Periodontal Regeneration

Research, Science and Therapy Committee

Available through: The American Academy of Periodontology Scientific, Clinical and Educational Affairs Departmnet 737 North Michigan Avenue, Suite 800 Chicago, Illinois 60611-2690 Phone: (312) 787-5518 Fax: (312) 573-3234

Approved by The Board of Trustees May 1993

PREFACE
Progressive periodontitis leads to tooth loss through destruction of a tooth's attachment apparatus. In teeth in which continued function requires additional periodontal support, optimal treatment involves not only controlling periodontal infection, but also regeneration of the lost periodontium. This paper reviews the results of commonly-used surgical procedures having the objective of regeneration of the lost periodontium. Reports of successful periodontal regeneration have occurred throughout the history of periodontal treatments.1-4 Results following the use of autogenous and allogenic bone grafts, guided tissue regeneration procedures, and alloplastic (synthetic bone substitute) grafts are reviewed. The affect of root surface demineralization and flap management techniques on results following regenerative attempts are also reviewed. Comparisons between clinical studies dealing with periodontal regeneration are difficult because of widely varied methodologies. A synopsis of results and methodology of human clinical studies cited is found in Table I. Results of human histologic studies cited are summarized in Table II. Despite conclusive evidence that some regeneration may occur following regenerative procedures,6-9 complete regeneration is an unrealistic goal. Currently, osseous grafting and guided tissue regeneration are the two techniques with the most histologic documentation of periodontal regeneration.8-12 Other regenerative therapies have also demonstrated merit in terms of significantly improving clinical conditions and demonstrating substantial bone fill.

Copyright 1993 by The American Acedemy of Periodontology; all rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, or otherwise without permission of the Academy.

DEFINITIONS Regenerative therapy refers to procedures used in the treatment of periodontal disease to achieve replacement/reconstitution of lost periodontal tissues. 5 Therefore, periodontal regeneration is defined as restoration of lost supporting tissues including new alveolar bone, new cementum, and a new periodontal ligament. New connective tissue attachment is defined as development of a new connective tissue with a root surface that has been deprived of its periodontal ligament. This occurs by formation of new cementum with inserting collagen fibers. 5 Bone fill is defined as clinical restoration of bone tissue in a previously treated periodontal defect. Bone fill does not address the presence of absence of histologic evidence of new connective tissue attachment. 5 Guided cell repopulation or guided tissue regeneration (GTR) describes procedures designed to manipulate the cells that repopulate the wound healing site to ensure that this repopulation includes cells that lead to regeneration.

BONE GRAFTS Autogenous Bone Grafts, Extraoral Autogenous iliac cancellous bone and marrow is a graft material of high osteogenic potential. Case reports demonstrating successful bone fill after their use in furcations, dehiscences, and intraosseous defects of various morphologies have been reported. 13-16 Case reports showing a mean bone fill of 3.3 to 3.6 mm in a large number of intraosseous defects and a 2.5 mm increase in crestal bone height have been reported.13 Histologic evaluation of treated sites in which a reference notch was placed at the alveolar crest demonstrated some supracrestal bone apposition and was strongly suggestive of some periodontal regeneration.l6 Iliac grafts have been used either fresh or frozen. Root resorption may be a complication following use of fresh grafting techniques. 16-l8 While case reports indicate bone fill and some regeneration may occur following use of grafts of iliac autogenous cancellous bone and marrow, the difficulties in obtaining the graft material and the possibility of root resorption with fresh grafts have limited their use in clinical practice. Autogenous Bone Grafts, Intraoral Intraoral cancellous bone and marrow grafts are usually obtained from the maxillary tuberosity or a healing extraction site. Initially published case reports from studies including a large number of intraosseous defects grafted with intraoral bone demonstrated bone fill equal to that obtained with iliac grafts. l9-24 A mean bone fill of 3.4 mm, which predictably filled greater than 50% of the initial defect, was reported.19-20 A controlled study has indicated a more modest bone fill of 1.2 mm in defects treated with autogenous intraoral grafts. 21 Other case reports have shown bone fill following use of cortical bone chips22 and osseous coagulum or bone blend type grafts. 23,24 Histologic evaluations of autogenous intraoral grafts come from case reports. 19, 25-30 Authors have presented histologic evidence of regeneration and new connective tissue attachment following these procedures.25-28 Others have reported the presence of a long junctional epithelium between the regenerated alveolar bone and the root surface in histologic studies of healing following grafting procedures.29,30 This evidence would suggest that clinically present bone fill is not necessarily a reliable prediction of histologic regeneration of a periodontal attachment apparatus following regenerative procedures.

Allogenic Bone Grafts There are several types of bone allografts available from commercial tissue banks; i.e. iliac cancellous bone and marrow, freeze-dried bone allografts, and decalcified freeze-dried bone allografts. Allografts from the iliac crest of donors have been used both frozen and sterilized with radiation. Iliac allografts require cross-matching to decrease the possibility of graft rejection as well as careful screening to prevent the transmission of infectious diseases. Although favorable clinical results have been reported in case reports31 and more modest results in controlled clinical trials 32, the difficulties in graft procurement and the need for extensive laboratory facilities and testing limit the clinical usefulness of this material. Freeze-drying bone allograft material markedly reduces the antigenicity of the allograft. 33 Field trials have indicated approximately 63% of defects treated with freeze-dried cortical bone allografts show >50% bone fill.34 Controlled clinical trials indicate bone fill ranging from 1.3 to 2.6 mm. 35-37 However, in one controlled clinical study, freeze-dried bone allografts were compared with nongrafted controls and demonstrated no greater bone fill than the non-grafted controls. 35 Combining freeze-dried bone allografts with tetracycline has shown some promise in treating intraosseous defects resulting from juvenile periodontitis. 38,39 Animal studies 40 indicate that demineralizing bone in 0.6N HC1 followed by freeze drying significantly enhances the osteogenic potential of the allograft, supposedly by exposing a boneinducing agent called, "bone morphogenetic protein" (BMP). 41 However, other studies suggested that the quantity of BMP in periodontal grafts was too small to induce bone formation 42 and that other proteins may be involved in the osteo-induction process. 42,43 Human trials using cortical demineralized freeze-dried bone allografts have demonstrated bone fill similar to that achieved with freeze-dried bone allografts ranging from 1.7 to 2.9 mm. 36,44-46 Controlled human histologic studies with this material, using root notches into existing calculus as the histologic reference point, have demonstrated periodontal regeneration. Regeneration achieved with the grafts was significantly more than that in non-grafted controls. 8, 9 Grafts using decalcified freezedried cancellous bones47 have shown less bone fill (mean 1.4 mm). This variation may reflect differences in the amount of bone-inductive proteins in the two tissues. 48 A major concern in the use of allografts is the risk of disease transmission. Potential donors should be screened for histories of neoplastic or infectious disease and materials obtained should be tested for the presence of potential pathogens. Tissues banks have established protocols for obtaining and testing donor materials. With proper laboratory techniques and testing, the risk of disease transfer is calculated to be less than 1/1.67 million or l/8.0 million if the graft is frozen as a part of processing.49,50 Tissue banks accredited by the American Association of Tissue Banks are required to have procedures in place for testing graft materials for the presence of pathogens. 51

Summary
There is conclusive evidence that significant bone fill may result after using either autogenous or allogenic bone grafts. However, there are also occasional human studies that indicate similar amounts of bone fill may be achieved following the use of surgical procedures that do not include bone grafts. 4,52-53 Histologic analysis following grafting procedures indicate that partial periodontal
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regeneration may occur following use of autogenous and allogenic bone grafts. The presence of clinical bone fill does not necessarily indicate periodontal regeneration. Some histologic studies indicate the possibility that a long junctional epithelium may exist between newly regenerated alveolar bone and the root surface.29,30

GUIDED CELL REPOPULATION/GUIDED TISSUE REGENERATION It was suggested in 1976 that cells that repopulate the root surface after periodontal surgery will determine the type of attachment that form on the root surface during healing. 54 From this hypothesis have come procedures using barrier membranes to allow selective cellular repopulation of the root surface during periodontal regenerative attempts. In theory, these barriers retard apical migration of epithelium and exclude gingival connective tissue from the healing wound, thus favoring healing influenced primarily from the periodontal ligament space and adjacent alveolar bone. Several different materials have been used in case reports and clinical studies. Early studies used a millipore filter l1 while more recent studies have evaluated an expanded polytetrafluoroethylene membrane.55-58 The fact that this membrane requires a second surgical procedure to remove led to studies reports using biodegradable membranes 37,59 and autogenous connective tissue grafts as membranes.60 Results using polytetrafluoroethylene membranes to treat intraosseous defects show substantial bone fill averaging approximately 3.0 to 5.0 mm either with or without augmentation with graft materials.55-58 Defect selection seems particularly important, with 3-wall defects responding best.57 When this same type of membrane was used in controlled clinical trials treating mandibular Class II furcation defects, significant clinical improvement and a number of complete clinical defect closures were noted. 6l,62 Histologically these changes appear to result from new connective tissue attachmentl1,63 as little bone fill was noted with reentry procedures. 57,64 Results using the polytetrafluoroethylene membrane augmented with decalcified freeze-dried bone allograft 65 or composite grafts of autogenous intraoral grafts and tricalcium phosphate and/or demineralized freezedried bone allografts61 showed substantially more bone fill on reentry of treated furcations. However, the majority of the defects were still considered open" on reentry.61,65 Treatment of maxillary Class II furcation defects and mandibular Class III defects with similar membranes demonstrated clinical improvements as well, but of a more modest and unpredictable degree. 57,65-67

Summary
Case reports and clinical trials indicate that periodontal intraosseous defects, especially those characterized by 3 bony walls, respond favorably with substantial bone fill when treated with guided tissue regeneration techniques including a polytetrafluoroethylene membrane. Clinically, results using this approach to treating intraosseous defects seem maintainable over long periods of time. 56 Histologic case reports indicate that periodontal regeneration and new connective tissue attachment may also be achieved. 11,63, 68, 69 Similar techniques applied to mandibular Class II furcation defects have produced clinical improvements in terms of decreased probing depths and improved clinical attachment levels. 6l, 62 When these procedures are augmented with either autogenous or allogenic grafts, significant bone fill has been reported. However, the majority of these treated sites have had a remaining residual
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furcation defect. 6l, 65 Use of polytetrafluoroethylene membranes in treating maxillary Class II and mandibular Class III defects has produced inconsistent results. Clinical trails using various resorbable membranes and connective tissue grafts are very preliminary and conclusions regarding their efficacy are premature.57, 65-67

FLAP MANAGEMENT
Animal research has demonstrated that periodontal wounds can be expected to go through the same generally acknowledged sequence of healing events as all wounds, with the formation of a fibrin clot between the flap margin and the root surface, followed by replacement of this fibrin clot by a connective tissue matrix attached to the root surface. 70, 71 Data from animal models suggest that when this initial "fibrin linkage" is maintained during early healing, a new connective tissue attachment to the root surface develops. If the fibrin linkage is disrupted, a long junctional epithelium type attachment results. 7l Recently it was suggested that if the tensile strength of the adhering fibrin clot is exceeded, the resulting tear could lead to a regenerative failure. 72 In regenerative attempts, the flap (wound) margin is generally positioned so that it directly approximates the critical healing area. Mobility of the flap (wound margin) directly adjacent to the potential regenerative site may overcome the root surface/fibrin clot interface leading to a rupture. These tears or ruptures would delay healing, possibly allowing apical migration of the junctional epithelium.73 Recently, human clinical trials using flap management techniques designed to enhance clot protection and wound stability have been reported. 74-76 The coronally-positioned flap procedure has been used to treat mandibular Class II furcation detects. This procedure positions the flap margin away from the critical healing area (the furcal site) and secures it in that position during early healing time points.77 Reentry results from two studies74,75 indicated an approximate mean 65%, by volume, bone fill in Class II mandibular furcation defects. Sites also showed a mean 2.0 mm vertical bone fill and 2.6 mm horizontal bone fill. Twenty-two of 46 furcation defects assessed for bone closure after reentry were judged closed. In other words, the horizontal portion of the furcation defect had been closed via bone fill. It is interesting to note that before reentry the large majority of these "closed" defects demonstrated residual furcal involvement clinically. These results suggest that coronally positioned flaps minimize the influence of the flap (wound) margin during early healing which may influence furcal healing favorably. Histologic results following treatment of supracrestal periodontal defects with this procedure have demonstrated new connective tissue attachment formation with some periodontal regeneration.77 When coronally-positioned flaps were used to treat mandibular Class III furcations, improvements in probing depths and probing attachment levels were reported. However, at the conclusion of the study 28 of 32 treated furcations were still clinically classified as Class III defects.78

Summary
The concept of wound protection and stability during early healing time points is an appealing one which could conceptually enhance results of regenerative therapy irrespective of the particular surgical technique. Continued clinical research is needed to define the role of this concept in periodontal regeneration.
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Perhaps successful results following procedures that use guided tissue regeneration may provide additional support for the concept of wound protection. With placement of a membrane, the root surface/wound healing interface is separated from the flap margin. Thus, unwanted trauma or movement at the flap margin would have little impact on the root surface/fibrin clot interface. 72,79

BONE SUBSTlTUTES/ALLOPLASTS These are presently four basic types of alloplastic materials commercially available: nonporous hydroxyapatite, porous hydroxyapatite (replamineform), beta tricalcium phosphate, and HTR polymer (a calcium layered polymer of polymethylmethacrylate and hydroxyethylmethacrylate). It has been reported that porous and nonporous hydroxyapatite materials and HTR are nonresorbable while tricalcium phosphate is resorbable. In controlled clinical trials using both nonporous and porous materials as grafts, the grafted sites have shown significant clinical improvement compared to non-grafted controls.80-83 The magnitude of defect closure ranged from 1.6 to 3.5 mm for grafted sites and 0.5 to 0.7 mm for non-grafted sites. Mandibular Class II furcation defects grafted with porous materials have also shown significantly better clinical improvements than non-grafted controls both with and without adjunctive guided tissue regeneration techniques.84,85 A 5-year followup of non- porous hydroxylapatite implanted intraosseous sites indicated continued clinical stability.86 Case reports also indicate defect closure is possible following grafts of tricalcium phosphate.87,88 Defects grafted with HTR have also shown significant clinical improvements when compared to non-grafted controls.89 While clinical results appear promising, histologically the grafts tend to be encapsulated by connective tissue with minimal or no bone formation. 88,90,91 Some histologic studies have demonstrated limited new bone in close approximation to the implant material 92,93 or alongside or within porous graft particles.94 A single histologic case report suggested that some regeneration may be possible with porous hydroxyapatite grafts. 95 There is also some histologic evidence that a very limited amount of regeneration may be possible following HTR grafts. 96 However, at present it appears that alloplastic materials function as a non-irritating filler. Comparisons between bone allografts and hydroxyapatite suggest that they produce clinically similar results. 97-98 However, if regeneration is the desired outcome of the surgical procedure, guided tissue regeneration or osseous grafting seem the more appropriate choice.

Summary
When used as grafts, all the alloplast materials seem to produce significantly improved clinical conditions. However, histologically they act as biologic fillers and induce little or no bone fill and very limited if any periodontal regeneration.

ADDITIONAL AREAS OF INTEREST Root Surface Demineralization/Citric Acid Root surface demineralization, usually with citric acid, 99,l00 is often used as a part of regenerative procedures. This technique has been suggested because of its ability to modify the root surface by "detoxifying the surface10l and exposing collagen fibrils in the cementum or dentin matrix. 102

Animal studies demonstrated substantial, new connective tissue attachment following citric acid demineralization71,103,l04 though a favorable response was not universal. 105 Histologic evaluation in some human clinical, trials demonstrated new connective tissue attachment and some regeneration following citric acid demineralizatino. 6,76,106 Again, these histologic results have not been universal. 107 Results from clinical, trials indicate no additional improvement in clinical, conditions when citric acid treatment is used in conjunction with surgical, procedures, either withoutl08,l09 or in combination with, osseous grafts21 or guided tissue regeneration techniques. 58,108 Attempts to combine root surface demineralization and fibronectin to induce a more significant regenerative response have shown promise during in-vitro experimentation. 110 However, when used in humans, this technique did not provide significant clinical, improvements. 111 In summary, human trials with root surface demineralization have failed to show significant clinical improvement when compared to non-demineralized controls. Histologic evidence seems to suggest that new connective tissue attachment and limited regeneration may result from root surface demineralization. However, this histologic healing pattern does not result in significant improvement in clinical conditions beyond non-demineralized control sites. Matrix proteins/growth factors Periodontal research using matrix derived proteins and/or growth factors to expand the amount of predictable regeneration is in the early stages of development. The first human trials were reported in 1991. 1l2 This interesting and promising area of research is discussed in another research update paper available from the AAP.

CONCLUSION Autogenous and allogenic bone grafts have resulted in substantial bone fill in reports involving a large number of case studies. Controlled clinical trials have shown more modest success. There is sufficient clinical and histologic documentation of bone fill and some periodontal regeneration to recommend their inclusion in techniques available to the clinician. Guided tissue regeneration has value as a regenerative procedure particularly in 3-wall intrabony defects. These procedures have shown favorable, although less predictable, results in treating class II furcation defects, particularly those involving mandibular teeth. Clinical and histologic documentation attesting to bone fill and limited periodontal regeneration is sufficient to recommend inclusion of this technique in clinical practice. Flap management techniques to enhance wound stability during early healing time points have produced substantial bone fill in mandibular Class II furcations and limited clinical improvement in mandibular Class III furcations. Clinical studies using these techniques to treat other types of periodontal defects have not been reported. Alloplastic materials (synthetic bone substitutes) function primarily as biocompatible space fillers. Use of these materials will produce clinical results similar to osseous grafts or guided tissue regeneration procedures. However, little if any periodontal regeneration can be expected with their use.

ABBREVIATION KEY

SYMBOLS: ALG ALI AUCT AUE AUI AUO CA CG CP CPA CM CT DEB DFDBA DMM DR F FN FDBA FGG H HA HTR ID MF P PAL PhA PPD NAA NB NC PTFE r ra RP RPC SC SM TP X

= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = =

Allogenic graft Allogenic graft/iliac crest Autogenous connective tissue graft Autogenous graft Autogenous graft/iliac crest Autogenous graft/oral site Citric Acid Collagen Gel Coronally positional flap Coronally positioned flap secured by crown attached sutures Collagen membrane New connective tissue attachment Flap debridement Demineralized freeze dried bone allograft Dura matter membrane Descriptive results Furcation Fibronectin Freeze dried bone allograft Free gingival graft (See table 2 histologic summary) Hydroxyapatite Polymethylmethacrylate + hydroxyethylmethacrylate + calciurn Intraosseous defect Millipore filter Probing bone Change probing attachment level Porous hydroxyapatite Change probing pocket depth New attachment apparatus New bone New cementum Polytetrafluoroethylene membrane Reentry Radiographic assessment Root planed Root planed/currettage Supracrestal defect Submerged defect site Tricalcium phosphate Composite graft autogenous bone + DFDBA or TP

Table I. Summary of Clinical Studies Continued

Table I. Summary of Clinical Studies

Table I. Summary of Clinical Studies

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Table II Summary of Histologic Studies Continued

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Table II Summary of Histologic Studies Continued

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Table I. Summary of Clinical Studies Continued

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Acknowledgments
This position paper was authored by Dr. Steven J. Garrett. Members of the 1992-1993 Research, Science and Therapy Committee include Drs. Ray C. Williams, Chairman; William F. Ammons, Jr.; Robert E. Cohen; Steven J. Garrett; Gary Greenstein; Ira Lamster; Roland M. Meffert; Thomas E. Van Dyke; Gary C. Armitage, Consultant; Robert J. Genco, Consultant; Kenneth S. Kornman, Consultant; Terry D. Rees, Consultant; and W. Lee Young, Jr., Consultant. Drs. William Becker, Max Crigger, Everett B. Hancock, Max Listgarten, and Walter T. McFall contributed to this paper through peer review.

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