膜在没有移植材料支撑的情况下似乎很容易断裂，这表明膜的机械稳定性不足以满足这类应用的要求（112）。与移植材料结合使用时，PLGA 的表现与天然胶原相似。在最近的一项多中心随机对照试验中，包括 40 名种植体周围开裂的患者，使用 PLGA 膜或钛增强 e-PTFE 膜进行引导骨再生（187）。在 6 个月的再入路手术中，PLGA 组的平均垂直缺损填充率为 ，e-PTFE 组的平均垂直缺损填充率为 。与 PLGA 膜相比，钛增强 e-PTFE 膜能更有效地保持再生区域的水平厚度，并减少软组织并发症。
A new approach, aiming at simplifying the clinical handling, was taken with a synthetic in-situ polymerizing membrane made of polyethylene glycol (Fig. 1) (115, 135, 231). In situ, polyethylene glycol is degraded by hydrolysis with no acidic byproducts, which have been shown to trigger foreign-body reactions in the surrounding tissues (97, 231). Preclinical studies indicated that this material is highly biocompatible and cell-occlusive and allowed the formation of similar amounts of new bone compared with other types of materials, such as e-PTFE and polylactic acid 一种旨在简化临床处理的新方法是使用由聚乙二醇制成的合成原位聚合膜（图 1）（115、135、231）。聚乙二醇在原位水解降解，不会产生酸性副产品，而酸性副产品已被证明会引发周围组织的异物反应（97、231）。临床前研究表明，这种材料具有高度的生物相容性和细胞闭锁性，与其他类型的材料（如 e-PTFE 和聚乳酸）相比，可以形成类似数量的新骨。
Fig. 1. (A, B) Dehiscence-type bone defect at an implant position 21. (C) The defect is treated by guided bone regeneration applying particulate bovine-derived bone mineral and synthetic hydrogel made of polyethylene glycol (D, E) In-situ polymerized polyethylene glycol membrane. (F) Re-entry surgery 6 months after implant placement. 图 1. (A, B) 21 号种植体位置的开裂型骨缺损。(C）应用微粒牛骨矿物质和聚乙二醇合成水凝胶引导骨再生治疗缺损 D、E）原位聚合聚乙二醇膜。(F）植入种植体 6 个月后再次进行手术。 . In a randomized controlled trial, the polyethylene glycol membrane was as successful as native collagen membrane in terms of vertical defect repair of peri-implant osseous dehiscences (111). Moreover, in recent preclinical studies, polyethylene glycol membranes showed promising results for staged augmentation of challenging lateral ridge defects in terms of bone ingrowth and preservation of the ridge contours (142, 191, 214). 。在一项随机对照试验中，聚乙二醇膜与原生胶原膜一样成功地修复了种植体周围骨性裂隙的垂直缺损（111）。此外，在最近的临床前研究中，聚乙二醇膜在分期增量修复具有挑战性的侧脊缺损时，在骨的生长和脊轮廓的保留方面显示出了良好的效果（142、191、214）。
Bone grafts and bone-graft substitutes 骨移植和骨替代物
Due to its potential osteogenic, osteoinductive and osteoconductive properties, autogenous bone has long been considered the ideal grafting material for bone augmentation procedures (26, 98). However, morbidity and complications related to the donor site, limited graft availability and unpredictable graft resorption are major limitations related to the use of autogenous grafts (41, 43, 107, 155, 183, 227, 233). To overcome these shortcomings, bone-graft substitutes have been developed as adjuncts to, or replacements for autografts in bone augmentation procedures. 自体骨具有潜在的成骨性、骨诱导性和骨诱导性，长期以来一直被认为是骨增量手术的理想移植材料（26，98）。然而，与供体部位相关的发病率和并发症、有限的移植物可用性和不可预测的移植物吸收是使用自体移植物的主要局限性（41、43、107、155、183、227、233）。为了克服这些缺点，人们开发了骨移植替代物，作为骨增量手术中自体移植物的辅助或替代物。
Bone grafts and bone substitutes can be classified into four groups, according to their origin: autografts, from the same individual; allografts, from another individual within the same species; xenografts, from another species; and alloplasts, synthetically produced (Table 2). Their application modality encompasses several forms for application, such as block, granular, moldable, injectable or in-situ hardening materials. 骨移植和骨替代物按其来源可分为四类：自体移植物，来自同一个体；异体移植物，来自同一物种的另一个体；异种移植物，来自另一物种；异体材料，人工合成（表 2）。它们的应用方式包括多种应用形式，如块状、颗粒状、可成型、可注射或原位硬化材料。
It has been claimed that grafts and bone-graft substitutes for guided bone regeneration need to fulfill the following requirements: biocompatibility; osteoconductivity; adequate mechanical support of the membrane to provide the volume for the regenerated bone; biodegradability; and replacement with the patient's own bone (77, 78, 103). Recent studies have suggested that a slow substitution may be advantageous for maintenance of the augmented volume (104, 105). 据称，用于引导骨再生的移植物和骨移植物替代物需要满足以下要求：生物相容性；骨传导性；膜有足够的机械支撑，为再生骨提供容积；生物可降解性；用患者自身骨替代（77、78、103）。最近的研究表明，缓慢替代可能有利于维持增大的体积（104、105）。
A multitude of xenografts, consisting of minerals derived from animals, corals or algae, are commercially available. The best-documented bone substitute used in implant dentistry, and currently accepted as the gold standard, is a deproteinized bovine-derived bone mineral (106). Biocompatibility and osteoconductivity of deproteinized bovinederived bone mineral have been demonstrated in several preclinical studies (94, 120, 184). However, whether deproteinized bovine-derived bone mineral 由动物、珊瑚或藻类提取的矿物质组成的异种移植体在市场上可以买到。在种植牙中使用的骨替代物中，目前公认的黄金标准是去蛋白牛源性骨矿物质（106）。一些临床前研究已经证实了去蛋白牛源骨矿的生物相容性和骨传导性（94、120、184）。然而，去蛋白牛源性骨矿物质是否具有生物相容性和骨传导性？
Table 2. Grafting materials used for guided bone regeneration procedures 表 2.用于引导骨再生手术的移植材料
Graft material 移植材料
Origin 起源
Examples 实例
Autograft 自体移植
Patient's own tissue 患者自身组织
Intra-orally or extra-orally harvested 口内或口外采集
Allograft 同种异体移植
同一物种个体的组织
Tissue from individuals of the same
species
Fresh-frozen bone, freeze-dried bone, demineralized freeze-dried bone 新鲜冷冻骨、冻干骨、去矿物质冻干骨
Xenograft 异种移植
Tissue from other species 其他物种的组织
Bovine-, porcine-, equine-derived bone mineral 源自牛、猪、马的骨矿物质
is bioresorbable still remains controversial (19, 77, 148). The presence of cells with osteoclastic characteristics was interpreted as a sign of ongoing resorption of the deproteinized bovine-derived bone mineral bone-graft substitute (170). A recent clinical trial including 20 patients found deproteinized bovine-derived bone mineral particles unchanged and integrated in the bone 11 years after sinus floor augmentation (148). The clinical consequences of the rate and the pattern of resorption of deproteinized bovine-derived bone mineral in a given patient situation remain to be investigated. 是否具有生物可吸收性仍存在争议（19、77、148）。具有破骨细胞特征的细胞的存在被解释为脱蛋白牛源骨矿物质骨移植替代物正在被吸收的迹象（170）。最近一项包括 20 名患者的临床试验发现，在窦底隆鼻术 11 年后，去蛋白牛源性骨矿物质颗粒仍未改变并融入骨中（148）。在特定患者情况下，去蛋白牛源性骨矿物质的吸收率和吸收模式对临床的影响仍有待研究。
Recently, several new bovine-, porcine- and equine-derived bone substitutes have been developed. Preclinical studies and clinical case series demonstrated that these materials are biocompatible and osteoconductive, and can be used as bone substitutes without interfering with the normal reparative bone process (30, 174, 175, 182, 189, 213). 最近，人们开发出了几种新的牛源、猪源和马源骨替代物。临床前研究和临床病例系列证明，这些材料具有生物相容性和骨传导性，可用作骨替代物而不会干扰正常的骨修复过程（30、174、175、182、189、213）。
Deproteinized bovine-derived bone mineral is the best documented bone substitute for guided bone regeneration of dehiscence- and fenestration-type defects concomitant with implant placement (106). In contrast, there are only limited clinical data reporting on the application of deproteinized bovine-derived bone mineral in combination with resorbable membranes for bone augmentation before implant placement (74, 91, 240). In a clinical study, deproteinized bovine-derived bone mineral blocks and collagen membranes were applied to 12 patients to treat horizontal bone deficiencies before implant placement (Fig. 2) (91). After 9-10 months, in 11 of 12 patients the resulting bone volume was sufficient to allow implant placement in the prosthetically optimal position. It was therefore concluded that the procedure was effective for horizontal ridge augmentation. These results are in agreement with a preclinical study comparing autogenous bone blocks with deproteinized bovine-derived bone mineral blocks for lateral ridge augmentation, in which a similar increase of ridge augmentation was clinically mea- sured in both groups (59). In fact, all sites treated with deproteinized bovine-derived bone mineral blocks for horizontal bone ridge augmentation appeared, clinically, to be suitable for implant placement. Histologically, however, several studies found that deproteinized bovine-derived bone mineral blocks were mainly embedded in connective tissue and only a moderate amount of new bone formation was observed in peripheral parts of the graft (8, 59, 189, 192). These results may explain the clinical finding that the deproteinized bovine-derived bone mineral blocks were firmly integrated within the surrounding host tissues and were mechanically stable, as observed at re-entry surgery . 牛源性脱蛋白骨矿是有据可查的最佳骨替代物，可在植入种植体的同时引导开裂型和栅栏型缺损的骨再生（106）。相比之下，仅有有限的临床数据报告了在植入种植体前将脱蛋白牛源性骨矿与可吸收膜结合用于骨增量的情况（74、91、240）。在一项临床研究中，12 位患者在植入种植体前应用了去蛋白牛源性骨矿块和胶原蛋白膜来治疗水平骨缺损（图 2）（91）。9-10 个月后，12 位患者中有 11 位的骨量足以将种植体植入修复体的最佳位置。因此得出结论，该手术对水平牙脊增量有效。这些结果与一项临床前研究的结果一致，该研究比较了自体骨块和去蛋白牛源性骨矿物质块对横向牙槽嵴增量的作用，结果显示两组患者的牙槽嵴增量在临床上有相似的增长（59）。事实上，所有使用牛源性骨矿物质块进行横向骨脊增量的部位在临床上似乎都适合植入种植体。但从组织学角度来看，一些研究发现，去蛋白牛源性骨矿物质块主要嵌入结缔组织中，移植物的外围部位仅有少量新骨形成（8、59、189、192）。 这些结果可能解释了临床发现的原因，即去蛋白牛源性骨矿物质块与周围宿主组织牢固结合，并具有机械稳定性，正如在再入路手术 中观察到的那样。
Examples of allografts include fresh-frozen bone, freeze-dried bone and demineralized freeze-dried bone. Their main limitation is derived from the risk of immunologic reactions and possible disease transmission as a result of their protein content (71). Successful use of freeze-dried bone and demineralized freeze-dried bone for bone augmentation concomitant to implant placement has been reported in clinical studies (76, 167). Furthermore, case series demonstrated that block allografts, in conjunction with placement of resorbable membranes, may be a viable treatment option for augmentation of atrophic alveolar ridges in two-stage implant placement procedures (117, 152, 153). During a recent clinical trial including 40 patients, the use of freeze-dried bone block allografts and collagen membranes for primary augmentation of anterior atrophic maxilla was evaluated (154). After 6 months, bone samples were harvested and 83 implants were placed. The histomorphometric analysis found the mean percentage of newly formed bone to be and of residual allograft to be . The implant survival rate was after a mean follow up of (range: 14-82) months. A previous systematic review concluded that clinical studies on allograft blocks included a relatively small number of interventions and implants without long-term follow-up periods 同种异体移植的例子包括新鲜冷冻骨、冻干骨和脱矿冻干骨。它们的主要局限性在于其蛋白质含量可能导致免疫反应和疾病传播的风险（71）。有临床研究报告称，在植入种植体的同时成功使用冻干骨和去矿物质冻干骨进行骨增量（76，167）。此外，一系列病例表明，在两阶段种植体植入手术中，块状同种异体骨与可吸收膜的结合可能是增量萎缩牙槽脊的可行治疗方案（117、152、153）。在最近一项包括 40 名患者的临床试验中，对使用冻干骨块异体移植物和胶原蛋白膜对前部萎缩的上颌骨进行初次增量进行了评估（154）。6 个月后，采集了骨样本，并植入了 83 个种植体。组织形态学分析发现，新形成骨的平均百分比为 ，残留同种异体骨的平均百分比为 。在平均随访 （范围：14-82）个月后，种植体存活率为 。之前的一项系统性综述认为，关于异体移植块的临床研究包括相对较少的干预和植入物，且没有长期的随访期
Fig. 2. (A, B) A horizontal ridge defect at an implant site 22. (C, D) A block of bovine-derived bone mineral is placed to support a resorbable collagen membrane. (E, F) At re-entry surgery 9 months later, the ridge volume is adequate for the placement of an implant in the prosthodontically ideal position. 图 2：（A、B）种植部位的水平脊缺损 22。(C、D）植入牛源性骨矿物质块，以支撑可吸收胶原膜。(E、F）9 个月后再次进行手术时，牙槽嵴的体积足以将种植体植入理想的修复位置。
and therefore implied that they do not provide sufficient evidence to establish the treatment efficacy relative to graft incorporation, alveolar ridge augmentation and long-term dental implant survival (228). 因此，他们认为这些研究没有提供足够的证据来证明植牙结合、牙槽嵴增高和长期牙种植体存活的治疗效果（228）。
Alloplastic bone substitutes represent a large group of chemically diverse synthetic biomaterials, including calcium phosphate (e.g. tricalcium phosphate, hydroxyapatite and calcium phosphate cements), calcium sulfate, bioactive glass and polymers. These materials vary in structure and in chemical composition, as well as in mechanical and biological properties. Porous calcium phosphates have been under intense investigation for more than 20 years and constitute a high number of commercially available bone substitutes (13, 49). Hydroxyapatite is the main mineral component of natural bone and the least soluble of the naturally occurring calcium phosphate salts. It is therefore highly resistant to physiologic resorption (83). In contrast, tricalcium phosphate is characterized by rapid resorption and replacement with host tissue (12, 105). Although bone ingrowth regularly occurred into the area intended for regeneration, this ingrowth did not fully compensate for the resorption of the tricalcium phosphate, resulting in a reduction of the augmented volume (105). 异体骨替代物是一大类化学性质不同的合成生物材料，包括磷酸钙（如磷酸三钙、羟基磷灰石和磷酸钙水泥）、硫酸钙、生物活性玻璃和聚合物。这些材料的结构、化学成分以及机械和生物特性各不相同。20 多年来，人们一直在对多孔磷酸钙进行深入研究，并发现了大量商业化的骨替代品（13、49）。羟基磷灰石是天然骨的主要矿物成分，也是天然磷酸钙盐中溶解度最低的一种。因此，它具有很强的抗生理性吸收能力（83）。相比之下，磷酸三钙的特点是快速吸收并被宿主组织取代（12，105）。虽然骨质会有规律地向再生区域生长，但这种生长并不能完全补偿磷酸三钙的吸收，从而导致增量的减少（105）。
Biphasic compounds of hydroxyapatite and tricalcium phosphate have been developed to combine the features of space maintenance and bioresorption, allowing space for bone ingrowth (50, 104, 130). Preclinical studies using different experimental models provided histological evidence that particulate or moldable in-situ hardening hydroxyapatite/tricalcium phosphate shows osteoconductivity and resorption properties similar to those of deproteinized bovine-derived bone mineral (104, 142, 185, 191). In recent human controlled trials, hydroxyapatite/tricalcium phosphate and deproteinized bovine-derived bone mineral were found to produce similar amounts of newly formed bone for grafting of the maxillary sinus (42, 75). Another study compared hydroxyapatite/tricalcium phosphate and deproteinized bovinederived bone mineral, in conjunction with collagen membranes, for guided bone regeneration of extraction sockets (137). After 8 months, the bucco-oral dimension of the alveolar ridge decreased by 1.1 mm in the hydroxyapatite/tricalcium phosphate group and by 2.1 mm in the deproteinized bovine-derived bone mineral group with a statistically significant difference. A randomized controlled trial found that hydroxyapatite/tricalcium phosphate performs similarly to deproteinized bovine-derived bone mineral for guided bone regeneration of peri-implant dehiscencies with respect to vertical defect reduction (220). Based on these findings, the combination of 目前已开发出羟基磷灰石和磷酸三钙的双相化合物，结合了空间维持和生物吸收的特点，为骨的生长提供了空间（50、104、130）。使用不同实验模型进行的临床前研究提供了组织学证据，表明颗粒状或可塑形的原位硬化羟基磷灰石/磷酸三钙具有类似于去蛋白牛骨矿物质的骨传导性和吸收特性（104、142、185、191）。在最近的人体对照试验中，发现羟基磷灰石/磷酸三钙和去蛋白牛源性骨矿在上颌窦移植中产生的新形成骨量相似（42，75）。另一项研究比较了羟基磷灰石/磷酸三钙和去蛋白牛源性骨矿以及胶原蛋白膜在引导下用于拔牙窝骨再生的效果（137）。8 个月后，羟基磷灰石/磷酸三钙组的牙槽嵴颊口尺寸减少了 1.1 毫米，而去蛋白牛源骨矿组则减少了 2.1 毫米，差异具有统计学意义。一项随机对照试验发现，羟基磷灰石/磷酸三钙与去蛋白牛源性骨矿在引导种植体周围开裂处骨再生方面的垂直缺损缩小效果相似（220）。基于这些研究结果，将
hydroxyapatite/tricalcium phosphate for alveolar ridge augmentation holds some promise for the future. However, further long-term clinical studies are necessary to demonstrate its equivalence to deproteinized bovine-derived bone mineral. 羟基磷灰石/磷酸三钙用于牙槽嵴增量在未来大有可为。不过，还需要进一步的长期临床研究来证明其与脱蛋白牛源性骨矿物质的等效性。
Choice of material 材料的选择
There are an increasing number of different materials that can be used in bone augmentation procedures. However, most have not been sufficiently documented in clinical studies (64). In dehiscence- and fenestration-type defects, deproteinized granular xenografts and particulate autograft covered with native collagen or e-PTFE membranes are the best-documented augmentation materials . These procedures may be considered as safe and predictable therapies for long-term performance of implants. 可用于骨增量手术的不同材料越来越多。然而，大多数材料还没有在临床研究中得到充分证明（64）。在开裂型和栅栏型缺损中，去蛋白颗粒异种移植物和颗粒自体移植物外覆天然胶原或e-PTFE膜是文献记载最好的增骨材料 。这些程序可被视为安全、可预测的植入物长期性能疗法。
The use of resorbable membranes offers several advantages over nonresorbable membranes. These include: no need for membrane-removal surgery; simplification of methods; elimination of exposure of the regenerated bone; a wider range of surgical techniques possible at abutment connection; better cost-effectiveness; and decreased patient morbidity. Consequently, resorbable membranes are preferred, whenever possible, for the treatment of horizontal bone defects. 与不可吸收膜相比，使用可吸收膜有几个优点。这些优势包括：无需进行膜去除手术；方法简化；无需暴露再生骨；在基台连接处可以使用更多的手术技术；成本效益更高；以及降低了患者的发病率。因此，在可能的情况下，可吸收膜是治疗水平骨缺损的首选。
e-PTFE membranes have been demonstrated to lead to successful bone regeneration without the additional use of graft material (53, 108). Nevertheless, a combination of membrane and bone graft or bone substitute is generally recommended for guided bone regeneration procedures to provide adequate support of nonstable membranes and to enhance bone ingrowth into the defect. e-PTFE 膜已被证明可成功实现骨再生，而无需额外使用移植材料（53，108）。不过，一般建议在引导骨再生手术中结合使用膜和骨移植或骨替代物，以便为不稳定的膜提供足够的支撑，并促进骨在缺损处的生长。
In clinical studies, autogenous bone has not been demonstrated to promote better bone regeneration at dehiscence- and fenestration-type defects compared with some bone-substitute materials (38). In order to avoid additional morbidity associated with bone harvesting, the use of bone substitute materials is therefore recommended for bone regeneration at exposed implant surfaces. 临床研究表明，与某些骨替代材料相比，自体骨并不能更好地促进开裂和瘘管型缺损的骨再生（38）。因此，为了避免取骨带来的额外发病率，建议在暴露的种植体表面使用骨替代材料进行骨再生。
A recent systematic review divided the results of studies on augmentation of dehiscence- and fenestration-type defects according to the membrane used (106). For nonresorbable membranes the percentage defect fill was , the percentage of cases with complete defect fill was and the rate of mucosal dehiscence was . When resorbable membranes were used, the corresponding values were and , respectively. The implant survival rates ranged from 92.9 to (median ) with nonresorbable membranes and from 94 to (median ) with resorbable membranes. It was concluded that the heterogeneity of the available data precludes clear recommendations regarding the choice of a specific membrane and a specific supporting material (106). In addition, comparative studies using different augmentation protocols were rarely found. 最近的一项系统性综述根据所使用的膜对开裂和瘘管型缺损的增量研究结果进行了划分（106）。对于不可吸收膜，缺损填充百分比为 ，完全缺损填充的病例百分比为 ，粘膜开裂率为 。使用可吸收膜时，相应的数值分别为 和 。使用不可吸收膜时，植入物存活率在 92.9 到 之间（中位数 ）；使用可吸收膜时，植入物存活率在 94 到 之间（中位数 ）。得出的结论是，现有数据的不一致性导致无法就选择特定膜和特定支持材料提出明确建议（106）。此外，很少发现使用不同增强方案的比较研究。
In a split-mouth prospective study, a total of 84 implants were placed into partially resorbed alveolar ridges (238). The resulting peri-implant defects were treated with deproteinized bovine-derived bone mineral covered either with a resorbable collagen membrane or with an e-PTFE membrane. After 4-6 months, a mean vertical bone fill was found, amounting to in the collagen-treated defects and to in the sites treated with e-PTFE. This difference was not statistically significant. Nonetheless, membrane dehiscences occurred more frequently within e-PTFE than within collagen membranes. Membrane dehiscences significantly reduced new bone formation in e-PTFE-treated sites but not in dehisced collagen-treated sites. A recent three-arm clinical trial evaluated the long-term outcome of implants placed simultaneously with guided bone regeneration using e-PTFE and collagen membranes and that of implants placed into pristine bone without the need for guided bone regeneration (109). After a mean follow-up of 12.5 years, 58 patients participated in the investigation, corresponding to of the original study population. Resorbable collagen membranes and nonresorbable e-PTFE membranes exhibited similar results with respect to the implant survival rate, the interproximal marginal bone level and the peri-implant soft-tissue parameters. In another study, a cone-beam CT examination of implants that were treated using nonresorbable and resorbable membranes was performed 6-57 months after insertion of the abutment (147). The thickness of the buccal bone in the cervical region was significantly higher in the group treated with nonresorbable membranes. A recent multicenter randomized controlled trial compared titanium-reinforced e-PTFE with modified PLGA membranes for guided bone regeneration of dehiscence-type defects at implants (187). At re-entry surgery, 6 months after implant placement and guided bone regeneration, the e-PTFE membrane provided better maintenance of the horizontal thickness of the regenerated region. 在一项分口前瞻性研究中，共有 84 个种植体被植入部分吸收的牙槽脊 (238)。由此产生的种植体周围缺损用去蛋白牛源性骨矿物质进行处理，并覆盖一层可吸收胶原膜或一层 e-PTFE 膜。4-6 个月后，发现平均垂直骨填充，胶原处理的缺损为 ，e-PTFE 处理的缺损为 。这一差异没有统计学意义。然而，e-PTFE 膜的开裂发生率高于胶原膜。在 e-PTFE 处理过的部位，膜开裂会明显减少新骨形成，而在胶原蛋白处理过的部位，膜开裂则不会。最近的一项三臂临床试验评估了使用 e-PTFE 和胶原蛋白膜同时植入引导骨再生的种植体的长期疗效，以及无需引导骨再生即可植入原始骨的种植体的长期疗效（109）。经过平均 12.5 年的随访，58 名患者参与了调查，相当于最初研究人群的 。在种植体存活率、近端边缘骨水平和种植体周围软组织参数方面，可吸收胶原膜和不可吸收 e-PTFE 膜显示出相似的结果。在另一项研究中，在基台植入 6-57 个月后，对使用不可吸收膜和可吸收膜治疗的种植体进行了锥形束 CT 检查（147）。在使用非吸收膜治疗的组别中，颈部颊骨的厚度明显更高。 最近的一项多中心随机对照试验比较了钛增强 e-PTFE 膜和改良 PLGA 膜在引导种植体开裂型缺损骨再生方面的效果（187）。在种植体植入并引导骨再生 6 个月后再次进行手术时，e-PTFE 膜能更好地保持再生区域的水平厚度。
Preclinical and clinical studies thus demonstrate that both resorbable and nonresorbable mem- 因此，临床前研究和临床研究都证明，可吸收和不可吸收的膜
branes are successful for guided bone regeneration of peri-implant defects. Owing to the higher risk of complications and the increased surgical trauma, the use of e-PTFE membranes for the treatment of peri-implant defects is justified only when the volume stability of the region to be augmented is not provided by the adjacent bone walls . The use of titanium-reinforced e-PTFE membranes and membrane-supporting materials is recommended for the treatment of such challenging defects. 在引导骨再生治疗种植体周围缺损方面，e-PTFE 膜是成功的。 由于并发症的风险较高，手术创伤增大，只有在邻近骨壁无法提供增量区域体积稳定性的情况下，才有理由使用e-PTFE膜治疗种植体周围缺损。建议使用钛增强型 e-PTFE 膜和膜支持材料来治疗这类具有挑战性的缺损。
In a recent systematic review, the results after horizontal ridge augmentations were divided according to whether a space-maintaining autogenous bone block was used as opposed to a particulate bone graft or a granular bone substitute material (106). In studies utilizing autogenous bone blocks, alone, or in combination with a membrane and/or a bone substitute material, the mean gain in ridge width was 4.4 mm , the complication rate was and the percentage of cases that needed additional grafting was . When no autogenous block graft was used, the corresponding values were and , respectively. These findings indicate that autogenous bone blocks, alone, or in combination with particulate bone substitute and/or membranes, are the most reliable and secure procedure for staged augmentation of large bone defects before implant placement . 在最近的一篇系统性综述中，根据是否使用保持空间的自体骨块，而不是颗粒状骨移植或颗粒状骨替代材料，对水平牙脊增量术后的结果进行了划分（106）。在单独使用自体骨块或与骨膜和/或骨替代材料结合使用的研究中，脊宽平均增加 4.4 毫米，并发症发生率为 ，需要额外移植的病例百分比为 。如果不使用自体骨块移植，相应的数值分别为 和 。这些研究结果表明，在植入种植体 之前，单独使用自体骨块或与颗粒骨替代物和/或膜结合使用，是对大面积骨缺损进行分期增量的最可靠、最安全的方法。
The use of membranes and bone substitutes, in conjunction with autogenous bone blocks, has been demonstrated, in preclinical and clinical studies, to reduce the resorption of the autogenous bone grafts . In a recent randomized controlled trial, patients were treated with autogenous bone blocks, either alone or covered with a xenograft and a collagen membrane (44). Four months later, the resorption for the autograft alone with respect to the initial width was and for the autograft with collagen membrane and xenograft it amounted to . The difference between the groups was statistically significant. 临床前和临床研究证明，在使用自体骨块的同时使用骨膜和骨替代物可减少自体骨块的吸收 。在最近的一项随机对照试验中，患者接受了单独的自体骨块或覆盖有异种移植骨和胶原膜的自体骨块治疗（44）。四个月后，与初始宽度相比，单独自体骨块的吸收率为 ，而自体骨块与胶原膜和异种骨块的吸收率为 。两组之间的差异具有统计学意义。
e-PTFE membranes, in combination with bone grafts or bone substitutes, are a valuable treatment option for primary ridge augmentation. In horizontal ridge augmentations performed before implant placement, e-PTFE membranes were mainly used to cover granular grafting materials ( ) and only seldom were they used to cover autogenous bone blocks (28, 29). For this clinical indication, the use of nonresorbable membranes presented less gain in ridge width, increased need for additional grafting procedures and higher complication rates, compared with the use of resorbable membranes or no membrane at all (106). e-PTFE膜与骨移植或骨替代物结合使用，是一种很有价值的初级牙脊增量治疗方法。在种植体植入前进行的水平脊增量术中，e-PTFE 膜主要用于覆盖颗粒状移植材料（ ），很少用于覆盖自体骨块（28, 29）。在这一临床适应症中，与使用可吸收膜或完全不使用膜相比，使用不可吸收膜增加的骨嵴宽度较少，需要更多的移植手术，并发症发生率较高（106）。
Despite the promising results of allogenic blocks, it is clear that more clinical evidence is needed for the use of bone substitutes, alone or in combination with resorbable membranes, for primary bone augmentation. When looking at materials recently introduced for guided bone regeneration, there is limited clinical documentation for the use of cross-linked collagen and polyethylene glycol membranes, and for synthetic and new xenogenic bone substitutes. 尽管异种骨块取得了令人鼓舞的成果，但很明显，将骨替代物单独或与可吸收膜结合用于初级骨增量还需要更多的临床证据。纵观最近用于引导骨再生的材料，交联胶原和聚乙二醇膜以及合成骨替代物和新型异种骨替代物的临床文献有限。
Long-term results 长期成果
There is a high level of evidence that survival rates of dental implants placed simultaneously with, or after, bone augmentation are similar to survival rates of implants placed into pristine bone (61, 89, 106). The majority of studies providing internal controls found implant survival rates for a period between 1 and 5 years ranging from 95 to at both augmented and control sites (17, 139, 164, 239, 241). In a recent prospective study, the survival rates, after a mean observation period of 12.5 years, for implants either placed simultaneously with guided bone regeneration or placed into native bone were and , respectively (109). The analysis of intra-oral radiographs within controlled studies did not reveal any difference of the interproximal marginal bone levels between implants placed into augmented sites and those placed into pristine bone (17, 109, 139, 241). 有大量证据表明，与骨增量同时或之后植入的牙科植入体的存活率与植入原始骨的植入体的存活率相似（61、89、106）。大多数提供内部对照的研究发现，在增量部位和对照部位，种植体 1 到 5 年的存活率从 95 到 不等（17、139、164、239、241）。在最近的一项前瞻性研究中，经过 12.5 年的平均观察期，与引导骨再生同时植入的种植体或植入原生骨的种植体的存活率分别为 和 （109）。对照研究中的口内X光片分析显示，植入增量部位的种植体与植入原始骨的种植体在近端边缘骨水平上没有任何差异（17、109、139、241）。
Although the high survival rates of implants placed in conjunction with bone augmentation are well documented, the long-term stability of the regenerated bone has been assessed in very few studies (38, 61). In addition, when bone defects are present at the time of implant placement, very little evidence is available that assesses the long-term outcome when comparing situations in which this defect was augmented with situations in which this defect was not augmented. In other words, in many situations it is currently impossible to conclude whether bone augmentations are needed in order to allow the longterm survival of implants. 虽然结合骨增量植入的种植体存活率很高，但很少有研究对再生骨的长期稳定性进行评估（38，61）。此外，如果在植入种植体时存在骨缺损，那么在对这种缺损进行增量和不进行增量的情况进行比较时，很少有证据能对长期结果进行评估。换句话说，在很多情况下，目前还无法断定是否需要进行骨增量以保证种植体的长期存活。
In a recent study, implants placed immediately into extraction sockets were evaluated at 7 years of function using cone-beam computed tomography (18). At implant placement, infrabony defects and dehiscences were grafted with a xenogenic bone substitute and covered with a collagen membrane without over-augmenting the buccal bone plate. At the 7 -year followup, in five out of 14 implant sites almost no buccal bone was radiographically detected, whereas, within the other nine implant sites, the buccal bone plate 在最近的一项研究中，使用锥形束计算机断层扫描对立即植入拔牙窝的种植体在 7 年后的功能进行了评估（18）。在植入种植体时，用异种骨替代物移植了骨缺损和裂隙，并用胶原膜覆盖，但没有过度增生颊骨板。在 7 年的随访中，在 14 个种植部位中，有 5 个部位几乎没有发现颊骨，而在其他 9 个种植部位，颊侧骨板的骨量都在增加。
covered the entire rough implant surface. Despite this difference, all implants exhibited clinically successful tissue integration. The mucosal margin was located 1 mm more apically within the group of implants without radiographically detectable buccal bone. Future research should determine the need for augmentation procedures for the long-term success of the implants. In addition, the long-term stability of the augmented bone should be assessed and monitored (121). 覆盖整个粗糙的种植体表面。尽管存在这种差异，但所有种植体在临床上都成功地实现了组织整合。在没有影像学检测到颊骨的种植体组中，粘膜边缘位于种植体顶端多 1 毫米处。未来的研究应确定是否需要进行增量手术，以确保种植体的长期成功。此外，还应评估和监测增量骨的长期稳定性（121）。
Clinical concept 临床概念
Case evaluation and treatment planning 病例评估和治疗计划
Analysis of the patient situation, identifying the objective of the therapy and assessing the risks involved, leads to the choice of treatment steps and of the materials. The primary aim of implant therapy is to provide the patient with a reconstruction and, hence, all clinical procedures need to be prosthodontically driven. A detailed preoperative prosthodontic diagnostics is essential for identifying the best treatment plan and achieving an optimal result of the therapy with dental implants. 通过对患者情况的分析，确定治疗目标并评估所涉及的风险，从而选择治疗步骤和材料。种植治疗的主要目的是为患者提供重建，因此，所有临床程序都需要以修复为导向。详细的术前修复诊断对于确定最佳治疗方案和实现种植牙治疗的最佳效果至关重要。
Assessment of the risks related to implant therapy includes evaluation of the patient's condition, the soft tissue and the bone morphology. Patient's behaviors and systemic and local conditions, which may lead to impaired tissue healing, represent relative or absolute contraindications for implant placement and regenerative procedures. An intact and well-dimensioned soft tissue, allowing tension-free coverage of the augmented region, is a prerequisite for successful bone regeneration. In situations where the quantity or quality of mucosa at the implant site is inadequate, augmentation of the soft tissue may be indicated before performing the bone regeneration procedure. In addition, in areas of esthetic priority, the appearance of the soft tissue determines whether or not the result of the reconstructive therapy is esthetically pleasing. When evaluating the soft-tissue condition, the following aspects are assessed: the presence and extent of softtissue defects; gingival biotype; level of the soft tissue at the teeth neighboring the gap; the amount of keratinized mucosa; and the presence of invaginations, scars, discolorations and pathologies in the mucosa at the site to be augmented. The clinical and radiographic examination of the bone at the implant site includes assessment of the bone defect morphology, the mesio-distal size of the edentulous area and the bone level at the teeth adjacent to the gap. 与种植治疗相关的风险评估包括对患者状况、软组织和骨形态的评估。患者的行为以及全身和局部状况可能会导致组织愈合受损，这些都是种植体植入和再生手术的相对或绝对禁忌症。完整且尺寸适中的软组织可以无张力地覆盖增量区域，是骨再生成功的先决条件。如果种植部位粘膜的数量或质量不足，可能需要在进行骨再生手术前对软组织进行增量。此外，在美观优先的区域，软组织的外观决定了重建治疗的结果是否美观。在评估软组织状况时，要从以下几个方面进行评估：软组织缺损的存在和程度；牙龈生物类型；间隙邻近牙齿的软组织水平；角质化粘膜的数量；待增量部位粘膜是否存在内陷、疤痕、变色和病变。种植部位骨质的临床和影像学检查包括对骨质缺损形态、缺牙区域的中远径大小以及间隙邻近牙齿的骨质水平进行评估。
The decision regarding the optimal bone augmentation protocol and the selection of materials is primarily based on the defect morphology and on whether or not the ridge contour needs to be augmented. Based on this, a classification of bone defects has been developed, aiming to simplify the decisionmaking process regarding choice of the strategy for bone augmentation (Fig. 3, Table 3). Bone augmentations can be performed simultaneously with (combined approach) or prior to (staged approach) implant placement. The combined approach is preferred, whenever permitted by the clinical situation, as this approach results in decreased patient morbidity, treatment time and costs. 决定最佳骨增量方案和材料选择的主要依据是缺损形态以及是否需要增量牙脊轮廓。在此基础上，我们对骨缺损进行了分类，旨在简化骨增量策略选择的决策过程（图 3，表 3）。骨增量可以与种植体植入同时进行（联合方法），也可以在种植体植入之前进行（分阶段方法）。在临床条件允许的情况下，首选联合方法，因为这种方法可以减少患者的发病率、治疗时间和费用。
In the case of intra-alveolar defects and periimplant dehiscences, in which the volume stability of the region to be augmented is provided by the adjacent bone walls, a bioresorbable membrane, in combination with a particulate bone substitute, represents the treatment of choice. Where the volume stability of a peri-implant dehiscence-type defect is not provided by the adjacent bone walls, an e-PTFE membrane and particulate bone substitute are used. The staged approach is chosen when large bone defects are present that, either preclude anchorage of the implant in the prosthodontically correct position or result in an unfavorable appearance of the soft tissue due to the lack of hard-tissue support. In such situations the alveolar ridge is first augmented and, after the appropriate healing time, the implant is placed in the prosthodontically correct position. 在牙槽内缺损和种植体周围开裂的情况下，如果需要增量的区域的体积稳定性由邻近的骨壁提供，那么生物可吸收膜与微粒骨替代物的组合就是首选的治疗方法。如果邻近骨壁无法保证种植体周围开裂型缺损的体积稳定性，则可使用 e-PTFE 膜和微粒骨替代物。如果存在大的骨缺损，导致无法将种植体固定在修复体的正确位置，或者由于缺乏硬组织的支持而导致软组织外观不佳，则可以选择分期修复。在这种情况下，首先要对牙槽嵴进行增量，经过适当的愈合时间后，再将种植体植入修复体的正确位置。
Ridge preservation 山脊保护
The alveolar ridge undergoes a significant remodeling process following tooth removal. In a recent systematic review it was described that during the 6 months after tooth extraction, the mean width reduction of the alveolar ridge is 3.8 mm and the mean height reduction is 1.2 mm (209). These hard- and soft-tissue changes may affect the outcome of treatment with implants, either by limiting the bone volume needed for anchorage of the implant or by compromising the esthetic result regarding the appearance of the soft tissue at the final implant-supported reconstruction. 拔牙后，牙槽嵴会经历一个显著的重塑过程。最近的一项系统性研究表明，在拔牙后的 6 个月内，牙槽嵴的平均宽度减少了 3.8 毫米，平均高度减少了 1.2 毫米（209）。这些硬组织和软组织的变化可能会影响种植治疗的效果，因为它们会限制种植体锚定所需的骨量，或者影响最终种植体支持重建时软组织外观的美学效果。
When implant placement is planned at a time point after the tooth extraction, it may be advisable to perform a ridge preservation procedure to counteract the subsequent reduction of the ridge dimension. This may simplify the subsequent implantation procedure and reduce the need for hard- and soft-tissue regeneration. There are, however, no data available 当计划在拔牙后的某个时间点植入种植体时，最好进行牙槽嵴保留手术，以抵消随后牙槽嵴尺寸的缩小。这样可以简化后续的种植程序，减少硬组织和软组织再生的需要。但是，目前还没有以下数据
Fig. 3. Schema displaying bone defect Classes and the corresponding bone augmentation procedures. 图 3.显示骨缺损等级 和相应骨增量程序的示意图。
Table 3. Classification of bone defects 表 3.骨缺损的分类
Bone defect 骨缺损
Description 说明
Class 0 0 级
Site with a ridge contour deficit and sufficient bone volume for standard implant placement 有脊柱轮廓缺陷且有足够骨量进行标准种植体植入的部位
Class 1 一级
Intra-alveolar defect between the implant surface and intact bone walls 种植体表面与完整骨壁之间的牙槽内缺损
Class 2 二级
种植体周围开裂，在这种情况下，需要增量的区域的体积稳定性由邻近的骨壁提供
Peri-implant dehiscence, in which the volume stability of the area to be augmented is provided by the
adjacent bone walls
Class 3 第三类
种植体周围开裂，即邻近骨壁无法提供待增量区域的体积稳定性
Peri-implant dehiscence, in which the volume stability of the area to be augmented is not
provided by the adjacent bone walls
Class 4 四级
Horizontal ridge defect requiring bone augmentation before implant placement 水平脊缺损，需要在植入种植体前增加骨量
Class 5 第五班
Vertical ridge defect requiring bone augmentation before implant placement 垂直脊缺损，需要在植入种植体前增加骨量
regarding the benefit of ridge preservation procedures on the long-term outcomes of implant therapy. 关于牙槽嵴保存术对种植治疗长期效果的益处。
The techniques aimed at ridge preservation encompass two different approaches: maintain the ridge profile; or enlarge the ridge profile (84). Recent systematic reviews concluded that these techniques cannot prevent physiological bone resorption after tooth extraction, but they may aid in reducing bone dimensional changes . A meta-analysis of the literature found 1.4 mm less reduction of the ridge width and 1.8 mm less reduction of the ridge height after applying ridge preservation procedures in comparison with untreated control sites (221). The scientific evidence does not provide clear guidelines regarding the surgical procedure or the type of biomaterial to be used for ridge preservation (221). Positive effects have been observed resulting from procedures involving flap elevation, the use of a grafting material and/or a barrier membrane, and the achievement of a wound closure. It remains, however, unclear which is the most adequate technique for achieving a wound closure. Disadvantages of the current ridge preservation procedures include the postponement of implantation, as well as the costs of the treatment. When flaps are raised to enlarge the ridge contour, achieving primary wound closure becomes increasingly difficult. Moreover, such surgical procedures cause additional patient morbidity. 旨在保留牙脊的技术包括两种不同的方法：保持牙脊轮廓；或扩大牙脊轮廓 (84)。最近的系统综述认为，这些技术不能防止拔牙后的生理性骨吸收，但可以帮助减少骨的尺寸变化 。一项文献荟萃分析发现，与未经处理的对照部位相比，采用牙脊保留程序后，牙脊宽度减少了 1.4 毫米，牙脊高度减少了 1.8 毫米（221）。科学证据并没有对保存牙脊的手术方法或生物材料类型提供明确的指导（221）。据观察，皮瓣抬高、使用移植材料和/或屏障膜以及实现伤口闭合等手术方法都能产生积极的效果。不过，目前仍不清楚哪种技术最适合实现伤口闭合。目前的牙脊保存术的缺点包括推迟种植时间和治疗费用。为了扩大牙脊轮廓而隆起皮瓣时，实现初级伤口闭合变得越来越困难。此外，此类手术还会增加患者的发病率。
An approach has been developed with the aim of achieving optimal soft-tissue conditions at the time of implant placement (113, 125, 126). Following tooth extraction, a bone substitute is placed into the extraction socket. Subsequently, a soft-tissue graft is harvested from the palate and sutured against the 为了在植入种植体时达到最佳的软组织条件，我们开发了一种方法（113、125、126）。拔牙后，将骨替代物植入拔牙窝。随后，从上颚采集软组织移植物，并将其缝合在种植体上（113、125、126）。
soft-tissue margins of the extraction socket, thus covering the grafting material. Preclinical studies investigating this method have demonstrated uneventful graft integration and beneficial effects in terms of maintenance of the ridge contour . In a prospective clinical study including 20 patients in need of tooth extraction, soft-tissue grafts were applied to seal the extraction socket that was filled with deproteinized bovine-derived bone mineral (113). Six weeks later, the grafts had healed very well, as indicated by integration of the soft-tissue graft area. In addition, the color match with the surrounding tissues was excellent, as the mean color difference between the graft and the adjacent tissues did not reach the threshold value for distinction of the intra-oral color by the human eye. The technique presented achieved the desired aim, namely to optimize the quality and the quantity of soft-tissue for early implant placement at around 6 weeks after tooth extraction. Early implant placement (Type 2 placement), combined with bone regeneration, can then be performed under optimized soft-tissue conditions (86). Due to the effort and the costs needed to perform this treatment, it is mainly indicated in esthetically sensitive situations. 在拔牙窝的软组织边缘覆盖移植材料。对这种方法进行的临床前研究表明，移植物可以顺利地与牙槽骨融合，并在保持牙脊轮廓 方面产生有益的效果。在一项包括 20 名需要拔牙的患者的前瞻性临床研究中，使用软组织移植物来封闭用去蛋白牛源性骨矿填充的拔牙窝（113）。六周后，软组织移植区的 整合显示，移植物愈合得非常好。此外，移植物与周围组织的颜色匹配非常好，因为移植物与周围组织的平均色差没有达到人眼区分口腔内颜色的阈值。该技术达到了预期目的，即优化软组织的质量和数量，以便在拔牙后 6 周左右进行早期种植。这样就可以在优化的软组织条件下进行早期种植体植入（2 类植入）和骨再生（86）。由于进行这种治疗需要花费大量精力和成本，因此主要适用于对美观敏感的情况。
Contour deficit: Class 0 轮廓缺陷：0 级
This situation occurs when an implant can be placed in a prosthetically correct position within the bony envelope but a bone augmentation procedure is indicated to improve the contour of the ridge. This is often the case in esthetically sensitive sites with a healed alveolar ridge (Type 4 placement) (86). As a result of post-extractive ridge resorption, such sites generally present a reduced dimension of the alveolar ridge. The guided bone regeneration procedure with a resorbable membrane and particulate bone substitute, described for Class 2 dehiscence-type defects, is performed in these situations. 当种植体可以在骨包膜内的正确位置进行修复，但需要进行骨增量手术以改善牙槽嵴的轮廓时，就会出现这种情况。这种情况通常发生在牙槽嵴已愈合的美学敏感区域（第 4 类植入）（86）。由于拔牙后牙槽嵴吸收，这些部位的牙槽嵴尺寸通常会缩小。在这种情况下，可以使用针对 2 类开裂型缺损描述的可吸收膜和颗粒骨替代物引导骨再生程序。
Intra-alveolar defect: Class 1 齿槽内缺损1 级
Class 1 defects are characterized by gaps between the implant surface and the intact bone walls. Owing to the resorptive processes starting immediately following extraction of the tooth, Class 1 defects are mostly limited to situations where immediate implant placement is performed (Type 1 placement) (86). In some situations the bone walls of the socket may still be intact at a later time point, when implants are placed following soft-tissue healing (Type 2 placement). 1 类缺损的特征是种植体表面与完整骨壁之间存在间隙。由于拔牙后立即开始吸收过程，1 类缺损主要限于立即植入种植体的情况（1 类植入）（86）。在某些情况下，软组织愈合后植入种植体（第 2 类植入），此时牙槽窝的骨壁可能仍然完好无损。
After implant placement, the site is analyzed and one of the following strategies for the management of Class 1 defects is selected: (i) no guided bone regeneration; (ii) guided bone regeneration of the residual socket; or (iii) guided bone regeneration of the residual socket and over-augmentation of the buccal bone wall. 种植体植入后，要对植入部位进行分析，并选择以下策略之一来处理 1 类缺损：(i) 无引导骨再生；(ii) 引导残余牙槽骨再生；或 (iii) 引导残余牙槽骨再生并过度增大颊骨壁。
Data from different preclinical experiments suggest that the horizontal dimension of the gap between the bone and the implant is of critical importance for spontaneous osseous healing of this defect. The results indicate that wider gaps lead to less favorable histological outcomes (2, 57, 171). For implants placed in sockets immediately after extraction, both preclinical and clinical studies show that spontaneous bone fill, without the use of grafting materials, occurs in the peri-implant marginal defects when the horizontal defect size is 2 mm or less (9, 47). Other animal and human studies concluded that the placement of grafting material filling the marginal infrabony defects around implants, that were placed in the sockets immediately after tooth extraction, contributes to a more complete resolution of the defect and preservation of the alveolar process (7, 31, 32, 36, 46). However, even when guided bone regeneration of peri-implant intra-alveolar defects is performed, considerable resorption of the alveolar ridge may occur after immediate implant placement (7, 18, 32). 来自不同临床前实验的数据表明，骨与种植体之间间隙的水平尺寸对该缺损的自发性骨愈合至关重要。结果表明，间隙越宽，组织学结果越差（2、57、171）。对于拔牙后立即植入牙槽窝的种植体，临床前研究和临床研究都表明，当水平缺损大小为 2 毫米或更小时，种植体周围边缘缺损会发生自发性骨填充，而无需使用移植材料（9、47）。其他动物和人体研究认为，在拔牙后立即植入牙槽窝的种植体周围边缘骨性缺损中植入移植材料，有助于更彻底地解决缺损问题并保留牙槽突起（7、31、32、36、46）。然而，即使对种植体周围的牙槽内缺损进行引导性骨再生，牙槽嵴也可能在即刻种植后发生大量吸收（7、18、32）。
Therefore, for Class 1 defects the decision regarding the need for, and the extent of, guided bone regeneration is based on the horizontal dimension of the intra-alveolar defect and the need for augmentation of the ridge contour. In posterior sites the guided bone regeneration procedure primarily aims to resolve the peri-implant osseous defect (Fig. 4). In anterior sites the therapy is also directed at increasing the buccal contour to achieve a pleasing appearance of the peri-implant soft tissues (Fig. 5). Based on this, the following procedure is recommended (Table 4). The mucoperiostal flap is elevated in order to gain access for implant placement and to obtain an adequate overview of the surrounding bone. In posterior sites in which the residual gap between the implant and the wall of the socket is , a guided bone regeneration procedure is generally not needed for successful tissue integration and defect healing. In contrast, if the horizontal defect dimension exceeds , bone substitute is applied in the infrabony defect and covered with resorbable membrane (Fig. 4). In esthetically sensitive areas, a verticalrelease incision is placed in order to gain adequate approach to the buccal bone. Subsequently, a bone 因此，对于 1 类缺损，是否需要引导骨再生以及引导骨再生的程度取决于牙槽骨内缺损的水平尺寸以及是否需要扩大牙脊轮廓。在后牙区，引导骨再生术的主要目的是解决种植体周围的骨缺损（图 4）。在前牙部位，治疗的目的还包括增加颊面轮廓，使种植体周围软组织的外观更加美观（图 5）。在此基础上，建议采用以下程序（表 4）。抬高粘骨膜瓣，以获得种植体植入的通道，并充分了解周围骨质的情况。在种植体与牙槽骨壁之间的残余间隙为 的后牙部位，一般不需要引导骨再生手术就能成功实现组织整合和缺损愈合。相反，如果水平缺损尺寸超过 ，则需要在骨性缺损处使用骨替代物，并用可吸收膜覆盖（图 4）。在审美敏感区域，为了充分接近颊骨，需要进行垂直松解切口。随后，将骨
Fig. 4. (A) Intra-alveolar defect (Class 1) at an implant position 46. The distance between the implant surface and the bone walls exceeds 2 mm . (B) Guided bone regeneration by applying particulate bone substitute into the residual socket and covering the grafted area with a resorbable collagen membrane. (C) The flaps are adapted and sutured to allow transmucosal healing of the implant site. (D) Clinical situation 4 months after implant placement. 图 4. (A) 46 号种植体位置的牙槽内缺损（1 级）。种植体表面与骨壁之间的距离超过 2 毫米。 (B) 在残留牙槽窝内应用颗粒骨替代物，并用可吸收胶原膜覆盖移植区，引导骨再生。(C) 调整并缝合皮瓣，使种植部位的粘膜愈合。(D) 植入 4 个月后的临床情况。
Fig. 5. (A) Extraction socket at position 22 with intact bone walls. (B, C) Guided bone regeneration of an intra-alveolar Class 1 defect by application of particulate bone substitute into the residual socket and over the buccal bone. (D, E) A resorbable collagen membrane is adapted to cover the grafted area and fixed by attaching the membrane around the healing abutment. (F) Clinical situation 8 months after implant placement. 图 5. (A) 22 号位置的拔牙窝，骨壁完整。(B、C）通过在残留牙槽窝和颊骨上应用颗粒状骨替代物，引导牙槽窝内1级缺损的骨再生。(D、E）用可吸收胶原膜覆盖移植区，并将膜固定在愈合基台周围。(F）种植体植入 8 个月后的临床情况。
Table 4. Guided bone regeneration for Class 1 defects 表 4.引导骨再生治疗 1 级缺损
Site 网站
Guided bone regeneration procedure 引导骨再生程序
Esthetically non-sensitive site 不影响美观的场地
HDD
No guided bone regeneration 无引导骨再生
HDD
在牙槽内缺损处应用骨替代物并用可吸收膜覆盖
Application of bone substitute into the intra-alveolar defect and coverage with
resorbable membrane
Esthetically sensitive site 景观敏感区
在牙槽内缺损和颊骨壁上应用骨替代物，并用可吸收膜覆盖
Application of bone substitute into the intra-alveolar defect and over the buccal bone wall and
coverage with resorbable membrane
substitute is applied into the residual socket and over the buccal bone (Fig. 5). The resorbable membrane is adapted to extend 2 mm beyond the grafted area. If needed, the membrane is stabilized using resorbable pins made of polylactid acid and/or the implant cover screw. Thereafter, the flap is adapted and sutured to allow submucosal or transmucosal healing of the implant site. 将替代物植入残留牙槽窝并覆盖颊骨（图 5）。可吸收膜延伸至移植区域外 2 毫米处。必要时，使用聚乳酸制成的可吸收针和/或种植体覆盖螺钉固定膜。然后对皮瓣进行调整和缝合，使种植部位的粘膜下或粘膜上愈合。
The clinical outcomes of the submerged and the transmucosal healing modes for implants placed in fresh extraction sockets were compared in a recent multicenter randomized controlled trial (45). After 1 year, there were no differences between the treatment groups in the survival rate, the marginal bone loss and the recession of the mid-buccal mucosa and of the interproximal papillae. However, in the submerged group, 1 mm more loss of the width of keratinized mucosa was observed in comparison with the transmucosal group. This finding was explained by the fact that, in the submerged group, the flap was coronally repositioned to reach primary wound closure. This procedure probably caused coronal displacement of the mucogingival junction, which led to the reduced width of keratinized mucosa at the buccal aspect. In the event of partial or complete loss of the buccal bone wall of the socket at the time of implant placement, the procedure described for dehiscence-type defects is performed. 在最近的一项多中心随机对照试验（45）中，对在新鲜拔牙窝中植入种植体的浸没式和经粘膜式愈合模式的临床效果进行了比较。一年后，治疗组之间在存活率、边缘骨质流失、颊中粘膜和颊间乳头的退缩方面没有差异。不过，与经粘膜组相比，浸没组的角化粘膜宽度减少了 1 毫米。这一发现的原因是，在浸没组中，为了达到伤口的初步闭合，皮瓣被重新定位到冠状面。这一过程可能会造成粘龈交界处的冠状移位，从而导致颊侧角化粘膜的宽度减小。如果种植体植入时牙槽骨的颊侧骨壁部分或完全缺失，则应采用针对开裂型缺损的手术方法。
Dehiscence-type defect: Class 2 开裂型缺损第 2 级
Class 2 defects are characterized by peri-implant dehiscences, in which the volume stability of the area to be augmented is provided by the adjacent bone walls. Dehiscence of the buccal bone is the most frequently encountered situation needing bone regeneration at implants. A large number of preclinical and clinical studies demonstrated that dehisced implant surfaces successfully osseointegrate following combined guided bone regeneration procedures (123, 165, 166, 230, 234). 第二类缺损的特点是种植体周围开裂，在这种情况下，需要增量的区域的体积稳定性由邻近的骨壁提供。颊骨开裂是需要在种植体上进行骨再生的最常见情况。大量临床前和临床研究表明，在联合引导骨再生手术后，开裂的种植体表面能成功实现骨结合（123、165、166、230、234）。
After implant placement, analysis of the dehiscence-type defect is performed and the decision regarding the need for augmentation of the ridge contour is taken. In posterior sites, which generally do not require augmentation of the ridge contour, a bioresorbable membrane in combination with particulate bone substitute is the treatment of choice (Fig. 6). Similarly, in esthetically sensitive sites, in which the volume stability of the bone defect is provided by the adjacent bone walls, a bioresorbable membrane in combination with particulate bone substitute is the treatment of choice (Fig. 7). 种植体植入后，要对开裂型缺损进行分析，并决定是否需要增加牙脊轮廓。后牙部位一般不需要增加牙脊轮廓，生物可吸收膜结合颗粒骨替代物是首选的治疗方法（图 6）。同样，在对美观敏感的部位，骨缺损的体积稳定性由邻近的骨壁提供，生物可吸收膜结合微粒骨替代物是首选的治疗方法（图 7）。
Subsequent to implant placement, the cortical bone around the dehiscence defect is perforated to allow earlier vascularization and thus to improve bone repair (179). A particulate bone substitute material is applied onto the exposed implant surface and a resorbable membrane is shaped and adapted to extend 2 mm beyond the defect margins (Figs 6 and 7). It is important to bear in mind that particulate grafting material, in combination with a resorbable membrane, does not provide complete volume stability. During healing, compressive forces at the site to be regenerated may result in membrane collapse and displacement of parts of the grafting material (140, 190, 207, 236). A small over-augmentation of the dehiscence defect by placement of some additional bone substitute material is therefore recommended when applying this procedure. For adequate stabilization of the area to be augmented, additional fixation of the membrane is recommended by using resorbable pins, by attaching the membrane around the implant or healing cap, or by a combination of both. Thereafter, the flap is adapted and sutured to allow submucosal or transmucosal healing of the implant site. No scientific evidence is available on whether or not adding autogenous bone to the bone substitute will lead to more successful clinical results. In numerous clinical studies it has been demonstrated that the application of bone substitute alone, together with a barrier membrane, leads to successful bone coverage of previously dehisced implant surfaces (85, 93, 149). An adjunct of autogenous bone to the bone substitute can therefore be considered unnecessary for the successful treatment of dehiscence-type defects. As scientific data are lacking on the influence of guided bone regeneration on the survival and the success rates of implants, a statement on the need for guided bone regeneration in cases of small bone dehiscences cannot be made (38, 61). However, augmentation of buccal bone defects may play an important role as far as the esthetic outcome of the rehabilitation is concerned. 植入种植体后，在开裂缺损周围的皮质骨上穿孔，使血管尽早形成，从而改善骨修复（179）。将颗粒状骨替代材料应用于暴露的种植体表面，然后将可吸收膜塑形并调整至超出缺损边缘 2 毫米（图 6 和图 7）。需要注意的是，颗粒状植骨材料与可吸收膜的结合并不能提供完全的体积稳定性。在愈合过程中，再生部位的压迫力可能会导致膜塌陷和部分移植材料移位（140、190、207、236）。因此，在采用这种方法时，建议通过放置一些额外的骨替代材料，对开裂缺损进行小幅过度增量。为了充分稳定需要增量的区域，建议使用可吸收针、将骨膜固定在种植体或愈合帽周围，或两者结合使用，对骨膜进行额外固定。之后，对皮瓣进行调整和缝合，使植入部位的粘膜下或粘膜上愈合。关于在骨替代物中添加自体骨是否会带来更成功的临床效果，目前尚无科学证据。大量临床研究表明，单独使用骨替代物，再加上一层隔离膜，就能成功覆盖之前开裂的种植体表面（85、93、149）。因此，要成功治疗开裂型缺损，无需在骨替代物中添加自体骨。 由于缺乏关于引导性骨再生对种植体存活率和成功率影响的科学数据，因此无法对小的骨缺损情况下引导性骨再生的必要性做出说明（38，61）。不过，就修复的美学效果而言，颊骨缺损的增量可能会起到重要作用。
It has been demonstrated clinically that guided bone regeneration of peri-implant defects, in conjunction with transmucosal healing, is a successful procedure with a high degree of defect repair (24, 87, 93, 127). A multicenter randomized controlled trial compared the submerged and the transmucosal healing modalities at single-crown two-piece implants placed in the anterior maxilla and mandible (90). The implants were placed as Type 2, Type 3 or Type 4 implant-placement procedures (86). Guided bone regeneration of peri-implant bone defects was performed in of the patients. One-hundred and twenty-seven subjects completed the 1-year 临床实践证明，种植体周围缺损的引导性骨再生与经黏膜愈合相结合是一种成功的手术，缺损修复的程度很高（24、87、93、127）。一项多中心随机对照试验比较了在上颌骨和下颌骨前部植入单冠两件式种植体时的浸没式和经粘膜式愈合方式（90）。这些种植体是作为 2 型、3 型或 4 型种植体植入手术植入的（86）。其中 名患者在引导下进行了种植体周围骨缺损的骨再生。127名受试者完成了为期一年的
Fig. 6. (A, B) Dehiscence of the buccal bone at an implant position 36. The defect is treated by guided bone regeneration, applying (C) particulate bovine-derived bone mineral and (D, E) a resorbable collagen membrane. (F) At re-entry surgery 6 months later, the initially exposed implant surface is covered by newly formed bone. 图 6：（A、B）种植体 36 号位置的颊骨开裂。采用引导骨再生法治疗缺损，应用（C）微粒牛源性骨矿物质和（D，E）可吸收胶原膜。(F）6 个月后再次进行手术时，最初暴露的种植体表面被新形成的骨覆盖。
examination. It was concluded that the submerged and the transmucosal healing modes achieved similar outcomes with regard to implant survival, interproximal bone level, soft-tissue parameters and patient satisfaction. These results were confirmed by other recent randomized controlled trials, which found equivalent clinical performances for submerged and transmucosal healing modes (34, 35, 62, 63, 208). Nevertheless, in the following clinical situations the submerged healing mode may be desirable: when the implant does not exhibit optimal primary stability; when it cannot be excluded that a removable mucosa-supported provisional denture could transmit excessive forces onto the healing abutment; and in cases where surgical corrections of the soft tissue following the implant placement are planned. 检查结果结论是，在种植体存活率、近端骨水平、软组织参数和患者满意度方面，浸没式和经粘膜式愈合模式取得了相似的结果。最近的其他随机对照试验也证实了这些结果，发现浸没式和经粘膜式愈合模式的临床表现相当（34、35、62、63、208）。然而，在以下临床情况下，浸没式愈合模式可能是可取的：当种植体没有表现出最佳的初期稳定性时；当不能排除可摘粘膜支持临时义齿可能将过大的力传递到愈合基台上时；以及计划在种植体植入后对软组织进行手术矫正时。
Dehiscence-type defect: Class 3 开裂型缺损第 3 级
Class 3 defects are characterized by peri-implant dehiscences, in which the volume stability of the area to be augmented is not provided by the adjacent bone walls. In situations requiring optimal support of the peri-implant soft tissue, the use of titanium-reinforced e-PTFE membranes, in combination with a particulate bone substitute, is recommended for the treatment of Class 3 defects (Fig. 8). 第 3 类缺损的特点是种植体周围开裂，邻近骨壁无法提供待增量区域的体积稳定性。在需要对种植体周围软组织提供最佳支持的情况下，建议使用钛增强型 e-PTFE 膜和微粒骨替代物来治疗 3 级缺损（图 8）。
The clinical protocol for guided bone regeneration at Class 3 defects includes the following steps: perforation of the cortical bone around the dehiscence defect; application of particulate bone substitute; and adaptation of a titanium-reinforced e-PTFE membrane over the bone dehiscence without over-building the area (Fig. 8). The use of titanium tacks is recommended to provide adequate adaptation and stabilization of the membrane. A resorbable membrane may be applied over the e-PTFE membrane with the aim of facilitating spontaneous wound healing in the event of soft-tissue dehiscence. Thereafter, the flap is adapted and sutured to allow submerged healing of the regeneration site. 3 级缺损引导骨再生的临床方案包括以下步骤：在开裂缺损周围的皮质骨穿孔；应用颗粒状骨替代物；以及在不过度构建该区域的情况下在骨开裂处适应钛强化 e-PTFE 膜（图 8）。建议使用钛钉以充分适应和稳定薄膜。可在 e-PTFE 膜上覆盖一层可吸收膜，以便在软组织开裂时促进伤口自发愈合。之后，对皮瓣进行适配和缝合，使再生部位在水下愈合。
As premature exposure of e-PTFE membranes often leads to infectious complications and failure of guided bone regeneration, attention should be paid to achieve complete and tension-free soft-tissue coverage at the regenerated area . In cases where the mucosal quantity and/or quality in the defect area are deemed deficient, a soft-tissue grafting procedure may be indicated before implant placement. 由于 e-PTFE 膜的过早暴露往往会导致感染并发症和引导骨再生失败，因此应注意在再生区域实现完整、无张力的软组织覆盖 。如果认为缺损区的粘膜数量和/或质量不足，可能需要在植入种植体之前进行软组织移植。
The staged guided bone regeneration approach has been claimed as advantageous for achieving successful outcomes of bone augmentation at periimplant dehiscences. In a recent preclinical study, the staged and the combined approaches showed 分阶段引导骨再生方法被认为是在种植体周围开裂处成功实现骨增量的有利方法。在最近的一项临床前研究中，分阶段和联合方法显示
Fig. 7. (A) Dehiscence-type defect (Class 2) at an implant position 21. (B) The volume stability of the region to be augmented is provided by the adjacent bone walls. (C) Bovinederived bone mineral containing collagen is applied onto the exposed implant surface. (D, E) A resorbable collagen membrane is adapted to extend beyond the defect margins and fixed by two resorbable polylactide pins placed in the apical region. (F) Clinical situation 9 months after implant placement. 图 7. (A) 21 号种植体位置的开裂型缺损（2 级）。(B）邻近的骨壁为需要增量的区域提供了体积稳定性。(C) 将含有胶原蛋白的牛源骨矿应用于暴露的植入物表面。(D、E）将可吸收的胶原蛋白膜延伸至缺损边缘以外，并通过放置在顶端区域的两个可吸收的聚乳酸钉进行固定。(F）植入 9 个月后的临床情况。
similar implant osseointegration levels over time (10). However, the histological analysis found slightly better vertical bone fill for the staged approach compared with the combined approach at 8 and 16 months. Another histological study in a dog model concluded that the combined approach is preferable to the staged approach in terms of alveolar crest maintenance (5). A prospective cohort study including 45 patients reported that implant placement combined with, or staged after bone augmentation resulted in predictable treatment outcomes at 3 years of function (39). Owing to the lack of prospective controlled clinical trials, there is no clear evidence regarding the influence of the timing of augmentation procedures on the outcome of guided bone regeneration at peri-implant bone defects (61, 216). 随着时间的推移，种植体的骨结合水平相似（10）。然而，组织学分析发现，在8个月和16个月时，分期法的垂直骨充填度略高于联合法。另一项在狗模型中进行的组织学研究认为，就牙槽嵴的维护而言，联合方法优于分期方法（5）。一项包括 45 名患者的前瞻性队列研究报告称，种植体植入与骨增量术相结合或在骨增量术后分阶段植入种植体，可在 3 年后获得可预测的治疗效果（39）。由于缺乏前瞻性对照临床试验，目前还没有明确的证据表明骨增量手术的时机对种植体周围骨缺损引导骨再生的效果有影响（61，216）。
In a prospective clinical study including 16 patients, peri-implant dehiscences at single implants were augmented using e-PTFE membranes and deproteinized bovine-derived bone mineral (186). The labial gain of peri-implant tissue obtained by guided bone regeneration and soft-tissue augmentation was assessed using a new method for volumetric measurements. Implant placement with simultaneous guided bone regeneration using e-PTFE membranes resulted in a gain of labial volume in all cases. In the majority of patients treated, the gain of peri-implant tissue in the labial direction ranged from 1 to 1.5 mm and remained stable to a high degree within the first year after crown insertion. The guided bone regeneration procedure contributed more to the volume gain than did the soft-tissue grafting. 在一项包括 16 名患者的前瞻性临床研究中，使用 e-PTFE 膜和去蛋白牛源性骨矿对单个种植体的种植体周围裂隙进行了增量（186）。使用一种新的体积测量方法评估了通过引导骨再生和软组织增量获得的种植体周围组织的唇增量。在所有病例中，种植体植入同时使用 e-PTFE 膜引导骨再生可获得唇部体积的增加。在大多数接受治疗的患者中，种植体周围组织在唇侧方向的增量为 1 至 1.5 毫米，并且在牙冠植入后的第一年内保持高度稳定。与软组织移植相比，引导骨再生手术对体积增加的贡献更大。
Horizontal defect: Class 4 水平缺陷：第 4 级
Class 4 defects are characterized by reduced ridge width precluding the primary stability of the implant in the prosthodontically correct position. In such situations, the staged approach for bone regeneration and implant placement is chosen (Fig. 9). Autogenous bone blocks, alone, or in combination with bone substitute and/or collagen membranes, are the most reliable and successful procedures for staged augmentations of large bone defects before implant placement (106, 119). 第 4 类缺损的特点是牙脊宽度减小，无法将种植体稳定在修复正确的位置上。在这种情况下，可以选择分阶段的骨再生和种植体植入方法（图 9）。自体骨块单独使用或与骨替代物和/或胶原膜结合使用，是种植体植入前对大面积骨缺损进行分期增量的最可靠、最成功的方法（106，119）。
The clinical procedure for primary horizontal ridge augmentation starts with the preparation of the site to be augmented. After elevation of the mucoperiostal flap, the cortical bone at the recipient bed is perforated in order to allow earlier vascularization and to improve integration of the bone block (58, 65, 169). Subsequently, the autogenous bone block is harvested, adapted to achieve 原发性水平嵴增高术的临床程序首先是准备要增高的部位。抬高粘骨膜瓣后，在受区的皮质骨上穿孔，以便更早地形成血管，提高骨块的整合度（58、65、169）。随后，获取自体骨块，并对其进行调整，以达到以下目的
Fig. 8. (A, B) Dehiscence-type defect (Class 3) at an implant position 22. (C, D) The defect is treated by guided bone regeneration applying particulate bovine-derived bone mineral and an expanded polytetrafluoroethylene titanium-reinforced membrane. (E) Six months later, the flap is raised to gain access for the membrane removal. (F) Note the substantial volume of the newly formed bone. 图 8：（A、B）种植体 22 号位置的开裂型缺损（3 级）。(C、D）使用牛源性骨矿物质颗粒和膨体聚四氟乙烯钛增强膜引导骨再生治疗缺损。(E）6 个月后，翻起皮瓣，以便取出骨膜。(F）注意新形成的骨量很大。
intimate contact between the graft and the bone at the recipient site and rigidly fixed with metal screws (Fig. 9). To reduce its resorption, the bone block is covered with particulate bone substitute and a resorbable membrane ( . The donor defect in the chin region is filled with bone substitute and covered with a resorbable membrane, in order to enhance bone repair (188). The flap is coronally advanced by periosteal release, adapted and sutured to allow a tension-free primary closure at the augmented site. A healing time of 4-6 months before the second surgical intervention for placement of the implants is commonly accepted . 移植物与受体部位的骨亲密接触，并用金属螺钉严格固定（图 9）。为减少骨块的吸收，在骨块上覆盖颗粒状骨替代物和可吸收膜（ 。下巴区域的供体缺损用骨替代物填充，并覆盖一层可吸收膜，以加强骨修复（188）。通过骨膜松解将皮瓣向冠状方向推进，调整并缝合皮瓣，以便在增量部位进行无张力的初次闭合。 一般认为，在第二次手术植入种植体之前，需要 4-6 个月的愈合时间。
Several techniques for harvesting autogenous bone blocks from intra- and extra-oral donor sites have been described in the literature (134, 145). For the treatment of localized jaw defects, intra-oral sites generally offer a sufficient amount of bone (41, 102, 124, 146). Intra-oral sites for the harvesting of bone blocks encompass the chin and the retromolar mandibular region, including the mandibular ramus. When selecting the site for intra-oral autogenous bone harvesting, the amount of bone needed for grafting and the risk of complications should be considered. The chin generally offers a larger bone volume for harvesting compared with the retromolar mandibular area (43). However, large interindividual variability exists regarding the amount of bone that can be harvested, and this is determined by the location of anatomical boundaries such as teeth, blood vessels and nerve bundles (48). Postoperative complications related to the harvesting of bone include pain, wound dehiscences, pulp necrosis of teeth and temporary and permanent neurosensory disturbances (43, 155, 173, 227, 232). It has been reported that autogenous bone harvesting from the chin region is related to increased postoperative morbidity and number of complications, in comparison with autogenous bone harvesting from the retromolar region ( 40,43 , 173). This may be explained by the presence of blood vessels and nerve bundles in the anterior mandible (131, 212). In a recent cone-beam CT examination, bone canals in the anterior mandible were found in of the patients examined (178). Owing to the potentially lower risk of complications, the retromolar mandibular area is, whenever possible, the preferable site for intra-oral harvesting of autogenous bone blocks. Cross-sectional diagnostic imaging may enhance the ability to assess the topography and dimension of bone available for grafting (96). 文献中介绍了几种从口内和口外供体部位获取自体骨块的技术（134、145）。对于局部颌骨缺损的治疗，口内部位通常能提供足够的骨量（41、102、124、146）。采集骨块的口内部位包括下巴和下颌后磨区，包括下颌横突。在选择口内自体骨采集部位时，应考虑移植所需的骨量和并发症的风险。与下颌后磨牙区域相比，颏部通常可提供更大的骨量（43）。然而，可采集的骨量存在很大的个体差异，这是由牙齿、血管和神经束等解剖界限的位置决定的（48）。与取骨有关的术后并发症包括疼痛、伤口裂开、牙髓坏死以及暂时性和永久性神经感觉障碍（43、155、173、227、232）。据报道，与从后磨牙区自体取骨相比，从下巴区自体取骨会增加术后发病率和并发症的数量（40、43、173）。这可能与下颌骨前部存在血管和神经束有关（131，212）。在最近的一项锥形束 CT 检查中， 受检患者中发现了下颌骨前部的骨管（178）。由于并发症的潜在风险较低，在可能的情况下，下颌后磨牙区域是口内采集自体骨块的首选部位。 横断面诊断成像可提高评估可供移植骨地形和尺寸的能力（96）。
Fig. 9. (A) A horizontal and vertical ridge defect (Class 5) in a maxillary front. (B, C) Two autogenous bone blocks harvested from the chin are adapted to the recipient sites and rigidly fixed with metal screws. (D, E) The bone blocks are covered with particulate bovine-derived bone mineral and a resorbable collagen membrane. (F) Placement of the implants at positions 11 and 13, 6 months after primary bone augmentation (staged approach). 图 9：（A）上颌前牙的水平和垂直脊缺损（5 级）。(B、C）两个从下巴采集的自体骨块与受体部位相适应，并用金属螺钉固定。(D、E）骨块上覆盖了牛源性骨矿物质颗粒和可吸收胶原膜。(F）初次骨增量术后 6 个月，在第 11 位和第 13 位植入假体（分阶段方法）。
e-PTFE membrane, in combination with particulate deproteinized bovine-derived bone mineral, is a welldocumented alternative procedure for primary ridge augmentation, permitting drawbacks related to the harvesting of autogenous bone to be avoided (106). Compared with the use of autogenous bone blocks, this procedure appears to permit less gain in ridge width and to be associated with an increased need for additional grafting and a higher complication rate. e-PTFE 膜与微粒脱蛋白牛源性骨矿物质相结合，是一种有据可查的初级牙脊增量替代方法，可以避免与采集自体骨相关的缺点（106）。与使用自体骨块相比，这种方法增加的牙脊宽度较小，而且需要更多的移植，并发症发生率也更高。
In contrast, only limited clinical data are available reporting the successful use of particulate or block deproteinized bovine-derived bone mineral in combination with resorbable membranes for bone augmentation before implant placement (74, 91, 240). Healing times ranging from 7 to 10 months have been recommended when using deproteinized bovine-derived bone mineral without autogenous bone for various bone augmentation procedures (74, 77, 91, 219). Recent clinical case series demonstrated that block allografts, in conjunction with the placement of resorbable membranes, represent a viable treatment option for augmentations of atrophic alveolar ridges in a two-stage implant-placement procedure (117, 152, 154). More clinical evidence is needed to recommend the use of bone substitutes and resorbable membranes for horizontal bone augmentation. 相比之下，仅有有限的临床数据报告了在植入种植体前成功使用颗粒状或块状去蛋白牛源骨矿物质与可吸收膜相结合进行骨增量的情况（74、91、240）。在使用去蛋白牛源骨矿而不使用自体骨进行各种骨增量手术时，建议使用 7 到 10 个月的愈合时间（74、77、91、219）。最近的临床病例系列表明，在两阶段种植体植入手术中，块状同种异体骨与可吸收膜的植入相结合，是一种可行的牙槽脊萎缩增量治疗方案（117、152、154）。要推荐使用骨替代物和可吸收膜进行水平骨增量，还需要更多的临床证据。
Vertical defect: Class 5 垂直缺陷：第 5 级
Class 5 defects are characterized by reduced ridge height. Vertical ridge augmentation is indicated in situations in which the remaining amount of vertical bone is insufficient for anchorage of the implant or in which an unfavorable appearance of the soft tissue is expected owing to the lack of hard-tissue support. This procedure is performed using the staged approach for bone augmentation and implant placement. Similarly to horizontal ridge augmentation, autogenous bone block, alone, or in combination with bone substitute and/or collagen membrane, is the treatment of choice for vertical ridge defects . When performing vertical ridge augmentation, the autogenous bone block is partially or completely fixed on the coronal surface of the alveolar ridge in order to augment the bone height. Apart from that, the same clinical procedure is performed as described for horizontal augmentations with autogenous bone blocks (Fig. 9). The rate of soft-tissue complications appears to be considerably higher for vertical ridge augmentations than for horizontal augmentations (177). This may be because a tension-free primary wound closure is more difficult to achieve as a result of the increased volume to be covered. The clinical use of bone-substitute 第 5 类缺损的特点是牙脊高度降低。如果剩余的垂直骨量不足以固定种植体，或者由于缺乏硬组织的支持，预计软组织的外观会不理想，就需要进行垂直骨嵴增量术。这种手术采用分阶段的骨增量和种植体植入方法。与水平牙脊增量术类似，自体骨块单独或结合骨替代物和/或胶原膜是治疗垂直牙脊缺损 的首选方法。在进行垂直嵴增高术时，自体骨块会部分或全部固定在牙槽嵴的冠状面上，以增高骨高度。除此之外，临床程序与使用自体骨块进行水平增高时相同（图 9）。软组织并发症的发生率在垂直牙脊增高术中似乎要比水平增高术高得多（177）。这可能是因为需要覆盖的面积增大，因此更难实现无张力的初级伤口闭合。骨替代物的临床应用
materials for the regeneration of vertical ridge defects is not sufficiently documented . 用于垂直脊缺损再生的材料还没有充分的记录。
Current research trends 当前的研究趋势
The aim of the current research in bone augmentation procedures is to develop more effective strategies that promote the body's ability to regenerate lost tissues, to increase treatment predictability and to reduce surgical invasiveness. Major efforts in this research field are focusing on growth and differentiation factors and their delivery systems. One aim is to identify bioactive molecules that regulate wound and tissue regeneration and apply them to induce bone growth in the area to be regenerated. In order to deliver these molecules in therapeutically suitable concentrations at the site of regeneration, biomaterials with adequate mechanical properties and the capacity to release these factors with tailor-made kinetics are needed. 目前骨质增生手术研究的目标是开发更有效的策略，促进人体再生失去的组织，提高治疗的可预测性，减少手术的创伤性。这一研究领域的主要工作集中在生长和分化因子及其输送系统上。其中一个目标是确定调节伤口和组织再生的生物活性分子，并将其用于诱导待再生区域的骨生长。为了在再生部位输送治疗浓度合适的这些分子，需要具有适当机械性能的生物材料，并能以定制的动力学释放这些因子。
Growth factors and carrier systems 生长因子和载体系统
Research has been directed toward growth factors, aiming at overcoming the long treatment time and the limited predictability of bone regeneration of extensive bone defects . Various growth factors, including bone morphogenetic proteins, growth and differentiation factors, platelet-derived growth factor, vascular endothelial growth factor, insulin-like growth factor, peptides of the parathyroid hormone and enamel matrix derivative, have been evaluated for bone regeneration procedures. 研究的方向是生长因子，旨在克服大面积骨缺损治疗时间长和骨再生可预测性有限的问题 。各种生长因子，包括骨形态发生蛋白、生长和分化因子、血小板衍生生长因子、血管内皮生长因子、胰岛素样生长因子、甲状旁腺激素肽和釉质基质衍生物，都已被评估用于骨再生程序。
A recent systematic review assessed the preclinical and human studies regarding the clinical, histological and radiographic outcome of the use of growth factors for localized alveolar ridge augmentation (114). Different levels and quantity of evidence were available for the growth factors evaluated, revealing that bone morphogenetic protein-2, bone morphogenetic protein-7, growth and differentiation factor5, platelet-derived growth factor and parathyroid hormone may stimulate local bone augmentation to various degrees. In six clinical studies, bone morphogenetic protein- 2 positively affected the outcome of local bone augmentation, with increasing effects for higher doses ( . It was therefore concluded that clinical data support the use of bone morphogenetic protein- 2 in the promotion of bone healing for socket preservation, sinus floor elevation and horizontal ridge augmentation (114). Recent case series clinically and histologically demonstrated the effectiveness of platelet-derived growth factor for the treatment of alveolar ridge defects in humans (56, 150, 202, 203). Future controlled clinical trials are required to demonstrate the outcomes of growth factor-mediated regeneration of alveolar ridge defects. Follow-up studies examining implants placed in these augmented areas are needed to determine the long-term success of this combined therapy in bone augmentation procedures. 最近的一项系统性综述对临床前研究和人体研究进行了评估，内容涉及使用生长因子进行局部牙槽嵴增高的临床、组织学和放射学效果（114）。所评估的生长因子具有不同程度和数量的证据，显示骨形态发生蛋白-2、骨形态发生蛋白-7、生长与分化因子5、血小板衍生生长因子和甲状旁腺激素可在不同程度上刺激局部骨质增生。在六项临床研究中，骨形态发生蛋白-2对局部骨质增生的结果有积极影响，剂量越大，影响越大（ 。因此得出结论，临床数据支持使用骨形态发生蛋白- 2促进骨愈合，用于牙槽窝保存、上颌窦底抬高和水平牙脊增高（114）。最近的病例系列从临床和组织学角度证明了血小板衍生生长因子治疗人类牙槽嵴缺损的有效性（56、150、202、203）。未来需要进行对照临床试验，以证明生长因子介导的牙槽嵴缺损再生效果。还需要对植入这些增量区域的种植体进行跟踪研究，以确定这种联合疗法在骨增量手术中的长期疗效。
The regenerative potential of growth and differentiation factors is dependent on a carrier material that serves as a delivery system and as a scaffold for cellular ingrowth (100, 197). Various carrier materials for the delivery of growth factor, including collagen, hydroxyapatite, tricalcium phosphate, allografts, deproteinized bovine-derived bone mineral, polylactic acid, polyglycolic acid and polyethylene glycol, have been evaluated for use in bone regeneration procedures (222). The ideal carrier, which should be able to provide space for bone regeneration, allow cell ingrowth and provide controlled release of bioactive molecules, has not yet been discovered. Research should address the questions regarding the clinically effective doses required, the properties of an ideal carrier material and the optimal release kinetics for the clinical applications of growth factors (216). 生长因子和分化因子的再生潜力取决于作为输送系统和细胞生长支架的载体材料（100，197）。目前已对用于骨再生手术的各种生长因子输送载体材料进行了评估，包括胶原蛋白、羟基磷灰石、磷酸三钙、同种异体移植物、去蛋白牛源性骨矿、聚乳酸、聚乙醇酸和聚乙二醇（222）。理想的载体应能为骨再生提供空间，允许细胞生长，并能控制生物活性分子的释放，但这种载体尚未被发现。研究应解决生长因子临床应用所需的临床有效剂量、理想载体材料的特性和最佳释放动力学等问题（216）。
Bone substitutes 骨替代品
New bone substitute materials have been developed with the aim of simplifying the clinical steps of boneaugmentation procedures. These include injectable forms of calcium phosphate cement and moldable synthetic hydroxyapatite/tricalcium phosphate coated with PLGA and modified with N -methyl-2pyrrolidone as plasticizer ( 6,185 ). Both materials exhibit a self-setting process to a hard mass following contact with blood or saline. The use of such products may offer the following clinical advantages: more efficient in-situ application; improved mechanical retention of bone substitute within the defect; and enhanced volume stability of the regenerated area. Consequently, the use of devices for mechanical stabilization of the regenerated area, such as titaniumreinforced membranes and stabilization pins, may potentially decrease. 为了简化骨增量手术的临床步骤，新的骨替代材料应运而生。这些材料包括可注射的磷酸钙骨水泥和可成型的合成羟基磷灰石/磷酸三钙，其表面涂有聚乳酸甘油酯（PLGA），并以 N-甲基-2-吡咯烷酮作为增塑剂进行改性（6,185）。这两种材料在与血液或生理盐水接触后都会自凝成硬块。使用这类产品具有以下临床优势：更有效的原位应用；改善骨替代物在缺损处的机械固定；提高再生区域的体积稳定性。因此，用于再生区域机械稳定的装置，如钛增强膜和稳定针的使用可能会减少。
Currently, there are no clinically well-documented alternatives to autogenous bone blocks for the grafting of larger defects. An equine-derived block of bone mineral containing collagen was recently introduced for primary ridge augmentations at large 目前，在移植较大的缺损时，还没有经临床证实的自体骨块替代品。最近，一种含有胶原蛋白的马源性骨矿物质块被引入用于大面积缺损的初级牙脊增量。
defects (70, 189). This material showed good clinical handling and high biocompatibility. Two preliminary preclinical trials using prototypes of this type of block material reported an invasion of connective tissue with limited bone formation (70, 201). In contrast, in another preclinical study, the prototype equine-derived scaffold exhibited high osteoconductive properties, as indicated by pronounced bone ingrowth and graft integration at the recipient sites (189). At the same time, the graft material was characterized by an active cell-mediated degradation. It was speculated that these contrasting findings might be explained by different physiochemical properties of the material prototypes. 缺陷（70，189）。这种材料具有良好的临床操作性和较高的生物相容性。使用这种块状材料原型的两项初步临床前试验报告称，结缔组织受到侵袭，骨形成有限（70，201）。与此相反，在另一项临床前研究中，马源性支架原型表现出很高的骨诱导性，受体部位明显的骨生长和移植物整合表明了这一点（189）。与此同时，移植材料的特点是细胞介导的降解活跃。据推测，这些截然不同的发现可能是由于材料原型的理化特性不同造成的。
A technique has recently been described for threedimensional printing of a bone substitute block made of synthetic calcium phosphate (79). A preclinical study evaluated the use of such synthetic block graft for vertical ridge augmentation (217). The blocks were easy to handle and sufficiently stable to allow rigid fixation onto the host bone, using metal screws. Histological evaluation revealed a high degree of bone ingrowth and no signs of a foreign-body reaction. The amount of new bone within the graft was similar to that reported in previous studies applying established bone augmentation procedures (11, 19, 33). Although it is too early to draw clinical conclusions, it will be interesting to observe the development of these modern techniques. 最近有一项三维打印合成磷酸钙骨替代块的技术（79）。一项临床前研究评估了这种合成块状移植物在垂直脊增量中的应用（217）。这种骨块易于处理，而且足够稳定，可以使用金属螺钉将其刚性固定在宿主骨上。组织学评估显示，骨的生长程度很高，没有异物反应的迹象。移植物内新骨的数量与之前采用成熟骨增量程序的研究报告相似（11、19、33）。虽然现在得出临床结论还为时尚早，但观察这些现代技术的发展将是非常有趣的。
Outlook into the future 未来展望
Future developments in bone regeneration procedures will aim at simplifying the clinical handling and influencing the biologic processes. 骨再生程序的未来发展将以简化临床操作和影响生物过程为目标。
New materials should allow optimal cell ingrowth and present adequate mechanical properties sufficient to maintain space for bone regeneration. To simplify clinical handling, no membranes or procedures for mechanical fixation should be needed. The use of synthetic bone substitutes would eliminate the risk of disease transmission and immunologic reactions potentially inherent to the use of nonsynthetic materials. In turn, this would result in lower morbidity of surgical procedures compared with the transplantation of autogenous tissue. Customized devices for bone regeneration, produced using three-dimensional imaging and computer-aided design/computer-aided manufacturing technologies, could represent a very efficient new process for treatment. 新材料应允许最佳的细胞生长，并具有足够的机械性能，足以保持骨再生的空间。为了简化临床操作，不需要薄膜或机械固定程序。使用合成骨替代物将消除使用非合成材料可能固有的疾病传播和免疫反应风险。与移植自体组织相比，这将降低外科手术的发病率。利用三维成像和计算机辅助设计/计算机辅助制造技术生产的定制骨再生设备，可能是一种非常有效的新治疗方法。
From a biological point of view, application of growth and differentiation factors may induce faster growth of bone into the area to be regenerated, thus reducing the healing time and treatment efforts of extended bone defect volumes. Modification of the biomaterial surface, achieved by coating with cell-adhesion molecules or nanoparticles, may lead to more desirable tissue responses. The incorporation of antimicrobial substances might minimize the influence of bacterial contamination at the regenerated site. Additional efforts of future research should focus on understanding the regulation of gene expression and the molecular features of the bone regeneration process. Cell-based tissue engineering and gene-delivery therapy represent new therapeutic strategies that have the potential to overcome several shortcomings associated with the existing bone regeneration techniques. 从生物学的角度来看，应用生长因子和分化因子可促使待再生区域的骨骼更快地生长，从而缩短愈合时间，减少骨缺损面积扩大时的治疗工作量。通过涂覆细胞粘附分子或纳米颗粒来修饰生物材料表面，可能会产生更理想的组织反应。抗菌物质的加入可能会将再生部位的细菌污染影响降至最低。未来研究的其他重点应放在了解基因表达的调控和骨再生过程的分子特征上。基于细胞的组织工程和基因递送疗法是一种新的治疗策略，有可能克服现有骨再生技术的一些不足之处。
Conclusions 结论
There is a large body of evidence demonstrating the successful use of guided bone regeneration to regenerate missing bone at implant sites with insufficient bone volume. 大量证据表明，引导骨再生技术可成功用于骨量不足的植入部位缺失骨的再生。
Many of the materials and techniques currently available for bone regeneration of alveolar ridge defects were developed many years ago. Recently, various new materials and techniques have been introduced. The limited number of comparative studies does not provide sufficient evidence to select the most appropriate procedure. 目前用于牙槽嵴缺损骨再生的许多材料和技术都是多年前开发的。最近，各种新材料和新技术相继问世。数量有限的比较研究无法提供足够的证据来选择最合适的程序。
The influence of guided bone regeneration on implant survival and success rates, and the longterm stability of the augmented bone, remain unknown. 引导性骨再生对种植体存活率和成功率的影响以及增量骨的长期稳定性仍是未知数。
The presented classification of bone defects is meant as a basis on which to create the decisionmaking process regarding the choice of strategy for bone augmentation. 本文所介绍的骨缺损分类方法可作为选择骨增量策略的决策依据。
There is active research in different areas focusing on simplification of clinical handling and on the development of more effective strategies to promote the body's ability to regenerate lost tissues. 目前，不同领域的研究都在积极开展，重点是简化临床操作和开发更有效的策略，以促进人体再生失去的组织的能力。
Acknowledgments 致谢
The authors gratefully acknowledge Dr Dominik Büchi, PD Dr Ronald Jung, Dr Dr David Schneider and Dr Daniel Thoma for providing the photographs of Figs 1, 4, 5 and 8. The valuable support of Dr Javier Mir Mari and Gisela Müller during the preparation of this review is highly appreciated. This review was 作者感谢 Dominik Büchi 博士、Ronald Jung 博士、David Schneider 博士和 Daniel Thoma 博士提供图 1、图 4、图 5 和图 8 的照片。在本综述的撰写过程中，哈维尔-米尔-马里博士和吉塞拉-米勒博士给予了宝贵的支持，在此一并致谢。本综述
supported by the Clinic of Fixed and Removable Prosthodontics and Dental Material Science, Center of Dental Medicine, University of Zurich, Switzerland. 由瑞士苏黎世大学牙科医学中心固定和可移动义齿修复及牙科材料科学诊所提供支持。
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