Guided tissue regeneration, periodontal

引导组织再生,牙周
  • 文章类型: Journal Article
    目的:外周血间充质干细胞(PBMSCs)和富血小板纤维蛋白基质(PRFM)的组合可能是一种可能的牙周再生材料,具有每种材料的协同作用。这项随机对照临床试验旨在评估人牙周下颌骨内缺损(IOD)中超细胞(PRFM和PBMSCs)与单独PRFM的再生能力。
    方法:这项研究包括17名男女患者(12名男性,5名女性),年龄30-55岁(平均年龄=37.7±4.4岁),符合纳入标准(双侧IOD的影像学和临床评估,探查袋深度(PPD≥6mm)。每位患者都使用了裂口设计。下颌弓中共有34个部位随机接受单独PRFM+开放皮瓣清创(OFD)[对照部位]或超级细胞(PRFM+PBMSCs)+OFD[测试部位]。临床参数菌斑指数(PI),牙龈指数(GI),PPD,临床依恋水平(CAL),在射线照相参数中;在基线记录缺陷深度(DD)和缺陷填充百分比(DFP),术后3个月和6个月。在1周时使用早期伤口愈合指数(EHI)来评估伤口愈合能力。
    结果:在6个月时,影像学参数显示,与对照组相比,试验组的DD值显著降低(P<0.001),DFP值显著降低.超级细胞在6个月结束时显示PPD和CAL的显着改善(P<0.001)。1周时的EHI评分在测试组和对照组之间没有统计学上的显着差异。
    结论:Supercell可以被认为是治疗牙周IOD的再生材料。
    OBJECTIVE: A combination of peripheral blood mesenchymal stem cells (PBMSCs) and platelet rich fibrin matrix (PRFM) could be a probable periodontal regenerative material with the synergy of the added benefits of each material. This randomized controlled clinical trial aimed to evaluate the regenerative capacity of supercell (PRFM and PBMSCs) compared with that of PRFM alone in human periodontal mandibular intraosseous defects (IOD).
    METHODS: This study included 17 patients of both sexes (12 men, 5 women) aged 30-55 years (mean age = 37.7±4.4 years) who fulfilled the inclusion criteria (radiographic and clinical evaluation for bilateral IOD with probing pocket depth (PPD ≥ 6 mm). A split-mouth design was used in each patient. A total of 34 sites in the mandibular arch randomly received PRFM alone + open flap debridement (OFD) [Control sites] or supercell (PRFM+PBMSCs) + OFD [Test sites]. The clinical parameters plaque index (PI), gingival index (GI), PPD, clinical attachment level (CAL), and in the radiographic parameters; defect depth (DD) and defect fill percentage (DFP) were recorded at baseline, 3 and 6 months postoperatively. Early wound healing index (EHI) was used at 1 week to assess wound healing ability.
    RESULTS: At 6 months, radiographic parameters revealed significant reduction in DD (P<0.001) and significant DFP values in the test group compared with the control group. The supercell showed significant improvement in PPD and CAL at the end of 6 months (P<0.001). EHI scores at 1 week showed no statistically significant difference between the test and control groups.
    CONCLUSIONS: Supercell can be considered a regenerative material in the treatment of periodontal IODs.
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  • 文章类型: Journal Article
    The masticatory organ is at the center of dental practice. Tooth loss, regarded as an organ failure, is a core dispute in our profession, as it more often than not does not happen spon-taneously but is influenced by the dentist\'s treatment plan. Despite the prosthetic possibili-ties of tooth replacement, efforts should be made to preserve as many teeth as possible. Decisions between tooth preservation and extraction are complex and have far-reaching consequences. This article discusses this problem using a clinical case study of a 43-year-old female patient with pronounced localized periodontitis. After a comprehensive diagnosis and treatment planning, a daring regenerative therapy was carried out to try to preserve the tooth. The case shows that even seemingly hopeless teeth can be successfully treated syn-chronously using modern therapeutic approaches. Initial literature data supports the possi-bility of preserving severely compromised teeth in the long term in compliant patients. An integrative treatment approach based on individual patient factors and modern regenerative techniques may well be a viable alternative to tooth extraction and prosthetic restoration, albeit not inexpensive and uncomplicated. This communication emphasizes the need for precise diagnostics, a comprehensive treatment plan, and honest communication with pa-tients about the prospects of success and possible risks, and highlights the strengths of con-sistent tooth preservation.
    Das Kauorgan steht im Mittelpunkt der zahnärztlichen Praxis. Zahnverlust wird als Organver-sagen betrachtet und stellt ein bedeutendes Problem dar. Trotz prothetischer Möglichkeiten sollte der Erhalt möglichst vieler Zähne angestrebt werden. Entscheidungen zwischen Zahn-erhalt und Extraktion sind komplex und haben weitreichende Folgen. Dieser Artikel behan-delt das Thema anhand eines klinischen Falls einer 43-jährigen Patientin mit ausgeprägter lokalisierter Parodontitis. Nach umfassender Diagnose und Behandlungsplanung wurde eine regenerative Therapie durchgeführt, um den Zahn zu erhalten. Der Fall zeigt, dass auch scheinbar hoffnungslose Zähne mit modernen Therapiemethoden bei zu guter Mundhygiene motivierbaren Patienten erfolgreich behandelt werden können. Erste Literaturdaten unter-stützen die Möglichkeit, stark beeinträchtigte Zähne langfristig zu erhalten. Ein integrativer Behandlungsansatz, basierend auf individuellen Patientenfaktoren und modernen Regenera-tionstechniken, kann eine Alternative zur Extraktion und prothetischen Versorgung sein, ob-wohl er kostspielig und kompliziert ist. Dieser Artikel betont die Notwendigkeit präziser Di-agnostik, umfassender Behandlungspläne und ehrlicher Kommunikation mit den Patienten über Erfolgsaussichten und Risiken sowie die Stärken des konsequenten Zahnerhalts.
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  • 文章类型: Journal Article
    牙周炎是一种严重的口腔牙龈炎症,牙龈软组织萎缩,牙周膜的破坏,和牙槽骨的吸收。牙周组织和骨破坏的管理,随着功能和结构完整性的恢复,单独使用常规临床治疗是不可能的。引导骨和组织再生疗法采用闭塞性生物可降解屏障膜和移植生物材料来引导牙槽骨和组织的形成,以进行牙周修复和再生。在几种嫁接方法中,异体移植物/生物材料,要么来自自然来源,合成,或者两者的结合,提供适合多种需求的各种资源。检查几个相关的科学数据库(WebofScience,Scopus,PubMed,MEDLINE,和Cochrane图书馆)提供了涵盖合成移植材料和膜文献的基础,致力于实现牙周组织和骨再生。通过强调潜在的嫁接和屏障生物材料,他们的特点,效率,再生能力,治疗结果,以及牙周引导再生治疗的进展。这项工作已记录了由移植物和膜生物材料制成的市场和标准化优质产品。最后,本文阐述了挑战,危险因素,以及生物材料和药物递送系统的组合,用于重建分级牙周组织。
    Periodontitis is a serious form of oral gum inflammation with recession of gingival soft tissue, destruction of the periodontal ligament, and absorption of alveolar bone. Management of periodontal tissue and bone destruction, along with the restoration of functionality and structural integrity, is not possible with conventional clinical therapy alone. Guided bone and tissue regeneration therapy employs an occlusive biodegradable barrier membrane and graft biomaterials to guide the formation of alveolar bone and tissues for periodontal restoration and regeneration. Amongst several grafting approaches, alloplastic grafts/biomaterials, either derived from natural sources, synthesization, or a combination of both, offer a wide variety of resources tailored to multiple needs. Examining several pertinent scientific databases (Web of Science, Scopus, PubMed, MEDLINE, and Cochrane Library) provided the foundation to cover the literature on synthetic graft materials and membranes, devoted to achieving periodontal tissue and bone regeneration. This discussion proceeds by highlighting potential grafting and barrier biomaterials, their characteristics, efficiency, regenerative ability, therapy outcomes, and advancements in periodontal guided regeneration therapy. Marketed and standardized quality products made of grafts and membrane biomaterials have been documented in this work. Conclusively, this paper illustrates the challenges, risk factors, and combination of biomaterials and drug delivery systems with which to reconstruct the hierarchical periodontium.
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  • 文章类型: Journal Article
    背景:由于相邻的第三磨牙,第二磨牙(d-M2)的远端方面通常表现出缺陷。虽然缺损可以在切除第三磨牙后通过引导组织再生(GTR)进行治疗,在临床决策中,第三磨牙摘除后的最佳时机仍不确定.这项研究旨在比较延迟和立即GTR治疗以协助临床决策。
    方法:收集至少1年随访的D-M2缺陷,分为三组:即刻GTR组,行第三磨牙拔除并同时接受GTR;延迟GTR组,第三磨牙拔除后至少3个月接受延迟GTR;对照组,在第三磨牙拔除过程中只进行了结垢和根部平整。使用Kruskal-Wallis检验或单向ANOVA评估与GTR前和手术后缺陷相关的临床和影像学参数,随后进行事后邓恩测试或Bonferroni测试,以进行成对比较。
    结果:共评估109d-M2次生缺陷。两组GTR之间无显着差异,尽管两者均显示出明显的缺陷深度降低:直接GTR组(2.77±1.97mmvs.0.68±1.03mm,p<0.001)和延迟GTR组(2.98±1.08mmvs.0.68±1.03mm,p<0.001)与对照组相比。
    结论:GTR可有效改善第三磨牙拔除后的d-M2次生缺陷,无论是同时还是延迟。患者在立即GTR治疗时可能会经历较少的不适,因为它只需要一次手术。
    BACKGROUND: The distal aspect of the second molar (d-M2) often exhibits infrabony defects due to the adjacent third molar. Although the defects can be treated by guided tissue regeneration (GTR) after removing the third molar, the optimal timing remains uncertain following third molar removal in clinical decision-making. This study aimed to compare delayed and immediate GTR treatments to assist in clinical decision-making.
    METHODS: D-M2 infrabony defects with a minimum 1-year follow-up were collected and divided into three groups: Immediate GTR group, which underwent third molar extraction and received GTR simultaneously; Delayed GTR group, which underwent delayed GTR at least 3 months after third molar extraction; and Control group, which underwent only scaling and root planing during third molar extraction. The clinical and radiographic parameters related to the infrabony defect before GTR and post-surgery were evaluated using the Kruskal-Wallis test or one-way ANOVA, followed by post-hoc Dunn\'s test or the Bonferroni test for pairwise comparisons.
    RESULTS: A total of 109 d-M2 infrabony defects were assessed. No significant differences were found between the two GTR groups, although both of them showed significant reductions in infrabony defect depth: the immediate GTR group (2.77 ± 1.97 mm vs. 0.68 ± 1.03 mm, p < 0.001) and the delayed GTR group (2.98 ± 1.08 mm vs. 0.68 ± 1.03 mm, p < 0.001) compared to the control group.
    CONCLUSIONS: GTR can effectively improve d-M2 infrabony defects when the third molar is removed, whether simultaneously or delayed. Patients may experience less discomfort with immediate GTR treatment as it requires only one surgery.
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    文章类型: Journal Article
    随着意识的提高,无论是在牙科文献中还是在公众中,种植体周围疾病,牙科的一个增长趋势是保存牙周预后“可疑”的牙齿。这项涉及此类患者的前瞻性研究旨在评估生物活性屏障和移植物相结合的效果。不是在牙槽上,而是在拔除相邻牙齿时增加严重牙周骨丢失的牙齿的相邻牙周状况。选择了15名患者;拔牙,地面,用pH值11的清洁剂制备,部分去矿化,制成移植物。该混合物用于增加牙槽体积并进行牙周再生手术。移植物覆盖有生物活性羊膜-绒毛膜屏障膜。生物活性膜可以刺激周围牙龈和骨膜组织中的宿主细胞,以加速部位的闭合和愈合,同时对下面的骨和移植材料产生积极作用,与其他膜没有相同的程度。这可以改善愈合和部位再生,如本报告中临床和影像学所示。这些生物活性屏障膜和牙本质移植材料的使用可具有累加效应,并在部位愈合后提供转化为宿主骨的刺激。羊膜-绒毛膜与自体牙本质移植物的结合似乎可以最大程度地发挥各种材料的益处。改善引导组织再生结果和牙周病相关牙齿的预后。
    With increased awareness, both in the dental literature and by the general public, of peri-implant disease, a growing trend in dentistry is to save teeth with a \"questionable\" periodontal prognosis. This prospective study involving such patients was designed to evaluate the effects of combining a bioactive barrier and graft, not on the socket but to augment adjacent periodontal conditions on teeth with severe periodontal bone loss at the time of extraction of an adjacent tooth. Fifteen patients were selected; teeth were extracted, ground, prepared with a pH 11 cleanser, partially demineralized, and made into a graft. This mixture was used to augment socket volume and perform periodontal regenerative surgery. The graft was covered with a bioactive amnion-chorion barrier membrane. Bioactive membranes can stimulate host cells in the surrounding gingival and periosteal tissues to accelerate site closure and healing, simultaneously exerting positive effects on the underlying bone and graft material not observed to the same extent with other membranes. This can improve healing and site regeneration as shown clinically and radiographically in this report. Use of these bioactive barrier membrane and dentin graft materials may have additive effects and provide stimulus for conversion to host bone after site healing. The combination of an amnion-chorion membrane with autologous dentin graft appears to maximize the benefits of the individual materials, improving guided tissue regeneration results and the prognoses of periodontally involved teeth.
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    文章类型: Journal Article
    用牙科植入物治疗无牙症通常与硬组织和软组织移植手术相结合,作为改善边缘骨骼稳定性和美学结果的手段。一种这样的硬组织移植方法涉及使用钛膜作为空间维持装置以容纳移植材料并支撑软组织。这些膜,然而,通常在定制能力方面受到限制,因此,通常不适合不同的临床情况。此病例报告介绍了与基台相关的钛膜的简化原型设计。这种设计可以实现更高水平的定制,并在2年的随访后显示出稳定的临床和影像学结果。
    The treatment of edentulism with dental implants is often combined with hard- and soft-tissue grafting procedures as a means to improve marginal bone stability and esthetic outcomes. One such method of hard-tissue grafting involves the utilization of a titanium membrane as a space maintenance device to contain the graft material and support the soft tissue. These membranes, however, are typically limited in their ability to be customized and, therefore, are often unsuitable for varying clinical situations. This case report presents a simplified prototype design of an abutment-associated titanium membrane. This design enables a greater level of customization and demonstrates stable clinical and radiographic results after 2 years of follow-up.
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  • 文章类型: Journal Article
    用于牙周缺损修复的引导组织再生(GTR)的商业哺乳动物胶原基膜仍然面临重大挑战,包括伦理问题,成本效益,牙周骨再生能力有限。在这里,开发了一种增强的仿生矿化羟基磷灰石(HAp)-鱼鳞胶原蛋白(FCOL)/壳聚糖(CS)纳米纤维膜。具体来说,从草鱼鱼鳞中提取的生态友好且生物相容的胶原蛋白与CS共静电纺丝以产生仿生的细胞外基质膜。增强的仿生矿化HAp涂层提供了丰富的活性钙和磷酸盐位点,促进细胞成骨分化,并显示更大的体内吸收。体外实验表明,HAp-FCOL/CS膜表现出理想的特性,没有细胞毒性,为干细胞募集提供了模拟的微环境,诱导牙周膜细胞成骨分化。在大鼠牙周缺损中,HAp-FCOL/CS膜显著促进牙周新骨的形成和再生。这项研究的结果表明,低成本,环保,仿生HAp-FCOL/CS膜可能是临床上用于牙周再生的GTR膜的有希望的替代品。
    Commercial mammalian collagen-based membranes used for guided tissue regeneration (GTR) in periodontal defect repair still face significant challenges, including ethical concerns, cost-effectiveness, and limited capacity for periodontal bone regeneration. Herein, an enhanced biomimetic mineralized hydroxyapatite (HAp)-fish-scale collagen (FCOL)/chitosan (CS) nanofibrous membrane was developed. Specifically, eco-friendly and biocompatible collagen extracted from grass carp fish scales was co-electrospun with CS to produce a biomimetic extracellular matrix membrane. An enhanced biomimetic mineralized HAp coating provided abundant active calcium and phosphate sites, which promoted cell osteogenic differentiation, and showed greater in vivo absorption. In vitro experiments demonstrated that the HAp-FCOL/CS membranes exhibited desirable properties with no cytotoxicity, provided a mimetic microenvironment for stem cell recruitment, and induced periodontal ligament cell osteogenic differentiation. In rat periodontal defects, HAp-FCOL/CS membranes significantly promoted new periodontal bone formation and regeneration. The results of this study indicate that low-cost, eco-friendly, and biomimetic HAp-FCOL/CS membranes could be promising alternatives to GTR membranes for periodontal regeneration in the clinic.
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  • 文章类型: Journal Article
    目的:比较交联透明质酸(xHyA)与釉基质蛋白(EMD)在牙周内缺损再生治疗后六个月的再生临床和影像学效果。
    方法:将60例出现一个骨内缺损的患者随机分为对照组(EMD)和试验组(xHyA)。临床依恋水平(CAL)增加是主要结果,而口袋探测深度(PPD),牙龈衰退(REC),探查出血(BOP),全口斑块评分(FMPS),全口出血评分(FMBS),和射线照相参数,如缺陷深度(BC-BD),缺损宽度(DW)被认为是次要结果变量。在基线和6个月后记录参数。
    结果:在6个月的随访中,54例患者可进行统计分析。在对照组和测试组中,在组内比较中,平均CAL增益具有统计学意义(p<0.001).48.1%的测试部位显示CAL增益≤2mm,而对照组为33.3%。在两组的组内比较中,平均PPD降低具有统计学显著性(p<0.001)。两组的平均REC增加相似:1.04±1.29mmvs1.11±1.22mm(测试与对照)。平均BC-BD,DW,FMPS,FMBS,BOP仅在组内比较中发生统计学上的显着变化,不在组间比较中。
    结论:两种治疗方法,EMD和xHyA,与基线相比,6个月后的临床和影像学改善具有相似的统计学意义.
    OBJECTIVE: To compare the regenerative clinical and radiographic effects of cross-linked hyaluronic acid (xHyA) with enamel matrix proteins (EMD) at six months after regenerative treatment of periodontal intrabony defects.
    METHODS: Sixty patients presenting one intrabony defect each were randomly assigned into control (EMD) and test (xHyA) groups. Clinical attachment level (CAL) gain was the primary outcome, while pocket probing depth (PPD), gingival recession (REC), bleeding on probing (BOP), full-mouth plaque score (FMPS), full-mouth bleeding score (FMBS), and radiographic parameters such as defect depth (BC-BD), and defect width (DW) were considered secondary outcome variables. Parameters were recorded at baseline and after 6 months.
    RESULTS: At the 6-month follow-up, 54 patients were available for statistical analysis. In the control and test groups, the mean CAL gain was statistically significant in the intragroup comparison (p < 0.001). 48.1% of test sites showed a CAL gain ≤ 2 mm compared with 33.3% of control sites. The mean PPD reduction was statistically significant in the intragroup comparison in both groups (p < 0.001). The mean REC increase was similar in the two groups: 1.04 ± 1.29 mm vs 1.11 ± 1.22 mm (test vs control). The mean BC-BD, DW, FMPS, FMBS, and BOP changed statistically significantly only in the intragroup comparison, not in the intergroup comparison.
    CONCLUSIONS: Both treatments, EMD and xHyA, produced similar statistically significant clinical and radiographical improvements after six months when compared with baseline.
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  • 文章类型: Journal Article
    目的:比较单独或与牙釉质基质衍生物(EMD)联合使用的无舌手术治疗深部骨内缺损的临床和影像学结果。
    方法:46例非手术治疗后重新评估的患者被随机分配到试验组(无折叠和EMD)或对照组(单独无折叠)。手术前和手术后6个月和12个月记录临床测量结果,术前和术后12个月进行影像学检查.
    结果:46名患者完成了研究。在12个月时观察到两组的平均临床依恋水平(CAL)增益的改善,试验组(3.9±1.1mm)和对照组(3.0±1.2)之间存在显着差异(p=.017)。探测袋深度(PPD)减少(4.0±0.7vs.3.3±1.4mm)也接近统计学意义(p=.051)。此外,对于无瓣+EMD组的再生治疗,更多的部位获得了成功的复合结局测量(最终PPD≤4mm,CAL增益≥3mm)(82.6%vs.52.2%;p=.028)。就放射结果而言,EMD产生的缺损骨填充比单独的无瓣治疗更大(3.0±1.0mm与1.8±1.5mm;p<.001)。
    结论:在无瓣手术中额外应用EMD治疗骨内缺损略微改善了临床和影像学结果。
    结果:政府标识号:NCT05456555。
    OBJECTIVE: To compare the clinical and radiographic outcomes of flapless procedure alone or in combination with enamel matrix derivatives (EMD) in the treatment of deep intrabony defects.
    METHODS: Forty-six patients re-evaluated after non-surgical therapy were randomly assigned to the test (flapless with EMD) or control group (flapless alone). Clinical measurements were recorded pre-surgery and at 6 and 12 months after surgery, and radiographic measurements were taken pre-surgery and after 12 months.
    RESULTS: Forty-six patients completed the study. Improvements were observed in both groups at 12 months for mean clinical attachment level (CAL) gain, with significant differences between test (3.9 ± 1.1 mm) and control groups (3.0 ± 1.2) (p = .017). Probing pocket depth (PPD) reduction (4.0 ± 0.7 vs. 3.3 ± 1.4 mm) was also near to statistical significance (p = .051). Also, more sites achieved successful composite outcome measure (final PPD ≤ 4 mm and CAL gain ≥3 mm) for the regenerative treatment in the flapless + EMD group (82.6% vs. 52.2%; p = .028). In terms of radiographic outcomes, EMD yielded a greater defect bone fill than flapless treatment alone (3.0 ± 1.0 mm vs. 1.8 ± 1.5 mm; p < .001).
    CONCLUSIONS: The additional application of EMD during the flapless procedure for intrabony defects slightly improved clinical and radiographic outcomes.
    RESULTS: gov identification number: NCT05456555.
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  • 文章类型: Journal Article
    目的:本研究旨在评估在实验性裂开缺损中使用骨替代物移植物进行引导骨再生(GBR)的膜使用。
    方法:取9只犬上颌第二切牙(I2)。六周后,插入植入物,并在颊侧产生实验性开裂缺损(5×3mm)。用去蛋白的牛骨矿物质移植缺损和周围的骨。一侧(测试)覆盖有可再吸收的胶原膜,而对侧(对照)则没有。6周后,进行组织形态计量学分析以评估:(a)首次骨与植入物接触(FBIC),(b)距植入物肩部1mm增量的颊骨厚度,(c)再生面积(RA),(d)新骨的面积和百分比(B),骨替代物(BS)和矿化组织(MT)。
    结果:测试部位和对照部位的组织学外观相似。在中央和侧面部分,fBIC组间没有差异,颊骨厚度,RA,BS,B,%B,MT和%MT。在中央部分,膜使用有利于更多的%BS和%MT(p=0.052)。有更多的B,与中央部分相比,横向的B和MT占%。
    结论:膜使用倾向于保留更多的骨替代物,但对新骨向内生长没有影响。与中央切片相比,外侧切片显示出更多的骨向内生长和矿化组织,确认新骨向内生长主要来自缺损的侧壁。
    结论:阐明GBR手术中骨再生动力学的临床前研究与临床实践有关。
    OBJECTIVE: This study aimed to assess membrane use with a bone substitute graft for guided bone regeneration (GBR) in experimental dehiscence defects.
    METHODS: Maxillary second incisors (I2) in 9 dogs were extracted. Six weeks later, implants were inserted and experimental dehiscence defects (5 × 3 mm) created on the buccal aspect. The defects and surrounding bone were grafted with deproteinized bovine bone mineral. One side (test) was covered with a resorbable collagen membrane whereas the contralateral side (control) was not. After 6 weeks, histomorphometrical analysis was performed to evaluate: (a) first bone-to-implant contact (fBIC), (b) buccal bone thickness at 1 mm increments from implant shoulder, (c) regenerated area (RA), (d) area and percentages of new bone (B), bone substitute (BS) and mineralized tissue (MT).
    RESULTS: The histological appearance was similar between test and control sites. At central and lateral sections, there were no differences between groups for fBIC, buccal bone thickness, RA, BS, B, %B, MT and %MT. At central sections, membrane use favoured more %BS and %MT (p = 0.052). There was significantly more B, %B and MT at lateral compared to central sections.
    CONCLUSIONS: Membrane use tended to retain more bone substitute, but had no effect on new bone ingrowth. Lateral sections showed significantly more bone ingrowth and mineralized tissue compared to central sections, confirming that new bone ingrowth takes place mainly from the lateral walls of the defect.
    CONCLUSIONS: Preclinical research to clarify the dynamics of bone regeneration in GBR procedures is relevant in clinical practice.
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