Australian Dental Journal 2009; 54:(1 Suppl): S118S128 doi: 10.1111/j.1834-7819.2009.01150.

Periodontal regeneration
S Ivanovski*
*School of Dentistry and Oral Health, Grifth University, Gold Coast, Queensland.

ABSTRACT
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 conrm 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.
Keywords: Periodontal regeneration, guided tissue regeneration, enamel matrix derivative, platelet derived growth factor, platelet rich plasma. Abbreviations and acronyms: CAL = clinical attachment level; EMD = enamel matrix derivative; ePTFE = expanded polytetrafluroethelene; GTR = guided tissue regeneration; OFD = open flap debridement; PDGF = platelet derived growth factor; RR = relative risk ration.

INTRODUCTION Periodontitis results in soft and hard tissue destruction around teeth. Periodontal defects resulting from periodontitis exhibit signicant destruction of alveolar bone, periodontal ligament and gingiva, and as a consequence, the root cementum may become contaminated by exposure to the oral environment. Once the inammatory aspect of the disease has been controlled, the ultimate goal of periodontal therapy is the regeneration of the destroyed tissues. Periodontal regeneration is dened as the reproduction or reconstitution of a lost or injured part so that the form and function of lost structures is restored. This should be distinguished from the term new attachment which describes the formation of new cementum with inserting collagen bres on a root surface deprived of its periodontal ligament tissue, but does not necessarily describe complete regeneration of the entire periodontium. Indeed, periodontal regeneration can only be demonstrated histologically whereby the various components of the periodontium can be visualized.
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The periodontium is a complex organ consisting of epithelial tissue and both soft and mineralized connective tissues, and includes the gingiva, periodontal ligament, cementum and alveolar bone. The unique anatomy and composition of the periodontium make periodontal wound healing a more complex process than general soft tissue healing because of the requirement for interaction between hard and soft connective tissues as well as epithelium.1 Hence, periodontal wound healing is a unique and complex process requiring the coordinated response of four distinct soft and hard tissues gingival connective tissue, periodontal ligament, cementum and bone. In general, periodontal wound healing studies indicate that conventional periodontal therapy most commonly results in repair by collagenous scar tissue and is accompanied by the apical migration of gingival epithelium between the gingival connective tissue and the root surface.2 This healing process does not fully restore either the form or the function of the lost structures and hence does not constitute regeneration.
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Periodontal regeneration Current regenerative techniques are aimed at the treatment of intrabony and furcation defects. Intrabony defects are dened by the apical location of the base of the defect in relation to the residual alveolar crest, in contrast to suprabony defects whose base is located coronal to the crest. Infrabony defects are commonly referred to as vertical defects, whereas suprabony defects are often called horizontal defects. Intrabony defects can further be classied as one-wall, two-wall or three-wall defects, according to the number of residual alveolar bone walls surrounding the tooth surface. Clinically, most periodontal bone defects have a complex anatomy, with the apical aspect being a three-wall defect, while the supercial component is often a one- or two-wall defect. Biological principles Periodontal regeneration requires new attachment to the root surface, a process that involves the regeneration of periodontal ligament bres and the insertion of these bres into newly formed cementum on a root surface that has been exposed previously to periodontal pathogens. It has been shown that cells derived from the gingival connective tissues and the alveolar bone lack the ability to form such an attachment.3,4 On the other hand, if preference is given to repopulation of the root surface by periodontal ligament cells, new connective tissue attachment including new cementum with inserting collagen bres can be formed.5 Hence, the periodontal ligament is of critical importance in the regenerative process. In order for periodontal regeneration to occur, progenitor periodontal ligament cells must migrate to the denuded root surface, attach to it, proliferate and mature into an organized and functional brous attachment apparatus that inserts into newly formed cementum. Likewise, progenitor bone cells must also migrate, proliferate and mature in conjunction with the regenerating periodontal ligament. Hence, the concept of periodontal regeneration is based on the principle that remaining healthy cells, and or cells attracted to the healing site, have the potential to promote regeneration. However, achieving conditions that allow selective repopulation by periodontal ligament cells is difcult to obtain clinically. Historical perspective The concept that new attachment was a clinically achievable technique was established by the work of Pritchard who showed that three-wall defects could ll with bone following routine surgical subgingival debridement.6 These results were attributed to the favourable anatomy of the treated intrabony defects (three-wall), and several subsequent histological studies
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have demonstrated that new attachment is not routinely achieved following subgingival debridement, with the formation of a long junctional epithelium along the root surface being the routine response.2 However, the work by Pritchard provides proof of principle evidence that periodontal regeneration is achievable in ideal clinical situations by surgical debridement without the need for supplementary techniques. Needless to say, these ideal clinical situations are rarely encountered in the clinic. Therefore, over the years, a number of different techniques have been attempted in order to achieve periodontal regeneration. Root surface conditioning Considerable research has been directed at altering the periodontitis-affected root surface, in addition to root surface debridement, in order to promote new attachment formation. Both citric acid and tetracycline have been applied to the root surface during periodontal surgery in order to demineralize the dentine and expose collagen brils. The biological rationale behind this approach was the belief that it would enhance cementum formation by inducing mesenchymal cells in the adjacent tissue to differentiate into cementoblasts. Initial studies using animal models yielded encouraging results with new connective tissue attachment being demonstrated histologically.7,8 However, subsequent controlled clinical trials in humans failed to demonstrate any improvement in clinical parameters following root surface conditioning.911 Indeed, a recent systematic review of the effectiveness of root surface conditioning concluded that the use of citric acid, tetracycline or ethylenediaminetetraacetic acid (EDTA) to modify the root surface provides no benet of clinical signicance to regeneration in patients with chronic periodontitis.12 Therefore, the use of root surface conditioning as an adjunct to surgical debridement for the purpose of promoting periodontal regeneration is not supported by the literature. Bone grafting In conjunction with surgical access, bone or bone substitutes have been placed in the debrided periodontal defect with the aim of promoting periodontal regeneration. The rationale for this approach is that the promotion of bone formation would also induce new attachment formation along the adjacent tooth root surface. The types of grafts that were utilized included autogenous grafts (derived from the same individual), allogenic grafts (derived from a different member of the same species), xenografts (derived from different species) and alloplastic materials (synthetic products). The clinical performance of bone grafting procedures in the regeneration of intrabony and
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S Ivanovski furcation defects has been comprehensively assessed in a recent systematic review.13 This review included data from 49 randomized clinical trials that studied the management of intrabony defects and 17 studies that included furcation defects. With respect to the treatment of intrabony defects, the authors concluded that bone grafts increased clinical attachment level, and reduced probing depth compared to open ap debridement (OFD) procedures. No differences in clinical outcome measures were noted between different grafting materials. With respect to the treatment of furcation defects, some positive clinical benets with noted in relation to the treatment of Class II furcations, but the lack of consistent comparisons did not allow a meaningful assessment. In contrast, another systematic review did not nd sufcient evidence to support the use of bone replacement graft materials because of the signicant difference in study design and materials used, as well as the small adjunctive effect that was reported.14 The conicting evidence regarding the clinical effectiveness of bone grafts is matched by conicting histological data on whether bone grafting results in true regeneration involving new attachment onto the root surface or repair via a long junctional epithelium. Although there are some studies that provide histological evidence that autogenous and demineralized allogeneic bone grafts support the formation of new attachment,1518 there are also reports of no new attachment following the use of both of these types of grafts.19,20 Furthermore, the clinical signicance of these results are complicated by the fact that demineralized allogenic bone grafts are not readily available in many parts of the world including Australia, while the use of autogenous bone grafts in periodontal regeneration is often not practical due to the need for a second surgical site and the associated morbidity. It is far more practical to use off the shelf xenografts or alloplastic materials. However, essentially all available data indicate that alloplastic grafts support periodontal repair rather than regeneration.13 Overall, the available evidence does not support the use of bone grafts in conjunction with surgical debridement for the purpose of promoting periodontal regeneration. Guided tissue regeneration Guided tissue regeneration (GTR) is a clinical technique based on the observations that only the periodontal ligament, but not gingival connective tissue4 or bone,3 contains cells capable of forming new cementum on the root surface and establishing new attachment bres between cementum and bone.21 GTR involves the use of a barrier membrane to promote the selective repopulation of the periodontal defect by cells derived from the periodontal ligament at the expense of gingival
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cells. The rst report of GTR use in the human was in 1982, whereby a bacterial lter produced from cellulose acetate (Millipore) was used as the barrier membrane and histological evidence of new attachment was presented.22 Subsequently, a purpose designed membrane made of expanded polytetrauroethelene (e-PTFE) was introduced (Gore Tex Periodontal Material, WL Gore and Assoc, Flagstaff, AZ, USA). Early GTR studies utilized this non-resorbable membrane,5,23,24 which was left in place for a period of six weeks and was then removed using a re-entry surgical procedure. Histological evidence of regeneration was demonstrated.5 The non-resorbable ePTFE membrane had the desirable characteristics of being biocompatible, occlusive for undesirable cells, space maintaining and available in a range of congurations. However, non-resorbable membranes were also prone to exposure and infection, which negatively affected the outcomes of the regenerative therapy.25,26 Subsequently, resorbable membranes were introduced to the market, with the obvious advantage that a re-entry procedure was not required. Resorbable membranes came in a variety of materials, the most common being collagen and copolymers of polylactic polyglycolic acid. The use of a porcine collagen membrane (Bio-Gide, Geistlich, Wolhuse, Switzerland), which has gained considerable popularity due to the ease of handling and lack of postoperative complications, is supported by long-term data from randomized controlled clinical trials.27,28 Due to its non-supportive structure, it is often used in a combination with a bone replacement grafting material. Clinical outcomes The vast majority of clinical studies involving GTR identify signicant benets in the management of intrabony defects and mandibular Class II furcations. The treatment of Class III furcations with GTR is not supported by the literature.29 Furthermore, while statistically signicant results can be obtained in relation to Class II maxillary furcations,30 the benets are thought to be limited and hence clinically insignificant.29 Therefore, GTR treatment is not recommended for Class III furcations. Meta-analysis of controlled clinical trials indicate that GTR can result in average probing depth reductions of 3.21 1.36 mm and attachment gain of 4.37 1.32 mm in deep intrabony defects.31 In relation to the treatment of mandibular Class II furcations with GTR, average horizontal clinical attachment gains of 2 mm and vertical attachment gains of 2.5 mm have been reported.29 However, the elimination of the furcation rarely occurs and the conversion of Class II to Class I furcations occurs in less than 50 per cent of cases.29 No differences have been reported between
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Periodontal regeneration different barrier types in relation to the treatment of either intrabony32 or furcation defects.29 Several systematic reviews have compared the clinical effectiveness of GTR with that of conventional OFD. In one comprehensive review,33 including 16 randomized controlled clinical trials comparing GTR with OFD in the treatment of intrabony defects, GTR has a statistically signicant positive effect on clinical outcomes compared with OFD, including improved attachment gain (additional 1.22 mm (0.81.64)), reduced pocket depth (additional 1.21 mm (0.531.88)), less increase in gingival recession (0.26 mm (0.080.43)) and more gain in hard tissue probing at re-entry surgery (1.39 mm (1.081.71). GTR showed a signicant benet when comparing the numbers of sites failing to gain 2 mm attachment with a risk ratio of 0.54 (0.310.96), suggesting that this clinical goal was reached in twice as many GTR cases compared with OFD. However, there is a lack of evidence with regards to more denitive clinical goals such as tooth retention. Furthermore, this systematic review noted that there was marked variability between studies. As a result, the authors concluded that it is difcult to draw general conclusions about the clinical benet of GTR. A systematic review and meta-analysis was also carried out of 14 randomized controlled clinical trials investigating the effectiveness of GTR compared to OFD in the treatment of Class II furcations.30 The primary outcome measure was reduction in open horizontal furcation depth, with secondary outcomes being frequency of furcation closure, gain in horizontal and vertical probing attachment and reduction of vertical probing depth. For the primary outcome, reduction in horizontal furcation depth assessed during re-entry, the difference between GTR and control was 1.51 mm (0.392.62) in mandibular Class II furcations, 1.05 mm (0.461.64) in maxillary Class II furcations, and 0.87 mm ()0.081.82) in studies that had combined mandibular and maxillary Class II furcations. For the secondary outcomes, GTR treatment led to significantly better results than OFD. The authors concluded that overall, GTR was consistently more effective than OFD in reducing open horizontal furcation depths, horizontal and vertical attachment levels and pocket depths for mandibular or maxillary Class II furcation defects. However, these improvements were modest, variable and there were only a limited number of studies available to appraise the effects, thus limiting general conclusions about the clinical benet of GTR. GTR has also been combined with bone grafts, the main advantage being the support of resorbable membranes, which often lack the necessary rigidity to maintain space and prevent collapse into the defect. In the management of intrabony defects, GTR combined with bone substitutes yielded similar results to GTR alone,32,33 with the exception of a greater
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difference in hard tissue probing gain at re-entry compared to OFD (3.37 mm (3.143.61).33 In relation to the management of mandibular Class II furcations, the addition of a bone replacement graft to the GTR procedure resulted in improved vertical probing depth reduction and attachment gain, especially when combined with a non-resorbable ePTFE membrane.32 It is noteworthy that most of the studies reporting on the combined use of GTR with a bone replacement graft have used an allogenic grafting material or a xenograft. Allografts are not available in many parts of the world, including Australia, and hence the use of off the shelf xenogenic products is becoming more popular. Most of the recent studies which have utilized a xenograft as a bone replacement material have used a bovine deproteinized product (Bio-Oss, Geistlich, Wolhuse, Switzerland).27,28 In terms of patient centred outcomes, healing associated with GTR is largely uneventful, and does not differ greatly from OFD.34 Exposure of the GTR barrier membrane was the major complication that was reported but the effect was generally modest, with the major impact relating to the possibility of the patient requiring additional postoperative appointments or the use of systemic antibiotics.34 The long-term stability of the clinical outcomes obtained with GTR using both resorbable and nonresorbable membranes has been demonstrated in a 10-year follow-up of both intrabony35 and Class II furcation defects.36 Indeed, long-term stability of the clinical outcome following GTR has been shown to result in 96 per cent tooth retention in a study of 175 severely compromised teeth at more than 10-year follow-up.37 Biologically active regenerative materials Enamel matrix derivative (EMD) EMD (Emdogain-Straumann, Basel, Switzerland) is the most widely studied commercially available bioactive agent used for the purpose of promoting periodontal regeneration. It is derived from the tooth pouches of unerupted porcine teeth and composed of amelogenins and enzyme components.38 The biological rationale for the use of EMD is to recapitulate developmental mechanisms whereby enamel matrix proteins are proposed to play a critical role in stimulating cementogenesis.39 Based on this rationale, preliminary studies were carried out in animal and human models, and histological evidence of regeneration was demonstrated.4042 Clinical outcomes The clinical effectiveness of EMD was evaluated in a meta-analysis of 28 studies, including 955 intrabony
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S Ivanovski defects, that presented baseline and nal data on probing depth and clinical attachment level (CAL) gain.43 The results showed that the treatment of intrabony defects with EMD resulted in a mean initial probing depth of 7.94 0.05 mm that was reduced to 3.63 0.04 mm. The mean clinical attachment level changed from 9.4 0.06 mm to 5.82 0.07 mm. The effectiveness of EMD compared to other surgical procedures has been evaluated in several systematic reviews.14,4446 The systematic review with the most stringent inclusion criteria assessed randomized controlled clinical trials comparing the clinical performance of EMD with OFD or GTR in the treatment of intrabony defects with a minimum of one-year followup.44 A meta-analysis of eight trials comparing EMD with OFD showed that EMD treated sites displayed statistically signicant attachment gain improvements (mean difference 1.2 mm (0.7 1.7)) and probing depth reduction (0.8 mm (0.5 1.0)). Control sites had an approximately 50 per cent greater chance of achieving less than 2 mm attachment gain (relative risk ration (RR) = 0.48 (95% CI 0.29 to 0.80)). Comparing EMD with GTR (ve trials), no differences were found in relation to attachment gain or probing depth reduction. GTR showed a statistically signicant increase of recession (0.4 mm) and signicantly more postoperative complications. The authors of the review noted that, as was the case with the GTR studies, there was signicant heterogeneity in the treatment outcomes, and the results should be interpreted with caution. In a systematic review of studies assessing the adjunctive use of EMD with other regenerative procedures, no advantage was found for combining EMD and GTR in the treatment of intrabony defects.46,47 However, there is evidence that the combination with a variety of bone grafting materials, including autogenous grafts, allogenic grafts, xenografts and alloplastic materials may enhance the effectiveness of EMD.46 This is particularly relevant since it has been recommended that the gel like, non-supportive consistency of EMD could be combined with grafting materials in order to prevent ap collapse, especially in one- and two-wall non-contained periodontal defects. The most widely studied bone replacement grafting material which has been used in combination with EMD is a bovine deproteinized xenograft (Bio-Oss, Geistlich, Wolhuse, Switzerland).4850 There are no randomized controlled clinical trials comparing EMD with OFD in the treatment of furcation defects. However, a randomized controlled clinical trial has examined the regeneration of buccal Class II mandibular furcation defects with either EMD or GTR. Similar results were obtained for most clinical parameters, although signicantly greater reduction in
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horizontal furcation depth and a comparatively lower incidence of postoperative pain swelling was noted following EMD therapy.51 The clinical safety of EMD has been demonstrated by a lack of cellular or humoral immune response, suggesting that EMD has a low immunogenic potential.52,53 Furthermore, long-term results show that the stability of clinical outcomes can be maintained for 10 years following the use of EMD alone or in combination with GTR.54 Platelet derived growth factor (PDGF) The use of polypeptide growth factors has been proposed based on their ability to promote a variety of cellular functions that are associated with wound healing, including migration, attachment, proliferation and differentiation. Although a number of different growth factors have been assessed in in vitro laboratory studies and animal models,55 PDGF has been the main growth factor studied in terms of its potential to induce periodontal regeneration in human clinical trials.46 PDGF has been characterized as a competence factor, which means that it makes a cell competent for cell division; a progression factor, such as IGF-1 or dexamethasone, is then necessary to induce mitosis, although in some osteoblast and periodontal ligament cell cultures PDGF alone stimulates proliferation.56 Although PDGF alone has not been assessed in controlled clinical trials in humans, the combination of PDGF and IGF, delivered in a methylcellulose gel, was assessed in a randomized controlled clinical trial for its regenerative potential in intrabony defects.57 It was shown that high concentration (150 ng ml for both growth factors) yielded greater bone ll compared to the control of OFD at 69 months. However, abnormal laboratory events were reported for 5 out of 38 patients and included elevated liver enzymes, lymphocytosis and haematuria, which were present at both baseline and 28 days following surgery, raising safety concerns about this mode of therapy. PDGF has also been used in association with allogenic bone grafts and shown to induce substantial attachment gain and probing depth reduction in case reports on the treatment of Class II furcation58,59 and intrabony59,60 defects. In a large multi-centre randomized controlled clinical trial, two different doses of recombinant human PDGF (rhPDGF 0.3 and 1.0 mg ml) combined with an alloplastic material (b-tricalcium phosphate (b-TCP)) were compared with b-TCP alone in deep intrabony defects. Although both PDGF formulations were signicantly more effective than the control group in the improvement of radiographically determined bone defect ll at six months, no signicant differences were found in the extent of clinical attachment gain after six
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Periodontal regeneration months of healing.61 No adverse effects were reported with this material61 and the clinical outcomes were stable following 24 months.62 Based on these results, a commercial product containing PDGF and b-TCP called GEM 21S (Osteohealth, Shirley, NY, USA) has been approved for the treatment of intrabony and furcation periodontal defects in the USA and Canada, but isnt currently available in Australia. Although recent histological evidence of the regenerative capacity of rhPDGF b-TCP has been demonstrated,63 further studies are needed to assess the clinical effectiveness of this product. P-15 P-15 is a 15-amino-acid peptide that mimics the cellbinding part of the a1 chain of Type I collagen, which has been shown to have the capacity to enhance the rate and the extent of attachment and migration of periodontal cells on root surfaces.64 Clinical results indicate that the commercially available combination of P-15 and a bovine derived hydroxyapatite matrix (ABM) (PEPGEN P-15, Dentsply Friadent, Mannheim, Germany) results in a signicant improvement of clinical and radiographic parameters when compared with either OFD65 or ABM alone66 in the treatment of intrabony defects. Although these results were shown to be maintained for at least three years,67 the effectiveness of P-15 ABM in promoting periodontal regeneration needs to be conrmed by large cohort, controlled trials. Notably, the commercially produced combination of ABM P-15 is not currently available in Australia. Platelet rich plasma PRP is a platelet concentrate which contains a number of different growth factors including PDGF, TGF-b and IGF68 that have been shown to exert a positive effect on periodontal wound healing. PRP has the advantage of being able to be prepared chairside and safety issues are minimal as autologous material is being used. There are no randomized controlled clinical trials evaluating the clinical effect of PRP alone in periodontal regeneration. However, the use of PRP combined with several types of grafts for the treatment of intrabony defects resulted in contradictory results ranging from a signicant enhancement of clinical attachment gain6971 to no effect.72,73 No additional benet of PRP has been shown when combined with a graft and GTR, compared with the use of only a graft and GTR in intrabony defects.74,75 The discrepancy in clinical outcomes using PRP may be partly due to differences in the methods used to obtain the PRP preparations, which may in turn affect the content of platelets and inammatory cytokines, as
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well as lead to contamination of the platelet preparation with leucocytes and erythrocytes.76 The use of PRP does not result in adverse healing events following surgery and there are some reports that suggest that PRP may lead to more rapid healing, less postoperative pain and less membrane exposure.74,75,77 Factors affecting the clinical outcome of regenerative procedures The clinical outcomes using regenerative therapy vary extensively between different studies, with some reports describing average attachment gains as high as 5.3 mm,78 while others reporting far inferior outcomes of as little as 0.6 mm.79 Therefore, it is important to consider the factors that inuence the clinical outcomes in regenerative procedures. These factors can broadly be divided into factors associated with the patient, tooth, defect and surgical technique. Patient factors Patient related factors which inuence the success of regenerative therapy include oral hygiene and smoking. It is important that the patients periodontitis is successfully treated prior to the commencement of periodontal regeneration. As part of this treatment, it is essential that the patient achieves a high level of selfperformed oral hygiene as superior results have been obtained in patients with optimal compared to less ideal oral hygiene.80,81 Furthermore, cigarette smoking has also been shown to negatively affect the clinical outcomes following regenerative therapy.80 Other patient related factors such as genetics, age, various systemic conditions and stress have been proposed to adversely affect the outcome of regenerative procedures, but since there is no evidence to support these assumptions, they should not inuence the decision to proceed with regenerative therapy unless there is a contraindication for elective surgery (e.g., uncontrolled diabetes). Tooth factors Tooth related factors that may affect the treatment response to periodontal regenerative therapy include the endodontic status of the tooth and hypermobility. It has been reported that endodontically compromised or inadequately treated teeth respond less favourably to periodontal treatment.82,83 However, it has also been shown that adequately performed root canal therapy does not affect the success of regenerative therapy.84 Tooth mobility has reported to be negatively and dose dependently associated with inferior outcomes following periodontal regeneration,85
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S Ivanovski although it has been shown that teeth with baseline horizontal mobility of less than 1 mm can be successfully treated.86 Defect factors The nature of the periodontal defect can have a signicant impact on the success of periodontal regeneration. Generally, it is recognized that currently available clinical techniques are limited to the treatment of intrabony and Class II furcation defects, and there is no evidence that suprabony (horizontal), interdental craters, supracrestal components of intrabony defects or Class III furcations can be predictably regenerated. The anatomy of the periodontal defect can inuence the outcome of the regenerative procedure, with superior regeneration associated with deep, narrow defects, and increased number of residual bony walls.81,87 This is particularly the case with nonsupported defects, and it has been shown that the adjunctive use of a bone replacement graft for its supportive and space-making properties can overcome the detrimental effects of adverse intrabony defect morphology.88 Surgical factors The realization that membrane exposure adversely affects the outcome of regenerative techniques, especially when associated with non-resorbable materials, led to the development of modied surgical techniques specically designed to preserve interdental tissues.25,26 Indeed, these clinical procedures, which utilize papilla preservation ap designs and suturing techniques that provide tissue stability and allow primary closure of interdental tissues, have been shown to be associated with superior regenerative outcomes.89,90 Furthermore, the additional use of a minimally invasive, high magnication assisted technique has been shown to enhance the regenerative outcomes, especially when using biologically active agents such as EMD.91,92 It has been demonstrated that superior regenerative outcomes can be obtained when a careful pre-surgical assessment is carried out that takes into account the extent of the interdental space (to choose the papilla preservation surgery), the morphology of the defect (to choose the regenerative material) and the type of material used local anatomy of the defect (to select the suturing approach).93 Future perspectives Tissue engineering In light of the clinical unpredictability of currently available surgical techniques to treat all types of periS124

odontal defects, it would appear that these approaches are too simplistic to facilitate the coordinated wound healing events required for the regeneration of a complex organ such as the periodontium. Consequently, a tissue engineering approach has been proposed, whereby periodontal tissues would be constructed in the laboratory under controlled conditions and then surgically implanted into defects.94 In principle, evidence for the viability of this approach has been demonstrated in animal studies showing that autologous cultured periodontal cells can support regeneration in vivo.95 This approach is further supported by evidence that periodontal ligament cells have stem cell properties.96,97 A new and promising approach to periodontal tissue engineering involves using periodontal cell sheets prepared in vitro and subsequently transplanted into periodontal defects. It has been reported that periodontal ligament cells cultured using this cell sheet technique can regenerate periodontal ligament tissues after transplantation in animal models.98,99 Gene therapy One of the major drawbacks related to the use of biologically active agents, such as growth factors, is their short biological half-life which results in their rapid degradation following application. Gene therapy can be used to facilitate extended local delivery of growth factors by transferring the growth factor genes into the local cell population. Gene delivery of PDGF has been accomplished by the successful transfer of the platelet-derived growth factor gene into cementoblast and other periodontal cell types.100102 Animal studies have demonstrated that gene delivery of PDGF stimulated more cementoblast activity and improved regeneration compared with a single application of recombinant platelet derived growth factor.99101 Although our understanding of gene regulation of PDGF has improved with experimental gene therapy studies, the safety and efcacy of using gene therapy for regeneration have yet to be fully evaluated. CONCLUSIONS Over the past 25 years, periodontal regeneration has been the focus of considerable laboratory and clinical research. Indeed, numerous randomized controlled clinical trials have been carried out in order to assess the clinical effectiveness of several surgical techniques aimed at achieving periodontal regeneration. From the evidence available in the literature, the following conclusions can be reached: (1) Currently, there are two well-documented clinical techniques, GTR and EMD, which can be utilized for the regeneration of intrabony and Class II mandibular furcation periodontal defects.
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Periodontal regeneration (2) In cases where additional support and spacemaking requirements are necessary, both of these procedures can be combined with a bone replacement graft. (3) 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. (4) 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. (5) There is limited data available for the clinical effectiveness of the commercially manufactured products PDGF b-TCP and P-15 ABM, and further studies are required to test the clinical performance of these two products. (6) The use of PRP for periodontal regeneration has yielded contradictory results and further studies are required to determine the optimal conditions and methods of preparation. REFERENCES
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65. Yukna RA, Callan DP, Krauser JT, et al. Multi-center clinical evaluation of combination anorganic bovine-derived hydroxyapatite matrix (ABM) cell binding peptide (P-15) as a bone replacement graft material in human periodontal osseous defects. 6-month results. J Periodontol 1998;69:655 663. 66. Yukna RA, Krauser JT, Callan DP, Evans GH, Cruz R, Martin M. Multi-center clinical comparison of combination anorganic bovine-derived hydroxyapatite matrix (ABM) cell binding peptide (P-15) and ABM in human periodontal osseous defects. 6-month results. J Periodontol 2000;71:1671 1679. 67. Yukna R, Salinas TJ, Carr RF. Periodontal regeneration following use of ABM P-15: a case report. Int J Periodontics Restorative Dent 2002;22:146155. 68. Okuda K, Kawase T, Momose M, et al. Platelet-rich plasma contains high levels of platelet-derived growth factor and transforming growth factor-beta and modulates the proliferation of periodontally related cells in vitro. J Periodontol 2003;74: 849857. 69. Hanna R, Trejo PM, Weltman RL. Treatment of intrabony defects with bovine-derived xenograft alone and in combination with platelet-rich plasma: a randomized clinical trial. J Periodontol 2004;75:16681677. 70. Okuda K, Tai H, Tanabe K, et al. Platelet-rich plasma combined with a porous hydroxyapatite graft for the treatment of intrabony periodontal defects in humans: a comparative controlled clinical study. J Periodontol 2005;76:890898. 71. Ouyang XY, Qiao J. Effect of platelet-rich plasma in the treatment of periodontal intrabony defects in humans. Chin Med J (Engl) 2006;119:15111521. 72. Demir B, Sengun D, Berberoglu A. Clinical evaluation of platelet-rich plasma and bioactive glass in the treatment of intra-bony defects. J Clin Periodontol 2007;34:709715. 73. Yassibag-Berkman Z, Tuncer O, Subasioglu T, Kantarci A. Combined use of platelet-rich plasma and bone grafting with or without guided tissue regeneration in the treatment of anterior interproximal defects. J Periodontol 2007;78:801 809. 74. Christgau M, Moder D, Hiller KA, Dada A, Schmitz G, Schmalz G. Growth factors and cytokines in autologous platelet concentrate and their correlation to periodontal regeneration outcomes. J Clin Periodontol 2006;33:837845. 75. Dori F, Huszar T, Nikolidakis D, Arweiler NB, Gera I, Sculean A. Effect of platelet-rich plasma on the healing of intrabony defects treated with an anorganic bovine bone mineral and expanded polytetrauoroethylene membranes. J Periodontol 2007;78:983990. 76. Weibrich G, Kleis WK, Hafner G, Hitzler WE, Wagner W. Comparison of platelet, leukocyte, and growth factor levels in point-of-care platelet-enriched plasma, prepared using a modied Curasan kit, with preparations received from a local blood bank. Clin Oral Implants Res 2003;14:357362. 77. Papli R, Chen S. Surgical treatment of infrabony defects with autologous platelet concentrate or bioabsorbable barrier membrane: a prospective case series. J Periodontol 2007;78:185 193. 78. Tonetti MS, Pini Prato G, Stalpers G, Cortellini P. Guided tissue regeneration of deep intrabony defects in strategically important prosthetic abutments. Int J Periodontics Restorative Dent 1996; 16:378387. 79. Chung KM, Salkin LM, Stein MD, Freedman AL. Clinical evaluation of a biodegradable collagen membrane in guided tissue regeneration. J Periodontol 1990;61:732736. 80. Tonetti MS, Pini-Prato G, Cortellini P. Effect of cigarette smoking on periodontal healing following GTR in infrabony defects. A preliminary retrospective study. J Clin Periodontol 1995;22:229234.
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81. Tonetti MS, Prato GP, Cortellini P. Factors affecting the healing response of intrabony defects following guided tissue regeneration and access ap surgery. J Clin Periodontol 1996;23:548556. 82. Ehnevid H, Jansson L, Lindskog S, Blomlof L. Periodontal healing in teeth with periapical lesions. A clinical retrospective study. J Clin Periodontol 1993;20:254258. 83. Ehnevid H, Jansson LE, Lindskog SF, Blomlof LB. Periodontal healing in relation to radiographic attachment and endodontic infection. J Periodontol 1993;64:11991204. 84. Cortellini P, Tonetti MS. Evaluation of the effect of tooth vitality on regenerative outcomes in infrabony defects. J Clin Periodontol 2001;28:672679. 85. Cortellini P, Tonetti MS, Lang NP, et al. The simplied papilla preservation ap in the regenerative treatment of deep intrabony defects: clinical outcomes and postoperative morbidity. J Periodontol 2001;72:17021712. 86. Trejo PM, Weltman RL. Favorable periodontal regenerative outcomes from teeth with presurgical mobility: a retrospective study. J Periodontol 2004;75:15321538. 87. Tonetti MS, Pini-Prato G, Cortellini P. Periodontal regeneration of human intrabony defects. IV. Determinants of healing response. J Periodontol 1993;64:934940. 88. Linares A, Cortellini P, Lang NP, Suvan J, Tonetti MS. Guided tissue regeneration deproteinized bovine bone mineral or papilla preservation aps alone for treatment of intrabony defects. II: radiographic predictors and outcomes. J Clin Periodontol 2006;33:351358. 89. Cortellini P, Prato GP, Tonetti MS. The modied papilla preservation technique. A new surgical approach for interproximal regenerative procedures. J Periodontol 1995;66:261266. 90. Cortellini P, Prato GP, Tonetti MS. The simplied papilla preservation ap. A novel surgical approach for the management of soft tissues in regenerative procedures. Int J Periodontics Restorative Dent 1999;19:589599. 91. Cortellini P, Tonetti MS. A minimally invasive surgical technique with an enamel matrix derivative in the regenerative treatment of intra-bony defects: a novel approach to limit morbidity. J Clin Periodontol 2007;34:8793. 92. Cortellini P, Tonetti MS. Improved wound stability with a modied minimally invasive surgical technique in the regenerative treatment of isolated interdental intrabony defects. J Clin Periodontol 2009;36:157163. 93. Cortellini P, Tonetti MS. Clinical performance of a regenerative strategy for intrabony defects: scientic evidence and clinical experience. J Periodontol 2005;76:341350. 94. Bartold PM, McCulloch CA, Narayanan AS, Pitaru S. Tissue engineering: a new paradigm for periodontal regeneration based on molecular and cell biology. Periodontol 2000 2000;24:253 269. 95. Lang H, Schuler N, Nolden R. Attachment formation following replantation of cultured cells into periodontal defectsa study in minipigs. J Dent Res 1998;77:393405. 96. Seo BM, Miura M, Gronthos S, et al. Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet 2004;364:149155. 97. Lin N-H, Gronthos S, Bartold PM. Stem cells and periodontal regeneration. Aust Dent J 2008;53:108121. 98. Iwata T, Yamato M, Tsuchioka H, et al. Periodontal regeneration with multi-layered periodontal ligament-derived cell sheets in a canine model. Biomaterials 2009;30:27162723. 99. Flores MG, Yashiro R, Washio K, Yamato M, Okano T, Ishikawa I. Periodontal ligament cell sheet promotes periodontal regeneration in athymic rats. J Clin Periodontol 2008;35:10661072. 100. Anusaksathien O, Webb SA, Jin QM, Giannobile WV. Plateletderived growth factor gene delivery stimulates ex vivo gingival repair. Tissue Eng 2003;9:745756.

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Address for correspondence: Professor Saso Ivanovski School of Dentistry and Oral Health Gold Coast Campus Griffith University QLD 4222 Email: s.ivanovski@griffith.edu.au

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