Vertical ridge augmentation using an equine bone and collagen block infused with recombinant human platelet-derived growth factor-BB: a randomized single-masked histologic study in non-human primates

Background: This study tests the effectiveness of hydroxyapatite and collagen bone blocks of equine origin (eHAC), infused with recombinant human platelet‐derived growth factor‐BB (rhPDGF‐BB), to augment localized posterior mandibular defects in non‐human primates (Papio hamadryas). Methods: Bilateral critical‐sized defects simulating severe atrophy were created at the time of the posterior teeth extraction. Test and control blocks (without growth factor) were randomly grafted into the respective sites in each non‐human primate. Results: All sites exhibited vertical ridge augmentation, with physiologic hard‐ and soft‐tissue integration of the blocks when clinical and histologic examinations were done at 4 months after the vertical ridge augmentation procedure. There was a clear, although non‐significant, tendency to increased regeneration in the test sites. As in the first two preclinical studies in this series using canines, experimental eHAC blocks infused with rhPDGF‐BB proved to be a predictable and technically viable method to predictably regenerate bone and soft tissue in critical‐sized defects. Conclusion: This investigation supplies additional evidence that eHAC blocks infused with rhPDGF‐BB growth factor is a predictable and technically feasible option for vertical augmentation of severely resorbed ridges.     

Significance of the platelet-derived growth factor in periodontal tissue regeneration

Aim

The aim was to review the significance of the platelet derived growth factor (PGDF) in periodontal tissue regeneration.

Methods and results

Databases were searched using the following terms in different combinations: “growth factors”, “guided bone regeneration”, “guided tissue regeneration”, “periodontal”, “platelet rich plasma” and “platelet derived growth factor”. Titles and abstracts of articles obtained using the above-described criteria were then screened by the authors and checked for agreement. The next step was to hand-search the reference lists of original and review studies that were found to be relevant in the previous step. PDGF has a stimulatory effect on the DNA replication and chemotaxis of osteoblasts, fibroblasts, leukocytes, monocytes, neutrophils periodontal and alveolar bone cells. Proliferation of mesenchymal stem cells is also promoted by supplement treatment with PDGF. PDGF in combination with other growth factors enhances periodontal tissue repair.

Conclusions

The PDGF plays a significant role in periodontal bone and tissue regeneration.     

生长因子智能控释与牙周组织再生

牙周骨移植、引导组织再生术（guided tissue regeneration，GTR）为牙周病的治疗和牙周缺损的修复带来了新的希望，但在恢复牙周组织的结构和功能方面还远不能达到理想的目标。组织工程和基因技术才刚刚起步，离临床应用还有较远的距离；药物控释技术的迅猛发展和活性牙周生物材料的研制与开发，为损害牙周组织结构功能的修复重建开辟了新的研究空间。     

A comparative study of root defect coverage using an acellular dermal matrix with and without a recombinant human platelet-derived growth factor

Background: The objective of this case series is to compare root defect coverage results and healing responses of bilateral recession defects treated with acellular dermal matrix (ADM) with and without recombinant human platelet‐derived growth factor (rhPDGF). Methods: Seventeen patients with 40 bilateral gingival recession defects were compared. Each defect was ≥2 mm and treated with ADM and a coronally advanced flap. Using split‐mouth design, the control‐side ADM was hydrated in sterile saline, whereas the test‐side ADM was hydrated in rhPDGF. The patients were evaluated at 1 week, 1 month, 3 months, and 6 months. Standardized measurements were taken preoperatively at 3 and 6 months. Healing was clinically assessed at 1 week and 1 month post‐surgically. Results: Both test and control groups showed significant gain in root defect coverage over the 6‐month period for all individuals, with the test group showing a 69.0% gain and the control group showing a 76.7% gain. Patients divided into Miller Class I and Class III defects were also found to have a significant gain in root defect coverage over 6 months. The test group showed 84.1% gain, and the control group showed 84.7% gain for Miller Class I defects. For Miller Class III defects, the test group showed 51.5% gain, and the control group showed a 60.8% gain. One week after surgery, 35% of the test group showed better healing, whereas 15% of the control group showed better healing. One month after surgery, 20% of the test group showed better healing, whereas 15% of the control group showed better healing. Conclusion: Based on the results of this case series, there were no statistically or clinically significant differences in root defect coverage, keratinized tissue, clinical attachment level, or clinical healing for treatment of root recession with a coronally advanced flap and ADM with and without rhPDGF.     

引导组织和骨组织再生术及其生长因子在牙周骨缺损治疗中的应用

引导组织再生术和引导骨再生术广泛用于牙周骨缺损的治疗中,给牙周组织再生开辟了广泛的空间,但二者单独使用却存在一定的局限性。因此,目前的研究多趋向于将骨移植材料和膜材料与多肽生长因子联合应用于牙周骨缺损的修复。下面就引导组织再生膜材料、引导骨再生支架材料和碱性成纤维细胞生长因子的理化性质、生物学功能,以及三者联合应用于牙周骨缺损治疗中的作用作一综述。     

A combination of platelet-derived and insulin-like growth factors enhances periodontal regeneration

Abstract The combination of platelet-derived growth factor (PDGF) and insulin-like growth factor one (IGF-1) has previously been shown to enhance repair of soft tissue wounds. Here we report initial observations following application of PDGF and IGF-1 to periodontitis-affected teeth in beagle dogs, 1 μg of PDGF and IGF-1 in an aqueous gel was applied to the root surfaces of test teeth following open flap debridement. Control sites received the gel alone. Block biopsies of the teeth and surrounding bone were taken 2 weeks after treatment. Histologic analyses of control specimens revealed a long junctional epithelial attachment, and no new bone or cementum formation. In contrast, growth factor treated sites exhibited significant amounts of new bone and cementum formation. A nearly continuous layer of osteoblasts lined the newly formed bone, and there was a dense cellular “front” at the coronal extent of the new bone. These preliminary results suggest that in vivo application of the combination of PDGF and IGF-1 may enhance regeneration of the periodontal structures.     

Periodontal regeneration

The ultimate goal of periodontal therapy is the regeneration of the tissues destroyed as a result of periodontal disease. Currently, two clinical techniques, based on the principles of "guided tissue regeneration" (GTR) or utilization of the biologically active agent "enamel matrix derivative" (EMD), can be used for the regeneration of intrabony and Class II mandibular furcation periodontal defects. In cases where additional support and space-making requirements are necessary, both of these procedures can be combined with a bone replacement graft. There is no evidence that the combined use of GTR and EMD results in superior clinical results compared to the use of each material in isolation. Great variability in clinical outcomes has been reported in relation to the use of both EMD and GTR, and these procedures can be generally considered to be unpredictable. Careful case selection and treatment planning, including consideration of patient, tooth, site and surgical factors, is required in order to optimize the outcomes of treatment. There are limited data available for the clinical effectiveness of other biologically active molecules, such as growth factors and platelet concentrates, and although promising results have been reported, further clinical trials are required in order to confirm their effectiveness. Current active areas of research are centred on tissue engineering and gene therapy strategies which may result in more predictable regenerative outcomes in the future.     

Prognostic factors for alveolar regeneration: bone formation at teeth and titanium implants

OBJECTIVES: There is a limited understanding of the effect of defect characteristics on alveolar bone healing. The objectives of this study were to assess the effect of alveolar bone width and space provision on bone regeneration at teeth and titanium implants, and to test the hypothesis that the regenerative potentials at teeth and implants are not significantly different. METHODS: Critical size, 5-6-mm, supra-alveolar, periodontal defects were surgically created in 10 young adult dogs. Similarly, critical size, 5-mm, supra-alveolar, peri-implant defects were created in four dogs. A space-providing expanded polytetrafluoroethylene device was implanted for guided tissue regeneration/guided bone regeneration. The animals were euthanized at 8 weeks postsurgery. Histometric analysis assessed alveolar bone regeneration (height) relative to space provision by the device and the width of the alveolar crest at the base of the defect. Statistical analysis used the linear mixed models. RESULTS: A significant correlation was found between bone width and wound area (r=0.55892, p<0.0001). Generally, bone width and wound area had statistically significant effects on the extent of bone regeneration (p<0.0005 and p<0.0001, respectively). Bone regeneration was linearly correlated with the bone width at periodontal (p<0.001) and implant (p=0.04) sites, and with the wound area at periodontal (p<0.0001) and implant (p=0.03) sites. The relationships of bone regeneration with these two variables were not significantly different between teeth and implants (bone width: p=0.83; wound area: p=0.09). When adjusted for wound area, bone regeneration was significantly greater at periodontal than at implant sites (p=0.047). CONCLUSIONS: The horizontal dimension of the alveolar bone influences space provision. Space provision and horizontal dimension of the alveolar bone appear to be important determinants of bone regeneration at teeth and implants. The extent of alveolar bone formation at implant sites is limited compared with that at periodontal sites.     

Periodontal repair in dogs: effect of recombinant human bone morphogenetic protein-12 (rhBMP-12) on regeneration of alveolar bone and periodontal attachment

OBJECTIVES: Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been shown to stimulate alveolar bone and cementum formation in periodontal defects but not a functionally oriented periodontal ligament (PDL). Subcutaneous and intramuscular implants of BMP-12 have been shown to induce tendon formation and ligament-like tissue. The objective of this study was to evaluate rhBMP-12 for periodontal regeneration, in particular PDL formation. METHODS: Six young adult Hound Labrador mongrel dogs were used. Routine supraalveolar periodontal defects were created around the mandibular premolar teeth. Three animals received rhBMP-12(0.04 mg/ml) in an absorbable collagen sponge (ACS) carrier vs. rhBMP-12(0.2 mg/mL)/ACS in contralateral defects. Three animals received rhBMP-12(1.0 mg/ml)/ACS vs. rhBMP-2(0.2 mg/ml)/ACS (total implant volume/defect approximately 1 ml). The animals were euthanized 8 weeks postsurgery and block biopsies were processed for histometric analysis. RESULTS: Bone regeneration appeared increased in sites receiving rhBMP-2/ACS compared to sites receiving rhBMP-12/ACS. Cementum regeneration was similar comparing sites implanted with rhBMP-2/ACS to sites implanted with rhBMP-12/ACS. In contrast, sites receiving rhBMP-12/ACS exhibited a functionally oriented PDL bridging the gap between newly formed bone and cementum whereas this was a rare observation in sites receiving rhBMP-2/ACS. Ankylosis appeared increased in sites receiving rhBMP-2/ACS compared to those receiving rhBMP-12/ACS. CONCLUSIONS: The outcomes of this study suggest that rhBMP-12 may have significant effects on regeneration of the PDL. Additional preclinical evaluation is needed to confirm these initial observations prior to clinical application.     

Prognostic factors for alveolar regeneration: effect of tissue occlusion on alveolar bone regeneration with guided tissue regeneration

OBJECTIVES: Design criteria for guided tissue regeneration (GTR) devices include biocompatibility, cell occlusion, space-provision, tissue integration, and ease of use. The objective of this study was to evaluate the effect of cell occlusion and space-provision on alveolar bone regeneration in conjunction with GTR. METHODS: Routine, critical-size, 6 mm, supra-alveolar, periodontal defects were created in 6 young adult Beagle dogs. Space-providing ePTFE devices, with or without 300-microm laser-drilled pores were implanted to provide for GTR. Treatments were alternated between left and right jaw quadrants in subsequent animals. The gingival flaps were advanced for primary intention healing. The animals were euthanized at week 8 post surgery. The histometric analysis assessed regeneration of alveolar bone relative to space-provision by the ePTFE device. RESULTS: A significant relationship was observed between bone regeneration and space-provision for defect sites receiving the occlusive (beta = 0.194; p < 0.02) and porous (beta = 0.229; p < 0.0004) GTR devices irrespective of treatment (p = 0.14). The bivariate analysis showed that both space-provision and device occlusivity significantly enhanced bone regeneration. Hence, sites receiving the occlusive GTR device and sites with enhanced space-provision showed significantly greater bone regeneration compared to sites receiving the porous GTR device (p = 0.03) or more limited space-provision (p = 0.0002). CONCLUSIONS: Cell occlusion and space-provision may significantly influence the magnitude of alveolar bone regeneration in conjunction with guided tissue regeneration.     

Prognostic factors for alveolar regeneration: osteogenic potential of resident bone

OBJECTIVES: There is a limited understanding of the role of resident bone in periodontal regeneration. The objective of this study was to evaluate the influence of the resident alveolar bone on bone regeneration in conjunction with guided tissue regeneration (GTR) in the presence or the absence of cell occlusivity. METHODS: Critical-size, 6-mm, supra-alveolar periodontal defects were created in six young adult Beagle dogs. Space-providing, occlusive or porous expanded polytetrafluaroethylene devices were implanted to provide for GTR. Treatments were alternated between left and right jaw quadrants in subsequent animals. The gingival flaps were advanced for primary intention healing. The animals were euthanized at week 8 postsurgery. The histometric analysis assessed regeneration of alveolar bone relative to space-provision by the GTR device and width of the alveolar crest at the base of the defect. RESULTS: There were no significant differences in mean alveolar regeneration between sites receiving the porous GTR device with a narrow versus a wide alveolar ridge after adjusting for wound area (2.22 versus 2.50 mm, respectively; p=0.36). In contrast, analysis using sites receiving the occlusive GTR device revealed significantly greater bone regeneration at sites with a wide compared with a narrow alveolar ridge (3.34 versus 2.53 mm, respectively; p=0.02). Regression analysis showed a significant relationship (p< or =0.05) between space-provision and bone regeneration for all groups except for sites with a wide alveolar ridge receiving the occlusive GTR device (p=0.5). CONCLUSIONS: The resident alveolar bone may significantly influence the magnitude of alveolar bone regeneration. The relative presence of cells from the gingival connective tissue may attenuate this effect.     

Evaluation of Recession Defects Treated With Coronally Advanced Flaps and Either Recombinant Human Platelet‐Derived Growth Factor‐BB Plus β‐Tricalcium Phosphate or Connective Tissue: Comparison of Clinical Parameters at 5 Years

Background: In a previously reported split‐mouth, randomized controlled trial, Miller Class II gingival recession defects were treated with either a connective tissue graft (CTG) (control) or recombinant human platelet‐derived growth factor‐BB + β‐tricalcium phosphate (test), both in combination with a coronally advanced flap (CAF). At 6 months, multiple outcome measures were examined. The purpose of the current study is to examine the major efficacy parameters at 5 years. Methods: Twenty of the original 30 patients were available for follow‐up 5 years after the original surgery. Outcomes examined were recession depth, probing depth, clinical attachment level (CAL), height of keratinized tissue (wKT), and percentage of root coverage. Within‐ and across‐treatment group results at 6 months and 5 years were compared with original baseline values. Results: At 5 years, all quantitative parameters for both treatment protocols showed statistically significant improvements over baseline. The primary outcome parameter, change in recession depth at 5 years, demonstrated statistically significant improvements in recession over baseline, although intergroup comparisons favored the control group at both 6 months and 5 years. At 5 years, intergroup comparisons also favored the test group for percentage root coverage and change in wKT, whereas no statistically significant intergroup differences were seen for 100% root coverage and changes to CAL. Conclusions: In the present 5‐year investigation, treatment with either test or control treatments for Miller Class II recession defects appear to lead to stable, clinically effective results, although CTG + CAF resulted in greater reductions in recession, greater percentage of root coverage, and increased wKT.     

Comparative effects of plateletderived growth factor-BB and insulin-like growth factor-I, individually and in combination, on periodontal regeneration in Macaca fascicularis

Platelet-derived growth factor (PDGF) and insulin-like growth factor I (IGF-I) in combination have previously been shown to enhance periodontal regeneration. The objective of this study was to further characterize the biological effects of this combination of growth factors in non-human primates and compare the effects to those of each growth factor individually. Ligature-induced periodontitis was initiated in 10 cynomolgus monkeys. After periodontal lesions were established, surgery was performed, and either a methylcellulose gel vehicle or vehicle containing 10 μg each of either PDGF-BB, IGF-I or both PDGF-BB and IGF-I was applied to exposed root surfaces. Biopsies were taken 4 and 12 wk after treatment and the extent of periodontal regeneration was assessed by histomorphometry. At both 4 and 12 wk vehicle-treated lesions generally revealed minimal osseous defect fill (ODF) (8.5±2.1% and 14.5±5.7%, respectively) and new attachment (NA) (34.1±5.2% and 26.6±10.5%, respectively). IGF-I treatment did not significantly alter healing compared to vehicle in any parameter at both 4 and 12 wk. PDGFBB-treated sites exhibited significant (p<0.05) regeneration of NA (69.6±12.0%) at 12 wk; trends for PDGF-BB treatment effect were also observed in other parameters at 4 and 12 wk. although these increases were not statistically significant. Treatment with PDGF-BB/IGF-I resulted in 21.6±5.1 % and 42.5±8.3% ODF at 4 and 12 wk, respectively, and 64.1±7.7% and 74.6±7.4% NA at 4 and 12 wk, respectively (all significantly greater than vehicle, p<0.05). The results from this study demonstrated that: 1) IGF-1 alone at the dose tested did not significantly alter periodontal wound healing; 2) PDGF-BB alone significantly stimulated NA, with trends of effect on other parameters; and 3) the PDGF-BB/IGF-I combination resulted in significant increases in NA and ODF above vehicle at both 4 and 12 wk.     

GBR技术引导颌骨再生的研究进展

引导骨再生（GBR）是修复种植体周围缺损的重要方法,但在成骨效果上仍有不足。理论上组织工程将生长因子和生物活性材料应用于GBR可以提高疗效,但是目前临床上尚未建立起可预测疗效的种植体周围缺损再生疗法,甚至有研究发现在GBR中使用生长因子后还存在成骨长期稳定性不良的现象,这与理论上预计的结果不符。解决这一问题是推进生长因子应用的关键,通过查阅文献与分析,文中给出了两种可能的原因：生长因子后期水平过低和加速屏障膜降解作用,并据此提出验证的方法,为进一步研究提供参考和依据。     

生长因子复合生物膜引导牙周组织再生

随着引导组织再生术(guided tissue regeneration，GTR)研究的不断深入，传统的生物膜已经逐渐被复合生长因子的功能性生物膜所替代。功能性复合膜的研制、开发和应用，已成为GTR研究的热点，越来越多的研究表明生长因子缓释生物膜将是未来GTR研究的趋势。